Alpha-(n-sulphonamido)acetamide derivatives as beta-amyloid inhibitors

The present invention relates to an α- (N-sulfonamido) acetamide derivative as a β-amyloid inhibitor and to a pharmaceutical composition. The new compounds exhibit biological and therapeutic effects because they have the unique properties of inhibiting the production of β-amyloid peptide (β-AP), thus preventing the accumulation of amyloid protein deposits in the brain. The invention finds utility in the treatment of Alzheimer's disease (AD) and Dawn's syndrome.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by impaired memory and cognitive impairment. Pathologically, AD is characterized by accumulation of senile (neurite) plaques, neurofibrillary tangles, amyloid deposits in nerve tissues and vessels, loss of synapses, and neuronal death. It is the most common form of dementia and is the third leading cause of death, after heart and circulatory disease and cancer. The cost of Alzheimer's disease is enormous (over $ 100 billion a year in the United States of America). These include losses due to patients' disease, losses in families, and loss of productivity for patients and carers. As the life expectancy of societies increases, the incidence of AD will increase significantly. It is estimated that by 2020 more than 10 million Americans will suffer from AD unless solutions are found to prevent and treat the disease. Currently, it is estimated that AD affects 10% of the population over the age of 65 and up to 50% of the population over the age of 85. To date, no treatment is available that effectively prevents or reverses the clinical manifestations of AD and the underlying pathophysiology (For review, see Selkoe D., J. Ann. Rev. Cell Biol. 1994, 10: 373-403).

There are many theories relating to the etiology and pathogenesis of AD. These theories are either based on analogies to other diseases and conditions (e.g., theories of slow-acting viruses and aluminum poisoning) or on observations of pathology (e.g., theories of cholinergic, amyloid or plexus disorders). Genetic analysis has the potential to validate competing theories. The identification of mutations in the β-amyloid precursor protein (β-APP) in individuals susceptible to forms of AD characterized by early onset and related disorders supports the amyloid theory.

Histopathological examination of the brain tissue obtained from autopsies or from neurosurgical samples of patients revealed the presence of amyloid plaques and neurofibrillary tangles in the cortex of these patients. Similar changes were observed in patients with trisomy 21 (Down syndrome). Biochemical and immunological studies have shown that the major protein component of the amyloid plaque is a protein of about 4.2 kilodaltons (kD), containing from about 39 to 43 amino acids. This protein is called the Ap protein, β-amyloid peptide, and is sometimes referred to by the term p / A4, which is equivalent to the term Ap as used herein. The Ap protein is not only deposited in amyloid plaques. They have also been found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes in venules. Evidence accumulated over the past decade has revealed that Aβ is an internal polypeptide derived from type 1 integral membrane protein, called β-amyloid precursor protein (APP; Selkoe D., Physiol. Rev. 2001, 81, 741-766; Wolfe M., J Med. Chem. 2001, 44, 2039-2060). pAPP is normally produced by many cells in vivo and in cell cultures of various animal and human origin. A number of APP proteolytic fragments have been obtained by the treatment of proteinases called secretases. A subset of these proteolytic fragments called p-amyloid peptide (Ap) is 39 to 43 amino acids long. It is produced by the combined action of γ-secretase and γ-secretase. ? -secretase is a membrane-bound aspartyl protease that forms the N-terminus of the Ap peptide. The C-terminus of the Ap peptide is formed by the action of γ-secretase. It appears to be an oligomeric complex that contains presenilin-1 and / or presenilin-2. Presenilin-1 and presenilin-2 are membrane resident polytopic proteins. They may contain γ-secretase catalytic components (Seiffert D, Bradley J et al., J. Biol. Chem. 2000, 275, 34086-34091).

Taken together, multiple lines of evidence lead to the suggestion that lowering A? Levels in the brain will prevent the onset and development of AD. First, A? Is the major component of the parenchymal plaques observed in all AD patients tested, and cerebrovascular amyloid deposits were observed in 90% of AD patients (reviewed in Selkoe D., Physiol. Rev. 2001, 81, 741-766; Wolfe M., J. Med. Chem. 2001, 44, 2039-2060). These plaques result from the aggregation of soluble Aβ whose levels in the brain correlate closely with the severity of AD neurodegeneration (McLean C, Cherny R. et al., Ann. Neurol. 1999, 46, 860-866). Second, mutations in three genes (APP, PS-1 or PS-2) that increase Αβ levels induce familial AD (FAD), the onset of which is accelerated by at least 10 years. In mutations that increase Ae levels, chromosome 21 of the trisomy is involved, which causes Down's syndrome. Third, transgenic mice expressing one or more mutant FAD genes have increased levels of Ae, parenchymal plaques develop, Ae-containing deposits build up in cerebral vessels, and memory impairment is revealed (Chapman P., White G. et al. ., Nature Neurosci. 1999, 2, 271-276). In addition, increased degeneration of neural fibrils is observed in mice that also overexpress the mutant tau gene (Lewis J., Dickson D. et al., Science 2001, 293, 1487-1491). Fourth, Ae is toxic to cultured cells (Dahlgren

K., Manelli A. et al., J. Biol. Chem., 2002, 277, 32046-32053), stimulates the formation of neurofibrillary tangles in mice with the mutated tau gene (Gotz J., Chen F. et al., Science 2001, 293, 1491-1495) and interferes with the long-term potentiation of the effect of one stimulus by the second stimulus, which is possibly a memory factor (Walsh D., Klyubin I. et al., Nature 2002, 416, 535-539 and references cited therein). Taken together, these data lead experts to conclude that excessive Ae production and / or decreased Ae clearance causes Alzheimer's disease. It follows that lowering the level of Ae in the brain by inhibiting γ-secretase will prevent the onset and development of AD.

In addition to Alzheimer's disease, excessive production and / or decreased clearance of Ae causes brain amyloid angiopathy (CAA) (reviewed by Thai D., Gherbremedhin E. et al., J. Neuropath. Exp. Neuro., 2002, 61, 282-293) . In these patients, vascular amyloid deposits cause vascular wall degeneration and aneurysms, which may be responsible for 10-15% of haemorrhagic strokes in elderly patients. As in AD, mutations in the Ae gene lead to the early onset of CAA, described herein as Dutch-type amyloidosis cerebral bleeding, and mice expressing this mutant protein develop CAA similar to patients.

It is presumed that inhibition of Ae production will prevent and reduce neurological degeneration, reduce neurotoxicity and generally affect the pathology associated with Ae production. Treatment methods could be targeted to influence Ae formation through enzymes involved in the proteolytic processing of the β-amyloid precursor protein. Compounds that inhibit β- or γ-secretase activity, directly or indirectly, could reduce Ae production. Advantageously, compounds that specifically act on γ-secretase could control Ae production. Such inhibition of β or γ-secretases could thus reduce Ae production, which could alleviate or prevent Ae-related neurological disorders.

Smith et al., In international patent application WO 00/50391 published on August 31, 2000, disclosed a series of sulfonamide compounds with properties to modulate e-amyloid protein production as agents for the treatment of many diseases, especially Alzheimer's disease and other diseases dependent on amyloid deposition. In Japan Patent No. 11343279 published on December 14, 1999 discloses a series of sulfonamide derivatives which are TNF-alpha inhibitors useful in the treatment of autoimmune diseases.

None of these references disclose or suggest the novel compounds of the invention or their use to inhibit e-AP production.

Summary of the invention

A series of α- (N-sulfonamido) acetamide derivatives was synthesized. These compounds specifically inhibit the production of e-amyloid peptide (e-AP) from the precursor protein e-amyloid (e-APP). The pharmacological activity of these compounds makes them useful in the treatment of conditions responsive to inhibition of e-AP in patients, e.g., Alzheimer's disease (AD) and Down's syndrome. Treatment by administering these compounds to patients suffering from, or prone to, the above diseases results in a reduction of the e-AP available for build-up and deposition in the brains of these patients.

Detailed Description of the Invention

The invention relates to compounds of formula I, pharmaceutical preparations containing them and their use for inhibiting e-AP production in patients suffering from or prone to developing AD or other diseases resulting from e-AP accumulation in brain tissue. The compounds of formula I, including the non-toxic pharmaceutically acceptable salts and / or hydrates of these compounds, have the following formula and meanings:

PL 204 281 B1

<img file="PL204281B1_D0001.tif" />

in which formula:

₁

R¹ is selected from the group consisting of (a) a straight or branched chain (C1-C6) -alkyl or (C2-C6) -alkenyl optionally substituted with substituents selected from the group consisting of hydroxyl, (C3-C7) -cycloalkyl, (C1-C4) -alkoxy, (C1-C4) -alkylthio and halogen;

(b) (C3-C7) cycloalkyl optionally substituted with hydroxyl or halogen;

R is hydrogen;

₂

R² is selected from the group consisting of:

(a) a straight or branched (C1-C6) alkyl or (C3-C6) alkenyl chain optionally substituted with substituents selected from halogen, (C1-C4) alkoxy and NR⁴R⁵;

(b) a (C3-C7) -cycloalkylmethyl group optionally substituted with substituents selected from the group consisting of amino, (C1-C4-alkyl) NH-, di (C1-C4-alkyl) N-, (C1-C4) -alkyl) C (= O) NHi (C1-C4) alkyl-OC (= O) NH-;

(c) straight or branched chain (C1-C6) -alkyl-C (= O) -A;

(d) -B-naphthyl;

(e) a group of formula

<img file="PL204281B1_D0002.tif" />

wherein D and E are independently a direct bond, straight or branched chain (C1-C6) alkyl, (C2-C6) alkenyl or (C3-C7) cycloalkyl;

Z is selected from the group consisting of hydrogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, halogen, cyano, hydroxy, -OCHF2, -OCF3, -CF3 and -CHF2;

X and Y are independently selected from the group consisting of hydrogen, hydroxy, halogen, (halogen) 3C-, (halogen) 2CH-, (C1-C4) -alkyl-S-, (C1-C4) -alkyl-S (O ) -, (C1-C4) -alkyl-SO2-, nitro, F3S- and cyano; -OR⁶; -NR⁴R⁵; -NR⁷C (= O) R⁸; NO⁷C (= O) OR⁸; -NHSO2- (C1-C4) -alkyl; -N (SO2-C1-C4-alkyl) 2-; C (= O) W, W is selected from the group consisting of hydroxy, (C1-C4) -alkyl, (C1-C4) -alkoxy, phenoxy and -NR⁴R⁵; -OC (= O) - (C1-C4) alkyl; -phenyl optionally substituted with cyano, halogen, (C1-C4) -alkoxy, (C1-C4) -alkyl-S-, CH3C (= O), (C1-C4) -alkyl-S (O) - or ( C1-C4) -alkyl-SO2-; and a heterocyclic group, which heterocyclic group is selected from the group consisting of furanyl, thiofuranyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, and isoxadiazolyl, optionally thaoxazolyl, and isoxiadiazolyl, substituents selected from the group consisting of cyano, halogen, (C1-C4) -alkyl, halo- (C1-C4) alkyl and CO2- (C1-C4) alkyl;

-B- (heterocycle) where the heterocycle is selected from the group consisting of furanyl, thiofuranyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl and optionally substituted with thiazocyclyl selected from the group consisting of cyano, halogen, (C1-C4) -alkyl, CO2- (C1-C4) -alkyl, amino, (C1-C4-alkyl) -NH-, di (C1-C4-alkyl) N -, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl and 4- (C1-C6-alkyl) -piperazin-1-yl;

-B- (piperidin-4-yl), wherein piperidin-4-yl is optionally substituted with substituents selected from the group consisting of straight or branched chain (C1-C6) alkyl, CH2C (= O) -phenyl, phenyl and phenylmethyl, wherein (C1-C6) -alkyl and phenyl are optionally substituted with selected substituents

From the group consisting of cyano, halogen, benzimidazol-2-yl, pyridyl and tetrahydrofuran-2-yl; and -C (= O) W ', W' is selected from the group consisting of] (C1-C4) -alkoxy, R⁹ and -NR⁴ R⁵;

A is hydroxy, (C1-C4) -alkoxy or -NR⁴R⁵;

B is a straight or branched chain (C1-C6) alkyl or (C3-C6) alkenyl;

R³ is phenyl or pyridyl, optionally substituted with substituents selected from the group consisting of halogen, hydroxy, (C1-C4) -alkoxy, (C1-C4) -alkyl, (halo) 3C-, (halo) 2CH- and halogen-CH2-;

R⁴ and r⁵ are independently hydrogen, straight or branched chain (C1-C6) -alkyl, (C3-C6) -alkenyl, (C3-C6) alkynyl, (C3-C7) -cycloalkyl, (C3-C7) -cycloalkylmethyl, group (C1 -C4) -alkoxy, phenyl, benzyl, pyridyl, piperidin-4-yl, indan-1-yl, indan-2-yl, tetrahydrofuran-3-yl or pyrrolidin-3-yl; each of these groups is optionally substituted with substituents selected from the group consisting of hydroxy, cyano, halogen, (halogen) 3C-, (halogen) 2CH- and halogen-CH2-, hydroxymethyl, benzyloxymethyl, phenyl, pyridyl, (C1-C4) -alkyl, (C1-C4) -alkoxy, (halogen) 3C-O-, (halogen) 2CH-O-, (C1-C4) -alkylthio, amino, (C1-C4-alkyl) -NH-, di (C1-C4-alkyl) N-, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4- (C1-C6-alkyl) piperazin-1-yl, 4-phenyl-piperazin-1-yl, 4-benzylpiperazin-1-yl, 4-pyridylpiperazin-1-yl, CO2H, CO2- ( C1-C4) -alkyl, C (= O) NH- (C1-C4) -alkyl and C (= O) N (C1-C4-alkyl) 2;

R⁴ and r⁵ taken together they can form morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, decahydroquinolin-1-yl, piperidin-1-yl, piperazin- 1-yl, [1,4] oxazepan-4-yl, azetidin-1-yl, 2,3-dihydro-1H-isoindol-2-yl or 2,3-dihydro-1H-indol-1-yl; each of the above groups is optionally substituted with substituents selected from the group consisting of hydroxy, cyano, halogen, (halo) 3C-, (halo) 2CH-, halo-CH2-, phenyl, pyridyl, benzyl, (C1-C6) -alkyl , (C3-C7) -cycloalkyl, (C1-C4) -alkoxy, (C1-C4) -alkylthio, amine, (C1-C4-alkyl) NH-, di (C1-C4-alkyl) N-, CO2H, CO2- (C1-C4) -alkyl, C (= O) NH- (C1-C4) -alkyl and C (= O) N (C1-C4-alkyl) 2;

R⁶ is a straight or branched chain (C1-C6) alkyl, (C3-C6) alkenyl, benzyl or phenyl; each of these groups is optionally substituted with substituents selected from the group consisting of halogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, amino, (C1-C4-alkyl) NH-, di (C1-C4-alkyl) ) N-, (C1-C4-alkyl) (phenyl) N-, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl and 4- (C1- C6-alkyl) piperazin-1-yl;

R⁷ is hydrogen, straight or branched chain (C1-C6) alkyl;

R⁸ is a straight or branched chain (C1-C6) alkyl, (C3-C7) cycloalkyl, phenyl, pyridyl or furanyl; each of these groups is optionally substituted with substituents selected from the group consisting of halogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, (C1-C4-alkyl) NH-, di (C1-C4-alkyl) N -, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl and 4- (C1-C6-alkyl) piperazin-1-yl;

R⁹ is a straight or branched chain (C1-C6) alkyl, (C3-C6) alkenyl, benzyl, phenyl, oxazolyl or pyridyl; each of these groups is optionally substituted with substituents selected from the group consisting of halogen, (halogen) 3C-, (halogen) 2CH-, halogen-CH2-, (C1-C4) -alkyl, (C1-C4) -alkoxy, amino, (C1-C4-alkyl) NH-, di (C1-C4-alkyl) N-, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl and 4- (C1-C6-alkyl) piperazin-1-yl;

or the non-toxic pharmaceutically acceptable salts of these compounds.

In a preferred embodiment, the present invention encompasses the compound of Formula Ia:

<img file="PL204281B1_D0003.tif" />

in which formula:

₁

R¹ is selected from the group consisting of

(A) a straight or branched chain (C1-C6) -alkyl or (C2-C6) -alkenyl optionally substituted with substituents selected from the group consisting of hydroxyl, (C3-C7) -cycloalkyl, (C1-C4) - alkoxy, (C1-C4) alkylthio and halogen;

(b) (C3-C7) cycloalkyl optionally substituted with hydroxyl or halogen;

R² is selected from the group consisting of:

(a) a straight or branched (C1-C6) alkyl or (C3-C6) alkenyl chain optionally substituted with substituents selected from halogen, (C1-C4) alkoxy and NR⁴R⁵;

(b) a (C3-C7) -cycloalkylmethyl group optionally substituted with substituents selected from the group consisting of amino, (C1-C4-alkyl) NH-, di (C1-C4-alkyl) N-, (C1-C4) -alkyl) C (= O) NHi (C1-C4) alkyl-OC (= O) NH-;

(c) straight or branched chain (C1-C6) -alkyl-C (= O) -A;

(d) -B-naphthyl;

(e) a group of formula

<img file="PL204281B1_D0004.tif" />

wherein D and E are independently a direct bond, straight or branched chain (C1-C6) alkyl, (C2-C6) alkenyl or (C3-C7) cycloalkyl;

Z is selected from the group consisting of hydrogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, halogen, cyano, hydroxy, -OCHF2, -OCF3, CF3 and -CHF2;

X and Y are independently selected from the group consisting of hydrogen, hydroxy, halogen, (halogen) 3C-, (halogen) 2CH-, (C1-C4) -alkyl-S-, (C1-C4) -alkyl-S (O ) -, (C1-C4) -alkyl-SO2-, nitro, F3S- and cyano;

-OR⁶;

-NR⁴R⁵ ;

-NR⁷C (= O) R⁸;

-NR⁷C (= O) OR⁸;

-NHSO2- (C1-C4) -alkyl;

-N (SO2-C1-C4-alkyl) 2-;

C (= O) W, W is selected from the group consisting of hydroxy, (C1-C4) -alkyl, (C1-C4) alkoxy, phenoxy and -NR⁴R⁵;

-OC (= O) - (C1-C4) -alkyl;

-phenyl optionally substituted with cyano, halogen, (C1-C4) -alkoxy, (C3-C4) -alkyl-S-, CH3C (= O), (C1-C4) -alkyl-S (O) - or ( C1-C4) -alkyl-SO2-;

and a heterocyclic group, which heterocyclic group is selected from the group consisting of furanyl, thiofuranyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl and optionally thiazolyl substituted with thiazolyl, and selected from the group consisting of cyano, halogen, (C1-C4) -alkyl, halo- (C1-C4) -alkyl and CO2- (C1-C4) -alkyl;

(f) -B- (heterocycle), where the heterocycle is selected from the group consisting of furanyl, thiofuranyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, and is a thiazocyclyl optionally substituted with substituents selected from cyano, halogen, (C1-C4) -alkyl, CO2- (C1-C4) -alkyl, amino, (C1-C4-alkyl) -NH-, di (C1-C4-) alkyl) N-, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl and 4- (C1-C6-alkyl) piperazin-1-yl;

(g) -B- (piperidin-4-yl), wherein piperidin-4-yl is optionally substituted with substituents selected from the group consisting of straight or branched chain (C1-C6) alkyl, CH2C (= O) -phenyl, phenyl and phenylmethyl, wherein (C1-C6) -alkyl and phenyl are optionally substituted with substituents selected from cyano, halogen, benzimidazol-2-yl, pyridyl and tetrahydrofuran-2-yl; and -C (= O) W ', W' is selected from the group consisting of (C1-C4) -alkoxy, R⁹ and -NR⁴ R⁵;

A is hydroxy, (C1-C4) -alkoxy or -NR⁴R⁵;

B is a straight or branched chain (C1-C6) alkyl or (C3-C6) alkenyl;

R³ is phenyl or pyridyl, optionally substituted with substituents selected from the group consisting of halogen, hydroxy, (C1-C4) -alkoxy, (C1-C4) -alkyl, (halogen) 3C-, (halogen) 2CH-, and halogen-CH2- ;

R⁴ and r⁵ are independently hydrogen, straight or branched chain (C1-C6) -alkyl, (C3-C6) -alkenyl, (C3-C6) -alkynyl, (C3-C7) -cycloalkyl, (C3-C7) -cycloalkylmethyl, group ( C1-C4) -alkoxy, phenyl, benzyl, pyridyl, piperidin-4-yl, indan-1-yl, indan-2-yl, tetrahydrofuran-3-yl or pyrrolidin-3-yl; each of these groups is optionally substituted with substituents selected from the group consisting of hydroxy, cyano, halogen, (halogen) 3C-, (halogen) 2CH-, and halogen-CH2-, hydroxymethyl, benzyloxymethyl, phenyl, pyridyl, (C1-C4) -alkyl, (C1-C4) -alkoxy, (halogen) 3C-O-, (halogen) 2CH-O-, (C1-C4) -alkylthio, amino, (C1-C4-alkyl) -NH-, di - (C1-C4-alkyl) N-, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4- (C1-C6-alkyl) piperazin-1-yl, 4-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, 4-pyridylpiperazin-1-yl, CO2H, CO2- ( C1-C4) -alkyl, C (= O) NH- (C2-C4) -alkyl and C (= O) N- (C1-C4-alkyl) 2;

R⁴ and r⁵ taken together they can form morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, decahydroquinolin-1-yl, piperidin-1-yl, piperazin- 1-yl, [1,4] oxazepan-4-yl, azetidin-1-yl, 2,3-dihydro-1H-isoindol-2-yl or 2,3-dihydro-1H-indol-1-yl; each of the above groups is optionally substituted with substituents selected from the group consisting of hydroxy, cyano, halogen, (halo) 3C-, (halo) 2CH-, halo-CH2-, phenyl, pyridyl, benzyl, (C1-C6) -alkyl , (C3-C7) -cycloalkyl, (C1-C4) -alkoxy, (C1-C4) -alkylthio, amine, (C1-C4-alkyl) NH-, di (C1-C4-alkyl) N-, CO2H, CO2- (C1-C4) -alkyl, C (= O) NH- (C1-C4) -alkyl and C (= O) N (C1-C4-alkyl) 2;

R⁶ is a straight or branched chain (C1-C6) alkyl, (C3-C6) alkenyl, benzyl or phenyl; each of these groups is optionally substituted with substituents selected from the group consisting of halogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, amino, (C1-C4-alkyl) NH-, di (C1-C4-alkyl) ) N-, (C1-C4-alkyl) (phenyl) N-, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl and 4- ( C1-C6-alkyl) -piperazin-1-yl;

R⁷ is hydrogen, straight or branched chain (C1-C6) alkyl;

R⁸ is a straight or branched chain (C1-C6) alkyl, (C3-C7) cycloalkyl, phenyl, pyridyl or furanyl; each of these groups is optionally substituted with substituents selected from the group consisting of halogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, (C1-C4-alkyl) NH-, di (C1-C4-alkyl) N -, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl and 4- (C1-C6-alkyl) -piperazin-1-yl;

R⁹ is a straight or branched chain (C1-C6) alkyl, (C3-C6) alkenyl, benzyl, phenyl, oxazolyl or pyridyl; each of these groups is optionally substituted with substituents selected from the group consisting of halogen, (halogen) 3C-, (halogen) 2CH-, halogen-CH2-, (C1-C4) -alkyl, (C1-C4) -alkoxy, amino , (C1-C4-alkyl) NH-, di (C1-C4-alkyl) N-, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1- yl and 4- (C1-C6-alkyl) -piperazin-1-yl;

or a non-toxic pharmaceutically acceptable salt thereof.

In another preferred embodiment, the invention relates to a compound of Formula Ia wherein R¹ is a straight or branched chain (C1-C6) -alkyl or (C2-C6) -alkenyl optionally substituted with substituents selected from the group consisting of hydroxy, (C3-C7) -cycloalkyl, (C1-C4) -alkoxy, (C1-C4) ) -alkylthio and halogen.

Another preferred compound of the invention is a compound of formula Ia, wherein R¹ is (C3-C7) -cycloalkyl optionally substituted with hydroxyl or halogen.

A further preferred compound of the invention is a compound of formula Ia in which R¹ is a straight or branched chain (C1-C6) alkyl optionally substituted with (C3-C7) cycloalkyl.

A further preferred compound of the invention is a compound of formula Ia in which R¹ is a straight or branched chain (C1-C6) alkyl optionally substituted with halogen.

PL 204 281 B1

A further preferred compound of the invention is a compound of formula Ia in which R³ is phenyl, optionally substituted with substituents selected from the group consisting of halogen, hydroxy, (C1-C4) -alkoxy, (C1-C4) -alkyl, (halo) 3C-, (halo) 2CH, and halogen-CH2.

A further preferred compound of the invention is a compound of formula Ia in which R³ is pyridyl, optionally substituted with substituents selected from the group consisting of halogen, hydroxy, (C1-C4) -alkoxy, (C1-C4) -alkyl, (halo) 3C-, (halo) 2CH, and halogen-CH2.

A further preferred compound of the invention is a compound of formula Ia in which R³ is phenyl, optionally substituted with halogen.

A further preferred compound of the invention is a compound of formula Ia in which R² is a straight or branched chain (C1-C6) -alkyl or (C3-C6) -alkenyl optionally substituted with substituents selected from the group consisting of halogen, (C1-C4) -alkoxy and -NR⁴ R⁵.

A further preferred compound of the invention is a compound of formula Ia in which R² is (C3-C7) -cycloalkylmethyl optionally substituted with substituents selected from the group consisting of amino, (C1-C4-alkyl) NH-, di (C1-C4-alkyl) N-, (C1-C4) -alkyl) -C ( = O) NH- and (C1-C4) -alkyl-OC (= O) NH-.

A further preferred compound of the invention is a compound of formula Ia in which R² is straight or branched (C1-C6) -alkyl-C (= O) -A.

A further preferred compound of the invention is a compound of formula Ia in which R² stands for B-naphthyl.

A further preferred compound of the invention is a compound of formula Ia, wherein said compound₂ towards R.² means

4— (E) —Y

Χχ · z

A particularly preferred compound of the invention is a compound of formula Ia in which R² is -B- (heterocycle), wherein the heterocycle is selected from the group consisting of furanyl, thiofuranyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, and optionally substituted heterocyclyl and thiazocyclyl substituents selected from the group consisting of cyano, halogen, (C1-C4) -alkyl, CO2- (C1-C4) -alkyl, amino, (C1-C4-alkyl) -NH-, di (C1-C4-alkyl) N-, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl and 4- (C1-C6-alkyl) piperazin-1-yl.

Another particularly preferred compound of the invention is a compound of formula Ia, wherein R² is -B- (piperidin-4-yl), wherein piperidin-4-yl is optionally substituted with substituents selected from the group consisting of straight or branched chain (C1-C6) alkyl, CH2C (= O) -phenyl, phenyl or phenylmethyl , (C1-C6) -alkyl and phenyl are optionally substituted with substituents selected from the group consisting of cyano, halogen, benzimidazol-2-yl, pyridyl and tetrahydrofuran-2-yl; and -C (= O) W ', W' is selected from the group consisting of (C1-C4) -alkoxy, R⁹and -NR⁴R⁵, especially a compound in which compound B is straight chain (C1-C4) -alkyl.

A further particularly preferred compound is a compound of formula Ia in which Z is hydrogen.

A further particularly preferred compound is a compound of formula Ia in which X is C (= O) W, E is a direct bond and Y is hydrogen.

A further particularly preferred compound is a compound of formula Ia in which X is -NR⁴ R⁵, E is a direct bond and Y is hydrogen.

A further particularly preferred compound is a compound of formula Ia in which X is -OR⁶, E is a direct bond and Y is hydrogen.

A further particularly preferred compound is a compound of formula Ia in which X is -NR⁷C (= O) R⁸, E is a direct bond and Y is hydrogen.

PL 204 281 B1

The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an active ingredient, which according to the invention comprises as active ingredient a therapeutically effective amount of a compound of formula I as defined above.

The invention further relates to the a- (N-sulfonamido) -acetamide derivative of formula I as defined above for the treatment of Alzheimer's disease and Down's syndrome.

Due to their unique pharmacological properties, the compounds of the invention find use in the treatment or alleviation of β-amyloid peptide related disorders, especially Alzheimer's disease and Daw's syndrome. In this method of treatment, a therapeutically effective amount of a compound of formula I or a non-toxic pharmaceutically acceptable salt, solvate or hydrate thereof is administered in conjunction with a known adjuvant, carrier or diluent.

The term "(C1-C6) alkyl as used in the specification and in the claims (unless otherwise specified) denotes straight chain or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, 3-methylbutyl, hexyl and the like. The term "(C2-C6) alkenyl (unless otherwise specified) as used in the specification and claims means straight or branched alkenyl groups such as ethenyl (vinyl), propenyl, allyl, butenyl, 3-methylbutenyl, pentenyl). , hexenyl and the like. As used in the specification and claims, the term "halogen (unless otherwise indicated) includes bromine, chlorine, iodine and fluorine, and the term" halide includes bromide, chloride and iodide anions.

The term "(C3-C7) cycloalkyl group means a carbocyclic ring system such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "(C1-C4) haloalkyl means a straight or branched (C1-C4) alkyl group containing 1 to 3 halogen atoms, such as trifluoromethyl, fluoroethyl, 1,2-dichloroethyl, trichloroethyl and the like.

The term "(C2-C5) -alkylene denotes a straight or branched alkylene group such as methylene, ethylene, propylene, methylethylene, butylene, methylpropylene, pentylene, methylbutylene and ethylpropylene.

The compounds according to the invention have an asymmetric carbon, and therefore the racemates as well as the individual enantiomeric forms of the compounds of formula I described in the specification and claims are included in the invention. Generally, a single stereoisomer is designated by the symbol (R) or (S). Isomer mixtures can be separated into their individual isomers by methods known in the art, e.g., by fractional crystallization, adsorption, chromatography, or other appropriate separation processes. The resulting racemates can be resolved into the antipodes in the usual manner after introducing appropriate salt-forming groups, e.g. by forming a mixture of diastereomeric salts with optically active salt-forming agents, separating the mixture into diastereomeric salts and converting the resolved salts to free compounds. Possible enantiomeric forms can also be separated by fractionation over chiral high performance liquid chromatography columns.

The term "non-toxic pharmaceutically acceptable salt" as used herein and in the claims includes non-toxic base addition salts. Suitable salts are those derived from organic and inorganic acids such as, but not limited to, hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, acetic, tartaric, lactic, sulfinic, citric, maleic, fumaric, sorbic, aconitic, salicylic, phthalic, and the like.

In the method of the invention, the term "therapeutically effective amount means the total amount of each active ingredient used in the method, sufficient to bring about a significant benefit to the patient, and thus cure acute conditions characterized by inhibition of β-amyloid peptide production. When applied to an individual active ingredient alone, the term denotes the amount of that one ingredient. When used in combination, the term refers to the combined amounts of the active ingredients producing a therapeutic effect, whether administered in combination, serially or simultaneously. The term "treat, treatment as used herein and in the claims" means the prevention or alleviation of the course of β-amyloid peptide related diseases.

General reaction schemes

The general procedures used to synthesize compounds of formula I are shown in reaction schemes 1 to 23. Reasonable deviations from the procedures described should be apparent to the skilled artisan. They are within the scope of the invention.

PL 204 281 B1

<img file="PL204281B1_D0005.tif" />

The starting (α-amino) acetamides of formula II are used in either racemic or pure enantiomeric form. They are commercially available or can be prepared by commonly known methods described in the literature from commercially available (a-amino) acids (general methods for the preparation of amides are described in the textbook: RC Larock, "Comprehensive Organic Transformations, VCH Publishers, New York , 1989, pp. 972-976; see also Reaction Scheme 18 for the conversion of the acid of formula XLVIII to the amide of formula XLIX). A compound of formula II is treated with a suitable base and a sulfonylating reagent such as sulfonyl chloride in an aprotic solvent such as CH₂CI₂at room temperature to provide (α-sulfonamido) acetamide of formula III. Suitable bases include triethylamine and pyridine.

In one method for converting a compound of Formula III to a sulfonamide of Formula I, a compound of Formula III is treated with an appropriate base and an alkylating agent in an aprotic solvent with or without heating the reaction mixture. Suitable bases for this reaction are potassium carbonate and cesium carbonate. Alkyl halides (e.g. alkyl chloride, alkyl bromide or alkyl iodide) and alkyl sulfonates (toluene sulfonates, methyl sulfonates, trifluoromethyl sulfonates). Preferred solvents are DMF and acetonitrile. The reaction is generally carried out at a temperature between 20 ° C and 100 ° C.

In an alternative method for converting a compound of formula III to a compound of formula I, the compound of formula III is treated with triphenylphosphine, dialkyl azodicarboxylate, and an alcohol in an inert solvent with or without heating the reaction mixture.

Reaction scheme 1 - on a solid support

<img file="PL204281B1_D0006.tif" />

Compounds of formula I can also be prepared using solid phase methodology. For example, an FMOC-blocked Rink amide resin is treated with piperidine in DMF to remove the FMOC group. The resin is then coupled to an amino protected α-amino acid over a coupling agent such as 1-hydroxybenzotriazole and dialkyl carbodiimide in an inert solvent such as DMF with or without heating the reaction mixture. Upon deprotection of the α-amino group, the polymer bound amide of formula IV is obtained. In the case of the FMOC-blocked amino acid, deprotection is achieved by treatment with piperidine in DMF.

Reaction of a compound of Formula IV with a suitable base such as pyridine and a sulfonylating agent such as sulfonyl chloride in an inert solvent provides a resin bound sulfonamide of Formula V. Alkylation of a compound of Formula V with an alkyl halide (e.g., alkyl chloride, alkyl bromide, or iodide) alkyl) or an alkyl sulphonate (e.g. methylsulfonate, toluenesulfonate or trifluoromethanesulfonate) is carried out in the presence of a base in an inert solvent at room temperature. A recommended base for this reaction is 2-t-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphite. Cleavage from the resin yields the sulfonamide of formula I. When using the Rink amide resin, the cleavage reaction is preferably carried out using trifluoroacetic acid in an inert solvent such as CH2Cl2.

PL 204 281 B1

<img file="PL204281B1_D0007.tif" />

Compounds of formula I can also be prepared according to reaction scheme 2. Reductive alkylation of an amine of formula I to give an amine of formula VI is achieved by treatment with an aldehyde and hydride reducing agent in the presence of an acid catalyst, with or without heating the reaction mixture. The preferred reducing agent is sodium cyanoborohydride. A preferred acid catalyst is a Lewis acid such as ZnCl2. Preferably methanol is used as a solvent for this reaction. Then, the amine of formula VI is treated with a sulfonylating agent such as sulfonyl chloride in the presence of an amine such as triethylamine. The reaction is carried out in an inert solvent such as CH2Cl2 with or without heating the reaction mixture to provide a compound of Formula I. The reaction is typically conducted at room temperature.

Reaction scheme 3

<img file="PL204281B1_D0008.tif" />

Where the linker is (C1-C6) -alkyl or straight or branched (C3-C6) -alkenyl LG is a leaving group

Compounds of Formula VIII are prepared according to Reaction Scheme 3 by reacting a compound of Formula VII with an amine in an acid stripping agent such as triethylamine in an inert solvent such as CH 2 Cl 2 with or without heating the reaction mixture. The compound of Formula VII is prepared by the sequential reactions shown in Reaction Schemes 1 or 2.

<img file="PL204281B1_D0009.tif" />

Compounds of Formulas XI and XII are prepared according to Reaction Scheme 4. Reduction of the nitro group in the compound of Formula IX (prepared in the subsequent reactions shown in Schemes 1 or 2) with hydrogen gas under pressure in the presence of a palladium catalyst, acid and in a solvent such as methanol gives is an aniline derivative of formula X. Monomethylation of a compound of formula X to a compound of formula XI is carried out with 1.1 equivalents of a methyl halide or sulfo.

Of methylnate, e.g. dimethyl sulfate, in the presence of a base such as triethylamine, in an inert solvent such as DMF. This monomethylation reaction is generally carried out at a temperature ranging from 20 ° C to 40 ° C. The dimethylaniline of formula XII is prepared by treating the aniline of formula X with an excess of a methyl halide, such as methyl iodide or methyl sulfonate, in the presence of a base, e.g. cesium carbonate, in a solvent such as DMF, with or without heating the reaction mixture.

Reaction scheme 5

<img file="PL204281B1_D0010.tif" />

Reaction Scheme 5 shows the synthesis of esters of formula XIII, acids of formula XIV, and amides of formula XV. Reaction of a compound of formula III with an ester of a haloalkyl carboxylic acid, e.g. t-butyl bromoacetate in the presence of a base such as potassium carbonate in an inert solvent such as DMF provides the ester of formula XIII. The deprotection of this ester is carried out by methods known to specialists (e.g. described in the publication of TW Greene and PGM Wuts, protecting Groups in Organic Synthesis, Wiley Interscience, New York, 1999, pp. 373-442). For example, cleavage of t-butyl esters to give acids of formula XIV is accomplished by treatment with trifluoroacetic acid in a solvent such as CH2Cl2. The acid is converted to the amide of formula XV using amide coupling procedures generally known to those skilled in the art (RC Larock, "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp. 972-976). In a preferred process, the acid of formula XIV is treated with a primary or secondary amine over 1-hydroxybenzotriazole and 1,3-dicyclohexylcarbodiimide in an aprotic solvent such as CH2Cl2 or DMF.

Reaction scheme 6

<img file="PL204281B1_D0011.tif" />

PL 204 281 B1

Reaction Scheme 6 shows the preparation of acids of formula XVII and amides of formula XVIII. The ester of formula XVI (prepared according to reaction scheme 1 or 2) is converted to the acid of formula XVII using standard ester cleavage conditions known to those skilled in the art (TW Greene and PGM Wuts, "Protecting Groups in Organic Synthesis, Wiley Interscience, New York, 1999). , pp. 373-442). In the case of the methyl ester of formula XVI, treatment with aqueous sodium hydroxide in a solvent such as methanol or a mixture of methanol and THF at a temperature ranging from 20 ° C to 40 ° C provides the acid of formula XVII. The acid of formula XVII is converted to the amide of formula XVIII using amide coupling procedures generally known to those skilled in the art (RC Larock, Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp. 972-976). In a preferred process, the acid of formula XVII is treated with a primary or secondary amine over 1-hydroxybenzotriazole and a carbodiimide, e.g. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, in a solvent such as DMF or CH2Cl2. A base such as diisopropylethylamine can be added as an acid stripping agent.

Reaction scheme 7

<img file="PL204281B1_D0012.tif" />

Reaction scheme 7 shows the synthesis of piperidine derivatives of the formulas XIX, XX, XXI, XXII and XXIII. By reacting a compound of formula III with an N-protected piperidine substituted with a 4-haloalkyl or 4-sulfonyloxyalkyl group such as 4- (toluenesulfonyloxymethyl) -1- (t-butoxycarbonyl) piperidine, in the presence of a base such as cesium carbonate in a solvent such as With or without heating the reaction mixture with DMF, the carbamate of formula XIX is obtained. The cleavage of the carbamate group from the compound of formula XIX is carried out under standard conditions known to those skilled in the art (TW Greene and PGM Wuts, "Protecting Groups in Organic Synthesis, Wiley Interscience, New York, 1999, pp. 503-550) to give the piperidine of formula XX. In the case of the (t-butoxycarbonyl) piperidine derivative, the cleavage reaction is carried out by treatment with trifluoroacetic acid in CH2Cl2.

The piperidine derivative of formula XX is converted to the amide of formula XXI by the known amide coupling process (RC Larock, "Comprehensive Organic Transformations, VCH Pu14

PL 204 281 B1 blishers, New York, 1989, pp. 972-976). In a preferred method, the piperidine of formula XX is treated with an acyl chloride on an amine such as triethylamine in an inert solvent such as CH2Cl2 with or without heating the reaction mixture. Alternatively, the piperidine of formula XX can be acid-coupled to coupling agents such as hydroxybenzotriazole and carbodiimide to provide the c amide of formula XXI. A urea derivative of formula XXII is obtained by treating an amine of formula XX with an isocyanate and a base such as triethylamine in a solvent such as CH2Cl2 with or without heating the reaction mixture. Alkylation of the piperidine of formula XX provides the N-substituted piperidines of formula XXIII. In a typical method, the piperidine is treated with an alkyl halide or alkyl sulfonate against the base of triethylamine in a solvent such as CH2Cl2.

Reaction scheme 8

<img file="PL204281B1_D0013.tif" />

XXIV XXV XXVj

PG stands for an alcohol blocking group

D is not a bond

The alcohols of formula XXV and the amines of formula XXVI are synthesized by the subsequent reactions shown in reaction scheme 8. A blocked alcohol of formula XXIV is prepared as shown in reaction schemes 1 or 2. After deprotection of the alcohol under conditions suitable for a given blocking group (Greene's TW and PGM Wuts, "Protecting Groups in Organic Synthesis, Chapter 2), produces an alcohol of formula XXV. For example, if the blocking group is a tetrahydropyranyl residue, then the alcohol is released by treating the compound of Formula XXIV with p-toluenesulfonic acid in a solvent such as methanol. An alcohol of formula XXV is converted to a leaving group (e.g., a halide or sulfonate) and then treated with a primary or secondary amine to provide the amine of formula XXVI. For example, an alcohol can be converted to a methyl sulfonate derivative by reaction with methanesulfonyl chloride and a base such as triethylamine in CH2Cl2. Subsequent reaction of the methylsulfonate with a primary or secondary amine to a base such as triethylamine in a solvent such as CH2Cl2 provides the amine of formula XXVI.

Reaction scheme 9

<img file="PL204281B1_D0014.tif" />

PL 204 281 B1

As shown in Scheme 9, amides of Formula XXVIII are prepared from amines of Formula XXVII. The amines of formula XXVII in which D is a direct bond are prepared according to Reaction Scheme 1 or 4. Amines of Formula XXVII in which D is other than direct bond are prepared according to Reaction Scheme 8. The amines of formula XXVII are converted into into amides of formula XXVIII under amide coupling conditions well known to those skilled in the art (RC Larock, "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp. 972-976). For example, reaction of an amine of Formula XXVII with an acid chloride in the presence of a base such as triethylamine in a solvent such as CH 2 Cl 2 affords an amide of Formula XXVIII. The amines of formula XXVII are converted to the carbamate derivatives under conditions known to those skilled in the art (TW Greene and PGM Wuts, "Protecting Groups in Organic Synthesis, pp. 503-550). The sulfonamide derivatives can also be prepared from the amine of Formula XXVII by the methods described for the conversion of an intermediate of Formula II to the sulfonamide of Formula III.

Reaction scheme 10

<img file="PL204281B1_D0015.tif" />

The synthesis of the pyridine derivatives of formula XXX is carried out according to reaction scheme 10. The chloropyridine derivative of formula XXIX is prepared as shown in reaction schemes 1 or 2. Treatment of the compound of formula XXIX with a primary or secondary amine in a solvent such as THF at a temperature ranging from At 20 ° C to 100 ° C, the aminopyridine of formula XXX is obtained in a sealed pressure vessel under appropriate pressure.

<img file="PL204281B1_D0016.tif" />

As indicated in Reaction Scheme 11, the amino-substituted phenol-ethers of formula XXXII are prepared from (O-allyl) -phenols. The starting allylethers of formula XXXI are prepared as shown in Reaction Schemes 1 or 2. Treatment of the compound of formula XXXI with osmium tetroxide and trimethylamine N-oxide in a solvent such as acetone followed by sodium periodate gives the intermediate aldehyde which is generally used without purification. Reaction of this crude aldehyde with a primary or secondary amine and a reducing agent such as sodium triacetoxyborohydride in a solvent such as ethanol with or without heating the reaction mixture provides the amine of formula XXXII.

PL 204 281 B1

Reaction scheme 12

<img file="PL204281B1_D0017.tif" />

The conversion of the ester of formula XXXIII to the tertiary alcohol of formula XXXIV is carried out according to reaction scheme 12. Reaction of the ester of formula XXXIII with an excess of an organometallic methyl reagent such as methylmagnesium bromide in a solvent such as THF in a temperature range of 0 ° C to 25 ° C gives an alcohol of formula XXXIV.

Reaction Scheme 13

<img file="PL204281B1_D0018.tif" />

xxxv χχχνι

1,3,4-oxadiazole derivatives of formula XXXVI are prepared according to reaction scheme 13 using methods known to those skilled in the art (Joule JA, Mills K., Smith GF, Heterocyclic Chemistry, 3rd ed. Chapman &amp; Hall, London, 1995, 452-456. and references therein). For example, the ester of formula XXXV is treated with hydrazine in methanol, keeping the mixture refluxed. The resulting acylhydrazide intermediate is used without purification for the subsequent reaction with an alkyl acetimidate in pyridine, maintaining the mixture at reflux. An oxadiazole derivative of formula XXXVI is obtained.

Reaction scheme 14

<img file="PL204281B1_D0019.tif" />

The synthesis of the 1,2,4-oxadiazole derivative of formula XXXVII is carried out according to reaction scheme 14 using methods known to those skilled in the art (Joule JA, Mills K., Smith GF, Heterocyclic Chemistry, 3rd ed. Chapman &amp; Hall, London, 1995, 452- 456 and references cited therein). For example, by treating the acid of formula XVII with hydroxybenzotriazole, carbodiimide and acetamidoxime

(N-hydroxyethanimidamide) in the presence of a base such as triethylamine gives an intermediate which, when boiling pyridine, yields the oxadiazole of formula XXXVII.

Reaction Scheme 15

<img file="PL204281B1_D0020.tif" />

1,2,4-Oxadiazole of formula XXXIX is prepared from a nitrile of formula XXXVIII (reaction scheme 15) using methods known to those skilled in the art (Joule JA, Mills K., Smith GF, Heterocyclic Chemistry, 3rd ed. Chapman &amp; Hall, London, 1995, 452-456 and references cited therein). For example, reacting a nitrile of formula XXXVIII with hydroxylamine in a solvent such as ethanol in a temperature range up to reflux temperature produces an intermediate N-hydroxyamidine which is treated with acetyl chloride against a base such as triethylamine in a solvent such as CH 2 Cl 2 to give 1. 2,4-oxadiazole of formula XXXIX.

Reaction Scheme 16

<img file="PL204281B1_D0021.tif" />

Reaction Scheme 16 shows the transformation of an amide of formula XL to a ketone of formula XLI. The amide of formula XL, which is prepared in Reaction Scheme 6, is treated with an organometallic methyl reagent such as methylmagnesium bromide in a solvent such as THF to provide the ketone of formula XLI. The reaction is carried out in a temperature range of -20 ° C to 25 ° C.

Reaction Scheme 17

<img file="PL204281B1_D0022.tif" />

PL 204 281 B1

As shown in Reaction Scheme 17, the p-amino amides of formula XLIII are prepared from acrylamides of formula XLII. For example, an acrylamide of formula XLII, which is prepared according to Reaction Scheme 9, is treated with a primary or secondary amine in a solvent such as toluene to provide the p-amino amide of formula XLIII.

Reaction Scheme 18

<img file="PL204281B1_D0023.tif" />

The preparation of the sulfonamide intermediate of formula XLIX (single enantiomer of the compound of formula III) is shown in reaction scheme 18. The α-anion reaction of the intermediate of formula

XLIV (Josien H., Martin A, Chassaing G., Tetrahedron Lett. 1991, 32, 6547) with an alkylating agent such as an alkyl halide (e.g., alkyl chloride, alkyl bromide or alkyl iodide) or an alkyl sulfonate (e.g., alkyl methyl sulfonate, alkyl toluenesulfonate or alkyl triflate) gives an intermediate of formula XLV. The α-anion of a compound of formula XLIV is formed by treatment with a strong base such as an alkyl lithium (e.g. n-butyl lithium) or a dialkylamide (e.g. lithium diisopropylamide) in a solvent such as THF, with or without a co-solvent such as HMPA. The reaction is generally carried out at a temperature between -78 ° C and 25 ° C. The benzhydrylidene blocking group in the compound of formula XLV is removed under conditions well known to those skilled in the art (TW Greene and PGM Wuts, "Protecting Groups in Organic Synthesis, Wiley Interscience, New York, 1999, pp. 587-588). For example, a compound of Formula XLV is treated with an acid such as HCl in water in a solvent such as THF to hydrolyze the protective benzhydrylidene group. The resulting amine of Formula XLVI is treated with a sulfonylating agent as described in Reaction Scheme 1 to provide the sulfonamide of Formula XLVII. Hydrolysis of the acylsulfonamide of formula XLVII to give the acid of formula XLVIII is achieved by treatment with a hydroxide ion, e.g. in the form of lithium hydroxide, in the presence of additives such as lithium bromide and tetrabutylammonium bromide. The acid of formula XLVIII is converted to the amide of formula XLIX under conditions known to those skilled in the art (general reference for the preparation of amides: (RC Larock, "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp. 972-976). For example, reaction of a compound of Formula XLVIII with ammonium chloride in the presence of 1-hydroxybenzotriazole, a carbodiimide reagent, and an amine base such as diisopropylethylamine yields the amide of Formula XLIX. This reaction is typically performed in a polar solvent such as DMF at a temperature ranging from 0 ° C to 40 ° C. The amide of formula XLIX is converted to the compound of formula I as described in reaction scheme 1.

PL 204 281 B1

Reaction Scheme 19

<img file="PL204281B1_D0024.tif" />

Reaction Scheme 19 illustrates one method for synthesizing the α-substituted (N-sulfonamido) acetamide intermediate of Formula III starting from an activated glycine derivative of Formula I. Reaction of a compound of Formula L (Haufe G., Laue KW, Triller MU, Takeuchi Y., Shibata N., Tetrahedron 1998, 54, pp. 5929-5938; Kroger S., Haufe G., Amino Acids 1997, 12, pp. 363-372) with an alkylating agent such as an alkyl halide ( e.g. alkyl chloride, alkyl bromide or alkyl iodide) or an alkyl sulfonate (e.g., alkyl methyl sulfonate, alkyl toluenesulfonate or alkyl triflate) in the presence of a base such as potassium carbonate and additives such as tetrabutylammonium bromide in an inert solvent such as acetonitrile within the temperature range from 25 ° C to 70 ° C, a compound of formula LI is prepared. The benzhydrylidene blocking group is removed under conditions known to those skilled in the art (TW Greene and PGM Wuts, "Protecting Groups in Organic Synthesis, Wiley Interscience, New York, 1999, pp. 587-588). For example, a solution of a compound of Formula LI in a solvent such as diethyl ether is treated with an aqueous acid solution (e.g., aqueous HCl), typically at a temperature in the range of 0 ° C to 30 ° C, to provide the amino ester of Formula LII. The conversion of the ester of formula LII to the amide of formula II is carried out using procedures known in the art. For example, when the compound of Formula LII is an ethyl ester, hydrolysis of that ester is accomplished by treatment with an ethereal acid such as HCl, typically maintaining the reaction mixture at the reflux temperature of the solvent. The resulting intermediate acid is converted to the methyl ester of formula LII by conversion to the acid chloride under standard conditions (e.g. by treatment with thionyl chloride in methanol) and subsequent reaction with an aqueous solution of ammonia in a solvent such as toluene (RC Larock, "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp. 972-976). The amine of formula II is converted to the compound of formula I as described in reaction scheme 1.

Reaction Scheme 20

<img file="PL204281B1_D0025.tif" />

PL 204 281 B1

The preparation of the compound of formula LVII is illustrated in Reaction Scheme 20. An alkene of formula LIII is prepared as described in Reaction Scheme 18 from the intermediate of formula XLIV and 1-bromo-2-methyl-2-propene. Treatment of an alkene of formula LIII with pyridine hydrofluoride in a solvent such as THF in a temperature range of 0 ° C to 25 ° C provides the fluoroalkyl compound of formula LIV. The conversion of the compound of formula LIV to the amide of formula LV is carried out according to reaction scheme 18. The amide of formula LV is converted to the compound of formula LVI as described in reaction scheme 1.

<img file="PL204281B1_D0026.tif" />

The synthesis of compounds of formula LXII and formula LXIV is shown in reaction scheme 21. Na 2-amino-4-methyl-4-pentenoic acid ethyl ester [prepared according to reaction scheme 19 from (benzhydrylideneamino) acetic acid ethyl ester and 1-bromo-2 -methyl-2-propene] is treated with a sulfonylating agent such as sulfonyl chloride with a base such as triethylamine in an inert solvent such as CH2Cl2 to provide an ester of formula LVII. By reaction of an ester of formula LVII with pyridine. HF in a solvent such as THF operated at a temperature range of 0 ° C to 25 ° C produces a mixture of the fluoroalkyl derivative of formula LVIII and the lactone of formula LIX. These products are separated and used separately for the next reactions.

The ester of formula LVIII is hydrolyzed to the acid of formula LX by methods known in the art (TW Greene and PGM Wuts, "Protecting Groups in Organic Synthesis, Wiley Interscience, New York, 1999, pp. 373-442). For example, treatment of an ester of formula LVIII with aqueous sodium hydroxide in a solvent such as methanol provides the acid of formula LX. The acid of formula LX is converted to the amide of formula LXI using the procedure described in Reaction Scheme 18 for the preparation of the amide of formula XLIX. An amide of formula LXII is prepared from a compound of formula LXI as described in Reaction Scheme 1.

Treatment of the lactone of formula LIX with aqueous ammonia gives the amide of formula LXIII. The reaction is generally carried out by heating in a sealed tube. The reaction temperature is kept at 40 ° C to 80 ° C. Intermediate LXIII is converted to the sulfonamide LXIV as described in Reaction Scheme 1.

PL 204 281 B1

<img file="PL204281B1_D0027.tif" />

The synthesis route of the difluoroalkyl amide of formula LXIX is shown in Reaction Scheme 22. The compound of formula L is treated with 4-bromo-1-butene in the presence of a base such as potassium carbonate and in the presence of a tetraalkylammonium halide such as tetrabutylammonium bromide in a solvent such as CH3CN , in the temperature range from 20 ° C to 70 ° C. Removal of the benzhydrylidene protecting group as described in Reaction Scheme 19 provides an intermediate amine which is treated with a sulfonylating agent such as sulfonyl chloride to provide an ester of formula LXV. Alkylation of the sulfonamide nitrogen is carried out using the procedure described in Reaction Scheme 1. The compound of formula LXVI is obtained. The alkene of formula LXVI is converted to the aldehyde of formula LXVII by reacting the alkene with osmium tetroxide and trimethylamine N-oxide in a solvent such as acetone followed by treatment with sodium periodate. The reaction temperature is kept in the range of 20 ° C to 40 ° C. Reaction of an aldehyde of formula LXVII with a fluorine introducing agent such as DAST in a solvent such as CH2Cl2 provides the difluoroalkyl derivative of formula LXVIII. The compound of formula LXVIII is converted to the amide of formula LXIX by hydrolysis of the ester to the acid with a base such as sodium hydroxide in a solvent such as methanol. The intermediate acid is converted to the amide under conditions known to those skilled in the art (RC Larock, "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp. 972-976). For example, reaction of the acid with ammonium chloride in the presence of hydroxybenzotriazole and a carbodiimide reagent and an amine base such as diisopropylethylamine provides an amide of formula LXIX. This reaction is generally performed in a polar solvent such as DMF at a temperature ranging from 0 ° C to 40 ° C.

<img file="PL204281B1_D0028.tif" />

The α-amino-amide of Formula LXXI is prepared by the reaction outlined in Reaction Scheme 23.

The amide of formula LXX is prepared as described in Reaction Scheme 9. Treatment of a compound of formula LXX with a secondary or tertiary amine in a solvent such as THF at a temperature of 20 ° C to 40 ° C provides the amine of formula LXXI.

<img file="PL204281B1_D0029.tif" />

Biological research methods

Γ-secretase inhibitory activity is expected for compounds of formula (I). Detection of γ-secretase activity requires trials to reliably, accurately and conveniently detect the products cleaved by γ-secretase, especially Aβ. The γ-secretase inhibitory activity of the compounds of the invention has been demonstrated in assays for such activity, for example, by performing the assays described below. It was found that the compounds according to the invention inhibit the activity of γ-secretase, as determined in tests for such activity.

The compounds provided in the present invention can further serve as standards and reagents used to determine the ability of a candidate pharmaceutical to inhibit A? Production. These could be available in commercial kits containing a compound of the invention.

In vitro binding assay for the determination of γ-secretase inhibitors.

Competitive binding assays can be used to identify molecules that inhibit the binding of a radiolabeled γ-secretase inhibitor, and thus inhibit γ-secretase activity. For example, the relationship [³H] -A can be used in binding assays with membranes obtained from THP-1 cells (Seiffert D., Bradley J. et al., J. Biol. Chem. 2000, 275, 34086-34091). Compound A is (2R, 3S) -N1 - [(3S) -hexahydro-1- (3-phenoxybenzyl) -2-oxo-1H-azepin-3-yl] -2- (2-methylpropyl) -3- ( propyl) -butanediamide. Its synthesis is described in United States Patent 6,331,408 issued December 18, 2001 and in international patent applications WO 00/28331 and WO 00/07995 and by Seiffert D., Bradley J. et al., J Biol. Chem. 2000, 275, 34086-34091).

<img file="PL204281B1_D0030.tif" />

Relationship A

For the purposes of these tests, THP-1 cells are grown in centrifuged cultures in RPMI 1640 medium supplemented with L-glutamine and 10 μM β-mercaptoethanol to a density of 5 x 10⁵ cells / ml. Cells are harvested by centrifugation and cell pellets are rapidly frozen on dry ice with ethanol and stored at -70 ° C until used. Pellets containing approximately 2 x 10⁴ THP-1 cells are homogenized for 10 seconds in a Brinkman Polytron at setting 6. The homogenate is centrifuged at 48,000 xg for 12 minutes, the resulting pellet washed by repeated homogenization and centrifugation. The final cell pellet is resuspended in buffer until the protein concentration is approximately 0.5 mg / ml. Assays are started by adding 150 µl of membrane suspension to 150 µl of assay buffer containing 0.064 µCi of radioligand and various concentrations of unlabeled compounds. Two identical binding tests are performed in 96-well polypropylene plates in a final volume of 0.3 ml of a solution containing 50 mM Hepes (pH 7.0) and 5% dimethylsulfoxide. Nonspecific binding is set up relative to incubation with 300 nM Compound A (Seiffert D., Bradley J. et al., J. Biol. Chem. 2000, 275, 34086-34091). After incubation at 23 ° C for 1.3 hours, bound ligand is separated from free radioligand by filtration through GFF glass fiber filters pre-soaked with 0.3% ethyleneimine polymer solution. The filters are washed three times with 0.3 ml of ice-cold phosphate buffered saline (pH 7.0) containing 0.1% Triton X-100. Filter bound radioactivity is determined by scintillation. The IC50 values ​​are then determined and used to calculate the Ki values ​​using a Cheng-Prusoft correction for IC50 values. Compounds are classified as active γ-secretase inhibitors if their K values_and were less than 10 gM.

Examples of the results obtained with the compounds of the invention submitted to the test described above are shown in Table 1. In this table, inhibitory concentrations (IC50s) less than or equal to 50 nM are indicated as +++, inhibitory concentrations between 50 nM and 500 nM are indicated as ++ and inhibitory concentrations between 500 nM and 10,000 nM are marked with the + sign.

Table 1

Examples of Activity in the In Vitro Binding Assay

<td>Example</td><td>Order of activity³</td>

<td> 1</td><td> 2</td>

<td> 96</td><td> +++</td>

<td> 123</td><td> +++</td>

<td> 159</td><td> +++</td>

<td> 315</td><td> ++</td>

<td> 341</td><td> ++</td>

<td> 357</td><td> ++</td>

<td> 362</td><td> +++</td>

<td> 365</td><td> +++</td>

<td> 366</td><td> +++</td>

<td> 367</td><td> +</td>

<td> 376</td><td> ++</td>

<td> 379</td><td> +++</td>

<td> 385</td><td> +++</td>

<td> 389</td><td> +++</td>

<td> 394</td><td> +++</td>

<td> 403</td><td> ++</td>

<td> 405</td><td> +++</td>

<td> 408</td><td> +</td>

<td> 409</td><td> ++</td>

<td> 437</td><td> +++</td>

<td> 441</td><td> +++</td>

<td> 443</td><td> ++</td>

<td> 445</td><td> +++</td>

<td> 447</td><td> +++</td>

PL 204 281 B1 cont. table 1

<td> 1</td><td> 2</td>

<td> 450</td><td> ++</td>

<td> 451</td><td> +</td>

<td> 452</td><td> ++</td>

<td> 457</td><td> ++</td>

<td> 464</td><td> +</td>

<td> 474</td><td> +++</td>

<td> 476</td><td> +++</td>

<td> 479</td><td> ++</td>

<td> 486</td><td> +++</td>

^and - activity based on IC50 values ​​+++ = &lt;50 nM ++ = 50 - 500 nM + =&gt; 500 nM and &lt;10,000 nM

In vitro assay to identify a γ-secretase inhibitor based on the inhibition of Αβ formation from membrane preparations

The isolated membrane fraction that contains functionally active γ-secretase and β-APP substrates can generate γ-secretase cleavage products, including Ae (Roberts SB, Hendrick JP, Vinitsky A., Lewis M., Smith DW, Pak R ,, International Patent Application Publication, WO 01/0175435; Fechteler K., Kostka M., Fuchs M., Patent Publication DE 99-19941039; Shearman M., Beher D. et al., Biochemistry 2000, 39, 8698-8704; Zhang L., Song L. et al., Biochemistry 2001, 40, 5049-5055). The isolated membrane fraction can be prepared from human cell lines, such as HeLa and H4, previously transfected with wild-type or mutant β-APP or with the human alkaline phosphatase-β-APP fusion construct and stably producing high levels of γ-secretase substrates. Endogenous γ-secretase present in the isolated membranes prepared at 0-4 ° C cleaves the substrates of β-APP when the temperature of the membranes is increased from 0-4 ° C to 37 ° C. Cleavage products, including Aβ, can be detected and monitored using standard techniques such as immunoprecipitation (Citron M., Diehl TS et al., Proc. Natl. Acad. Sci. USA, 1996, 93, 13170-13175), blotting type western (Klafki HW, Ambramowski D. et al., J. Biol. Chem. 1996, 271, 28655-28659), an enzyme-linked immunosorbent assay (ELISA) described by Seubert P., Vigo-Pelfrey C. et al. (Nature, 1992, 359, 325-327) or preferably, by a method using time-released fluorescence of a homogeneous sample containing membranes and Aβ (Roberts SB, Hendrick JP, Vinitsky A., Lewis M., Smith DW, Pak R. international patent application, WO 01/0175435; Shearman M., Beher D. et al., Biochemistry 2000, 39, 8698-8704). Aβ present in a homogeneous membrane-containing sample can be detected by time-released fluorescence using two antibodies recognizing different epitopes on Aβ. One of these antibodies recognizes an epitope that is present on Aβ but not present in the precursor fragments. Preferably, this antibody binds to the carboxyl terminus of Ap resulting from cleavage with γ-secretase. The second antibody binds to any other epitope present on Aβ. There are e.g. antibodies that bind the N-terminal region (e.g., 26D6-B2-B3® provided by SIBIA Neurosciences, LaJolla, CA) or bind the C-terminal end (e.g., the 9S3.2® antibody provided by Biosolutions, Newark, DE) of the Ap peptide . These antibodies are labeled with a pair of fluorescent adducts that transfer fluorescence energy when these adducts come into close proximity by binding to the N- and C-terminal A termini or regions. Lack of fluorescence indicates the absence of cleavage products due to γ-secretase inhibition. The isolated membrane assay can be used to identify candidates that inhibit γ-secretase cleavage activity and Aβ production.

A typical membrane-based assay uses 45 µg of membrane protein per well in either 96-well or 384-well plate format. Membranes in inert buffer are combined with the test compound and the temperature is changed from 0-4 ° C to 37 ° C. Test agents can typically be synthetic compounds, second order metabolites from bacterial or fungal fermentation extracts, or plant extracts or samples of marine organisms. All synthetic compounds are initially screened in doses from 10 to 100 μΜ or, in the case of extracts, at the dilution necessary for

To minimize cytotoxicity. The membranes are incubated with the test agent for approximately 90 minutes. At this time, fluorescently labeled antibodies are added to each well to quantify A? Detection by fluorescence release method and quantification of A? Is described in the literature (Roberts SB, Hendrick JP, Vinitsky A., Lewis M., Smith D. W., Pak R, Publication of International Patent Application, WO 01/0175435; Shearman M., Beher D. et al., Biochemistry 2000, 39, 8698-8704). Results are obtained by analyzing the plate in a fluorescent plate reader and comparing with the mock-treated membranes and with samples to which known amounts of A? Were added to plot a standard concentration curve. A compound showing positive activity is taken to be a compound that inhibits A? Relative to the control by at least 50% of the initially tested concentration. If a compound is found to be active, a dose-response experiment is performed to determine the lowest dose of the compound needed to effect inhibition of A? Production. Compounds were classified as active γ-secretase inhibitors if their K values ​​were lower than 10 µM.

Examples of the results obtained with the compounds of the invention submitted to the test described above are shown in Table 2. In this table, inhibitory concentrations (IC50s) less than or equal to 50 nM are indicated as +++, inhibitory concentrations between 50 nM and 500 nM are indicated as ++ and inhibitory concentrations between 500 nM and 10,000 nM are marked with the + sign.

Table 2

Examples of activity in an in vitro assay based on the inhibition of A? Formation in membrane preparations

<td>Example</td><td>Order of activity³</td>

<td> 1</td><td> 2</td>

<td> 1</td><td> +++</td>

<td> 2</td><td> +++</td>

<td> 3</td><td> +++</td>

<td> 4</td><td> +++</td>

<td> 5</td><td> +++</td>

<td> 6</td><td> +++</td>

<td> 7</td><td> +++</td>

<td> 8</td><td> +++</td>

<td> 9</td><td> +++</td>

<td> 10</td><td> +++</td>

<td> 11</td><td> +++</td>

<td> 12</td><td> +++</td>

<td> 13</td><td> +++</td>

<td> 14</td><td> +++</td>

<td> 15</td><td> +++</td>

<td> 16</td><td> +++</td>

<td> 17</td><td> +++</td>

<td> 18</td><td> ++</td>

<td> 19</td><td> ++</td>

<td> 20</td><td> ++</td>

<td> 21</td><td> +++</td>

<td> 22</td><td> +++</td>

<td> 23</td><td> +++</td>

<td> 24</td><td> +++</td>

<td> 25</td><td> +++</td>

<td> 26</td><td> +++</td>

PL 204 281 B1 cont. table 2

<td> 1</td><td> 2</td>

<td> 27</td><td> ++</td>

<td> 28</td><td> ++</td>

<td> 29</td><td> +++</td>

<td> 30</td><td> ++</td>

<td> 31</td><td> ++</td>

<td> 32</td><td> +++</td>

<td> 33</td><td> +++</td>

<td> 34</td><td> +++</td>

<td> 35</td><td> ++</td>

<td> 36</td><td> ++</td>

<td> 37</td><td> +++</td>

<td> 38</td><td> +++</td>

<td> 39</td><td> +++</td>

<td> 40</td><td> +++</td>

<td> 41</td><td> +++</td>

<td> 42</td><td> +++</td>

<td> 43</td><td> +++</td>

<td> 44</td><td> +++</td>

<td> 45</td><td> +++</td>

<td> 46</td><td> +++</td>

<td> 47</td><td> +++</td>

<td> 48</td><td> +++</td>

<td> 49</td><td> ++</td>

<td> 50</td><td> +++</td>

<td> 51</td><td> +++</td>

<td> 52</td><td> +++</td>

<td> 59</td><td> ++</td>

<td> 61</td><td> +++</td>

<td> 83</td><td> +</td>

<td> 85</td><td> +</td>

<td> 87</td><td> +++</td>

<td> 89</td><td> +++</td>

<td> 95</td><td> +++</td>

<td> 103</td><td> +++</td>

<td> 113</td><td> ++</td>

<td> 122</td><td> +</td>

<td> 133</td><td> +++</td>

<td> 153</td><td> ++</td>

^and - activity based on IC50 values ​​+++ = &lt;50 nM ++ = 50 - 500 nM + =&gt; 500 nM and &lt;10,000 nM

PL 204 281 B1

In vitro assays to identify a γ-secretase inhibitor based on the inhibition of Ae formation in cell cultures

Cultures of human cell lines such as HEK293 and H4 that produce APP and have γ-secretase activity, or transfected cell lines that overexpress wild-type APP, mutant APP, or APP fusion proteins will secrete Ae peptides into the culture medium from where they can be assayed quantitatively as set forth above (Dovey H., John V. et al., J. Neurochem. 2001, 76, 173-181). Incubation of these cultured cells with γ-secretase inhibitors reduces the production of Ae peptides. For example, as described above, H4 cells stably transfected to overexpress the HPLAP-APP fusion protein described above are grown, isolated and adjusted to a concentration of 2 x 10⁵ cells / ml. 100 µl of the resulting suspension is then added to each well of the 96-well plate. After 4 hours, the media is removed and replaced with 100 μl of serum-free media containing various dilutions of the test compound. The plates are then incubated for 18 hours at 37 ° C and 100 µl of tissue culture supernatant are aliquoted for Ae levels determination by homogeneous sample time release fluorescence as described above. Alternatively, other Ae determination methods described above can be used. The degree of Ae inhibition is used to calculate the IC50 value for the test compound. The compounds of the invention are considered active if the IC value is in the above test₅₀ for the given test compound it is less than 50 µM.

Examples of the results obtained with the compounds of the invention subjected to the test described above are shown in Table 3. In this table, the inhibitory concentration (IC50) less than or equal to 50 nM is indicated by +++, the inhibitory concentration between 50 nM and 500 nM is indicated by the signs + + and the inhibitory concentration between 500 nM and 10,000 nM is indicated by the + sign.

Table 3

Examples of Activity in an In Vitro Assay Based on the Inhibition of Ae Formation in Cultured Cells

<td>Example</td><td>Order of activity³</td>

<td> 1</td><td> 2</td>

<td> 1</td><td> +++</td>

<td> 5</td><td> +++</td>

<td> 19</td><td> ++</td>

<td> 26</td><td> +++</td>

<td> 38</td><td> +++</td>

<td> 41</td><td> +++</td>

<td> 51</td><td> +++</td>

<td> 55</td><td> +++</td>

<td> 61</td><td> +++</td>

<td> 72</td><td> +++</td>

<td> 80</td><td> +++</td>

<td> 89</td><td> +++</td>

<td> 96</td><td> +++</td>

<td> 101</td><td> +++</td>

<td> 123</td><td> +++</td>

<td> 127</td><td> ++</td>

<td> 143</td><td> +++</td>

<td> 147</td><td> ++</td>

<td> 158</td><td> +++</td>

<td> 171</td><td> ++</td>

<td> 193</td><td> +++</td>

PL 204 281 B1 cont. table 3

<td> 1</td><td> 2</td>

<td> 203</td><td> +++</td>

<td> 205</td><td> ++</td>

<td> 207</td><td> +++</td>

<td> 245</td><td> +++</td>

<td> 246</td><td> +++</td>

<td> 249</td><td> ++</td>

<td> 254</td><td> +++</td>

<td> 256</td><td> +++</td>

<td> 260</td><td> +++</td>

<td> 272</td><td> +++</td>

<td> 280</td><td> ++</td>

<td> 282</td><td> +++</td>

<td> 288</td><td> ++</td>

<td> 301</td><td> ++</td>

<td> 302</td><td> +++</td>

<td> 321</td><td> ++</td>

<td> 322</td><td> +++</td>

<td> 329</td><td> +++</td>

<td> 330</td><td> ++</td>

<td> 331</td><td> +</td>

<td> 340</td><td> +++</td>

<td> 341</td><td> ++</td>

<td> 342</td><td> +++</td>

<td> 349</td><td> +++</td>

<td> 352</td><td> ++</td>

<td> 358</td><td> ++</td>

<td> 359</td><td> +++</td>

<td> 366</td><td> +++</td>

<td> 367</td><td> +</td>

<td> 378</td><td> +++</td>

<td> 383</td><td> +++</td>

<td> 394</td><td> +++</td>

<td> 403</td><td> ++</td>

<td> 416</td><td> +++</td>

<td> 418</td><td> +++</td>

<td> 424</td><td> +++</td>

<td> 433</td><td> +++</td>

<td> 434</td><td> +++</td>

PL 204 281 B1 cont. table 3

<td> 1</td><td> 2</td>

<td> 439</td><td> +++</td>

<td> 442</td><td> +++</td>

<td> 472</td><td> +++</td>

<td> 481</td><td> +</td>

<td> 492</td><td> ++</td>

<td> 495</td><td> +++</td>

<td> 497</td><td> +++</td>

^and - activity based on IC50 values ​​+++ = &lt;50 nM ++ = 50 - 500 nM + =&gt; 500 nM and &lt;10,000 nM

The compounds according to the invention were found to have IC values₅₀ less than 10 gM in one or all of the above trials. The compounds of formula I or the pharmaceutical compositions containing them are therefore useful in the treatment, amelioration or elimination of diseases or other disorders in which inhibition of the β-amyloid peptide is beneficial.

In addition to APP cleavage, γ-secretase also cleaves other substrates, including the Notch family of transmembrane receptors (reviewed in Selkoe D., Physiol. Rev. 2001, 81, 741-766; Wolfe M., J. Med. Chem. 2001, 44, 2039-2060), LDL receptor related protein (May P., Reddy YK, Herz J., J. Biol. Chem. 2002, 277, 18736-18743), ErbB-4 (Ni CY, Murphy MP, Golde TE, Carpenter G., Science 2001, 294, 2179-2181), E-cadherin (Marambaud P., Shioi J. et al., EMBO J., 2002, 21, 1948-1956) and CD44 (Okamoto I., Kawano Y. et al., J. Cell Biol. 2001, 155, 755-762). If inhibition of cleavage of non-APP substrates causes adverse effects in humans, then desired γ-secretase inhibitors would preferentially inhibit APP cleavage over undesirable substrates. Notch cleavage can be monitored directly by measuring the amount of cleavage product or indirectly by measuring the effect of the cleavage product on transcription (Mizutani T., Taniguchi Y. et al., Proc. Natl. Acad. Sci. USA 2001, 98, 9026-9031).

In vivo trials of Ae lowering by γ-secretase inhibitors

In vivo assays are available to demonstrate the inhibition of γ-secretase activity. In these trials, animals such as mice expressing normal levels of APP and γ-secretase or genetically engineered to produce higher levels of APP and thus Ae (Dovey H ., John V., et al., J. Neurochem. 2001, 76, 173-181). In these trials, animals were administered γ-secretase inhibitors and various body compartments such as plasma, cerebrospinal fluid, and brain extracts were monitored for Ae levels using the methods described above. For example, Tg2576 mice overexpressing human APP were dosed with γ-secretase inhibitors by oral gavage at doses that produce measurable Ae reduction, typically at doses below 100 mg / kg. Three hours after administration, plasma, brain, and cerebrospinal fluid (CSF) were collected, frozen in liquid nitrogen, and stored at -80 ° C until analyzed. For Ae detection, plasma was diluted 15-fold in PBS with 0.1% Chaps medium and CSF was diluted 15-fold in 1% Chaps with protease inhibitors (5 gg / ml leupeptin, 30 g / ml aprotinin, 1 mM fluoride phenylmethylsulfonyl, 1 gM pepstatin). Brains were homogenized in 1% Chaps medium with protease inhibitors using 24 ml of solution / g of brain tissue. The homogenates were then centrifuged at 100,000 xg for one hour at 4 ° C. The obtained supernatants were diluted 10-fold in 1% Chaps medium with protease inhibitors. Ae levels in plasma, CSF, and brain lysate were determined by the fluorescence time-released homogeneous sample or by any other method described above.

A γ-secretase inhibitor is presumed to be active in one of the above in vivo assays if it lowers Ae by at least 50% at a dose of 100 mg / kg.

Thus, compounds of Formula I, or pharmaceutical compositions containing them, are useful in the treatment, amelioration or relief of medical conditions or other disorders associated with the inhibition of the β-amyloid peptide.

PL 204 281 B1

In another embodiment, the invention includes pharmaceutical compositions comprising at least one compound of Formula I in association with a pharmaceutical adjuvant, carrier, or diluent.

For therapeutic use, the pharmacologically active compounds of formula I will generally be used in the form of a pharmaceutical composition containing at least one such compound as the primary active ingredient in combination with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and auxiliaries, which the composition is prepared by known, suitable techniques.

Such pharmaceutical compositions contain dosage forms suitable for oral, parenteral (including subcutaneous, intramuscular, intradermal, and intravenous), bronchial, or intranasal use. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in the form of a powder or pellets, or made into sachets or lozenges. The solid carrier may contain known excipients such as binders, fillers, tabletting lubricants, disintegrants, wetting agents, or the like. If desired, the tablet may be polymer coated using known techniques. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable preparation, an aqueous or non-aqueous liquid suspension, or it may be a dry product for reconstitution with water or other suitable vehicle just before use. Liquid preparations may contain known additives such as suspending, emulsifying, wetting agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring and / or coloring agents. In compositions for parenteral use, the carrier will generally comprise sterile water, at least in large part, although saline solutions, glucose solutions, and the like may also be used. Injectable suspensions, for the preparation of which commonly known suspending agents are used, can also be used. Known preservatives, buffers, and the like can also be added to parenteral dosage forms. The above pharmaceutical compositions are prepared using known techniques appropriate to the type of preparation desired containing appropriate amounts of the active ingredient, i.e. a compound of Formula I according to the invention. See e.g. Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17th Edition, 1985

The dosages of the compounds of formula I to achieve a therapeutic effect will depend not only on factors such as the age, weight and sex of the patient and the mode of administration, but also on the desired degree of inhibition of p-AP and the potency of the particular compound used in the particular disorder in the particular disease. . It is also noted that when treating and dosing a particular compound, the compound may be used in unit dosage form, and that unit dosage form should be selected by one of ordinary skill in the art taking into account the relative level of activity. It is up to the physician to decide on the exact dosage (and the number of doses to be administered throughout the day). Doses may be varied to adjust the dosage according to the particular circumstances of the present invention so as to obtain the desired therapeutic effect.

A suitable dose of a compound of Formula I or a pharmaceutical composition containing the same for a mammal, including a human suffering or likely to suffer from a condition caused by the production of p-AP, as described above, will generally be a daily dose of from about 0.05 mg / kg to about 10 mg / kg and preferably from about 0.1 to 2 mg / kg by parenteral administration. When administered orally, the dose will be in the range of about 1 to about 75 mg / kg, and preferably 0.1 to 10 mg / kg of body weight. The active ingredient will preferably be administered in equal doses, from once a day to 4 times a day. In general, however, low doses are administered, and the doses are gradually increased until optimal dosing has been established for the host treated. In accordance with good clinical practice, it is advisable to use the compounds of the invention at a concentration that will exert an effective anti-amyloid effect and not cause deleterious undesirable side effects. However, it should be understood that the amount of the compound actually administered will be determined by the physician, according to the circumstances, in view of the disease state to be treated, the particular compound selected, route of administration, age, weight, response of the individual patient to treatment, and severity of the disease symptoms in that patient.

To illustrate the invention, examples are given below which should not be construed as limiting the invention in any way, as many different embodiments are possible within the framework of the essence of the invention.

PL 204 281 B1

Description of particular embodiments of the invention

In the examples below, all temperatures are given in degrees Celsius. Melting points were determined on a Thomas Scientific Unimelt capillary apparatus. They were not corrected. Proton Magnetic Resonance Spectra (¹H NMR) were recorded on a Bruker Avance 300, Bruker Avance 400 or Bruker Avance 500 spectrometer. All spectra were determined in the given solvents, chemical shifts are reported in δ units relative to tetramethylsilane (TMS) as a reference substance and interproton coupling constants are given in Hertz (Hz ). The multiplet type (fold) was designated as follows: s - singlet; d - doublet; t - triplet, q - quartet; m multiplet; br - wide peak; dd - doublet of a doublet; br d - wide doublet; dt - triplet doublet; br s - broad singlet; dq - quartet doublet. Infrared spectra (IR) determined in the potassium bromide (KBr) or sodium chloride layer were recorded in Jasco FT / IR-410 or Perkin Elmer 2000 FT-IR spectrometers in the wavelength range from 4000 cm^-1 up to 400 cm^-1, calibrated against the absorption of a polystyrene membrane at 1601 cm¹. Spectrum values ​​are given as reciprocals of centimeters (cm^-1). Optical rotation [a]_D were determined in a Rudolph Scientific Autopol IV polarimeter in the indicated solvents. Concentrations are given in mg / liter. Low resolution mass spectra (MS) and apparent molecular weights (MH⁺) or (MH)⁺ was measured on a Finnegan SSQ7000 instrument. High resolution mass spectra were determined on a Finnegan MAT900 instrument. The liquid chromatography (LC) spectra in conjunction with mass spectrometry are derived from determinations on a Shimadzu LC instrument coupled to a Water Micromass ZQ instrument.

The following abbreviations have been used: DMF (dimethylformamide); THF (tetrahydrofuran); DMSO (dimethylsulfoxide), Leu (leucine); TFA (trifluoroacetic acid); DAST [(diethylamino) sulfur trifluoride]; HPLC (high pressure liquid chromatography); rt (room temperature); aq (water).

Illustration of the reaction diagram 1

<img file="PL204281B1_D0031.tif" />

(2R) -2- (4-Chlorobenzenesulfonylamino) -4-methylpentanoic acid amide:

380 mg (1.8 mmol) of 4-chlorobenzenesulfonyl chloride were added to a solution of 0.25 g (1.5 mmol) of (D) -leucinamide hydrochloride and 0.43 ml (3.0 mmol) of Et3N in 150 ml of CH2Cl2. stirred at room temperature for 18 hours. The reaction mixture was then diluted with 200 mL of CH2Cl2, washed with water, 0.5 N HCl, brine, and dried over MgSO4. 410 mg (90% yield) of the title compound were obtained as a white solid.

MS (ESI), (M + H)⁺ 305,2;

¹H NMR (DMSO-d6) δ 7.77 (d, 2H, J = 8.7), 7.62 (d, 2H, J = 8.7), 6.90 (br s, 1H), 3, 67 (m, 1H), 1.54 (m, 1H), 1.31 (m, 2H), 0.81 (d, 3H, J = 7.0), 0.71 (d, 3H, J = 7.0).

Method A for converting compound III to compound I:

<img file="PL204281B1_D0032.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4-methoxybenzyl) amino] -4-methylpentanoic acid amide (Example 1)

A mixture of 300 mg (1 mmol) of (2R) -2- (4-chlorobenzenesulfonylamino) -4-methylpentanoic acid amide, 170 mg (1.2 mmol) of K2CO3 and 170 mg (1.1 mmol) of 4-methoxybenzyl chloride in 25 ml DMF was kept at 60 ° C for 18 hours. Then, the reaction mixture was diluted 32

The mixture was quenched with 150 mL of ethyl acetate and washed with water, brine, dried over MgSO4, and concentrated to give a crude white wax. Further purification by flash chromatography (SiO2, 25% ethyl acetate in hexane) gave 297 mg (70% yield) of the title compound as a white solid.

[and]_D = +44.2 (c 1.00, MeOH)

MS (ESI), (MH)^- 422,9;

¹H NMR (CDCl3) δ 7.63 (d, 2H, J = 7.0), 7.42 (d, 2H, J = 7.0), 7.25 (d, 2H, J = 8.0) , 6.79 (d, 2H, J = 8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.36 (dd, 2H, J = 50.15) , 4.26 (t, 1H, J = 7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J = 7.0), 0.67 (d, 3H, J = 7.0);

IR (KBr): 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm^-1.

Method B for converting compound III to compound I:

<img file="PL204281B1_D0033.tif" />

Methyl 6-dimethylaminonicotinate

A solution of 4.0 g (23 mmol) of methyl 6-chloronicotinate in dimethylamine in methanol (2M, 80 ml, 160 mmol) placed in a pressure vessel was stirred at 95 ° C for 2 hours, then cooled to room temperature and concentrated. The residue was dissolved in 250 mL of ethyl acetate, washed with water (2 x 150 mL), dried over Na2SO4, and concentrated. 4.1 g (98% yield) of the title compound were obtained as a light brown solid.

MS (ESI), (M + H)⁺ 181,24;

¹H NMR (CDCl3) δ 8.79 (s, 1H), 7.99 (d, 1H, J = 9.2), 6.45 (d, 1H, J = 9.2), 3.85 (s , 3H). 3.15 (s, 6H).

<img file="PL204281B1_D0034.tif" />

2-Dimethylamino-5-hydroxymethylpyridine

Maintained at 0 ° C, a solution of 4.14 g (23.0 mmol) of methyl 6-dimethylaminonicotinate in 80 mL of anhydrous ether was treated with lithium aluminum hydride (1M in ether, 20 mL, 20 mmol). The mixture was stirred at room temperature for 0.5 h, cooled back to 0 ° C, and quenched slowly with saturated aqueous NaHCO3 (10 mL). The resulting mixture was stirred at room temperature for 0.5 h, filtered and washed with ether. The combined filtrates were dried over Na2SO4 and concentrated. 3.5 g (100% yield) of the title compound were obtained in the form of a beige-colored waxy solid.

MS (ESI), (M + H)⁺ 153,4;

¹H NMR (CDCl3) δ 8.06 (d, 1H, J = 2.4), 7.47 (dd, 1H, J = 2.4, 8.8), 6.45 (d, 1H, J = 8.8), 4.50 (s, 2H), 3.06 (s, 6H), 1.98 (br s, 1H).

PL 204 281 B1

<img file="PL204281B1_D0035.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (2-dimethylaminopyridin-5-yl) amino] -4-fluoro-4-methylpentanoic acid amide salt (TFA) (Example 49):

To a cloudy solution of 0.060 g (0.18 mmol) of (2R) -2 - [(4-chlorobenzenesulfonylamino) -4-fluoro-4-methylpentanoic acid amide (prepared according to reaction scheme 20 or from γ-fluoro-D-Leu methyl ester -OH, Papageorgiou et al., Bioorg. &amp; Med. Chem. Lett. 1994, vol. 4, pp. 267-272), 71 mg (0.46 mmol) 2-dimethylamino-5-hydroxymethylpyridine and 122 mg (0.464 mmol ) triphenylphosphine in 9.5 ml CH₂CI₂While maintaining at room temperature, 75 μl (0.46 mmol) of diisopropyl azodicarboxylate were added dropwise. The resulting pale yellow solution was stirred at room temperature for 2 hours then concentrated under reduced pressure. The residue was dissolved in methanol and purified by reverse phase preparative HPLC (YMC S5, ODS, MeOH-water-TFA). 90 mg (85% yield) of the title compound were obtained in the form of a white foam.

MS (ESI), (M + H)⁺ 457,2;

¹H NMR (CDCl3) δ 8.11 (s, 1H), 7.95 (d, 1H, J = 9.6), 7.77 (d, 2H, J = 6.8), 7.51 (d , 2H, J = 6.8), 6.76 (d, 2H, J = 9.6) 6.34 (s, 1H), 6.02 (s, 1H), 4.58 (br d, 1H , J = 8.4), 4.46 (d, 1H, J = 16.0), 4.06 (d, 1H, J = 16), 3.29 (s, 6H), 2.50 (m , 1H), 1.39 (m, 1H), 1.25 (d, 3H, J = 22.0), 1.17 (d, 3H, J = 22.0).

Illustration of the reaction scheme 1 - on a solid medium

Related to D-Leu-NH2 polymer:

FMOC-blocked Rink amide resin (30 g, 0.61 mmol / g, 18 mmol) was treated with piperidine / DMF solution (250 mL). The mixture was shaken at room temperature for 24 hours, filtered, washed with DMF (5 x 200 ml), CH2Cl2 (5 x 200 ml) and dried under reduced pressure. The resin was treated with FMOC-D-Leu-OH (22 g, 62 mmol), 1-hydroxybenzotriazole hydrate (2.5 g, 18 mmol), 1,3-diisopropylcarbodiimide (9.8 ml, 62 mmol) and DMF (250 ml ). The mixture was shaken for 20 hours, filtered, washed with DMF (4 x 200 ml), a mixture of DMF and water (1: 1, 3 x 200 ml), DMF (3 x 200 ml), methanol (3 x 200 ml), CH2Cl2 (3 x 200 ml) and dried. The completion of the reaction and the load of resin bound FMOC-D-Leu-NH2 (0.56 mmol / g) was determined by treating 52 mg of the resin with 10% (v / v) TFA in CH2Cl2 (2 ml). 11 mg of FMOC-D-Leu-NH2 was obtained. Resin bound FMOC-D-Leu-NH2 was deblocked by treatment with a 20% solution (v / v) of piperidine in DMF (250 ml). 20 g of polymer bound D-Leu-NH2 was obtained.

<img file="PL204281B1_D0036.tif" />

PL 204 281 B1

Polymer bound (R) -2- (4-chlorobenzenesulfonylamino) -4-methylpentanoic acid amide

The above polymer bound D-Leu-NH2 (20 g) was treated with CH2Cl2 (150 mL), pyridine (100 mL), and 4-chlorophenylsulfonyl chloride (20.0 g, 94.8 mmol). The mixture was shaken for 24 hours, filtered, washed with DMF (4 x 200 ml), CH2Cl2 (4 x 200 ml) and concentrated. 22 g of polymer bound (R) -2- (4-chlorobenzenesulfonylamino) -4-methylpentanoic acid amide are obtained in the form of a yellow gum. The completion of the reaction and the resin loading (0.57 mmol / g) was determined by treating 50 mg of the resin with 10% (v / v) TFA / CH2Cl2 (2 ml). 8.7 mg of (R) -2- (4-chlorobenzenesulfonylamino) -4-methylpentanoic acid amide was obtained.

<img file="PL204281B1_D0037.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4-methylbenzyl) amino] -4-methylpentanoic acid amide (Example 60):

To a mixture of polymer bound (2R) -2- [N- (4-chlorobenzenesulfonyl) amino] -4-methylpentanoic acid amide (0.45mmol / g load, 50.0mg, 0.0225mmol), 44mg ( 0.24 mmol) of 4-methylbenzyl bromide and 1.5 ml of DMF were added 0.10 ml (0.34 mmol) of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine and the resulting mixture was shaken at room temperature for 2 days. The resin was then filtered off and washed with DMF (4 x 2 mL), methanol (4 x 2 mL), and CH2Cl2 (4 x 2 mL).

The resin was then treated with 10% (v / v) TFA in CH2Cl2. The mixture was shaken for one hour, filtered and washed with CH2Cl2 (2 x 0.5 mL). The combined filtrates were concentrated under reduced pressure. 7.7 mg (100% yield) of the title compound were obtained as a light brown solid,&gt; 95% pure by HPLC.

HRMS (ESI), (MH)^- for the formula C20H24SClN2O3

Calculated: 407.1206

Received: 407.1201.

¹H NMR (CDCl3) δ 7.64 (d, 2H, J = 8.0), 7.44 (d, 2H, J = 8.0), 7.22 (d, 2H, J = 8.0) , 7.08 (d, 2H, J = 8.0), 6.29 (br s, 1H), 5.34 (br s, 1H), 4.53 (d, 1H, J = 15.2) , 4.34 (d, 1H, J = 15.2), 4.27 (t, 1H, J = 7.2), 2.32 (s, 3H), 1.84 (m, 1H), 1 . 30 (m, 1H), 1.21 (m, 1H), 0.75 (d, 3H, J = 6.8), 0.67 (d, 3H, J = 6.8);

IR (KBr): 3467, 3367, 2956, 2869, 1694, 1670, 1340, 1160 cm^-1.

Illustration of the reaction scheme 2

<img file="PL204281B1_D0038.tif" />

PL 204 281 B1

(2R) -2- (4-Methoxybenzylamino) -4-methylpentanoic acid amide:

A solution of 2.8 g (16.8 mmol) of D-leucinamide hydrochloride and 2.29 g (16.8 mmol) of p-anisaldehyde in 150 ml of methanol was treated with 538 mg (5 mmol) of anhydrous ZnCl2. 1.05 g (16.8 mmol) of NaCNBH3 was added portionwise to the suspension obtained and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 solution (3 mL), diluted with ethyl acetate (500 mL), and washed with brine. After concentration, 3.57 g (84%) of crude benzylamine were obtained as a white wax. This product was used for the next reaction without further purification.

MS (ESI), (M + H)⁺ 251,4;

¹H NMR (CDCl3) δ 7.20 (d, 2H, J = 6.6), 7.10 (br s, 2H), 6.88 (d, 2H, J = 8.4), 5.30 (br s, 1H), 3.80 (s, 3H), 3.63 (dd, 2H, J = 4.5, 12), 1.44-1.65 (m, 3H), 0.95 ( d, 3H, J = 6.3), 0.80 (d, 3H, J = 6.3).

<img file="PL204281B1_D0039.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4-methoxybenzyl ) amino] -4-methylpentanoic acid amide (Example 1):

3.57 g (14.3 mmol) of (2R) -2- [N- (4-methoxybenzyl) amino] -4-methylpentanoic acid amide was dissolved in 100 ml of CH2Cl2, 4.2 ml (29 mmol) of triethylamine were added and 3.6 g (17 mmol) of 4-chlorobenzenesulfonyl chloride and the mixture was kept at room temperature for 18 hours. The solvents were removed and the residue was dissolved in 500 ml of ethyl acetate. The organic solution was washed with water, brine, dried over MgSO4, and concentrated. The resulting material was further purified by flash chromatography (SiO2, 1% MeOH / CH2Cl2). 2.4 g (40% yield) of the title compound were obtained in the form of a slightly colored solid.

MS (ESI), (MH)^- 422,9;

¹H NMR (CDCl3) δ 7.63 (d, 2H, J = 7.0), 7.42 (d, 2H, J = 7.0), 7.25 (d, 2H, J = 8.0) . 6.79 (d, 2H,

J = 8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.36 (dd, 2H, J = 5.0, 15), 4.26 (t, 1H, J = 7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J = 7.0), 0.67 (d, 3H, J = 7.0);

IR (KBr): 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm^-1.

Illustration of the reaction diagram 3

<img file="PL204281B1_D0040.tif" />

PL 204 281 B1

(2R) -2- [N- (4-Morpholinohexyl) -N- (4-chlorobenzenesulfonyl) amino] -4-methylpentanoic acid amide (Example 25):

A solution of 0.20 g (0.44 mmol) of 2R) -2- [N- (4-bromohexyl) -N- (4-chlorobenzenesulfonyl) amino] -4-methylpentanoic acid amide (example 24; prepared according to reaction scheme 1) , 0.25 ml (1.7 mmol) of triethylamine and 150 mg (1.7 mmol) of morpholine in 2 ml of CH2Cl2 were stirred at room temperature for 18 hours. The reaction mixture was then concentrated to give a crude white wax which was purified by flash chromatography (SiO2, eluted with 85% ethyl acetate / 5% hexane / 10% methanol). 112 mg (54% yield) of the title compound were obtained in the form of a white solid.

MS (ESI), (M + H)⁺ 474,4;

¹H NMR (DMSO-d6) δ 7.82 (d, 2H, J = 8.0), 7.64 (d, 2H, J = 8.0), 7.42 (br s, 1H), 6, 99 (s, 1H), 4.25 (m, 1H), 3.51-3.60 (br s, 4H), 3.18-3.41 (m, 2H), 2.25-2.35 (br s, 4H), 2.27 (m, 2H), 1.15-1.62 (m, 9H), 0.80 (d, 6H, J = 6.0).

Illustration of the reaction diagram 4

<img file="PL204281B1_D0041.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4-aminobenzyl) amino] -4-methylpentanoic acid amide (Example 48):

The amount of 2.8 g (6.6 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4-nitrobenzyl) amino] -4-methylpentanoic acid amide (compound of Example 24, prepared according to the scheme reaction 1) suspended in a mixture of 10% Pd / C (1 g) and 1 mL of concentrated HCl in 100 mL of methanol and maintained under a hydrogen atmosphere at 40 psi.² for one hour . The slurry was then filtered through celite and concentrated. 2.4 g (88% yield) of the title compound were obtained as a light brown solid.

MS (ESI), (M + H)⁺ 410,1;

¹H NMR (CDCl3) δ 7.80 (d, 2H, J = 8.5), 7.63 (d, 2H, J = 8.5), 7.52 (br s, 1H), 7.46 ( d, 1H, J = 8.0), 7.26 (d, 1H, J = 8.0), 7.02 (br s, 1H), 4.70 (dd, 2H, J = 50.18) , 4.30-4.41 (m, 1H), 3.67 (br s, 2H), 1.28-1.33 (m, 3H), 0.86 (d, 3H, J = 7.0 ). 0.57 (d, 3H, J = 7.0).

<img file="PL204281B1_D0042.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4-methylaminobenzyl) amino] -4-methylpentanoic acid amide (Example 51):

A solution of 400 mg (1 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4-aminobenzyl) amino] -4-methylpentanoic acid amide (Example 48), 0.16 ml (1.1 mol) of triethylamine and 139 mg (1.1

The millimoles of dimethyl sulfate in 25 ml of toluene were stirred at room temperature for 18 hours. The reaction mixture was then concentrated, the residue was dissolved in ethyl acetate and washed with water and brine, dried over K2CO3 and concentrated. A crude mixture of starting compound and product was obtained. This material was further purified by flash chromatography (SiO2, 35% ethyl acetate in hexane). 195 mg (yield 46%) of the title compound were obtained.

MS (ESI), (M + H)⁺ 424,1;

¹H NMR (CDCl3) δ 7.65 (d, 2H, J = 8.0), 7.58 (d, 2H, J = 8.2), 7.47 (d, 2H, J = 8.0) , 7.31 (d, 2H, J = 8.5), 6.24 (br s, 1H), 5.16 (br s, 1H), 4.50 (dd, 2H, J = 50.17) , 4.27 (t, 1H, J = 10), 2.44 (s, 3H), 1.74-1.83 (m, 1H), 1.25-1.33 (m, 1H), 0 , 93-1.01 (m, 1H), 0.74 (d, 3H, J = 7.0), 0.63 (d, 3H, J = 7.0).

<img file="PL204281B1_D0043.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4-dimethylaminobenzyl) amino] -4-methylpentanoic acid amide (Example 65):

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4-aminobenzyl) amino] -4-methylpentanoic acid amide (Example 48, 0.10 g, 0.22 mmol) was dissolved in 5 mL of DMF. to this solution were added 62 mg (0.44 mmol) of iodomethane and 220 mg (0.66 mmol) of cesium carbonate, and the mixture was stirred at 40 ° C for 18 hours. The mixture was then poured into ethyl acetate and water. The organic layer was separated, dried over MgSO4, and concentrated to an oily residue. This residue was further purified (Biotage 40S column loaded in CH2Cl2 eluted with 25% ethyl acetate in hexane). 15 mg (yield 16%) of the title compound were obtained as a yellow powder.

MS (ESI), (M + H)⁺ 438,1;

¹H NMR (DMSO-d6, 500 MHz) δ 7.74 (dd, 2H, J = 1.9, 6.7), 7.54 (dd, 2H, J = 1.9, 6.8), 7 . 43 (s, 1H), 7.16 (d, 2H, J = 8.6), 7.01 (s, 1H), 6.61 (d, 2H, J = 8.8), 4.59 (q, 2H, J = 16.25), 4.34 (dd, 1H, J = 5.0, 9.3), 2.85 (s, 6H), 1.27-1.47 (m, 3H), 0.80 (d, 3H, J = 5.9), 0.52 (d, 3H, J = 6.1).

Illustration of the reaction diagram 5

<img file="PL204281B1_D0044.tif" />

{N - [(IR) -1-carbamoyl-3-methylbutyl] -N- (4-chlorobenzenesulfonyl) amino} acetic acid tert-butyl ester (example 46):

3.00 g (9.87 mmol) of (2R) -2- (4-chlorobenzenesulfonylamino) -4-methylpentanoic acid amide was dissolved in 50 ml of DMF. To this solution were added 6.0 g (39 mmol) of potassium carbonate and 6.0 ml (39 mmol) of bromoacetic acid tert-butyl ester, and the solution was kept at 70 ° C for 3 hours. The reaction mixture was quenched with ethyl acetate and saturated NaHCO3 solution. The organic layer was washed with brine, dried over MgSO4, and concentrated. Crude oil

The product was further purified on a Biotage 40M column (loaded in CH2Cl2, eluted with 30% ethyl acetate in hexane). 1.2 g (35% yield) of white powder was obtained.

MS (ESI), (M + H)⁺ 446,3;

¹H NMR (CDCl3) δ 7.76 (d, 2H, J = 8.0), 7.52 (d, 2H, J = 8.0), 6.61 (br s, 1H), 5.45 ( s, 1H), 4.15-4.18 (m, 1H), 3.09-3.24 (m, 2H), 2.50-2.58 (m, 4H), 2.31-2. 39 (m, 2H), 1.92-1.99 (m, 1H), 1.15-1.59 (m, 8H), 1.00-1.04 (m, 7H), 0.71- 0.74 (m, 6H).

<img file="PL204281B1_D0045.tif" />

{N - [(IR) -1-carbamoyl-3-methylbutyl] -N- (4-chlorobenzenesulfonyl) amino} acetic acid (Example 59):

To a solution of 0.50 g (1.2 mmol) of {N - [(1R) -1-carbamoyl-3-methylbutyl] -N- (4-chlorobenzenesulfonyl) amino} acetic acid tert-butyl ester in 15 ml of CH2Cl2 was added 15 ml of trifluoroacetic acid and the reaction mixture was stirred at room temperature for 4 hours. The mixture was then concentrated to a white solid (0.40 g, 92% yield). The precipitate was used without further purification.

MS (ESI), (M + H)⁺ 363,1;

¹H NMR (DMSO-d6, 500 MHz) δ 7.90 (dd, 2H, J = 2.0, 6.8), 7.65 (dd, 2H, J = 2.0, 6.8), 7 . 60 (s, 1H), 7.06 (s, 1H), 4.32 (d, 1H, J = 18), 4.12 (t, 1H, J = 8.0), 4.02 (d , 1H, J = 18), 1.55-1.65 (m, 1H), 1.35-1.45 (m, 2H), 0.78 (d, 3H, J = 6.1), 0 . 73 (d, 3H, J = 6.1).

<img file="PL204281B1_D0046.tif" />

(2R) -2- [N (4-chlorobenzenesulfonyl) -N- (cyclopropylcarbamoylmethyl) amino] -4-methylpentanoic acid amide (Example 88)

To a solution of 175 mg (0.480 mmol) of {N - [(1R) -1-carbamoyl-3-methylbutyl] -N- (4-chlorobenzenesulfonyl) amino} acetic acid (Example 59) and 41 g (0.58 mmol) of cyclopropylamine 47 mg (0.72 mmol) of 1-hydroxybenzotriazole and 144 mg (0.720 mmol) of 1,3-dicyclohexylcarbodiimide were added in 3 ml of CH2Cl2. The reaction mixture was stirred for 18 hours at room temperature and then poured into a mixture of ethyl acetate and water. The organic layer was separated, dried over MgSO4, and the residue was concentrated as a clear oil. This residue was further purified on a Biotage 40S column. Elution was done with 40% ethyl acetate in hexane. 54 mg (29% yield) of a white solid were obtained.

MS (ESI), (M + H)⁺ 402,2;

¹H NMR (CDCl3, 500 MHz) δ 7.85 (dd, 2H, J = 1.9, 8.9), 7.50 (dd, 2H, J = 2.0, 8.7), 7.40 (br s, 1H), 6.55 (br s, 1H), 6.30 (br s, 1H), 4.23 (dd, 1H, J = 2.9, 8.9), 3.92 ( d, 1H, J = 17), 3.83 (d, 1H, J = 17), 2.682.73 (m, 1H), 1.75-1.83 (m, 1H), 1.50-1, 57 (m, 1H), 1.40-1.49 (m, 1H), 0.88 (d, 3H, J = 6.4), 0.87 (d, 3H, J = 6.7), 0.80 (d, 2H, J = 7.0), 0.51 (t, 2H, J = 4.0).

PL 204 281 B1

Illustration of the reaction scheme 6

<img file="PL204281B1_D0047.tif" />

4- {N - [(1R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} -benzoic acid (Example 89)

The compound of Example 61, 4 - {[N - ((1R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} benzoic acid methyl ester (354 mg, 0.782 mmol) was dissolved in 4 ml of methanol. 1 ml of 5N NaOH solution was added followed by sufficient THF to obtain homogeneity (1 ml). After an hour, additional 5N NaOH (1 mL) was added and stirring was continued for 2.5 hours. The solution was acidified to pH 2 with 1N HCl solution and extracted with chloroform (2 times). The combined organic layers were dried over Na2SO4 and concentrated. 343 mg (100%) of a white solid were obtained.

MS (ESI), (M + H)⁺ 439,17;

¹H NMR (CDCl3, 300 MHz) δ 7.91 (d, 2H, J = 8.2), 7.81-7.84 (m, δ 3H), 7.56 (d, 2H, J = 8, 6), 7.49 (d, 2H, J = 8.2), 6.55 (br s, 1H), 5.10 (d, 1H, J = 15.4), 4.23 (dd, 1H , J = 4.6, 9.7), 4.05 (d, 1H, J = 15.4), 2.04-2.14 (m, 1H), 1.20-1.31 (m, 1H), 0.80-0.89 (m, 1H), 0.74 (d, 3H, J = 6.6), 0.68 (d, 3H, J = 6.6).

<img file="PL204281B1_D0048.tif" />

(2R) -2- {N- (4-chlorobenzenesulfonyl) -N- [4- (morpholine-4-carbonyl) benzyl] amino} -4-methyl-pentanoic acid amide (Example 101):

To a 0 ° C solution of 50.0 mg (0.114 mmol) of 4 - {[N - ((1R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} benzoic acid in 0.3 ml of DMF was added 12.9 mg (0.148 mmol) of morpholine, then 18.5 mg (0.137 mmol) of 1-hydroxybenzotriazole, 26.2 mg (0.137 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 26 μl (0.15 mmol) of diisopropylethylamine. After 2 hours, the solution was brought to room temperature. After 4 hours, this solution was poured into a 10% aqueous citric acid solution and extracted with ethyl acetate (2 times). The combined organic layers were washed successively with water and saturated aqueous NaHCO3 solution, dried over MgSO4, and concentrated. The product was purified by flash chromatography (SiO2, 40 to 100% ethyl acetate in hexane). 46.0 mg (79% yield) of the title compound were obtained as a white solid.

PL 204 281 B1

MS (ESI), (M + H)⁺ 508,22;

¹H NMR (CDCl3, 300 MHz) δ 7.68 (d, 2H, J = 8.6), 7.29-7.47 (m, 6H), 6.38 (br s, 1H), 5.75 (br s, 1H), 4.65 (d, 1H, J = 16.0), 4.42 (d, 1H, J = 16.0), 4.32 (t, 1H, J = 7.5 ), 3.30-3.85 (br m, 8H), 1.69-1.78 (m, 1H), 1.28-1.37 (m, 1H), 1.08-1.14 ( m, 1H), 0.76 (d, 3H, J = 6.5), 0.63 (d, 3H, J = 6.6).

Illustration of the reaction diagram 7

<img file="PL204281B1_D0049.tif" />

4 - {[N - ((1R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} piperidine-1-carboxylic acid tert-butyl ester (Example 92):

To a solution of 4.2 g (14 mmol) of (2R) -2- (4-chlorobenzenesulfonylamino) -4-methylpentanoic acid amide in 50 ml of DMF was added 13.6 g (417 mmol) of cesium carbonate. To this mixture was added 10.4 g (282 mmol) of 4- (toluene-4-sulfonyloxymethyl) -piperidine-1-carboxylic acid tert-butyl ester (Gilissen C., Bormans G., De Groot T., Verbruggen A., J. Labeled Cmpd. Radiopharm. 1999, 42, 1289). The reaction mixture was stirred at 70 ° C for 18 hours, then it was quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to a clear oil. The oil was purified on a Biotage 40S column (eluted with 30% ethyl acetate in hexane). 3.0 g (44% yield) of a white solid were obtained.

MS (ESI), (M + H)⁺ 502,1;

¹H NMR (DMSO-d6, 500 MHz) δ 7.86 (dd, 2H, J = 2.0, 6.8), 7.65 (dd, 2H, J = 2.0, 6.8), 7 . 37 (br s, 1H), 7.07 (br s, 1H), 4.19 (t, 1H, J = 7.6), 3.92 (br s, 2H), 3.35 (dd, 1H, J = 15.6.8), 3.05 (dd, 1H, J = 15.8.1), 1.85 (br s, 1H), 1.50-1.70 (m, 4H) , 1.38 (s, 9H), 1.10-1.20 (m, 1H), 0.80-1.00 (m, 3H), 0.82 (d, 6H, J = 7.6) .

<img file="PL204281B1_D0050.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (piperidin-4-ylmethyl) amino] -4-methylpentanoic acid amide (Example 126):

To a solution of 2.6 g (5.2 mmol) of 4 - {[N - ((1R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} piperidine acid tert-butyl ester 1-carboxylic acid (example 92) in 25 ml

CH2Cl2 was added 10 ml of trifluoroacetic acid. The mixture was stirred for one hour at room temperature and then concentrated. 1.6 g (84% yield) of a white solid was obtained.

MS (ESI), (M + H)⁺ 402,15;

¹H NMR (DMSO-d6, 500 MHz) δ 7.87 (d, 2H, J = 8.5), 7.66 (d, 2H, J = 8.6), 7.41 (s, 1H), 7.04 (s, 1H), 4.17 (t, 1H, J = 7.3), 3.40-3.50 (m, 1H), 3.20-3.25 (m, 1H), 3.03-3.10 (m, 1H), 2.65-2.80 (m, 2H),

PL 204 281 B1

1.85-2.00 (m, 1H), 1.20-1.85 (m, 2H), 1.45-1.60 (m, 1H), 1.30-1.40 (m, 1H ), 1.10-1.30 (m, 4H), 0.750.90 (m, 1H), 0.82 (d, 3H, J = 7.3), 0.80 (d, 3H, J = 7 , 0).

<img file="PL204281B1_D0051.tif" />

(2R) -2- {N- (4-Chlorobenzenesulfonyl) -N- [1- (pyridine-4-carbonyl) -piperidin-4-ylmethyl] amino} -4-methylpentanoic acid amide (Example 278):

To a solution of 0.10 g (0.22 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (piperidin-4-ylmethyl) amino] -4-methylpentanoic acid amide (example 126) and 0 .06 mL (0.5 mmol) of triethylamine in 3.0 mL of CH2Cl2 was added 56 mg (0.32 mmol) of isonicotinoyl chloride hydrochloride. The reaction mixture was stirred at room temperature for 18 hours and then poured into a mixture of ethyl acetate and saturated aqueous NaHCO3 solution. The organic solution was separated, washed with brine, dried over MgSO4, and concentrated to an oily residue. This residue was purified on a Biotage 10M column (eluted with 80% ethyl acetate in hexane). 36 mg (30% yield) of a white solid were obtained.

MS (ESI), (M + H)⁺ 509,20;

¹H NMR (CDCl3, 500 MHz) δ 8.66 (br s, 2H), 7.80 (d, 1H, J = 8.6), 7.73 (d, 2H, J = 8.5), 7 .51 (d,

2H, J = 7.6), 7.41 (br s, 1H), 6.64 (br s, 1H), 5.35 (br s, 1H), 7.40 (br s, 1H), 4 . 10 (br s, 1H), 3.71 (br s, 1H), 3.33 (br s, 1H), 3.02 (dd, 2H, J = 4.8, 16), 2.70- 2.85 (br s, 1H), 1.50-2.09 (m, 5H), 1.18-1.33 (m,

4H), 0.73 (d, 3H, J = 6.7), 0.68 (d, 3H, J = 6.5).

<img file="PL204281B1_D0052.tif" />

4 - {[N - ((1R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] -methyl} -piperidine-1-carboxylic acid phenethylamide (Example 256):

To a solution of 0.10 g (0.22 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (piperidin-4-ylmethyl) amino] -4-methyl-pentanoic acid amide (example 126) and 32 µl (0.25 mmol) of triethylamine in 3.0 ml of CH 2 Cl 2, 0.040 ml (0.30 mmol) of (2-isocyanatoethyl) benzene were added. The reaction mixture was stirred at room temperature for 18 hours, then poured into a saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated to an oily residue. This residue was purified

PL 204 281 B1 system by Biotage (eluting with 75% ethyl acetate in hexane). 67 mg (52% yield) of a white solid were obtained.

MS (ESI), (M + H)⁺ 549,00;

¹H NMR (CDCl3, 500 MHz) δ 7.71 (d, 2H, J = 8.6), 7.71 (d, 2H, 20J = 8.9), 7.15-7.35 (m, 5H), 6.64 (s, 1H), 5.86 (s, 1H), 4.15 (dd, 1H, J = 5.2, 9.5), 3.88 (d, 1H, J = 13), 3.76 (d, 1H, J = 13), 3.46 (t, 2H, J = 6.7), 3.21-3.29 (m, 1H), 2.97 (dd, 1H, J = 4.6, 14), 2.65-2.85 (m, 4H), 1.75-1.95 (m, 3H), 1.00-1.30 (m, 5H), 0.75-0.80 (m, 1H), 0.72 (d, 3H, J = 6.7), 0.67 (d, 3H, J = 6.7).

<img file="PL204281B1_D0053.tif" />

(2R) -2- (N- (4-Chlorobenzenesulfonyl) -N- {1- [2- (4-cyanophenyl) -2-oxo-ethyl] piperidin-4-ylmethyl} -amino) -4-methylpentanoic acid amide (Example 286):

To a solution of 0.050 g (0.12 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (piperidin-4-ylmethyl) amino] -4-methyl-pentanoic amide (example 126) and 0.040 ml (0.30 mmol) of triethylamine in 2.0 ml of CH2Cl2 were added 55 mg (0.30 mmol) of 4- (2-chloroacetyl) benzonitrile. The reaction mixture was stirred at room temperature for 18 hours, then it was concentrated to a residue. This residue was purified on a Biotage system (eluting with 80% ethyl acetate in hexane). 29 mg (48% of yield) of the desired product were obtained in the form of a white solid.

MS (ESI), (M + H)⁺ 545,16;

¹H NMR (CDCl3, 500 MHz) δ 7.72 (d, 2H, J = 8.5), 7.50-7.65 (m, 2H), 7.50 (d, 2H, J = 7.0 ), 7.357.45 (m, 2H), 6.67 (s, 1H), 5.32 (s, 1H), 4.14 (dd, 1H, J = 5.0, 9.0), 3. 52 (br s, 1H), 3.28 (t, 1H, J = 14), 2.97 (dd, 1H, J = 3.5, 14), 2.82 (br s, 5 1H), 1 .00-2.00 (m, 10H), 0.71 (d, 3H, J = 6.5), 0.66 (d, 3H, J = 6.5).

Illustration of the reaction diagram 8

<img file="PL204281B1_D0054.tif" />

(2R) -2- {N- (4-Chlorobenzenesulfonyl) -N- [4- (tetrahydropyran-2-yloxymethyl) benzyl] -amino} -4-methyl-pentanoic acid amide

PL 204 281 B1

A mixture of 6.35 g (196 mmol) of (2R) -2- (4-chlorobenzenesulfonylamino) -4-methylpentanoic acid amide, 5.62 g (196 mmol) of Cs2CO3 and 5.62 g (196 mmol) of 2 - [(4 -bromomethyl) benzyl] oxy) tetrahydrofuran in 200 ml of acetonitrile was refluxed for one hour. The reaction mixture was then filtered hot under reduced pressure through celite. The filtrate was evaporated under reduced pressure. 9.5 g (96%) of white foam were obtained. This foam was used for the next reaction.

MS (ESI), (M + H)⁺ 510,9;

¹H NMR (CDCl3) δ 7.83 (d, 2H, J = 8.0), 7.75 (d, 2H, J = 8.0), 7.39 (d, 2H, J = 8.0) , 7.24 (d, 2H, J = 8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.82 (d, 1H, Jab = 12), 4 . 65 (m, 1H), 4.52 (d, 1H, Jab = 12), 4.30 (d, 1H, Jab = 16), 4.20 (d, 1H, Jab = 16), 3.74 (m, 2H), 3.46 (m, 1H), 1.89 (m, 1H), 1.66 (m, 6H), 0.97 (d,

<img file="PL204281B1_D0055.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4-hydroxymethyl) benzylamino] -4-methylpentanoic acid amide (Example 95):

To a solution of 9.5 g (186 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- [4- (tetrahydropyran-2-yloxymethyl) benzylamino] -4-methyl-pentanoic acid amide in 200 ml methanol, a catalytic amount of p-toluenesulfonic acid was added, and the mixture was stirred at room temperature overnight. The solvent was then evaporated under reduced pressure, the resulting foam was dissolved in 100 ml of CH2Cl2, the solution was washed with 1N NaOH, water, brine and dried over MgSO4. The solvent was evaporated from the filtrate under reduced pressure and the resulting foam was crystallized from hot hexane. 7.7 g (92% yield) of the product are obtained in the form of a white solid.

MS (ESI), (M + H)⁺ 425,17;

¹H NMR (CDCl3) δ 7.68 d, 2H, J = 7.0), 7.46 (d, 2H, J = 7.0), 7.33 (d, 2H, J = 8.0), 7.28 (d, 2H, J = 8.0), 6.26 (br s, 1H), 5.35 (br s, 1H), 4.67 (br s, 2H), 4.59 (d , 1H, Jab = 16), 4.37 (d, 1H, Jab = 16), 4.26 (t, 1H, 7.0), 1.86-1.80 (m, 2H), 1.34 -1.28 (m, 1H), 1.16-1.10 (m, 1H), 0.96 (d, 3H, J = 7.0), 0.93 (d, 3H, J = 7, 0).

<img file="PL204281B1_D0056.tif" />

4 - {[N - ((1R) -1-carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} benzyl ester with methanesulfonic acid

PL 204 281 B1

To a cooled to 0 ° C solution of 1.5 g (3.5 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4-hydroxymethyl) benzyl) amino] -4- of methylpentane in 15 ml of CH 2 Cl 2, 0.74 ml (5.3 mmol) of triethylamine was added. A solution of 0.29 ml (3.5 mmol) of methanesulfonyl chloride in 5 ml of CH 2 Cl 2 was then added dropwise and the reaction mixture was stirred at 0 ° C for 1 hour. The reaction mixture was diluted with 25 mL of CH2Cl2, washed quickly with 1N HCl, brine, and dried by passing the organic phase through a cotton wool plunger. The solvent was evaporated under reduced pressure. The title compound was obtained in quantitative yield. The resulting foam was used without purification for the following reactions.

MS (ESI), (M-95)⁺ 409,15;

¹H NMR (CDCl3) δ 7.70 (d, 2H, J = 8.0), 7.48 (d, 2H, J = 8.0), 7.41 (d, 2H, J = 8.0) , 7.38 (d, 2H, J = 8.0), 6.27 (br s, 1H), 5.32 (br s, 1H), 5.24 (s, 2H), 4.64 (d , 1H, Jab = 16), 4.43 (d, 1H, Jab = 16), 4.33 (t, 1H, J = 6), 2.90 (s, 3H), 1.90 (m, 1H ), 1.60 (m, 2H), 0.96 (d, 3H, J = 7.0), 0.91 (d, 3H, J = 7.0).

<img file="PL204281B1_D0057.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (4-dimethylaminomethylbenzyl) amino] -4-methylpentanoic acid amide (Example 110):

To a stirred solution of 0 ° C 150 mg (0.298 mmol) of 4 - {[N - ((1R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} benzyl ester with methanesulfonic acid in 3 mL CH2Cl2, added 1 equivalent of triethylamine and then dimethylamine (0.3 mL of a 2M solution in THF). The reaction mixture was stirred overnight at room temperature, then it was diluted with CH2Cl2, washed with water, brine, dried over MgSO4 and concentrated. The resulting amber glassy residue was purified by flash chromatography (SiO2, 10% methanol / CH2Cl2). 95 mg (71% yield) of the title compound were obtained.

MS (ESI), (M + H)⁺ 452,23;

¹H NMR (CDCl3) δ 7.94 (d, 2H, J = 8.0), 7.74 (d, 2H, J = 8.0), 7.63 (d, 2H, J = 8.0) , 7.38 (d, 2H, J = 8.0), 6.23 (br s, 1H), 5.35 (br s, 1H), 4.22 (d, 1H, Jab = 16), 4 , 14 (d, 1H, Jab = 16), 3.28-3.23 (m, 3H), 2.17 (br s, 6H), 1.95 (m, 1H), 1.55 (m, 2H), 0.96 (d, 3H, J = 7.0), 0.93 (d, 3H, J-7.0).

Illustration of the reaction diagram 9

<img file="PL204281B1_D0058.tif" />

(2R) -2- [N- (4-acetylaminobenzyl) -N- (4-chlorobenzenesulfonyl) amino] -4-methylpentanoic acid amide (Example 163)

Per solution 250 mg (0.60 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4-aminobenzyl) amino] -4-methylpentanoic acid amide (example 48) and 120 mg (1, 2 mmoles) of triethylamine in 20 ml

PL 204 281 B1

CH2Cl2 was treated with 56 mg (0.72 mmol) of acetyl chloride. The mixture was stirred for 18 hours, then concentrated and purified by flash chromatography (SiO2, 1% methanol / CH2Cl2). 110 mg (41% yield) of the title compound were obtained.

MS (ESI), (MH)^- 422,9;

¹H NMR (CDCl3) δ 7.67 (d, 2H, J = 8.0), 7.28-7.46 (m, 6H), 7.12 (br s, 1H), 6.24 (br s , 1H), 5.19 (br s, 1H), 4.48 (dd, 2H, J = 50.15), 4.27 (t, 1H, J = 7.0), 2.18 (s, 3H), 1.80-2.01 (m, 1H), 1.12-1.32 (m, 2H), 0.75 (d, 3H, J = 7.0), 0.67 (d, 3H, J = 7.0).

<img file="PL204281B1_D0059.tif" />

(2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4 - {[(2-dimethylaminoacetyl) methylamino] methyl} -benzyl) amino] -4-methylpentanoic acid amide (Example 272):

Amounts of 75 mg (0.17 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4-methylaminomethylbenzyl) amino] -4-methylpentanoic acid, 18 mg (0.17 mmol) of acid ( α-dimethylamino) acetic acid, 24 mg (0.17 mmol) of 1-hydroxybenzotriazole and 33 mg (0.17 mmol) of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride were combined in 3 ml of CH2Cl2 and stirred overnight. . The reaction mixture was diluted with 5 mL of CH2Cl2 and washed with 1N NaOH and brine. The organic phase is dried by filtration through a cotton wool pad and the solvent is evaporated off under reduced pressure. The product was purified by preparative HPLC. 61 mg (68% yield) of the title compound were obtained.

MS (ESI), (M + H)⁺ 523,4;

¹H NMR (CDCl3) δ 8.02 (d, 2H, J = 8.0), 7.71 (d, 2H, J = 8.0), 7.37 (d, 2H, J = 8.0) , 7.28 (d, 2H, J = 8.0), 6.23 (br s, 1H), 5.51 (br s, 1H), 4.46 (s, 2H), 4.70 (d , 1H, Jab = 16), 4.33 (d, 1H, Jab = 16), 3.25 (t, 1H, J = 6.0), 2.69 (s, 3H), 2.63 (s , 2H), 2.20 (s, 6H), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J = 7.0), 0.94 ( d, 3H, J = 7.0).

Illustration of the reaction diagram 10

<img file="PL204281B1_D0060.tif" />

(2R) -2- [N- (4-Chlorobenzenesulfonyl) -N- (2-dimethylaminopyridin-5-ylmethyl) amino] -4-methylpentanoic acid amide salt with trifluoroacetic acid (Example 254):

A solution of 1.18 mg (41 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (2-chloropyridin-5-ylmethyl) amino] -4-methylpentanoic amide (prepared according to reaction scheme 1) in chap46

The formation of dimethylamine in THF (2M, 20 ml, 40 mmol) was stirred at 95 ° C for 30 hours in a pressure vessel. Five ml of the reaction mixture (25% of total volume) was purified by preparative reverse phase HPLC (YMC S5 ODS, methanol-water-TFA). 17 mg (yield 30%) of the title compound were obtained in the form of a white foam.

HRMS (ESI), (MH)^- for pattern C20H26SCIN4O3

Calculated: 437.1426

Received: 437.1420.

¹H NMR (CDCl3) δ 8.04 (s, 1H), 8.03 (d, 1H, J = 9.8), 7.76 (d, 2H, J = 7.6), 7.54 ( d, 2H, J = 7.6), 6.83 (d, 1H, J = 9.8), 6.62 (br s, 1H), 6.40 (br s, 1H), 4.64 ( d, 1H, J = 15.9), 4.29 (m, 1H), 4.18 (d, 1H, J = 15.9), 3.30 (s, 6H), 1.84 (m, 1H), 1.29 (m, 1H), 0.93 (m, 1H), 0.77 (d, 3H, J = 6.5), 0.72 (d, 3H, J = 6.5) .

Illustration of the reaction diagram 11

<img file="PL204281B1_D0061.tif" />

(2R) -2- [N- (4-allyloxy-3-fluorobenzyl) -N- (4-chlorobenzenesulfonyl) amino] -4-methylpentanoic acid amide:

To a solution of 1.00 g (3.29 mmol) of (2R) -2- (4-chlorobenzenesulfonylamino) -4-methylpentanoic acid amide and 1.29 g (3.95 mmol) of Cs2CO3 in 25 ml of DMF was added 0.88 g (3.67 mmol) 1-allyloxy-4-bromomethyl-2-fluorobenzene (Graham Samuel L. et al., European Patent Application Publication, EP 487270, 1992). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was then diluted with 350 ml of ethyl acetate / hexane (9: 1), washed with water (4 x 200 ml) and brine, and dried over Na2SO4. 393 mg (yield 26%) of the title compound were obtained in the form of a white solid.

MS (ESI), (M + H)⁺ 469,1;

¹H NMR (CDCl3) δ 7.66 (d, 2H, J = 8.1), 7.45 (d, 2H, J = 8.1), 7.11 (d, 1H, J = 12.0) , 6.98 (m, 1H), 6.84 (t, 1H, J = 8.0), 6.22 (br s, 1H), 6.04 (m, 2H), 5.42 (m, 1H), 5.16 (br s, 1H), 4.59 (m, 2H), 4.40 (m, 3H), 1.83 (m, 1H), 1.32 (m, 1H), 1 , 14 (m, 1H), 0.76 (d, 3H, J = 7.0), 0.68 (d, 3H, J = 7.0).

<img file="PL204281B1_D0062.tif" />

(2R) -2- {N- (4-chlorobenzenesulfonyl) -N- [3-fluoro-4- (2-morpholin-4-yl-ethoxy) benzyl] amino} -4-5-methylpentanoic acid amide (Example 427) :

PL 204 281 B1

A mixture of 0.39 g (0.84 mmol) of the intermediate allyloxy compound from the previous example, 0.01 g (0.04 mmol) of osmium tetroxide and 0.140 g (1.81 mmol) of trimethylamine N-oxide was dissolved in 10 ml of acetone and the mixture stirred for 4 hours at room temperature. The solution was then concentrated under reduced pressure and dissolved in 15 ml of a mixture of dioxane and water (1.5: 1). 0.22 g (1.0 mmol) of sodium periodate was added and the solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water and brine, dried over Na2SO4, and concentrated. (2R) - {N- (4-chlorobenzenesulfonyl) -N- [3-fluoro-4- (2-oso-ethoxy) -benzyl] amino} -4-methylpentanoic acid amide was obtained as a crude beige solid. This crude material was used for the next step without further purification. Amide 0.16 g (0.34 mmol) of this acid amide (2R) -2- {N- (4-chlorobenzenesulfonyl) -N- [3-fluoro-4- (2-oso-ethoxy) benzyl] amino} - 4-methylpentane and 0.090 g (1.0 mmol) of morpholine were dissolved in 5 ml of ethanol and held at 80 ° C for about 15 minutes. The oil bath was removed, 0.290 g (1.36 mmol) of sodium triacetoxyborohydride was added and the suspension was stirred at room temperature for 16 hours. The solution was concentrated to dryness, taken up in brine and extracted with ethyl acetate (2 x 100 mL). The extract was dried over Na2SO4 and concentrated in vacuo to give a crude orange residue. This residue was purified by preparative HPLC (20 x 100 mm YMC S5 ODS C-18 column, 25 ml / minute, 0-100% methanol / water containing 0.1% TFA, 15 minutes). 69.5 mg (31% yield) of the TFA salt of the title compound were obtained as a light yellow solid.

[α] D = +23 (c 6.4, CH2Cl2);

LCMS (M + H)⁺ 542,25;

¹H NMR (CDCl3) δ 7.71 (d, 2H, J = 8.0), 7.50 (d, 2H, J = 8.0), 7.16 (d, 1H, J = 12.0) , 7.05 (d, 1H, J = 8.0), 6.87 (t, 1H, J = 8.0), 6.38 (br s, 1H), 5.91 (br s, 1H) , 4.41 (Abq, 2H, J = 16, Jab = 176), 4.45 (m, 2H), 4.27 (t, 1H, J = 8.0), 4.03 (m, 4H) , 3.70 (m, 2H), 3.51 (m, 2H), 3.10 (m, 2H), 1.83 (m, 1H), 1.29 (m, 1H), 1.05 ( m, 1H), 0.75 (d, 3H, J = 8.0), 0.68 (d, 3H, J = 8.0).

Illustration of the reaction diagram 12

<img file="PL204281B1_D0063.tif" />

(2R) -2- {N- (4-chlorobenzenesulfonyl) -N- [4- (1-hydroxy-1-methyl-ethyl) benzyl] amino} -4-methylpentanoic acid amide (Example 287):

A solution of 101 mg (0.221 mmol) of 4 - {[N - ((1R) -1-carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} -benzoic acid methyl ester (compound of Example 61) in 2 mL of THF was cooled to 0 ° C and a solution of methylmagnesium bromide (1.4 M in toluene / THF, 0.50 mL, 0.71 mmol) was added dropwise. The resulting dark yellow solution was stirred at 0 ° C and after 30 minutes additional methylmagnesium bromide solution (0.25 mL, 0.353 mmol) was added. After one hour, the solution was brought to room temperature. After 3.5 hours, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution and the mixture was extracted with ethyl acetate (2 times). The combined organic layers were dried over Na2SO4 and concentrated. Purification by flash chromatography (SiO2, 20 to 100% ethyl acetate in hexane) gave 62 mg (62% yield) of the title compound as a white foam.

MS (ESI), (M + H)⁺ 453,16;

¹H NMR (CDCl3, 300 MHz) δ 7.61 (d, 2H, J = 8.7), 7.40 (d, 2H, J = 8.7), 7.37 (d, 2H, J = 8 , 4), 7.26 (d, 2H, J = 8.4), 6.28 (br s, 1H), 5.25 (br s, 1H), 4.49 (d, 1H, J = 15 , 9), 4.41 (d, 1H, J = 15.9), 4.33 (t, 1H, J = 6.6), 1.73-1.80 (m, 1H), 1.55 (s, 6H), 1.28-1.35 (m, 1H), 1.20-1.25 (m, 1H), 0.77 (d, 3H, J = 6.5), 0.66 (d, 3H, J = 6.6).

PL 204 281 B1

Illustration of the reaction diagram 13

<img file="PL204281B1_D0064.tif" />

(2R) -2- {N- (4-Chlorobenzenesulfonyl) - [4- (5-methyl- [1,3,4] oxadiazol-2-yl) benzyl] -amino} -4-methylpentanoic acid amide (Example 436 ):

Step 1: A solution of 0.500 g (1.10 mmol) of 4 - {[N - ((1R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} benzoic acid methyl ester (compound with Example 61) was diluted in 10 ml of methanol and 2 ml of hydrazine were added. The starting material slowly dissolved within 5 minutes. After 30 minutes, the solution was heated to boiling. After 22 hours, this solution was cooled to room temperature and 15 ml of water was added. A white precipitate formed. The mixture was extracted with ethyl acetate (2 times). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The acylhydrazine derivative was obtained in the form of a white foam. It was used directly without further purification for the cyclization step.

Step 2. The crude acylhydrazide (0.150 g, 0.331 mmol) was dissolved in 2.2 ml of pyridine, 60.0 mg (0.364 mmol) of ethyl acetimidate hydrochloride were added and the mixture was refluxed for 1.25 hours. The solution was cooled to room temperature and concentrated to remove pyridine. The residue was dissolved in ethyl acetate and washed sequentially with water, 1N HCl (2 times), saturated aqueous NaHCO3, and brine. The solution was dried over MgSO4 and concentrated. Purification by flash chromatography (SiO2, 50 to 100% ethyl acetate in hexane) gave 138 mg (88% yield over two steps) of the title compound as a white solid.

[α] ο = +11.1 (c 7.0 mg / ml CHCle);

MS (ESI), (M + H)⁺ 477,22;

¹H NMR (CDCl3, 300 MHz) δ 7.94 (dd, 2H, J = 1.8, 8.4), 7.69 (dd, 2H, J = 1.8, 8.7), 7.45 -7.50 (m, 4H), 6.23 (br s, 1H), 5.19 (br s, 1H), 4.65 (d, 1H, J = 15.9), 4.46 (d , 1H, J = 15.9), 4.31 (dd, 1H, J = 6.6, 7.8), 2.61 (s, 3H), 1.75-1.85 (m, 1H) , 1.28-1.35 (m, 1H), 1.08-1.15 (m, 1H), 0.76 (d, 3H, J = 6.6), 0.64 (d, 3H, J = 6.6).

Illustration of the reaction diagram 14

<img file="PL204281B1_D0065.tif" />

PL 204 281 B1

(2R) -2- {N- (4-Chlorobenzenesulfonyl) -N- [4- (3-methyl- [1,2,4] oxadiazol-5-yl) benzyl] amino} -4-methylpentanoic acid amide (Example 437)

Step 1. To a room temperature solution of 520 mg (1.2 mmol) of 4 - {[N - ((1R) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} benzoic acid (compound of Example 89) in 2.4 ml of DMF and 7.1 ml of CH2Cl2, 192 mg (1.42 mmol) of 1-hydroxybenzotriazole, 272 mg (1.42 mmol) of 1- (3-dimethylaminopropyl) -3- hydrochloride were added. ethylcarbodiimide and 0.31 ml (1.8 mmol) diisopropyl ethylamine. 105 mg (1.42 mmol) of N-hydroxyacetamide were also added. After 21 hours, starting material was still detected, so additional aliquots of all reagents were periodically added to spur the reaction. After 3 days, the mixture was concentrated and partitioned between saturated aqueous NaHCO3 solution and ethyl acetate (extracted 2 times). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. A yellow oil was obtained which was used for the next step without purification.

Step 2: The crude acetamidoxime was dissolved in 10 ml of toluene and the solution was heated to reflux. After one hour, 2 ml of pyridine was added and heating was continued for another 15 hours. The mixture was concentrated and diluted with ethyl acetate. The organic phase was washed sequentially with water, 1N HCl (2 times), sat. Aq. NaHCO3, and brine then dried over MgSO4 and concentrated. Purification by flash chromatography (SiO2, 10 to 40% ethyl acetate in hexane) gave 238 mg (42% yield over two steps) of the title compound as a light yellow solid.

[and]²³D = +9.30 (c, 5.93, CHCl₃);

MS (ESI), (M + H)⁺ 477,18;

¹H NMR (CDCl3, 300 MHz) δ 8.04 (d, 2H, J = 8.4), 7.70 (dd, 2H, J = 1.8, 8.4), 7.45-7.52 (m, 4H), 6.23 (br s, 1H), 5.19 br s, 1H), 4.67 (d, 1H, J = 16.2), 4.47 (d, 1H, J = 15.9), 4.31 (t, 1H, J = 7.2), 2.47 (s, 3H), 1.75-1.85 (m, 1H), 1.28-1.35 ( m, 1H), 1.08-1.15 (m, 1H), 0.76 (d, 3H, J = 6.6), 0.64 (d, 3H, J = 6.6).

Illustration of the reaction diagram 15

<img file="PL204281B1_D0066.tif" />

(2R) -2- {N- (4-Chlorobenzenesulfonyl) -N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -amino} -4-methylpentanoic acid amide ( Example 465)

Per a solution of 0.20 g (0.47 mmol) of (2R) -2- [N- (4-chlorobenzenesulfonyl) -N- (4-cyanobenzyl) amino] -4-methylpentanoic acid amide (compound of Example 6) in 6 mL of ethanol was treated with hydroxylamine (50% water solution, 0.050 mL, 0.71 mmol) and the reaction mixture was held at 80 ° C for 18 hours. The mixture was then concentrated to a residue which was crystallized from ethyl acetate / hexane. 136 mg (51% yield) were obtained in the form of a white solid. This precipitate (0.18 mmol) was dissolved in chloroform and treated with 0.030 ml (0.24 mmol) of triethylamine and 0.020 ml (0.18 mmol) of acetyl chloride. The reaction mixture was stirred at room temperature for 2 hours then poured into ethyl acetate and brine. The organic layer was separated, dried over MgSO4, and concentrated to a residue. This residue was dissolved in toluene and refluxed for 24 hours. The mixture was concentrated to a residue and purified by Biotage (eluting with a mixture of ethyl acetate and hexane, 1: 1). 35 mg (39% yield) of the desired product were obtained in the form of a white solid.

MS (ESI), (M + H)⁺ 477,13;

PL 204 281 B1 ¹H NMR (CDCl3, 500 MHz) δ 7.98 (d, 2H, J = 8.2), 7.68 (d, 2H, J = 8.9), 7.45 (d, 4H, J = 8 , 5), 6.21 (s, 1H), 5.19 (s, 1H), 4.62 (d, 1H, J = 15), 4.48 (d, 1H, J = 16), 4. 31 (t, 1H, J = 7.0), 2.65 (s, 3H), 1.75-1.85 (m, 1H), 1.20-1.35 (m, 4H), 1.1 10-1.17 (m, 1H), 0.85-0.90 (m, 1H), 0.75 (d, 3H, J = 6.7), 0.64 (d, 3H, J = 6 , 4).

Illustration of the reaction diagram 16

<img file="PL204281B1_D0067.tif" />

(2R) -2- [N- (4-acetylbenzyl) -N- (4-chlorobenzenesulfonyl) amino] -4-methylpentanoic acid amide (Example 273):

Solution 0.100 g (0.207 mmol) 4 - {[N - ((1S) -1-carbamoyl-3-methylbutyl) -N- (4-chlorobenzenesulfonyl) amino] -methyl} -N-methoxy-N-methylbenzamide (compound from Example 251) in 2.1 mL of THF was cooled to 0 ° C and a solution of methylmagnesium bromide (1.4 M in toluene / THF, 0.178 mL, 0.249 mmol) was added dropwise. The resulting solution was stirred at 0 ° C for 3 hours while additional methylmagnesium bromide solution (0.178 mL, 0.249 mmol) was added. After a further 30 minutes, the last portion of the methylmagnesium bromide solution (0.3 ml) was added. After 15 minutes, the reaction was quenched by adding saturated aqueous NH4Cl and 1N HCl and the mixture was extracted with ethyl acetate (2 times). The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated. Purification by flash chromatography (SiO2, 20 to 60% ethyl acetate in hexane) provided 79 mg (87% yield) of the desired compound as an off-white foam.

[and]²³D = +20.4 (c, 7.57, CHCl₃);

MS (ESI), (M + H)⁺ 437,13;

¹H NMR (CDCl3, 300 MHz) δ 7.87 (d, 2H, J = 8.4), 7.67 (dd, 2H, J = 1.8, 8.7), 7.42-7.46 (m, 4H), 6.21 (br s, 1H), 5.28 (br s, 1H), 4.64 (d, 1H, J = 15.9), 4.45 (d, 1H, J = 15.9), 4.31 (t, 1H, J = 6.6), 2.58 (s, 3H), 1.73-1.80 (m, 1H), 1.25-1.35 (m, 1H), 1.05-1.14 (m, 1H), 0.74 (d, 3H, J = 6.5), 0.65 (d, 3H, J = 6.6).

Illustration of the reaction diagram 17

<img file="PL204281B1_D0068.tif" />

PL 204 281 B1

(2R) -2- {N- (4-Chlorobenzenesulfonyl) -N- [4- (3-piperidin-1-yl-propionylamino) benzyl] -amino} -4-methylpentanoic acid amide (Example 274)

To a solution of 0.10 g (0.22 mmol) N- (4 - {[N - ((1S) -1-carbamoyl-3-methyl-butyl) -N- (4-chlorobenzenesulfonyl) amino] methyl} phenyl) of acrylamide in 5 ml of toluene, 20 mg (0.24 mmol) of piperidine was added and the mixture was refluxed gently for one hour. The solvent was then removed under reduced pressure and the product was purified by flash chromatography (SiO2, 10% methanol / methylene chloride). 105 mg (86% yield) of the title compound were obtained.

MS (ESI), (M + H)⁺ 449,16;

¹H NMR (CDCl3, 400 MHz) δ 7.69 (d, 2H, J = 8.0), 7.63 (d, 2H, J = 8.0), 7.38 (d, 2H, J = 8 0.0), 7.23 (d, 2H, J = 8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.75 (d, 1H, Jab = 16 ), 4.38 (d, 1H, Jab = 16), 3.25 (t, 1H, J = 6.0), 2.65 (t, 2H, J = 6.0), 2.56-2 , 44 (m, 6H), 1.95 (m, 1H), 1.68-1.45 (m, 8H), 0.98 (d, 3H, J = 7.0), 0.94 (d , 3H, J = 7.0).

Illustration of the reaction diagram 18

<img file="PL204281B1_D0069.tif" />

klo- [5.2.1.0^1,5] dec-4'-yl} -4-fluorobutan-1-one

For a solution kept at -78 ° C, 30.0 g (68 mmol) of N-2- (benzhydrylideneamino) -1 - {(1'S), (5'S) -10 ', 10'-dimethyl-3', 3'- dioxo-3 '?.⁶-thia-4'-aza-tncyclo- [5.2.1.0^1,5] dec-4'-ylQ} -ethaneQnu (Josien H., Martin A, Chassaing G., Tetrahedron Lett. 1991, 32, 6547) in 60 ml HM PA and 300 ml THF n-butyllithium (1.6 M in hexane, 42.4 mL, 68 mmol) while keeping the temperature below -65 ° C. The mixture was allowed to warm to room temperature and a solution of 17.4 g (137 mmol) of 1-bromo-3-fluoroethane in 30 ml of THF was added dropwise at room temperature. After 18 hours, the reaction mixture was poured into water with acetic acid (200 ml / 2 ml), diluted with ethyl acetate, the organic layers were washed with saturated NH4Cl solution and brine, dried over MgSO4 and concentrated. The residual orange oil was further purified by silica gel chromatography (25% ethyl acetate in hexane). The resulting white solid was crystallized from 15% ethyl acetate in hexane. 24.3 g (70% yield) of the desired product were obtained.

MS (ESI), (M + H)⁺ 483,27;

¹H NMR (CDCl3) δ 7.66 (d, 2H, 3 = 1.2), 7.13-7.44 (m, 8H), 4.82-4.83 (m, 2H), 4.39 -4.81 (m, 2H), 3.84-3.87 (m, 1H), 3.28 (Abq, 2H, J = 18.10), 2.33-2.41 (m, 2H) , 2.02-2.04 (m, 2H), 1.84-1.87 (m, 2H),

1.32-1.39 (m, 2H), 1.10 (s, 3H), 0.91 (s, 3H).

<img file="PL204281B1_D0070.tif" />

(2R) -2-AminQ-1 - {(1'S), (5'S) -10 ', 10'-dimethylQ-3', 3'-diQksQ-3'λ⁶-thia-4'-aza-tricycleQ- [5.2.1.0¹’⁵] dec-4'-yl} -4-fluorobutan-1-one:

Per solution 20.0 g (41.0 mmol) (2R) -2- (benzhydrylidene-amino) -1 - {(1'S), (5'S) -10 ', 10'-dimethyl3', 3'-diQksQ-3 'λ⁶-thia-4'-aza-tricycleQ- [5.2.1.0¹’⁵] dec-4'-ylQ} -4-fluQrΌbutan-1-Qnu in 400 ml of THF was treated with 1N HCl (200 ml). After 3 hours, the reaction mixture was diluted with water and extracted

With diethyl ether. The aqueous phase was neutralized by adding 0.5 N NaOH. The basic phase was then extracted with dichloromethane, dried over MgSO4 and concentrated. 11.9 g (90% yield) of a white solid are obtained.

¹H NMR (CDCl3) δ 4.56-4.71 (m, 2H), 4.23-4.31 (m, 1H), 3.40-3.49 (m, 3H), 3.11 (d , 2H, J = 4.4),

1.17-2.23 (m, 8H), 1.13 (s, 3H), 0.93-1.12 (m, 3H).

<img file="PL204281B1_D0071.tif" />

(2R) -2- (4-Chlorobenzenesulfonylamino) -1 - {(1'S), (5'S) -10 ', 10'-dimethyl-3', 3'-dioxo-3 ^⁶-thia-4'-aza-tricyclo- [5.2.1.0^1,5] dec-4'-yl} -4-fluorobutan-1-one:

For a solution of 12 g (36 mmoles) of (2R) -2-amino-1 - {(1'S), (5'S) -10 ', 10'-dimethyl-3', 3'-dioxo-3'⁶-thia-4'-aza-tricyclo- [5.2.1.0^1,5] dec-4'-yl} -4-fluorobutan-1-one and 10.4 ml (72.0 mmol) of triethylamine in 350 ml of CH2Cl2 were added 9.1 g (43 mmol) of 4-chlorobenzenesulfonyl chloride in one portion. After 18 hours, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated. This product was further purified by silica gel chromatography (30% ethyl acetate in hexane). 16.0 g (92% yield) of the title compound were obtained in the form of a white wax.

¹H NMR (CDCl3) δ 7.79 (d, 2H, J = 8.0), 7.43 (d, 2H, J = 8.0), 5.69 (br d, 8.0), 4, 42-4.77 (m, 4H), 3.71-3.72 (m, 1H), 3.10 (ABq, 2H, J = 9.4), 2.11-2.29 (m , 2H), 1.33-1.99 (m, 6H), 1.04 (s, 3H), 0.91 (s, 3H).

<img file="PL204281B1_D0072.tif" />

(2R) -2- (4-Chlorobenzenesulfonylamino) -4-fluorobutanoic acid

To a vigorously stirred solution of 16 g (32 mmol) of (2R) -2- (4-chlorobenzenesulfonylamino) -1 - {(1'S), (5'S) -10 ', 10'-dimethyl-3', 3'-dioxo-3 ^⁶-thia-4'-aza-tricyclo [5.2.1O^1,5] dec-4'-yl} -4-fluorobutan-1-one in 200 ml of acetonitrile were added 13.9 g (16 mmol) of lithium bromide, 4.13 g (12.8 mmol) of tetrabutylammonium bromide and 5.45 g of ( 0.130 mol) LiOH. After 4.5 hours, the reaction mixture was concentrated to half its volume, then diluted with water and extracted with CH2Cl2. The aqueous layer was acidified with a 1N HCl solution and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over MgSO4, and concentrated. 9.4 g of a white solid were obtained and used directly for the next step.

¹H NMR (DMSO-d6) δ 8.39 (d, 1H, J = 9.0), 7.76 (d, 2H, J = 6.8), 7.64 (d, 2H, J = 6, 8), 7.00 (br s, 1H), 4.29-4.48 (m, 2H), 3.80-3.88 (m, 1H), 1.66-1.96 (m, 2H ).

<img file="PL204281B1_D0073.tif" />

(2R) -2- (4-Chloro-benzenesulfonylamino) -4-fluoro-butanoic acid amide

PL 204 281 B1

To a solution of 9.0 g (31 mmoles) of (2R) -2- (4-chlorobenzenesulfonylamino) -4-fluorobutanoic acid in 250 ml of DME was added, under nitrogen atmosphere, 6.2 g (46 mmoles) of 1-hydroxybenzotriazole hydrate, 23 ml (124 mmol) N, N-diisopropylethylamine, 3.34 g (62 mmol) ammonium chloride and 8.8 g (46 mmol) 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride. The solution was stirred at room temperature for 18 hours, then this solution was poured into ice water (500 ml), the resulting precipitate was filtered off and dried. This product was crystallized from 10% ethyl acetate in hexane. 4.5 g (50% yield) of a pure white solid were obtained.

[a] D = -21.0 (c, 1.00, DMF);

MS (ESI) (MH^-) 293,01;

¹H NMR (DMSO-d6) δ 8.12 (d, 1H, J = 8.8), 7.77 (d, 2H, J = 7.0), 7.62 (d, 2H, J = 7, 0), 7.38 (br s, 1H), 7.03 (br s, 1H), 4.22-4.47 (m, 2H), 3.71-3.85 (m, 1H), 1 , 65-1.92 (m, 2H).

<img file="PL204281B1_D0074.tif" />

(2R) -2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -4-fluorobutyramide (Example 360) (2R) -2- (4-Chlorobenzenesulfonylamino) -4-fluorobutyramide (20 mg, 0, 7 mmol) was converted into the title compound according to the reaction scheme 1, method A. 208 mg (yield 73%) of the title compound were obtained.

MS (ESI) (MH^-) 407,99;

[a] D = +39.13 (c 1.00, Methanol);

¹H NMR (CDCl3) δ 7.72 (d, 2H, J = 8.4), 7.58 (d, 2H, J = 8.4), 7.50 (d, 2H, J = 8.4) , 7.45 (d, 2H, J = 8.4), 6.29 (br s, 1H), 5.21 (br s, 1H), 4.19-4.67 (m, 5H), 2 , 17-2.28 (m, 1H), 1.49-1.61 (m, 1H).

Illustration of the reaction scheme 19

<img file="PL204281B1_D0075.tif" />

2- (4-Chlorobenzenesulfonylamino) -6-fluorohexanoic acid amide (III)

A mixture of 8.6 g (32 mmol) of ethyl (benzhydrylidene-amino) acetic acid, 10.0 g (64.5 mmol) of 4-bromo-1-fluorobutane, 13.4 g (96.9 mmol) of K2CO3, 2 1 g (6.5 mmol) of tetrabutylammonium bromide and 300 ml of acetonitrile were refluxed for 72 hours. Then, the reaction mixture was cooled to room temperature and filtered through a sintered glass filter. The filtrate was concentrated under reduced pressure, the residue was dissolved in 250 ml of diethyl ether. A white precipitate formed. The precipitate was filtered off under reduced pressure. 1N HCl (100 ml) was added to the filtrate, which contained the crude product, 2- (benzhydrylideneamino) -6-fluorohexanoic acid ethyl ester. The resulting biphasic mixture was vigorously stirred for 3 hours. The mixture was transferred to a separatory funnel and the aqueous layer was collected. The organic layer was extracted with 1N HCl (30 ml). The combined aqueous layers were washed with diethyl ether (200 ml). 10.8 ml of concentrated HCl was added to the aqueous portion and the resulting solution was refluxed for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure

Pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure. 2-amino-6-fluoro-hexanoic acid hydrochloride is obtained in the form of a white solid. The crude salt of this amino acid was used without purification or analysis. 2-Amino-6-fluorohexanoic acid hydrochloride (32.3 mmol, theoretically) was suspended in anhydrous methanol (300 ml) and cooled to 0 ° C. 10.3 mL (129 mmol) of thionyl chloride was slowly added over 5 minutes. The resulting solution was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure. The hydrochloride of 2-amino-6-fluoro-hexanoic acid methyl ester was obtained. 100 ml of toluene and 75 ml of 28% aqueous ammonia solution were added to the crude amino ester, the resulting biphasic mixture was vigorously stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residual solid was suspended in 200 ml of toluene and concentrated again under reduced pressure to give 6-fluoro-hexanoic acid amide (II) as a white solid. This crude amino acid amide was dissolved in 50 ml of anhydrous DMF and 350 ml of CH2Cl2 and reacted with 82 g (32.3 mmol) of 4-chlorobenzenesulfonyl chloride and 13.5 ml (96.9 mmol) of triethylamine. After 2 hours, a second portion (1.70 g, 8.1 mmol) of 4-chlorobenzenesulfonyl chloride was added. After an additional 18 hours, the mixture was poured into 500 ml of 1N hydrochloric acid. The organic layer was collected and washed with water (2 out of 500 ml). 600 mL of hexane was added to the organic layer. A white precipitate formed which was filtered off under reduced pressure, washed with cold ethanol (50 ml) and dried under reduced pressure. 4.95 g (48% yield from 6 steps) of 2- (4-chlorobenzenesulfonylamino) -6-fluorohexanoic acid amide (III) was obtained.

LCMS (M + Na)⁺ 345,2;

¹H NMR (400 MHz, DMSO-d6) δ 7.99 (d, 1H, J = 8.8), 7.77 (d, 2H, J = 8.8), 7.62 (d, 2H, J = 8.8), 7.29 (s, 1H), 6.95 (s, 1H), 4.34 (dt, 2H, Jd = 47.5, Jt = 6.1), 3.65 (dt , 1H, Jd = 5.6, Jt = 8.6), 1.60-1.39 (m, 4H), 1.36-1.15 (m, 2H).

Elemental analysis: For the formula C12H16CIFN2O3S

Found C 44.65; H 4.99; N 8.67;

Found: C 44.61; H 5.08; N 8.75.

<img file="PL204281B1_D0076.tif" />

2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) -amino] -6-fluorohexanoic acid amide (Example 333)

2- (4-Chlorobenzenesulfonylamino) -6-fluorohexanoic acid amide (0.500 g, 1.55 mmol) was converted to the title compound (360 mg, 50% yield) following reaction scheme 1, method A.

LCMS (M + Na)⁺ 459,9;

¹H NMR (400 MHz, DMSO-d6) δ 7.82 (d, 2H, J = 8.8), 7.79 (d, 2H, J = 8.5), 7.63 (d, 2H, J = 8.8), 7.58 (d, 2H, J = 8.3), 7.52 (s, 1H), 7.09 (s, 1H), 4.82 (ABq, 2H, Δν = 37 , 2, Jab = 17.6), 4.34 (dd, 1H, J = 8.0, 6.6), 4.25 (dt, 2H, Jd = 47.2, Jt = 5.7), 1.58 (m, 1H), 1.49-1.12 (m, 5H);

Elemental analysis: For the formula C20H21CIFN3O3S

Found C 54.85; H 4.83; N 9.59;

Found: C 54.92; H 4.76; N 9.54.

PL 204 281 B1

Illustration of the reaction diagram 20

<img file="PL204281B1_D0077.tif" />

(2R) -2- (4-Chlorobenzenesulfonylamino) -1 - {(1'S), (5'S) -10 ', 10'-dimethyl-3', 3'-dioxo-3 ^⁶-thia-4'-aza-tricyclo- [5.2.1.0^1,5] dec-4'-yl} -4-fluoro-4-methyl-pentan-1-one:

For a solution of 500 mg (1 mmol) of (2R) -2- (4-chlorobenzenesulfonylamino) -1 - {(1'S), (5'S) -10 ', 10'-dimethyl-3', 3'-dioxo-3 ^⁶-thia-4'-aza-tricyclo- [5.2.1.0^1,5] dec-4'-yl} -4-methyl-4-pentan-1-one [prepared according to reaction scheme 18 from N-2- (benzhydrylidene-amino) -1 - {(1'S), (5'S) -10 ' , 10'-dimethyl-3 ', 3'-dioxo-3'⁶-thia-4'-aza-tricyclo- [5.2.1.0^1,5] dec-4'-yl} -ethanone (Josien H., Martin A, Chassaing G., Tetrahedron Lett. 1991, 32, 6547) and 1 bromo-2-methyl-2-propene] in 5 ml THF was added at 0 ° C 10 ml pyridine hydrofluoride. The mixture was allowed to warm to room temperature and was stirred for 18 hours. The reaction mixture was then carefully poured into saturated aqueous NaHCO3 solution (300 ml). The aqueous mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed sequentially with 1N HCl (200 ml) and brine (100 ml). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. 490 mg (94% yield) of the title compound were obtained in the form of a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 7.83 (d, 2H, J = 8.8), 7.45 (d, 2H, J = 8.8), 5.37 (d, 1H, J = 8.1), 4.65 (m, 1H), 3.64 (t, 1H, J = 6.4), 3.43 (ABq, 2H, Δν = 5.4, Jab = 13.7) , 2.19-1.83 (m, 7H), 1.41-1.31 (m, 8H), 1.04 (s, 3H), 0.94 (s, 3H).

<img file="PL204281B1_D0078.tif" />

(2R) -2- (4-Chlorobenzenesulfonylamino) -4-fluoro-4-methylpentanoic acid amide (2R) -2- (4-Chlorobenzenesulfonylamino) -1 - {(1'S), (5'S) -10 ', 10'- dimethyl-3 ', 3'-dioxo-3'⁶-thia-4'-aza-tricyclo- [5.2.1.0^1,5] dec-4'-yl} -4-fluoro-4-methyl-pentan-1-one was converted to the title compound in two steps according to reaction scheme 18 (165 mg, 55% yield).

LCMS (M + Na)⁺ 345,1;

¹H NMR (500 MHz, DMSO-d6) δ 8.10 (d, 1H, J = 9.2), 7.77 (d, 2H, J = 8.5), 7.62 (d, 2H, J = 8.9), 7.34 (s, 1H), 6.92 (s, 1H), 3.85 (m, 1H), 1.89 (m, 1H), 1.74 (m, 1H) , 1.31 (d, 3H, J = 21.7), 1.29 (d, 3H, J = 21.9).

Illustration of the reaction diagram 21

<img file="PL204281B1_D0079.tif" />

PL 204 281 B1

2- (4-Chloro-benzenesulfonylamino) -4-methyl-4-pentenoic acid, ethyl ester

Per a solution of 2.84 g (18.1 mmol) of 2-amino-4-methyl-4-pentenoic acid ethyl ester [prepared according to reaction scheme 19 from (benzhydrylideneamino) acetic acid ethyl ester and 1-bromo-2-methyl-2-methyl ester -propene] in 250 mL of CH2Cl2 was treated with 4-chlorobenzenesulfonyl chloride (4.20 g, 19.9 mmol) and triethylamine (3.78 mL, 27.2 mmol). After 4 hours, the resulting mixture was poured into 500 mL of 1N aqueous HCl solution and extracted with ethyl acetate (3 x 150 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude concentrate was purified by silica gel column chromatography (hexane / ethyl acetate gradient, 10: 1 5 to 5: 1). 3.04 g (25% yield after 3 steps) of 2- (4-chlorobenzenesulfonylamino) -4-methyl-4-pentenoic acid ethyl ester were obtained.

LCMS (M + Na)⁺ 354,2;

¹H NMR (CDCl3, 400 MHz) δ 7.77 (d, 2H, J = 9.1), 7.46 (d, 2H, J = 8.8), 5.07 (d, 1H, J = 9 . 0), 4.84 (s, 1H), 4.73 (s, 1H), 4.05 (m, 1H), 3.95 (q, 2H, J = 7.1), 2.40 ( m, 2H), 1.66 (s, 3H), 1.13 (t, 3H, J = 7.1).

<img file="PL204281B1_D0080.tif" />

2- (4-Chlorobenzenesulfonylamino) -4-fluoro-4-methyl-pentanoic acid, 4-chloro-N- (5,5-dimethyl-2-oxo-tetrahydrofuran-3-yl) -benzenesulfonamide, ethyl ester

To a solution kept at 0 ° C of 1.0 g (3.0 mmol) of 2- (4-chlorobenzenesulfonylamino) -4-methyl-4-pentenoic acid ethyl ester in 15 ml of THF was added 10 ml of pyridine hydrofluoride and the reaction mixture was brought to a room temperature. After 5 hours, an additional portion (10 ml) of pyridine hydrofluoride was added, the mixture was stirred for 24 hours, then a third portion of pyridine hydrofluoride (10 ml) was added. After a total of 53 hours, the reaction was quenched with ice flakes (20 mL). This crude mixture was poured into ice water (500 mL) and extracted with CH2Cl2 (2 x 200 mL). The combined organic layers were washed with a saturated aqueous NaHCO3 solution (100 mL) and concentrated under reduced pressure. The crude concentrate was purified by silica gel column chromatography (hexane / ethyl acetate gradient, 10: 1 to 5: 1). 0.395 g (37% yield) of 2- (4-chlorobenzenesulfonylamino) -4-fluoro-4-methyl-4-pentanoic acid ethyl ester and 0.425 g (46% yield) of 4-chloro-N- (5,5-dimethyl) were obtained. -2-oxo-tetrahydrofuran-3-yl) -benzenesulfonamide.

Data for 2- (4-chlorobenzenesulfonylamino) -4-fluoro-4-methylpentanoic acid ethyl ester:

LCMS (M + Na)⁺ 374,1;

¹H NMR (CDCl3, 500 MHz) δ 7.78 (d, 2H, J = 8.9), 7.47 (d, 2H, J = 8.5), 5.19 (d, 1H, J = 7 , 9), 4.08 (m, 1H), 3.93 (m, 2H), 2.09-1.94 (m, 2H), 1.42 (d, 3H, J = 21.6), 1.37 (d, 3H, J = 21.6), 1.12 (t, 3H, J = 7.0).

Data for 4-chloro-N- (5,5-dimethyl-2-oxo-tetrahydrofuran-3-yl) -benzenesulfonamide:

LCMS (M + Na)⁺ 326,0;

¹H NMR (400 MHz, DMSO-d6) δ 8.41 (d, 1H, J = 9.1, 7.86 (d, 2H, J = 8.6), 7.67 (d, 2H, J = 8.8), 4.57 (m, 1H), 2.22 (dd, 1H, J = 12.4, 9.0), 1.72 (t, 1H, J = 12.0), 1. 33 (s, 3H), 1.31 (s, 3H).

<img file="PL204281B1_D0081.tif" />

PL 204 281 B1

2- (4-Chlorobenzenesulfonylamino) -4-fluoro-4-methyl-pentanoic acid amide

A solution of 457 mg (1.30 mmol) of 2- (4-chlorobenzenesulfonylamino) 4-fluoro-4-methyl-pentanoic acid ethyl ester in 20 ml of methanol was treated with 10N NaOH (780 g, 7.8 mmol) at room temperature at room temperature. time of 18 hours. The crude reaction mixture was concentrated under reduced pressure. The residue was treated with water (50 ml and 1N HCl (20 ml). The aqueous solution was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. A white solid was obtained containing 2- (4-chlorobenzenesulfonylamino) -4-fluoro-4-methyl-pentanoic acid.

A mixture of this crude precipitate, 1-hydroxybenzotriazole (263 mg, 1.95 mmol), diisopropylethylamine (670 mg, 5.2 mmol), ammonium chloride (140 mg, 2.6 mmol), 1- (3-dimethylaminopropyl) hydrochloride - 3-Ethylcarbodiimide (373 mg, 1.95 mmol) in 20 mL of DMF was stirred at room temperature for 24 hours. The crude mixture was poured into 500 ml of water and the aqueous solution was extracted with a mixture of ethyl acetate and hexane (90:10, 3 x 150 ml). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude concentrate was purified by silica gel column chromatography (chloroform / methanol 95: 5). 0.426 g (100% yield) of the title compound was obtained.

LCMS (M + Na)⁺ 345,3;

¹H NMR (400 MHz, DMSO-d6) δ 8.10 (d, 1H, J = 9.2), 7.77 (d, 2H, J = 8.5), 7.62 (d, 2H, J = 8.9), 7.34 (s, 1H), 6.92 (s, 1H), 3.85 (m, 1H), 1.89 (m, 1H), 1.74 (m, 1H) , 1.31 (d, 3H, J = 21.7), 1.29 (d, 3H, J = 21.9).

<img file="PL204281B1_D0082.tif" />

2 - [(4-Chlorobenzenesulfonyl) -4- (4-cyanobenzyl) amino] -4-fluoro-4-methyl-pentanoic acid amide (Example 357)

2- (4-Chlorobenzenesulfonylamino) -4-fluoro-4-methyl-pentanoic acid amide was converted to the title compound following reaction scheme 1, method A.

LCMS (M + Na)⁺ 460,2;

¹H NMR (400 MHz, DMSO-d6) δ 7.83 (d, 2H, J = 8.5, 7.75 (d, 2H, J = 8.3), 7.68 (s, 1H), 7 , 64 (d, 2H, J = 8.6), 7.49 (d, 2H, J = 8.1), 7.20 (s, 1H), 4.67 (ABq, 2H, Δν = 28, 3, Jab = 17.3), 4.54 (dd, 1H, J = 9.3, 3.2), 2.23 (m, 1H), 1.42 (m, 1H), 1.25 ( d, 3H, J = 21.6), 1.21 (d, 3H, J = 21.7).

<img file="PL204281B1_D0083.tif" />

2 - [(4-Chlorobenzenesulfonyl) -4- (4-cyanobenzyl) amino] -4-hydroxy-4-methyl-pentanoic acid amide (Example 443)

PL 204 281 B1

A sealed vial containing a mixture of 0.20 g (0.66 mmol) of 4-chloro-N- (5,5-dimethyl-2-oxo-tetrahydrofuran-3-yl) -benzenesulfonamide and 28% ammonia in water (3 ml) held at 80 ° C in a microwave reactor for 40 minutes. The reaction mixture was cooled to room temperature and concentrated to a dry residue under reduced pressure. 2- (4-Chlorobenzenesulfonylamino) -4-hydroxy-4-methyl-pentanoic acid amide was obtained in the form of a white solid. This crude solid was converted to the title compound (98 mg, 34% yield) following reaction scheme 1, method A.

LCMS (M + Na)⁺ 458,2;

¹H NMR (400 MHz, DMSO-d6) δ 7.84 (d, 2H, J = 8.6), 7.76 (d, 2H, J = 8.3), 7.62 (d, 2H, J = 8.8), 7.51 (d, 2H, J = 8.3), 7.40 (s, 1H), 7.11 (s, 1H), 4.63 (ABq, 2H, Δν = 5 , 9, Jab = 17.6), 4.56 (dd, 1H, J = 8.3, 2.5), 4.54 (s, 1H), 1.95 (dd, 1H, J = 13, 7, 8.6), 1.26 (dd, 1H, J = 13.6, 2.4), 1.04 (s, 3H), 0.99 (s, 3H). Elemental analysis: For the compound of formula C20H22ClN3O4S

Calculated: C 55.10; H 5.08; N 9.64,

Found: C 54.96; H 5.14; N 9.58.

Illustration of the reaction diagram 22

<img file="PL204281B1_D0084.tif" />

2- (4-Chloro-benzenesulfonylamino) -5-hexenoic acid ethyl ester

A mixture of 20 g (74.8 mmol) of ethyl (benzhydrylidene-amino) acetic acid, 10.1 g (74.8 mmol) of 4-bromo-1-butene, 31.0 g (224 mmol) of K2CO3, 2.41 g (7.48 mmol) of tetrabutylammonium bromide and 150 ml of acetonitrile are refluxed for 6 hours. The reaction mixture was then cooled to room temperature and filtered through a sintered glass filter. The filtrate was concentrated under reduced pressure. The residue was dissolved in 250 ml of diethyl ether. A white precipitate formed. This precipitate was removed by filtration under reduced pressure. 150 ml of 1N HCl were added to the filtrate containing the crude product, 2-20 (benzhydrylidene-amino) -hex-5-enoic acid ethyl ester. The resulting biphasic mixture was vigorously stirred for 18 hours. This mixture was then transferred to a separatory funnel, and the aqueous layer was collected and concentrated under reduced pressure. The residue was dissolved in toluene (2 x 200 ml) and concentrated. The crude aminoester was dissolved in CH2Cl2 and reacted with 15.8 g (74.8 mmol) of 4-chlorobenzenesulfonyl chloride and 31.2 ml (224 mmol) of triethylamine. After 18 hours, the resulting mixture was poured into 500 mL of 1N HCl. The organic layer was separated and washed successively with 1N HCl (500 ml) and brine (50 ml). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude concentrate was purified by silica gel column chromatography (hexane / ethyl acetate 5: 1). 5.57 g (23% yield over 3 steps) of the title compound were obtained.

LCMS (M + Na)⁺ 354,0;

¹H NMR (400 MHz, DMSO-d6) δ 8.47 (d, 1H, J = 8.8), 7.76 (d, 2H, J = 8.8), 7.66 (d, 2H, J = 8.8), 5.69 (m, 1H), 4.95-4.88 (m, 2H), 3.86 (q, 2H, J = 7.1), 3.76 (m, 1H ), 1.98 (m, 2H), 1.71-1.54 (m, 2H), 1.03 (t, 3H, J = 7.1).

<img file="PL204281B1_D0085.tif" />

PL 204 281 B1

2 - [(4-Chloro-benzenesulfonyl) - (4-cyanobenzyl) amino] -hex-5-enoic acid ethyl ester:

2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) amino] -hex-5-enoic acid ethyl ester was prepared in a similar manner to Reaction Scheme 1 starting from 2- (4-chlorobenzenesulfonamino) -hex ethyl ester -5-ene. 2 - [(4-Chloro-benzenesulfonyl) - (4-cyanobenzyl) amino] -hex-5-enoic acid ethyl ester was isolated as a crude yellow solid (1.14 g). This product was used for the next reaction without further purification.

¹H NMR (CDCl3) δ 7.71 (d, 2H, J = 8.0), 7.61 (d, 2H, J = 8.0), 7.53 (d, 2H, J = 8.0) , 7.46 (d, 2H, J = 8.0), 5.54 (m, 2H), 4.90 (m, 2H), 4.74 (d, 1H, J = 16.0), 4 , 48 (m, 2H), 3.90 (m, 1H), 1.95 (m, 2H), 1.81 (m, 1H), 1.48 (m, 1H), 1.11 (t, 3H, J = 8.0).

CN

<img file="PL204281B1_D0086.tif" />

2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) amino] -5-oxo-pentanoic acid ethyl ester

A mixture of 1.14 g (2.56 mmol) of (4-chlorobenzenesulfonyl) - (4-cyanobenzyl) amino] -hex-5-enoic acid ethyl ester, 0.030 g (0.13 mmol) of osmium tetroxide and 0.41 g of 20 (5.5 mmol) of trimethylamine N-oxide was dissolved in 50 ml of acetone and stirred for 4 hours at room temperature. After completion of the reaction, the solution was concentrated under reduced pressure, and the residue was dissolved in 50 ml of a dioxane / water mixture (1.5: 1). To this solution was added 0.66 g (3.07 mmol) of sodium periodate and stirred at room temperature for 18 hours. Then, the reaction mixture was diluted with ethyl acetate (500 mL), washed with water and brine, dried over Na2SO4, and concentrated to give a crude colorless oil. Further purification by flash chromatography (SiO 2, 5 to 75% ethyl acetate in hexane) provided 0.26 g (23% yield) of 2 - [(4-chlorobenzenesulfonyl) - (4-cyanobenzyl) amino] -5 acid ethyl ester - oxo-pentane in the form of a colorless oil.

¹H NMR (CDCl3) δ 9.57 (s, 1H), 7.69 (d, 2H, J = 8.0), 7.51 (m, 6H), 5.99 (ABq, 2H, Δν = 16 , Jab = 168), 4.47 (m, 1H), 3.89 (m, 2H), 2.53 (m, 1H), 2.32 (m, 1H), 2.11 (m, 1H) , 1.61 (m, 1H), 1.06 (t, 3H, J = 8.0).

<img file="PL204281B1_D0087.tif" />

2 - [(4-Chloro-benzenesulfonyl) - (4-cyanobenzyl) amino] -5,5-difluoro-pentanoic acid ethyl ester

0.05 g (0.11 mmol) of 2 - [(4-chlorobenzenesulfonyl) - (4-cyanobene) acid ethyl ester was slowly added to a solution of 0.020 ml (0.11 mmol) of DAST in 2 ml of CH2Cl2 at room temperature.

The mixture was stirred for 16 hours. At this time, the mixture was diluted with CH2Cl2 (20 mL) and extracted with water (2 x 25 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated. 61 mg of 2 - [(4-chlorobenzenesulfonyl) - (4-cyanobenzyl) amino] -5,5-difluoro-pentanoic acid ethyl ester were obtained in the form of a crude yellow residue. This crude residue was used in the next step without further purification.

<img file="PL204281B1_D0088.tif" />

2 - [(4-Chlorobenzenesulfonyl) - (4-cyanobenzyl) amino] -5,5-difluoro-pentanoic acid amide (Example 377)

The crude 2 - [(4-chlorobenzenesulfonyl) - (4-cyanobenzyl) amino] -5,5-difluoro-pentanoic acid ethyl ester (0.061 g, 0.13 mmol) was dissolved in 2 mL of methanol, 0.052 mL of a 10N solution was added to the mixture. Na-OH (0.52 mmol) and the resulting solution was stirred at room temperature for 16 hours. At this time, the reaction mixture was diluted with water (25 mL), acidified with 1N HCl, and extracted with CH2Cl2 (4 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The compound with the rest of the carboxylic acid was obtained as a crude colorless oil. This intermediate carboxylic acid was dissolved in DMF (10 ml), mixed with 0.030 g (0.20 mmol) of 1-hydroxybenzotriazole, 0.090 ml (0.52 mmol) of diisopropylethylamine, 0.01 g (0.26 mmol) of NH4Cl and 0, 04 g (0.20 mmol) 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and the mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with water (4 x 50 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. A crude, almost white precipitate was obtained. Further purification by flash chromatography (SiO2, 5 to 85% ethyl acetate in hexane) afforded 10.7 mg (19% yield) of the title compound as a white solid.

LCMS (M + Na)⁺ 464,01;

¹H NMR (CDCl3) δ 7.69 (d, 2H, J = 8.3), 7.60 (d, 2H, J = 8.3), 7.49 (m, 4H), 6.18 (br s, 1H), 5.67 (tt, 1H, J = 56, 4.0), 5.22 (br s, 1H), 4.52 (ABq, 2H, Δν = 16, Jab = 100), 4 , 34 (m, 1H), 2.03 (m, 1H), 1.68 (m, 1H), 1.38 (m, 1H), 0.86 (m, 1H).

Illustration of the reaction diagram 23

<img file="PL204281B1_D0089.tif" />

(2R) -2 - [[4- (2-bromo-acetylamino) benzyl] - (4-chlorobenzenesulfonyl) amino] -4-methyl-pentanoic acid amide

PL 204 281 B1

To a solution of 248 mg (0.56 mmol) of (2R) -2 - [(4-aminobenzyl) - (4-chlorobenzenesulfonyl) amino] -4-methylpentanoic acid amide and 176 mg (1.74 mmol) of triethylamine in 3 ml CH2Cl2 105 mg (0.67 mmol) of bromoacetyl chloride was added and the reaction mixture was stirred overnight at room temperature. The mixture was then diluted with CH2Cl2 (5 mL), washed with 1N HCl, brine, and dried by pushing through a cotton plunger. The solvent was removed under reduced pressure. Purification by flash chromatography (SiO2, 10% acetone in CH2Cl2) gave 124 mg (yield 42%) of the title compound.

MS (ESI), (M + H)⁺ 531,86;

¹H NMR (CDCl3, 400 MHz) δ 8.78 (br s, NH), 7.95 (d, 2H, J = 8.0), 7.82 (d, 2H, J = 8.0), 7 . 42 (d, 2H, J = 8.0), 7.33 (d, 2H, J = 8.0), 6.20 (br s, 1H), 5.20 (br s, 1H), 4 . 30 (s, 2H), 4.22 (d, 1H, Jab = 16), 4.14 (d, 1H, Jab = 16), 3.25 (t, 1H, J = 6.0), 1 , 95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J = 7.0), 0.94 (d, 3H, J = 7.0).

<img file="PL204281B1_D0090.tif" />

(2R) -2 - {(4-Chlorobenzenesulfonyl) - [4- (2-dimethylamino-acetylamino) benzyl] amino} -4-methyl-pentanoic acid amide (Example 308)

To a solution of 41 mg (0.77 mmol) of (2R) -2 - [[4- (2-bromo-acetylamino) benzyl] - (4-chlorobenzenesulfonyl) amino] -4-methylpentanoic acid amide in 2 ml of CH2Cl2 was added. excess of 2.0 M dimethylamine solution in THF and the reaction mixture was stirred overnight. The solvent was stripped off under reduced pressure and the residue was purified by flash chromatography (SiO2, 10% methanol in CH2Cl2). 24 mg (63% yield) of the title compound were obtained.

MS (ESI), (M + H)⁺ 495,14;

¹H NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.02 (d, 2H, J = 8.0), 7.75 (d, 2H, J = 8.0), 7, 38 (d, 2H, J = 8.0), 7.29 (d, 2H, J = 8.0), 6.23 (br s, 1H), 5.39 (br s, 1H), 4, 62 (m, 4H), 3.25 (t, 1H, J = 6.0), 2.95 (s, 6H), 1.95 (m, 1H), 1.60 (m, 2H), 0 . 98 (d, 3H, J = 7.0), 0.94 (d, 3H, J = 7.0).

Starting compounds

The following α-amino-amides are commercially available or can be obtained in a known manner from commercial amino acids:

<td>H.₂N&gt; 2 ^</td><td>H.₂N</td><td></td><td>h₂„^</td>

<td>Ί</td><td></td><td>V</td><td>Λ7</td>

<td> 0</td><td> 0</td><td>about</td><td></td>

<td>A ™ nh₂H.₂N *</td><td></td><td>X5&gt; nh₂h₂n</td><td></td>

<td>V</td><td>s</td><td>% Λ</td><td></td>

PL 204 281 B1

5,5,5-trifluoro-2-aminopentanoic acid amide and 6,6,6-trifluoro-2-amino-hexanoic acid were prepared as described by Ojima I., Kato K. and Nakahashi K. (J. Org. Chem 1989 , 54, 4511);

The benzyl bromide used in the synthesis of the compounds of Examples 100 and 155 was prepared by the method described by Ishihar, Y., Fujisawa Y., Furuyama N. (International Application Publication, WO 98/46590 and by Senanayake CH, Fang Q K., Wilkinson 'a SH (international application publication WO 98/33789);

The aldehydes required for the synthesis of the compounds of Examples 91, 248, 249, 289, 290 and 300 (reaction scheme 2) were prepared as described for example for 4- (piperidin-1-yl) benzaldehyde. A suspension of 0.48 ml (4 mmol) of 4-fluorobenzaldehyde, 522 mg (4 mmol) of K2CO3, 340 mg (4 mmol) of piperidine in 5 ml of DMSO was kept in a sealed tube at 150 ° C for 18 hours. At this time, the reaction mixture was concentrated and purified by silica gel column chromatography (CH2Cl2, then 2% methanol in CH2Cl2). 748 mg (98% yield) of 4- (piperidin-1-yl) benzaldehyde were obtained.

The aldehydes used to synthesize the compounds of Examples 317, 318 and 320 were prepared as described for example for 4- (piperidin-1-yl) -3-fluorobenzaldehyde. A suspension of 500 mg (3.5 mmol) 3,4-difluorobenzaldehyde, 483 mg (3.5 mmol) K2CO3, 298 mg (3.5 mmol) piperidine in 5 ml DMSO was kept in a sealed tube at 130 ° C for 18 hours. . At this time, the reaction mixture was cooled to room temperature, concentrated, and purified by silica gel chromatography (CH2Cl2, then 2% methanol in CH2Cl2). 740 mg (99% yield) of 4- (piperidin-1-yl) -3-fluorobenzaldehyde were obtained.

The benzyl chloride used in the preparation of the compounds of Examples 433, 474, 480 and 500 was prepared as follows. For a solution of 769 mg (4.16 mmol) 2 - [(4-chloromethyl) phenyl] propan-2-ol (Creary X., Mehrsheikh-Mohammadi ME, McDonald S., J. Org. Chem. 1987, 52, 3254 ) in 14 ml of CH2Cl2 kept at -78 ° C, 0.72 ml (5.4 mmol) of DAST was added. After 1.5 hours, the solution was quenched with water and brought to room temperature. The mixture was extracted with methylene chloride (3 times). The combined organic layers were dried over Na2SO4 and concentrated. Purification by flash chromatography (SiO2, 0 to 5% ethyl acetate in hexane) provided 512 mg (66% yield) of the desired chloride as a light yellow liquid.

¹H NMR (CDCl3, 300 MHz) δ 7.30-7.48 (m, 4H), 4.58 (s, 2H), 1.70 (s, 3H), 1.63 (s, 3H).

The preparation of 4-bromomethylbenzoic acid 2-trimethylsilanyl ethyl ester used in the synthesis of Example 470 is described by Graffner-Nordberg M., Sjoedin K., Tunek A. and Hallberg A. (Chem. Pharm. Pharm. Bull. 1998, 46, 591).

Chromatographic separation conditions for mixtures of enantiomers Condition 1: The compound of Example 345 was separated as follows: Chiracel OJ column size 4.6 x 250 mm, 10 µm, eluting at 1.0 ml / min with 85% hexane / ethanol, 0.1 1% DEA in 20 minutes.

Condition 2: The compound of Example 346 was separated as follows: Column Chiralpak AD 4.6 x 250 mm, 10 μm, eluting at 1.0 ml / min with 85% hexane / ethanol, 0.15% DEA over a period of Twenty minutes.

Condition 3: The compound of Example 347 was separated as follows: Chiralpak AD column size 4.6 x 250mm, 10mm, eluting 1.0ml / min with 65% hexane / IPA, 0.1% DEA over time. 18 minutes.

Condition 4: The compounds of Examples 365 and 366 were separated as follows: Column Chiralpak AD 4.6 x 250 mm, 10 μm, eluting at 1.0 ml / min with 75% hexane / ethanol, 0.15% DEA in 25 minutes.

Condition 5: The compounds of examples 408 and 409 were separated as follows: Chiracel OD column 4.6 x 250 mm, 10 μm, eluting at 1.0 ml / min, 90% hexane / ethanol, 0.15% DEA within 36 minutes.

PL 204 281 B1

Table 4

<img file="PL204281B1_D0091.tif" />

<td>ad S. WITH about part Q</td><td>and * śbs TS? ΐ 22 ° - AND. T- A _. · U d X bjf - Ś &lt;* 1 - 5 G &lt;=&gt; \ e; a &lt;d ¢ - λ ^N GS 'Ί ό ri'^1-'- T «Ξ Ξ ^M. 5-K 8§5§? GdtP§ 5 ¥ G- w O c- 23 A —- A ® (ί'Τ. ^ ΊΑ © ® ffi u 5? Pp a K jn &amp; A o 00 c * L * e; sS; Bs £ AS sb</td><td>"SheS ^ S TT and £ n ° S. '-. rn_Λ “_J '-i en - £ Ό K&gt; f ~ tgra— “corn CS U Β &lt;Ί 3 1? "B § Ή Ą .ja κ a cf h. Gss s- £ - Γ- '&gt; - »S» /</td><td>S * ® “o - 5 ° -? B, aiA £? 3 m., fN «m Lc ~ 3_Ό-κ_εΆ S ό 7! 5, »X O® * n R »2 Ό ^ ΛΛ&gt; π (^ο. iiJSfni • o C&gt; &lt;= »„ g xo hx§i si 31 ie Ό 'fl »* o -' r-&gt; Ą πί</td>

<td>£ + s</td><td> 425.1</td><td> 395.2</td><td> 463.1</td>

<td>Time retention / method</td><td>1.76 Method B</td><td>1.71 Method B</td><td>1.71 Method A</td>

<td>Out- connected mass part.</td><td> 424.95</td><td> 394.92</td><td> 1 462.92</td>

<td>Look</td><td>white precipitate</td><td>white precipitate</td><td>white precipitate</td>

<td>! - Scheme reaction</td><td></td><td> -</td><td> -</td>

<td>r&gt; those</td><td>ϋ fi</td><td>Q fi</td><td>ABOUT 0 X</td>

<td>ΓΊ Those</td><td>s about .</td><td>{fig</td><td>. iC at</td>

<td>axis</td><td></td><td></td><td></td>

<td>No Ex</td><td>* —Ł</td><td></td><td>n</td>

PL 204 281 B1

<img file="PL204281B1_D0092.tif" />

PL 204 281 B1

<img file="PL204281B1_D0093.tif" />

PL 204 281 B1

<td>NMR data</td><td>Sat »a F3 n R. g O fO (N ~ »S 2 2 IO * 7 R &lt;° oo r * « o .a «Ί aj w&gt; oS” S | aJ &lt;a - a</td><td>ABOUT ^N43 —i ffi g DO O what isiss · t- .c -o H jm 2 ii vo ΤΓό * am TT om in mr ~ -? about * s! - &lt;- &lt;a »-j ć n US? όη 1ϊ aS Ϊ s-jSil 1 aa '£ g ^ a' a SS-® · V ”S ~ - \ -rf * b- Η »ΓΩ</td><td>r- * n '' • S £ "X s ® S A ϊ ~ “Λ * - »ir— \ p, ^ _Γ = n £ B. £ £ $ gS $ £ Ύ 8 a ό § 2 2 o Ο'ΐα'οό'ίϊ'οο ^ - 'ΐϊ' A iS A £ 2 jS c? S§ uo 3 ς ▼ S sa ^ 'ΙΡΚΊΡΒ' ^ '^' ϊΓ Λ ^ ΛΞ ^ εΑ ę a ^ asa £ η.8§Λ? £^s? 3t &lt;W5A-3</td><td>a © 17 - * n Sat g “&gt; in ro n. g” «Α £ 2 'jr s 5 2x o A £ sJgS £ 3 * 2. e £ s ~ EG ^ - 'Ti * tj- _ «" ϋ'ίϊ'Ν ó »x“ - T? OS a 's' h 7 4 SUS £, S * S a, o 3 7 / T ° 6 4- -^-1 -4 7 A -ia 3 Ai - ^ AB tt7 w »&gt; '3 0S Si -² ĄgS ·⁰ ® K jS I?⁵ Ś? βιί A eiiBŚ</td>

<td> + +</td><td>l- “4 cn 'Τ</td><td>d &lt;n ie- tJ-</td><td>&lt;Ί - * T * T “4 Ie-</td><td>m ' axis §</td>

<td>Time retention / method</td><td>&lt; 00 « SD Ό £ 2 V s</td><td>&lt; ._ «« Κ T3 u -2</td><td>and 1</td><td>and °° -3 2 - u s</td>

<td>Out- connected mass and particles |</td><td>CS CT \ es . Ό T.</td><td>% r4 mp TJ-</td><td>ts o&gt; about * - ", T.</td><td>* n DOWN ABOUT This</td>

<td>Look</td><td>&gt; 1 Ό S £ X5 st</td><td>&gt; ł Ό 3 pp £ o</td><td>- £ 'Ό 5? x&gt; o</td><td>sticky brightly- yellow foam</td>

<td>Scheme reaction</td><td>ł— «</td><td></td><td>»—H</td><td>t— &lt;</td>

<td>n</td><td> 5</td><td>AT p</td><td>ΰ p</td><td>P.</td>

<td>rs CsS</td><td>* » LOAM AT</td><td>E. Wo \ 7</td><td>X about</td><td>β s u- O</td>

<td>ii</td><td></td><td>* -y</td><td></td><td></td>

<td>about-</td><td>fN ł—,</td><td>²</td><td>mp 1 ~ H</td><td>in</td>

PL 204 281 B1

<img file="PL204281B1_D0094.tif" />

PL 204 281 B1

<td>NMR data</td><td>pi Ξ2 -. τ K r- J (2 r- S - ES * 7 ® g 4 u-&gt; E 7 ot ~~ A - * —'oś -7? &lt;4 »3Β · *, ί35 r and gf _k- ±! L £ S *&gt; pp § x £ 5 £ s - ϊ 5? &amp; in ES βΓό ^IN· Ε £ όΓ</td><td>PI " g? uo d '»~ S 9 © hs °. s - Jl r- - Jj o.-Γ - 77¾ r- ιΑ «τι- S • o Ό PI -tf S Έ, '-' Κ 3 ^^ 2.3 ^ 2 □ SiS &lt;? &lt;n _ς * - 2-5- - • what q? -Ffi ”® ςτ ϊΡκ ^ κ ^ s'- - Ξ κ S τί 2 κ B “ig X) - -Xr- O ·· —-m ΟΌO</td><td>3 2 . c-Ξ g S s ° S -SsBcSg “00 όχΕ SE -n 3 - 1iśRS ąagł-233 g £££ · ££ · £ $ S £} ES T * \ db 35 * tf χΓ BJ? E Ew JST · C 'Ό * O- Ό \ O &lt;&gt;</td>

<td>£ c + s</td><td> 423.2</td><td> 423.2</td><td> 455.2</td>

<td>Time retention / method</td><td>AND 1.68 Method Β</td><td>1.67 Method B</td><td>1.94 Method B</td>

<td>Out- connected mass part.</td><td> 422.52</td><td> 422.52</td><td> 455.02</td>

<td>Look</td><td>light yellow oil</td><td>light yellow oil</td><td>transparent clear Oil</td>

<td>Scheme reaction</td><td> -</td><td>t— (</td><td>m</td>

<td>m ai</td><td>Β » £ 0</td><td>about E. fi</td><td>'ABOUT,</td>

<td>Pl 05</td><td>s What</td><td>ABOUT S. Of Laws of \ /</td><td>0 X</td>

<td>from</td><td></td><td></td><td></td>

<td>t-7 Ń from £</td><td>ABOUT rM</td><td> ·</td><td>CS oh</td>

PL 204 281 B1

<img file="PL204281B1_D0095.tif" />

PL 204 281 B1

<img file="PL204281B1_D0096.tif" />

PL 204 281 B1

<img file="PL204281B1_D0097.tif" />

PL 204 281 B1

<img file="PL204281B1_D0098.tif" />

PL 204 281 B1

<td>NMR data</td><td>r- o fM Os wi and o " Axis axis m r- ό ' t ae ι / Ί S m λθ 'ί · w &lt;N r- cT · * - &lt;* 5 Αϊί “ί ^ ΙΪ Ooftsrftjs® t / r- »Si- sja μ- g Λ Λ jgSKt-g ^ Kw £ S 222Λ 22</td><td>&lt;&lt; _ζ S * *. S »£ · c- rs -rs a E gea * '_e&gt; S rj g Ń * τ joh ri 2 n 3 ^. . ^ g-ig-Ś. sii-iSTsSS 2 g 2 · »· □ nu a, □ m =" · τ «1 η h Zr? £ · 3ό ^ · 'irJ o 2</td><td>fi i ϊ ξ! ϊ a. _ fi m -k in ". Es 35 - m gg ^ 32iÓS2 r ~ ce &amp; Ol 2 U at 51 what t - * - 2? y—&gt;. ł ^ - t ”- Γ-- '» OO U 7ΓΊα and? ν '¢ 5 "· τ»,' ν ' a S aaak jg _B- _E.- a (j N tn ir, in - &lt;* £ ,, £, 0 “* ww oo cc £ a -. r ~. &gt;&gt; n“ ®A S CC ΣΧ &amp; f ίΕ S txf £ cs, rs cs (S OJ £ £ gm -^and2222v6 Λ aa ^.</td>

<td>ΐΰ + 2</td><td> 413.2</td><td> 404.2</td><td> 454.1</td>

<td>Time retention / method</td><td>1.46 Method A</td><td>1.47 Method A</td><td>1.65 Method A</td>

<td>Out- connected mass part.</td><td>412.46 ! and_</td><td> 403.48</td><td> 453..49</td>

<td>Look</td><td>white precipitate</td><td>white precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td></td><td> -</td><td></td>

<td>Pi</td><td>fi</td><td>fi</td><td>Λ δ 0- '-ί</td>

<td>nł Pi</td><td>\ u- O</td><td>y about</td><td>^with\ θ</td>

<td>cć</td><td>K.</td><td>$ -y</td><td>Hy</td>

<td>No. For,</td><td>o. o m</td><td>ABOUT\ en</td><td>about M</td>

PL 204 281 B1

<td>NMR data</td><td>Ό 't? 2, pp £ ϊ - TT - * ΐ, X 'ν'Ε'Μ K 5- ίο ν '5 A. &gt; S. ^Ώ Β'ΐ '^ - ίΟ . . . . CNC *; Μ - οβκμβ Λ Zse tc uoSSin hS B c *. iXXX5s £ X2§a In ŚSSSi.T &lt;± »« about S.</td><td>- ** has (?_about oi B ® £ Ό and &lt;-? '_T S._about3s s «s r- o O L- Li A c A - &lt;co £ ~ ® 05 * - J.? vol «ITS» ~ 0®- ^ o ^ n · O Β B p «—— p · _r ffl B un cn - SS rt j T «- a 2 * - i I ęssSI a • Ξ'ΰίκ K 'ζι -σ to * W; &lt;Β2_ ·· σ * σ w · ϋ * s - »* CS m - *' · —- '</td><td>Ό · + S + M ui fd tN £ “§ n 2 a¹* · Ζ rn »-i Γζ kd _r Łd EG Πί ' ¢ - r- cn * - * j £ [6'A what o. A ^, r- \ o _ κοι o χ j¹ - - °° «ι β \ o aa U + n - '-4 S fiiSsSlocN. ^ g 'ij OO&gt; c * c O ·, sff T 5 ^ .4. ”? eta x SiSS K 33300 ^ o</td>

<td>4 B +^s</td><td> 400.2</td><td> 441.2</td><td>fa • e • ^ r</td>

<td>Time retention / method</td><td>1.53 Method A</td><td>1.27 Method A</td><td>1.29 Method A</td>

<td>Out- connected mass part.</td><td> 399.52</td><td> 441.0</td><td> 446.06</td>

<td>Look</td><td>£ 3 x&gt; o &gt;</td><td>transparent clear Oil</td><td>transparent clear Oil</td>

<td>Scheme reaction</td><td></td><td>m</td><td>en</td>

<td>en Βΰ</td><td> 0</td><td>5 0 Ή.</td><td>ABOUT '0</td>

<td>oh es</td><td> 2^</td><td> 0</td><td>{j X</td>

<td>p;</td><td></td><td> £~\&gt;_</td><td>We are</td>

<td>in N Z £</td><td></td><td>CS</td><td>m T.</td>

PL 204 281 B1

<img file="PL204281B1_D0099.tif" />

PL 204 281 B1

<td></td><td>NMR data</td><td>! 2 c? g ' A ffi er- = - c l 4 ~ g ~ ^ ό r- '«Σ- oo © 6 ~ B ~ o ~ "£ 2 'n'"! rs.ck - 'ν' ”· £ SO Ό ο» - J5 "O ęrs. i'6 S £ j 3 and MAS aS “i5BsMi g ϊ ~ «Σ-§4 ​​^ Ρί + ν + -⁴ .on SS «Μ'ο ^ - 'ο« Γ 11 5ΰ · β</td><td>&lt;O g j. Ό co μ P η 'I a jj es Uh t ~ - £ 0O Ό - »w-Γ O rZ / &lt; 3 ^.? S = £ a. g® ° w. «fn R f? PS 3L Ά —j * 25 cf c * 0 * 2L ϊζ-ΤΊ &lt;&gt; T 5 5 Sr- t ~ - τι- tj- - ® 2-</td><td>S. '£ s Ό O is g 0 ° 32 ąo _about-ιχ β a - '—4 “~ 00 X&gt; Ό - -H r-2 Ώ 2 ά 5 d O 'Ο.χ Oki jS. wf '“^ gS 2 here 5? 6 - «η * n oot ~ - o, -η o - 'oó oo e-! -j —i \ sj from Jl Jt * Pi rn Q « iS'S's2S ~ g ffi ό '-σ «Γ - 5 -rf - O-O-xZ&gt;</td>

<td></td><td>+ in + s</td><td> 440.2</td><td> 410.1</td><td> 432</td>

<td></td><td>Time retention / method</td><td>1.69 Method Α</td><td>and 1.26 Method A and 1</td><td>1.19 Method A</td>

<td></td><td>Out- connected mass part.</td><td>CS Ο \ σί m 5f</td><td>Axis οί about</td><td> 431.99</td>

<td></td><td>Look</td><td>yellow precipitate</td><td>beige precipitate</td><td>beige foam</td>

<td></td><td>- » Scheme reaction</td><td>ł — 1</td><td></td><td>en</td>

<td></td><td> 02</td><td>0 fi</td><td>5 fi</td><td>δ fi</td>

<td></td><td>'and!</td><td>in ABOUT WITH</td><td>X with</td><td>ΰ vol</td>

<td></td><td></td><td></td><td></td><td></td>

<td></td><td>ώ N * £ 1</td><td>r ~ -3-</td><td>What</td><td>Axis .</td>

PL 204 281 B1

<img file="PL204281B1_D0100.tif" />

PL 204 281 B1

<td>NMR data</td><td>It -o. . S '¹': o ° 'ó iSś§U5 · ed • o rs S ή oo * r * —io tt W-1 «32 1 Q 1 — ι-TS? ' ►ri ti-ffi KN -J CN t £ ko \ © &lt;- rn 5 -o 5 »II -d« -2! NX 'is o h- · «2 W tU r ^ co ^ cNTrm ^</td><td>23 3gS £ 2? A ts ό o .j · 53 ό g »T5 &lt;2 ^« · - / οΝοϊογ'ο ffi ii · u tn 53 33 p - A r- A sl ^ cn A</td><td>"-.» 5 In. c Σ ± * »« CS * ** ~ 5 ffl rr-Γ 33 t ~ - fi n §S ^ f? P5.S · VI S - «Μ _Λ 3 «ΧΊ II U m ϊ- ~ ir, r- κ, L 1 0" 0 "; - 'ό ° §, 3582 ^ § _- πΓ Ί3 Τ3 * ® © X 'Γ'Χ' - 'Ρ' II N TfO n P5 - v&gt; m oo .. * 2 S r4&gt; tt ij ZXXXjm K °? ° 1 “ΊΜΚ πί r⁴ r- »» r. -ui</td><td>- House £ ° £ 3jA2S ρ'ν ⁰⁵ * r UX® m ° o * j-t __ ^ Z x; 5 X 0Ó a OO -e. ol - P g ® js “ae ^.“ J · o = ^M. · * A ~ S Q «1 -CN“ S. , U 11 S m + £ ^. X » \ - · * - ł — 1. -y¹ O \ C&gt; Tj · _ t ^ · \ S | "Λ- - Ie- Ć / CN O7t n</td>

<td>Ϊ £</td><td>Si 3 </td><td>'ττ O ®ia</td><td>* - + ABOUT\ t&gt; tT</td><td>S. in What t3-</td>

<td>Time retention / method</td><td>&lt; OO, S at S. 4J s</td><td>1.81 min Method B</td><td> &lt; £ § - about - u 2</td><td>1.95 min Method A</td>

<td>Out- connected mass part.</td><td>»N ABOUT\ e. e-w</td><td>* X3 DOWN ABOUT ABOUT Ie-</td><td>PM AXIS OO Γ- «·</td><td>OO * n ie- cn ττ</td>

<td>Look</td><td>2? .2 in -O o</td><td>&gt; Ί O es .2 OT Xi o</td><td>_ £ / . £ OT x&gt; o</td><td>~ .2 OT _o c</td>

<td>Scheme reaction</td><td>&lt; AND 1 Ό __, OT ABOUT CL HIM</td><td>&lt; and € _ ^INabout CL &lt;Z)</td><td>&lt; 2, 1o CL tZ3</td><td>&lt;and € - S. ABOUT. CZj</td>

<td>n Pi</td><td>ABOUT 0</td><td>5 fi</td><td>at fi</td><td>LOAM fi</td>

<td>N</td><td> ® / \ '?</td><td>* 2 u. o</td><td>U- U- about y</td><td></td>

<td>Ρί</td><td></td><td> $-</td><td></td><td>^ -y</td>

<td>IJT Ń with ί</td><td>m ΜΊ</td><td>Tf m</td><td>in&gt;</td><td>'kC OTl</td>

PL 204 281 B1

<td>NMR data</td><td>^ώ - r— - Λ r- χ 5 _ ® ® «3 = A ®» i ^ .a * £ Sns. tfSsASSBiss? 87śs &lt;t * · ni-10O _. CA is-ll " a - ° - &lt;n ^ .t- ci ο © τΞ ^ -a - '«a &lt;35ti ? S 1 ^ -oicnMcsOO ©</td><td>Are: m EC * -_s- ^ ą Χ &amp; ^, Α ^ ΙΙ ί Σ2; 3 · η Λ-Λ® * π S «γ - Κ - □ ogS ^ O © Η Ο ^Μ ι ~: ₌* &lt;8 ο, -ς U »S- m 8 3? Τ ο?&gt; Η Η Τ ”£ S bK £? ? ί Α g Μ -Ί- «3 '-j ·' - Z • 'jn X .tSł- a? 7 ~ ss a - Ο Β 't ΓΊ G- - ©</td><td>0 - j. x and ν, -cT r ^ 3 3 s 'c' -'- i CO S. J what £? - «-&gt; -.ⁱⁿ, ffi 1 r ~ .-: N * UX ± Ό O ° || Σ v&gt; r * TW g \ © e- _-κ. © r &lt;- oo ^M. a ^ 2; TX ufW D ΙΛ 0 -XTffltc a ®- § 3 τ SB . —S 00 - &lt;w _ i © 2 a ® &lt;S aa a ξ 7 t © ea - 0- II 'T 00 Gm</td>

<td> 2</td><td>CS DOWN &gt; n ie-</td><td>CS «Μ Ο \ m</td><td>CA 0 en</td>

<td>Time retention / method</td><td>2.16 Method C</td><td>&lt; cc -σ Α Ο * —I ο 2</td><td>1.28 Method A</td>

<td>Out- connected mass part.</td><td>r- ABOUT 06 *AND * Φ</td><td>Ch WHAT ABOUT' ο&gt; m</td><td>ca 00 oi ό m</td>

<td>Look</td><td>brown Oil and</td><td>colorless oil</td><td>-ίΊ Ξ μ eats 0</td>

<td>Scheme reaction</td><td>m</td><td>m</td><td>AND</td>

<td></td><td>and □ fi</td><td>fi</td><td>□ 0 • H.</td>

<td>About £</td><td>Ϊ</td><td>'fi</td><td>X 0 r</td>

<td>those</td><td>$ -y</td><td>Ύ</td><td></td>

<td>ŁT Ń Z £</td><td>Γ- ° 1</td><td>00 AND</td><td>ABOUT\ m</td>

PL 204 281 B1

<img file="PL204281B1_D0101.tif" />

PL 204 281 B1

<td>NMR data</td><td>^R-S 'T 2 2; • o Σχ r- '-s * eeesjijgĘ ^, -, 3s £ ~. ^ “P A sf-σ w * about,¹ a '—a.-o5 2S ai £ « ZSr -.- iooJO '* · - ^^ a 2Β * π T “? ® w i ** Ui, r- ό · ό · ^ · - · * - «m</td><td>* CT "_vol \ D And Os Rl®a gJ® r * S = a 7th o ® • oa ς? 3 ft 8pSjaSSR | ig ^ s ^ sE a · m "o" in «Χ5isSś</td><td>_-ο³£ “-S £ ΪΓ ^ -! 2Ξ,. § a cf ¹¹ m ® - 2 La a «; § * »tc ^ο»II ° Λ ^ “° ϊκΊ. -Ses -wa er®. m&gt; - 7-i r- F; Ό _-m 5 RÓŻ-ró æ '' - '' β § a - °° '-ra * 3 S-ft »a» Α-Ί⁴ about § 45 l and&gt; 2- II? 2 o? ea / i a ^ K ^ Kiai Or-NlOtstOS</td>

<td>+ and + s</td><td>and 471.09 ......</td><td>* - β * £ 1 in * ψ 32</td><td>from 9</td>

<td>Time retention / method</td><td>2.04 min Method B</td><td>1.82 min Method B</td><td>1.39 Method A</td>

<td>Out- connected mass part.</td><td> 471.02</td><td> 372.92</td><td>ABOUT\ ABOUT\ Γ-- m t *</td>

<td>Look</td><td>light yellow precipitate</td><td>brightly- pink precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td></td>

<td>m oi</td><td>E5 0 H.</td><td>fi</td><td>δ fi</td>

<td></td><td>ABOUT about</td><td> 1</td><td>\ H—</td>

<td> *05</td><td></td><td>$ -y</td><td>iy</td>

<td>No. Ex.</td><td>rn \ABOUT</td><td>about</td><td>1 / Ί Ό</td>

PL 204 281 B1

<img file="PL204281B1_D0102.tif" />

PL 204 281 B1

<img file="PL204281B1_D0103.tif" />

PL 204 281 B1

<td>NMR data</td><td>_r S * A ίο ® a &lt;7^r'- to aj · - 43 -'ΐ'σ II nwXĆC and rC-S »δ S -? - 0 T. Ν p _ · 4 \ o J m, χ jjd ^ - '⁰ and _v 3 ga Q Ϊ “4 4 x 0 X ^M.. yeah l ^ I - g. 5 opp in a 5 s 7 n «, s: r JT¹ 2 Pl Pl 2u-i yr «m &lt;s |</td><td>Ό __ _ r C ^¹ -Τ '(“χ&gt; ΟΆ i» PI Έ * °! Ξ i 7 '4 II p ^ .5S PCBm- k-SsS- = - X - - 2 “7 ⁰⁴1 S ss 0 o r- * r -η m 2.h £ * to * = -w 2 47 ^ 53 2.7 *;} 5x5&gt; 5§ó 2 £ G "+ ΤΪ CM ffi g ps 0 &lt;s »E - Because ^ -ooo ^ W e n 2 February 222— m 2</td><td>I glish. 22 0 0 «Β Ρ-ΌριοοΧρ-2 S TO 17 H ®1 | J Ol sS3 32 ^^mtMp-PJMOBo, _ί 0'Λ ó -f “” OU ni Λ χ X Ί 2 A u ° ^. 5 Ei T, PI 2 y.&gt; O \ aaz c4 a '* i T ζS "¹222— a 'Τ -&gt; - «μ i3K^m. - 2 pl SD »n -ej- II PI</td>

<td>+ Ε ' + s</td><td> 427.09</td><td> 437.09</td><td>404.03 and</td>

<td>Time retention / method</td><td>1.86 min Method A</td><td>1 1.88 min Method A</td><td>1.63 min Method A</td>

<td>Out- connected mass part.</td><td>0 σ&gt; &lt;© en</td><td>EJ ABOUT\ Ό * ΠΊ</td><td>ABOUT\ DOWN rn 0 TT</td>

<td>Look</td><td>light yellow precipitate</td><td>colorless oil</td><td>—........ 1 white precipitate</td>

<td>Scheme reaction</td><td>1- Method A</td><td>1- Method A</td><td>1- Method A</td>

<td>σι</td><td>0 -fi</td><td>AT fi</td><td>23 0 -fi</td>

<td>cl ού</td><td></td><td>about^withy = O € 7</td><td>with with 0</td>

<td>and</td><td></td><td>w- \ //</td><td></td>

<td></td><td>m</td><td>with.</td><td>»N t-</td>

PL 204 281 B1

<td></td><td>rC Ό 3 gj - M g?</td><td>»-3 ® cr ^</td><td>- KI BT S? (S ^ ”· a® r. ° w. h *. izi »* &lt;« - · «. x-&gt;</td><td>ciS ^?</td>

<td>NMR data</td><td>H in 2? 11 s 2 ⁿ. + -ί « Β Ύ ιη η- x; NO £ oo »jg κι Λ 5 N every 1Γ, - pl, u S-kCj-jJ! ξ? ^ A i »5 31- g? $ £ u .Iw * »</td><td>OJ ό 2 &lt;Ί A " .-c ST m S r- «« m AU 8 to M. &lt;n nj. 2; śsV.si g to s * S a? and O &lt;O _vol&lt;O Ο, ΤΜ -η if _ _,.</td><td>«£ 5 &lt;oh, h : ś == &lt;óS- £ Fi o pi A in oo. IJ- 'P £ FJ IN HERE wm CC 22 A on m ! -¹ r * -. u * \ SC κι ,, - _ί * &lt;- Q from EK, £ c - &lt;! §</td><td>Ki SC λ I * Οκί a β K * a ό e ίο - »? «&gt;“ Ffi 3-3 KK-r a u- t zt «ό r? '²'^ S β&gt; this pS ε'κΛ ~ - °. £</td>

<td></td><td>_ jmw · ή « m * - 7 days ^ e gΒeesss ZN TJ- σ&gt; M • Ci 60</td><td rowspan="2">ΙΙ ^^ ί ”§Ι / t «Łj *&gt; Ο F \ J * ? ¥ + τ1? “S? *?</td><td rowspan="2">S.¹^ “Ρό^κ. 2 3, s53 κ wa Φ O. . _ "» —1 -F— * 5 * “· 00 m - 00 —3 * am «“ g ^ -o-</td><td rowspan="2">2 ®. “S- £ .— ES iiuKZOK ^ OZ</td>

<td></td><td>in N ą o ~ 1O</td>

<td></td><td>Γ¹ and «) Ζι V 8 KI</td><td>Γ 1,&gt; Vl - A</td><td>- * - »r * vs&gt; -»</td><td>- m&gt; or m -. - about</td>

<td>+ CC</td><td>»R&gt; ®</td><td rowspan="2">oh . yó</td><td>.S |</td><td>Ie- Γ3 aa</td>

<td> +</td><td>. Γ “~</td><td> ·* +</td><td> +</td>

<td> 2</td><td> .^. </td><td>Tt</td><td>m * g λ</td><td>43 M.</td>

<td>Time retention / method</td><td>2.04 min Method A</td><td>1.51min Method B</td><td> « ^Ώ»§ π 2 Ε »O &lt;2</td><td>1.89 Method B</td>

<td rowspan="2">.i «« u</td><td>WHAT</td><td> »—1</td><td>»N</td><td>On</td>

<td>o. o \ABOUT</td><td>° i vi</td><td>Cb o. o</td><td>axis o. o</td>

<td>&gt; NCN p&gt; OC q</td><td>* T.</td><td>about . Φ</td><td>about</td><td>ABOUT</td>

<td>Look</td><td>white precipitate</td><td>-1 white precipitate</td><td>White foam</td><td>colorless ny syrup</td>

<td>emat ction</td><td> &lt; 1 ³³! ό</td><td rowspan="2">&lt; £ 1 Ή SS</td><td> on | lyni ¹niku AND</td><td>«£ -S f £ =</td>

<td> 03</td><td></td><td>• «-w</td><td>'B «</td>

<td>Scl re</td><td>ABOUT cl CZł</td><td>CL «Zł</td><td>“C</td><td>TT! O cn ¢ 2</td>

<td></td><td>at</td><td>at</td><td> □</td><td>δ</td>

<td>m «</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td></td><td>γ</td><td>/ H.</td><td></td><td>• ^ r</td>

<td></td><td>L_</td><td></td><td></td><td></td>

<td></td><td>U .—) - li.</td><td>ch</td><td></td><td></td>

<td></td><td></td><td>and?</td><td>© s /^-¾</td><td> 00</td>

<td>cont</td><td>Y /</td><td>and</td><td></td><td>Ά</td>

<td></td><td> ?_.</td><td></td><td>fi</td><td>e__{_}</td>

<td></td><td></td><td></td><td> £—\</td><td>? —K</td>

<td></td><td> //</td><td></td><td></td><td></td>

<td>N</td><td>xo</td><td>r-</td><td>o. o</td><td>AXIS</td>

<td>With Cm</td><td>r-</td><td>r *</td><td>r-</td><td>P *</td>

PL 204 281 B1

<img file="PL204281B1_D0104.tif" />

PL 204 281 B1

<img file="PL204281B1_D0105.tif" />

PL 204 281 B1

<td>NMR data</td><td>5 »· β. 7 K sr SS *** ^ Γ— Vj ". *" · * Π _i sP, »- ii gag υ as? »M -s 5” m 8 ^ ”g ~ - From £ ft CN m from &lt;O. OX - Z, fe * - r βνΞ'Γ-¹^^ «* -cn</td><td>. «Κ. m - -j. U-, * —Γ _ £ '_ - a O °. sS-ssSb-sst 2 2- β 5 ”'? - go ^ 2- 11 -S «~ ® B S Ul E r, £ 7 ° u ΓΜ 2E. — Xu) _ ł «ł ¹ _ * ._? - S o \ u, S "go KU * | 3i * £ ®3s? I3 * y _ · w CA "£) o Π ii 5 ^m - g-ooh- Β-ξ 1 XS ^d ^ 'i ~ -OOi ^ rno B gw Π of P ® °. T g S 5 - Ό - Μ - - τ ag Ί. ® 3 A&gt; A wS ^ a ^ -ri ^ a ¹¹ · «A 2. ii 3 1 2 - 2 pp</td><td>Λ “c - ó P 2nd st 3 2 Ea =&gt; &lt;Ś 172 'Ξ-ό S "ό' Ip px A ο = λ if ~ oo B “- E - About fi “rf-c» A 2 Pa sPc s; «Lin u "1 and N". N r- O .K. pi * _- «% -: - ts g S g2.so 32. 3 BZ Es o -cĄs ó. and; ij * ł m A ® 2 «a¹r 2y-oo - - =} - 2-2-</td>

<td>+ X + 2</td><td>rs 00 cA -e</td><td> 402.2 </td><td>r- ABOUT\ σι</td>

<td>Time retention / method</td><td>2.37 Method C</td><td>1.94 Method C</td><td>1.67 min Method A</td>

<td>Out- connected mass part.</td><td> 437.95</td><td> 401.92</td><td>m crj ooh m Tf</td>

<td>Look</td><td>&gt; »“ O .2 They are o</td><td>white precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>* Λ</td><td>W-Ί</td><td>Ό</td>

<td>es</td><td>ABOUT P.</td><td>ABOUT 0</td><td>° xp</td>

<td>ri tsS</td><td>P. MA r</td><td>P. xz r</td><td>§ \ = o ΖΛ</td>

<td>es</td><td>$ -y_</td><td></td><td></td>

<td>- E2 Z £</td><td>roo -</td><td>o. o o. o</td><td>c * o. o</td>

PL 204 281 B1

<td>NMR data</td><td>* X &lt;, K - G Łi NO Tf total x? S rn O ΟΟ ^ Ε » m ui - «-: β ~ MCO \ X Ci. έ ^ ΐ Ξβ ^ Κ 12 «· β 5 '. »DS η N g af e 3 * s From cs rs r ~ in zA m £ X in cc * 1 &lt;&gt; xZ&gt; r ~ - tr. m th n</td><td>-o K m -X^S.i «B £ Róż - a £ A ek g -i χ - ττ. wp M a X 2? · Ο £, - ® a'— 'a ** ·. «In &amp; i n * «^ 1 r_ r *“ CS " and V ~ a EHκ s® -i— · r ~ - es tj- o- m</td><td>XO CN O «C? SX o. OO _at 3 co «z = h. ν '&lt;3 ST &lt;A 2 £ * 45 ο S - - II - m o A £ -s E «® β i" o og t &lt; A ίο £ s «-Γ 5 O« x r- '- 2 - _B- x&gt; o ti lax gj ^ ooccin-io - S ^ O ^ wS ^ SmS S S0 1 ^ 3- - © 2Όm ™ m * mχ-C. ό &lt;&lt;</td>

<td>+ K. +</td><td> 423.05</td><td>CS about un • 'Τ</td><td> 502.1</td>

<td>Time retention / method</td><td>1.41 min Method A</td><td>1.02min Method B</td><td>1.72 Method A _and</td>

<td>Out- connected mass part.</td><td>422.89 __ i</td><td>-η 1 450.0</td><td> 502.08</td>

<td>Look</td><td>white precipitate</td><td>beige precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td> \©</td><td>CS '</td><td>r- ~</td>

<td>Pi</td><td>ΰ 0 X</td><td> 5 ?</td><td>about 0 X</td>

<td>'you</td><td>δ \ = o ΛΛ</td><td> 0</td><td>H&gt; °. P.</td>

<td> 74</td><td> /</td><td>Ηγ_</td><td>^ ~ y</td>

<td>No. Ex.</td><td>about C7 \</td><td>ABOUT\</td><td>es Ch</td>

PL 204 281 B1

<td>NMR data</td><td>s © "a" Χζ / -ί · «Τ X ®⁴⁰ °° a - maa = 222S ^ 2x -θ 'S- 0? TT * n ”2 0 00 π- Ά 5 «= * 11 2 - =&gt;« 2 s * &lt;Ξ ° ι £ 2 - τ g Ul&gt; q rc S “oT μ © ® r - £ a B «" Op rr iiea</td><td>□ O / -K . - aa «au -sA prs" -32 S * rf »-r t3 S 58 2s&gt; 7 3 O ~ Ό Os 0 O 22 «" 3 2 « ABOUT ⁰⁰ --A'— 'Ctx _ w »aus aa £&gt; 2 ^ d-22 α, κ a23 2 £ Sig 5 ł_ T3 _h g r 'you O ZO&gt; C os so CM en * Ę un 7 n oo -q- n 'm Ό</td><td>a. g Si «A^s£ Tr * s' TiHi-S -2 τ ® - IUX «-r- D ntx ._; - Y 83 ^ js3p «; - S * II Ό \ © - n 11 00 - 32 © 'p ^ rs ^^ AtNjęg 2§S5sj5-4§i Pm co - —2 * 1 co Si ss0®a_ffi- with 2m 2 3V is ΧΪ- S Μ X η 2 · ° ϊ 5 · β - CS l- ^ AjD ^ TfrMĆtS '</td>

<td>+ and + s</td><td> 478.1</td><td> 531.2</td><td> 425.17</td>

<td>Time retention / method</td><td>1.60 Method A</td><td>1.59 Method A</td><td>1.49 min Method A ¹ • 1</td>

<td>Out- connected mass part.</td><td> 478.01</td><td>3 0 ΡΠ • Λ</td><td> 424.95</td>

<td>Look</td><td>white precipitate</td><td>-1 white precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>Vł</td><td>v&gt;</td><td>o. o</td>

<td>at 4</td><td>5 fi</td><td>fi</td><td>□ fi</td>

<td>Cci</td><td>r</td><td>2 ° Y '^J.¹ 0</td><td>X 0</td>

<td>Ti</td><td></td><td>^ ~ y-</td><td></td>

<td>No. Ex.</td><td>WHAT Axis</td><td>Tf axis</td><td>. m Axis</td>

PL 204 281 B1

<img file="PL204281B1_D0106.tif" />

PL 204 281 B1

<img file="PL204281B1_D0107.tif" />

PL 204 281 B1

<img file="PL204281B1_D0108.tif" />

PL 204 281 B1

<td>NMR data</td><td>Ex 00 $ a TT β 2 and &lt;g -o 2. s «a rose - ci¹o&gt; - ς&gt; D £ hp J -5 ^ S® rs d - * ° ίο OS - '' -'S ' qS®22-4 2 u. | m O ^ · d U Λ m Λ &lt;on -. gj 'u. ą oo. _ 2 agaas 3232 ^ 2222</td><td>au, * 5 a ® 5β 5η^β'«P t-ti- 3pp3e.3j ^ 2S® 1 ““ T - ^ - u »eS § 7 ο ID Jś - - 'du m ro in _about - _in- ---:twenty j os o 2- a - S a - a U -i Ci 17 bad 5 · =! - - fn A II 1! 3 C? £ -e Ssa ^ sSiSiii With T3 Ό Ϊ * S ζ, ® w&gt; 00 as S g- 2 a 2 a 2 °? a ώ - &lt;&gt; CK “+ W“ »Cfl» —i —1 Ό</td><td>WSF. 3 a £ as ~ g^and• o A «r rs '**' - ^ 00 _Λ rs m « - II in 2 Oi rn «CN S-ir IN i? r ~ a 4 ® d eo cs «, m -m _Λ^ χγ £ * ™ ΞΓ Sip- ^ f ^ d Ε3ΡΛ2Κ3Ε, ^ 2 ^ g 2 SU », B» d 3 S Ń U-. ® θί «lii T ° 9 E 'S¹ «&gt;" ΙΛ Oh no</td>

<td>+ and + s</td><td> 607.29</td><td> 554.19</td><td>455.1 (MIC)</td>

<td>Time retention / method</td><td>1.70 min Method A</td><td>1.75 min Method A</td><td>l.GOmin Method B</td>

<td>Out- connected mass part.</td><td> 607.17</td><td> 554,11</td><td>r— hey \ © WI τ</td>

<td>Look</td><td>white precipitate</td><td>white precipitate</td><td>transparent clear wax</td>

<td>Scheme reaction</td><td>\about</td><td>\ O&gt;</td><td>1- Method A</td>

<td>&lt;*! axis</td><td>δ fi</td><td>fi.</td><td>at and⁵</td>

<td>c4 oi</td><td>-Y o- &lt; about ?</td><td>fi</td><td>\ LOAM. 0</td>

<td>Ti</td><td>? -y</td><td>Sy_</td><td></td>

<td>£ N Z £</td><td>this e&gt;</td><td>Ό ABOUT</td><td> 107</td>

PL 204 281 B1

<img file="PL204281B1_D0109.tif" />

PL 204 281 B1

<img file="PL204281B1_D0110.tif" />

PL 204 281 B1

<td>NMR data</td><td>iS Ή 2 "E - χ; E. X. JS * li 'h - S 1? E - ““ - ° 4 pi : 3 -. C? £ d af £ n E ^. Sg Λ “| l« Π, P - E “ A3 » l2 li 3 “f E es ET 5 Lj ·». » - es .. r-- - o _, - § II -d tr! -about_— and? Z (NO .ChP / .M x ^ ® a p&gt; x ai a a. »</td><td>OW h. . S k- 'what_Λ£ - £ «« £ --2 £ 5 -: l7 &amp; ^ ® 1 13P o- ^ Erd ^ m ^ -007 ®2 ^ rLÓ ^. 2 S “ap? - - R. A η tc, 0 'f -¹ X and dA 21 Es χ; |] a Έ '—- χ _x * Λ Γ * Ί ΓΊ t- X »07-4 ® 7 § Es Ξ '*' - E 42, - 0 ς Z. CTi XX \ - 2 y - - II 2 m - - m</td><td>O m r. R * “_T * E (, T 4 NA = 4 - £ -adr S 0 Γ- ^M. r- '"^- II C3 'OO «£" 3 N 0 -2 u - “7&gt; 4 ę? aSCicN ^ E '/ - 5 2&gt; p 2: E - 5 Q j 3 -. - 2 Ί; H e »In“ 7 p =. ” m es - 2 «-'Κ '^ Χ- · _Ć - U - 0 en ffl £, -e u 11 ®e -? £, - ag ' g W 2 Ώ P .A! ^. 2 M | £ Ξ- «η_Μ-ΕΓη-Εξ —Γ ^ * '“' '.« I ®' S * R —1 5 * ϊ xi KX iu E 2p E ii 2id S&amp;S</td>

<td>E. + s</td><td> 453.22 1 1_</td><td> 420.23</td><td>475.26 and</td>

<td>Time retention / method</td><td>1.14 min Method A</td><td>1.29 Min Method A</td><td>1.16 min Method A i</td>

<td>T, § 3 £ 3 ΰ 6 8</td><td> 452.96</td><td>m D \ οί »-H χ</td><td> 475.01</td>

<td>Look</td><td>white precipitate</td><td>White foam</td><td>White foam</td>

<td>Scheme reaction</td><td></td><td>in</td><td>«Ο</td>

<td>m Pi</td><td>about fi</td><td>0 - 0 fi</td><td>5 0 fi</td>

<td>Pi</td><td>F. xz r</td><td> / 0 ^==0</td><td> 0 „1 7</td>

<td>Oi</td><td></td><td></td><td></td>

<td>sJ N Z £</td><td>ul t— ·</td><td> 116</td><td>r *</td>

PL 204 281 B1

<img file="PL204281B1_D0111.tif" />

PL 204 281 B1

<td>NMR data</td><td>ABOUT * CS ł OO O u oi PP «op T 3 Β¹⁰ «3 - hr, ά S. 2 a § g 3- P- s Sat g = j 2.T 3 te ™ bs P 5 £ -fh * '-A en m - ”7 O Λ P- τ en pj ..fi ^ PS ys-2; fi- «η τ p- · Q ° ί B &lt;i p6 riΓ τ 'Γ3 b D t \ - ePr 2 · 3 ® ao p £ ϊ tS A 00 tS PPP 3 W sr AFTER; 'e {5 = Γ B §^— sS - * ^ - βΧ¹ τ Ζ ^ οΧ '^ - ό, χ - · in A b £ "? o · a e3 Jr¹ Br- oo U di-rn - O— - 'Ό</td><td>. S? '“-J oo {Ę 3 β SAS p * »O, -, -ics p &lt;£ ya it - °! -a - E * SOP —k g ^ s · »ŁP-sis g&gt; -. S^N-^sa _z * —-11 - σ 'LB - 2 -r- &lt;5J 01 WQP ^IN Ο-, Q “ł r t- - · '—i β * θ' * ts nr * 'S ucc bo ŁiPcS 3- ^; II '-'s -'- “· ..Of.intn ^ ooo g KJ ici u. r, o, m, - £; S 2. «&gt; * 3 ts - -¹ -7 X ® ¹⁰ c? '? - * C- &lt;- II ϋ- cs - · - 'i</td><td>® ii χη _- °° a- P e- ^ j-oo-oc - ^ ts - ft 23 »Ξ ^ Ρ ^ .ΐχ ilsińsgslg Sg ^ SP £ | _J 2 $ pi ^ ęco β Ώ ~ · - 11 QS Pffl m ó * -, about,? ® - PK śⁿ bye pj “oT cfa 't - a fi ·⁴ * - * r £ * £ sm / -&gt; c r. | . £ »6 n ΰ? &lt;and g- S? r? Cd A 2 · -, ώ £ .4 i φ</td>

<td>+ X + 2</td><td> 489.26</td><td> 433.12</td><td>! - «. v5 Ό TT</td>

<td>Time retention / method</td><td>1.20 min Method A</td><td>1.59 min Method C</td><td>1.49 min Method A</td>

<td>Out- connected mass part.</td><td> 488.19</td><td> 432.16</td><td> 466.00.</td>

<td>Look</td><td>white precipitate</td><td>white precipitate</td><td>&gt; Ί Ό 3 8 X »O</td>

<td>Scheme reaction</td><td>V »</td><td>un</td><td>Ό</td>

<td>ΓΊ and</td><td>about 0</td><td>about 0 X</td><td> AND</td>

<td>Γ-1 and</td><td>about 3 0</td><td>\ with- J. f</td><td>&gt; xz V = Q</td>

<td>θΰ</td><td> and</td><td></td><td> ^~7“</td>

<td>No. Ex.</td><td>CS</td><td>CS CS</td><td> 123</td>

100

PL 204 281 B1

<img file="PL204281B1_D0112.tif" />

PL 204 281 B1

101

<td>NMR data</td><td>'-'EG ® -GE S © 55 T 7? o ©. e-. oo x&gt; E ° r- r ~ li —'o G t to .Ό ZŹ os -r ABOUT ^M. o xx^NM. Ο'σ'Ί i! £ 5 Έ 5? Π a O^-—'4; ϋ © - ® cfOi Ε? ϊ _ * om _e&gt; * - »n ® γα H «.J * E c oq * 2 »r &lt;12.5, © 5 l and 2 «W &lt;aa 'and o os σ&gt; i * ri &lt;CT r? Ό σ</td><td>$ Ia »· s'«_tf§2 A -o .3 * τ a »* and -gw saa χϊΗΟ · ττ m -toST gjii 'g "535' 25 t- «θ II m&gt; S S - II Ό -sS -e £ G ”CM -&gt; '= - ¢ 4-Ol ON Ł »and * OCA ^ Sa®. and ^ rOoJz-K - &lt;NL CA / *% 8 aw a-3 π 43 SASgKSsg-g AND¹ 2S DO «λ II _T m t ' s K *. γ A% EK i rn t- 4 .a τ Ą</td><td>FI hwJ¹ _ P PSStftE '? C- II \ D m1S 2 ^ 5 'C' p XD 11 m e&gt; in 'Tsa a * u? ot D. = fissSS ^ "g ^ t bf N 2, ts x A. JĘ fC te oo Ή, §, * «· S ίΓΛ -o · * «Λ gg -^mG. 1 I &amp; 3®5a5g κχτ '^ s ^? Γ¹ n r- λ -, rr, Aug © II</td>

<td>+ and + 2</td><td> !- 480.25</td><td> 504.25</td><td> 583.40</td>

<td>Time retention / method</td><td>1.34 min Method A</td><td>1.32 min Method A and 1 1</td><td>1.26 min Method A</td>

<td>Out- connected mass part.</td><td> 1 480.07</td><td> 504.1</td><td> 583.2</td>

<td>Look</td><td>white precipitate</td><td>white precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>OO</td><td>DOWN</td><td> 00</td>

<td>and</td><td>5 fi</td><td>ΰ 0 X</td><td>about fi</td>

<td>Cl Pi</td><td>Ό</td><td>'-with</td><td>P. about</td>

<td>and</td><td>hy_</td><td></td><td></td>

<td>kj N £ £</td><td>r- CS</td><td>o. o CS »4</td><td>s</td>

102

PL 204 281 B1

<img file="PL204281B1_D0113.tif" />

PL 204 281 B1

103

<img file="PL204281B1_D0114.tif" />

104

PL 204 281 B1

<img file="PL204281B1_D0115.tif" />

PL 204 281 B1

105

<img file="PL204281B1_D0116.tif" />

106

PL 204 281 B1

<td>NMR data</td><td>wSx - § In n A "j ® A" BA r&gt; C · * * -m Π fi ta E ϋm * Ώ A -En. , χς-τ Eg. g ^ S S. HK t * - X “xf * E —- · Γ“. and SX * a π «^s and ο ^ Ε- ^ ΐ'ΧσΕ -o XA 2 XN tN °? °° Β 'ΐ? · Scoti-B .u · ».43 2 TT r- ~ ćŁS 4J. (N - £&gt; g Ζ * Ί.σιΌ'ϊΓηχχοχ m a- pl ro - (Nr-uii-ifiT-Tt ·· —ιχ</td><td>sS '5 - E *^vol=&gt;^K,oo *ⁿ$’^andX .® 3® n £ 7 45 = ET_υ m r- 3 * Μ b ^H.Q -o -r? - i ° and M &amp; XSJSaińts^S.. N x S 45 ”. A 33 E STTPeEcnS ^ S'S '^,“^,tN,_M.'®X_E.rOl ® sh “u β E =&gt; χ PS χ τ ΐ ox | XEg £ a £ -5 iS. oo · - ΙΛ χζ aw T u &lt;as T</td><td>- &lt;$ CS IX ".77- t®.43_r is nr. · β 43 .. S a ca '' T rl of this θ 'OM -. X 00 cs i &lt;τ '"β« Γ2 7 «3' η.χ ts ΗΠ 3a he? 7 En3 β b O · ΰ 0 - ** - £ Ρ Ό SfnójSL · * © g S gA ^ 5S3; h «®Pa ^ e ^ S®</td>

<td>+ s + s</td><td> 521.31</td><td> 478.22</td><td> 468.25</td>

<td>Time retention / method</td><td>1.27 min Method A</td><td>1.31 min Method A</td><td>1.58 min Method A</td>

<td>Out- connected mass part.</td><td>52L13 and</td><td>478.06 i</td><td> 468.02</td>

<td>Look</td><td>amber- new glassy mass _1</td><td>white precipitate</td><td>White foam</td>

<td>Scheme reaction</td><td>OO</td><td>OO</td><td>oO</td>

<td>Βί</td><td>c fi</td><td>about 0 X</td><td>ABOUT fi</td>

<td>n Bi</td><td>( G.</td><td>Those</td><td>p —2:</td>

<td> 74</td><td></td><td></td><td>$ -y</td>

<td>and ^No* Ex.</td><td>⁸</td><td>and? ł — M</td><td>CS T. and</td>

PL 204 281 B1

107

<td>NMR data</td><td>ae &lt;-? . and - Γ¹³. g S Ń K w UA AU! them -μ o 55 o. 3 ® m. £&gt; '• “' {ZJ Ό - 00 O is3 * »Τ '° TO · jS ii 3 ao © sr g -τκ c ± Σ2. eT A § a £ /..=- £ «a ® a» «-a § 11 K ^ .Ś &amp; m + Ć SUT Ń ro 7 κ X u · o&gt; ki aaaa "and * to" aa</td><td>S) S_- u- ~~ S a .i, &amp; j&gt; "" C; N "mHH c Ul OO - OO _ 2L .-: SC 3 * © 0 «o ® nStitS _i £ ►ί Ά A · £ 't? S n 6. 2 A 2nd tu a § s ® AK ^ STg-rfTfTSN - &lt;S r- Ii X&gt; «£&gt; · -, Ol —J CS m</td><td>9 - i ^ SSi + - .a 2 A ki '-. XX b? ra _f £ UAU ΐ mr r ~ ii 3+ 43 '-'Es 3 S «Tt- es? - e tt jU A Ot κί.“. Ο' - 'ί o' TT a κ ti o. os o Qoo * 't AA O '- 42 b ρΓ rn * -¹ - &lt;42 t ^ ka ^ here. . ' here HSSslig; - aa T Zr Zr £ T «&amp; tr AA&gt;: A £ Ξ- &amp; -; © A</td>

<td>+ and + 2</td><td> 482.24</td><td> 512.25</td><td> 492.21</td>

<td>Time retention / method</td><td>1.28 min. Method A</td><td>1.22 min Method A</td><td>1.31 min Method A</td>

<td>Out- connected mass part.</td><td> 482.05</td><td> 512.07</td><td>s σ \ 3-</td>

<td>Look</td><td>Ό 3&gt; K x&gt; o</td><td>transparent clean glassy mass</td><td>white precipitate</td>

<td>Scheme reaction</td><td> 00</td><td> 00</td><td> 00</td>

<td>P4</td><td>δ fi</td><td>about fi</td><td>0 ' • X</td>

<td>rt Pi</td><td>X about $</td><td>r¹ CX HO</td><td>(fi \</td>

<td> £</td><td>S-y_</td><td></td><td>S-y_</td>

<td>No. Ex.</td><td>m T * A</td><td>• 'J ·</td><td>• About Φ · —-1</td>

108

PL 204 281 B1

<img file="PL204281B1_D0117.tif" />

PL 204 281 B1

109

<img file="PL204281B1_D0118.tif" />

110

PL 204 281 B1

<img file="PL204281B1_D0119.tif" />

PL 204 281 B1

111

<img file="PL204281B1_D0120.tif" />

112

PL 204 281 B1

<td>NMR data</td><td>_m- iLg-Y O - • ΰ -'- ί ϊΛ OT £ B iOi - (2 - g &lt;m r- © © “a 5 -X t ~ - u-&gt; · ΓΠ ° S r- χ F. X bf o o L - S + i S, oo ffl “Ί E5&gt;! TF ® 5 ^ 2 ^ 3- = e £ '-'ii'-' Z ΓΜ PM o oo \ O HH _r \ O “OO CM C2 £ 3&gt; Λ Z</td><td>“= T: K o -X 9 χ. 3 r ~ En r— S * oi, g. Tf 2_N'SH ° s ^ sś °: “b ' χ t-1 '—p ​​2 m' - 'Q 11 -θ' rf oo r- □ Λ «3 ©“ 1 ai r * - i Π t - 3 F 1 KZ 5 B Z -g 2 2 ® 4 x; 2 35 Ό S Ez ^M.- χ E - © rs © © —- Ό - ©</td><td>. 3 “- 3 © 0ó23 £ "« τί r &lt;2.3 3 ^ 3 = 3 ^ In 2x-en »« 3® «Μ-ΠίΧτη ^ -Χ § -ΰ Ή £ «γ« £ S &lt;-χ · Γ * Ul Ό O g Κ X j © X IZ zi; S © χ ~ Uff® Ξ * fS 5 - m 8 °° x§ &lt;sS JlS r? ΪΞ&gt; I] S, O "me" * 5 II -X _J 'r &lt;H Ζ ^ όχΙγπχοοχ Μτ, Τ'-ίΜ'ΟΜ ^ ΜΜ</td>

<td>+ and +</td><td> +</td><td> 478.17</td><td> 496.21</td>

<td>Time retention / method</td><td>1.32 min Method B</td><td>1.53 min Method A</td><td>1.50 min Method A</td>

<td>Out- connected mass part.</td><td> 391.08</td><td> 478.01</td><td> 496.03</td>

<td>Look</td><td>white precipitate</td><td>white precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>1- Method A</td><td>kO</td><td>kO</td>

<td>axis</td><td> 0</td><td>3 fi</td><td>0 fi</td>

<td>rs ού</td><td>X at</td><td>fi X2 \ = O</td><td>\ about $ xz AND</td>

<td></td><td></td><td></td><td></td>

<td>uZ N £ 2</td><td>r- * n</td><td>DOWN in and— &lt;</td><td>Ot un</td>

PL 204 281 B1

113

<td>NMR data</td><td>cn ₁₍ Ό W w, n £ «&gt; 2," A - = T - at - m II UO o U ° s 2 ^ 11 Pi ^ and £ i3si ϋ II t- 33. © ro '-'η * a π Pi “5 7 3 3 Ιη ^ χ ^ Ξ® Z cn "σ \ Ό Ol." X ro a -ć °. n 't 4 a * na 2h c&gt; rs r- * n —i * -i cs m Ći-</td><td>2 ^ 2 "o" 2 4 _oa T co _ »'h I ri S. ^x Ξ and 2 -o £ ί - with—. 2 33 4 ΑΑ'τ ua u, - 2 * ® S ci - os 4 -o ® lls^s4I ^ 2 | -7 · O&gt; - * ku * - »* 9 · sts π- μ * 7 Γ- fS r0 Γ- a ¥ a _B- ai 2 SA - * -&gt; CN -s ^ - CN · -&gt; O&gt; -&gt;</td><td>c? ec £ 4 -oo * Ό ^V'« ι_ΓΌ _ _r O. rs 2 Ś »eSV fs ~ 2ε ^ ®53 £ ε. OS - ± 3 - «- -J5 5 * 0 Ł a X Β Ό S &amp; '- o 4 ”uTn' — S a ^ T¹^ «Γ &amp; ® V r¹ &gt; A \ O 2-r-1 r- O</td>

<td>+ and + 2</td><td>60 CN Vł * n</td><td>CN Axis T.</td><td>ABOUT &gt; o</td>

<td>Time retention / method</td><td>a &lt; '3 5 Ό every 2 m qj s</td><td>- CQ • a sc 5 ό r- «O 'Ώ o -g</td><td>s " g -§ CN o Ό 35 - s</td>

<td>Out- connected mass part.</td><td>in * -r WI &lt;n</td><td>about about about • * T</td><td>1–1 about yy about m</td>

<td>Look</td><td>&gt; »Π3 «P. XO</td><td>&gt;&gt; Ό 5 P. XO,</td><td>&gt; S. £ Έ 3 g OO X</td>

<td>Scheme reaction</td><td>\ D</td><td>AXIS</td><td>Ch</td>

<td>about;</td><td>δ fi</td><td>G. 0</td><td>about 0 X</td>

<td>eł Pi</td><td>in with 12 F.</td><td>0 ZX</td><td>0 ^ z</td>

<td>~ you</td><td></td><td>y</td><td>Fy</td>

<td>ki N £ 2 AND</td><td>ABOUT \about</td><td></td><td>(No. \ABOUT «—1</td>

114

PL 204 281 B1

<td>NMR data</td><td>* r CS Λ&gt; About " . - xm KE PW p- 42-3 A £ 5? H4 uAi§ -A fj p. F- A a FH r \ 1 X CS p- F * H ŁJ oo 2 n 8 pl pi Ξ-Χ &amp; ΞΐΕ 'Τ, -χο cs Sm 4 P- £ χ'.Α 4&gt; | gB ^ 2cs o χ as T 7- Si A “! a'® Λ £ - d -H Sm</td><td>Ξ-tc ffi ^ 2ns P- II S 4! § B i ó II ® 0P * 0.® 07x0 3K a = · τ »* aa 0 eq ® L_N NT Q ιΑ c ^ sl ^ .s-ŚSS-s ίχλ3 7χ ® gE'® £ ξ§ «Ε a? A cs X (S · 3 U - A 5 f rfS χχ0. E 7 g A 3 ES®-2 ^ K Ε'Χ T x.n7-A « -ριη-Α.α22 · - m</td><td>- * 'TT · Γθ ΙΛ λ -.- .'ΐ cs 5 cs ga χ. χ -χ'- -ε ^ εε ^ CO - η ES ® A § cn OA 4B4ÓT 30? About SpE 5 Q if j ^K. 4 »a 4 tf x &lt;A Ad07x3aS 2 A E. 1 »is 2⁰ ”^ 7 xx 0, 2, ° e a'® “7 ^!uS 2- ^¹^ -f | Λ -S Sa ® § τ 3 a £ ® aa “u- -d7- 7 aa 7” - S? P (N r- H £) s_&gt; C&gt; ł-R Μ Ό- O Τ '</td>

<td>+ and + s</td><td>00 f • aa About JL S 2</td><td> 491.24</td><td> 520.32</td>

<td>Time retention / method</td><td>1.50min Method B</td><td>1.31 min Method A</td><td>1.40 min Method A</td>

<td>Out- connected mass part.</td><td>DOWN ° i FR in 'T</td><td>SO ABOUT ABOUT\ T.</td><td> 520.14</td>

<td>1 Look</td><td>white precipitate</td><td>white precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>O&gt;</td><td> 00</td><td> 00</td>

<td>Cl ai</td><td>C. fi</td><td>5 0 fi</td><td>0 0 fi</td>

<td>rj</td><td>° = \ zz ^ 5</td><td>with -with</td><td> 3 \ \</td>

<td>no</td><td></td><td></td><td></td>

<td>UN from £</td><td>m ABOUT</td><td>TT so</td><td>m 0</td>

PL 204 281 B1

115

<td rowspan="4">NMR data</td><td rowspan="4">s en Cp j&gt; eO r * s D and N X about about * 5 * af</td><td rowspan="4">and IN AND and CS • cT •&gt; ~ x m CJ Ie ffl about ooh AND and' CS</td><td colspan="3"></td><td colspan="2" rowspan="3">*about '-'SE »A S3 dp Cl Ό</td><td colspan="3">CS in -</td>

<td rowspan="3">J- tŚX jg B £ j Es »PgBn B-γ ^ P&gt; 3aP §5 = ^ 51 “Ρ'ό'B ® °« AS; « P VO —and it · » and ¹⁰ * L -i tr? Sg sag ¢ 5? »PpTs and AAjpPS</td><td colspan="2">1-5 sts</td><td rowspan="3">CS £? S 5 TUE, 3 es _M.at 7 r- 2h X cs * ~ p ^ ”3 a £ a '^m X3 ^έ·«^£Ρχ _Ώ axis s ^ p lS P ^ P ^ AP® &amp; f B 3 2 oo _. - WITH; || u-a</td><td colspan="2"></td>

<td rowspan="2">Sc and ο- »N tn £ g cn * n T “4 AND ABOUT CS</td><td rowspan="2">STS? cn o _Λ&gt; rs A · “* R ~ £ 2 -ap s? B x " X. ^m</td><td rowspan="2">· —1 1— &lt;\ D s oo Tt · —1 about 60 V — 4 s m about</td><td rowspan="2">3 Ol £ m about about 1 00 about about ffl ł — 4 Sr 2</td>

<td>AT N £ about about -e ffl</td><td>'m Ϊ5 f S. AND af CS</td>

<td> +</td><td></td><td></td><td>The ““ 4</td><td></td><td></td><td></td><td></td><td>ABOUT</td><td></td><td></td>

<td>X</td><td></td><td></td><td>ΓΊ</td><td></td><td></td><td></td><td></td><td>cn</td><td></td><td></td>

<td> +</td><td></td><td></td><td>\ d</td><td></td><td></td><td></td><td></td><td>about</td><td></td><td></td>

<td> 2</td><td></td><td></td><td>about m</td><td></td><td></td><td></td><td></td><td>about in</td><td></td><td></td>

<td rowspan="2">• * 3 W «* o” O Λ X o</td><td></td><td></td><td>g &lt;</td><td></td><td></td><td></td><td></td><td>a &lt;</td><td></td><td></td>

<td></td><td></td><td>'3 kj a P3</td><td></td><td></td><td></td><td></td><td>* 3 S P3</td><td></td><td></td>

<td>Th retei underworld</td><td></td><td></td><td>- about 'TV - 2</td><td></td><td></td><td></td><td></td><td> $ 3 - 2</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>«ΜΤ</td><td></td><td></td>

<td>SU £ 8 E 8</td><td></td><td></td><td>r — 4 \ e&gt; about in</td><td></td><td></td><td></td><td></td><td>\about about in</td><td></td><td></td>

<td>demand</td><td></td><td></td><td>£ Λ 3 NW -2 S</td><td></td><td></td><td></td><td></td><td rowspan="2">E 3 n £ · - 55 κ i</td><td></td><td></td>

<td></td><td></td><td></td><td>! &gt;&gt; »-« NN η * =</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> £</td><td></td><td></td><td>O- vo</td><td></td><td></td><td></td><td></td><td>Ł ^υ 8</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>rt</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>e 'a *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Łł - * -CE</td><td></td><td></td><td>OO</td><td></td><td></td><td></td><td></td><td> 00</td><td></td><td></td>

<td>Uy; * -</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 3</td><td></td><td></td><td></td><td></td><td> 3</td><td></td><td></td>

<td>ΓΊ and</td><td></td><td></td><td>P.</td><td></td><td></td><td></td><td></td><td>P.</td><td></td><td></td>

<td></td><td></td><td></td><td>“Ό</td><td></td><td></td><td></td><td></td><td>Q</td><td></td><td></td>

<td>c * ł</td><td></td><td></td><td> /</td><td></td><td></td><td></td><td></td><td> &gt;</td><td></td><td></td>

<td>Pi</td><td></td><td></td><td> 0?</td><td></td><td></td><td></td><td></td><td>about</td><td></td><td></td>

<td></td><td></td><td></td><td> \</td><td></td><td></td><td></td><td></td><td>c</td><td></td><td></td>

<td>and</td><td colspan="5">x__</td><td colspan="5"></td>

<td>No.</td><td></td><td></td><td> \©</td><td></td><td></td><td></td><td></td><td>Γ</td><td></td><td></td>

<td> 2 £</td><td></td><td></td><td>Ό r— &lt;</td><td></td><td></td><td></td><td></td><td>Ό</td><td></td><td></td>

116

PL 204 281 B1

<img file="PL204281B1_D0121.tif" />

PL 204 281 B1

117

<img file="PL204281B1_D0122.tif" />

118

PL 204 281 B1

<td>NMR data</td><td>£ pH E 2. x2 "P.«? 2 2 · * £ χ 3 ^M. u SB ~ _rf 2 5 ~ 2'θχ⁰’’^- e- A ° rf g Sj-oi? oo S pf E £ „a -t 'II ·? AW _2® r-2 nT .-? · Χ-ί rT -A * 7 r- 2 y; ffi © £&gt; α ® » S oo Ό 3 5 Εχ 6 X ~ S i&gt;. . o &lt;n 2-Ά © Ij-PEin ii £ 2 £ 2 Β γν. Tt σι ie- "r- x _ AH &lt;&gt; »—i f-» fw r * l x- «t — 4 rN</td><td>u · a " x R x E -g &lt;n ^ 2, S 'β ά »a AND and? Ά-χ £ § £ 83 W _ X Χχ S 3 -A a 'Q r and 4S-S ^m £ Bx2 - x © || ^ a | E ®ίί £ ί!</td><td>2 "Tn + B ^ gH * Χιη χΗ s2Ug &lt;* _ t ~ - b "a S 43t '; ° Sj 00 t- &lt;OXAA is. © '-ii EJA. 22 ^ xB S ** '-'o Η ^ ϊ 113 ^ 5 aas - Γ * - * CS -S-</td><td></td><td></td>

<td>+ B + 2</td><td> 437.16</td><td>M + Na 514.95</td><td>M + Na 471.97</td><td> 479.02</td><td>«Ν« A Ż 2&gt; +? S</td>

<td>Time retention / method</td><td>1.52 min Method A</td><td>2.13 min Method D</td><td>1.94 min Method D</td><td>1.86 Method B</td><td>1.82 j Method B</td>

<td>Out- connected mass part.</td><td> 436.92</td><td> 492.11</td><td> 449.12</td><td>ABOUT about\ 00 r- aj-</td><td> 426.90</td>

<td>Look</td><td>white precipitate</td><td>whitish precipitate</td><td>white precipitate</td><td></td><td></td>

<td>Reaction scheme '</td><td></td><td>1- Method A</td><td>1- Method A</td><td>1 - on a solid support</td><td>1 - on a solid support</td>

<td>d Oi</td><td>0 0 X</td><td>AT fi</td><td>about fi</td><td>ABOUT fi</td><td>AT fi</td>

<td>M. Pi</td><td>X about \ = o ABOUT</td><td>n LOAM AT &lt;ę ^</td><td>WITH</td><td>rt Ib ABOUT ABOUT</td><td>= I P.</td>

<td></td><td> - %</td><td> /</td><td>^{? X}° A</td><td>$ ~ y</td><td>S-y_</td>

<td>j No. And Prov.</td><td>m Γ</td><td> 174</td><td> 175</td><td> \1&lt;3</td><td> 177</td>

PL 204 281 B1

119

<td>NMR data</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>+ X + 2</td><td> 496.06</td><td> 413.04</td><td>445.02 M + Na</td><td>T- ed A 2 m + R2</td><td> 414.05</td><td> 423.08</td><td> 467.06</td><td> 505.07</td>

<td>Time retention / method</td><td>L81 Method B</td><td>1.72 Method B</td><td>1.86 Method B</td><td>1.94 Method B</td><td>1.53 Method B</td><td>1.88 Method B</td><td>1.60 Method B</td><td>1.89 Method B</td>

<td>Out- connected mass part.</td><td> 496.00</td><td> 412.90</td><td> 423.00</td><td> 501.10</td><td> 413.90</td><td> 423.00</td><td> 467.00</td><td> 505.00</td>

<td>Look</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Scheme reaction ί</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - Π3 solid support</td><td>1 - standing medium</td>

<td>Qł</td><td>AT fi</td><td>ΰ fi</td><td>fi</td><td>fi</td><td>L&gt; and⁵</td><td>fi</td><td>ABOUT .0</td><td>5 fi</td>

<td>ΓΊ</td><td>α AND ^withT.</td><td>Y</td><td>Y *</td><td> 9</td><td>Y</td><td>Y</td><td>^Ζ0Υ OH</td><td>.fi 9</td>

<td>until</td><td></td><td></td><td>Ύ</td><td></td><td></td><td></td><td></td><td></td>

<td>u Ń Z £</td><td>o. o tM W4</td><td> 179</td><td> 180</td><td>o. o</td><td>CS o. o in &lt;</td><td>m o. o T — 4</td><td>Tf o. o f-4</td><td> 185</td>

120

PL 204 281 B1

<td>NMR data</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>+ s + 2</td><td> 479.02</td><td> 505.06</td><td>O Ch 2 © + pp</td><td> 423.09</td><td> 425.11</td><td> 487.04</td><td>459.05 M + Na</td><td>381.07 M + Na</td>

<td>Time retention / method</td><td>1.84 Method B</td><td>1.93 Method B</td><td>1.80 Method B</td><td>1.89 Method B</td><td>1.92 Method B</td><td>1.91 Method B</td><td>1.95 Method B</td><td>1.67 Method B</td>

<td>Out- connected mass part.</td><td> 478.90</td><td> 505.00</td><td> 429.40</td><td>423.00 and</td><td> 425.00</td><td> 487.00</td><td> 437.00</td><td> 358.90</td>

<td>Look</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Scheme reaction</td><td>1 - on a solid support</td><td>1 - on Permanent medium</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td>

<td>en Pi</td><td>fi</td><td>δ 0</td><td>B 0</td><td>δ 0</td><td>fi</td><td>about fi</td><td> 5 9</td><td>ABOUT fi</td>

<td>Customs Pi</td><td>Y</td><td>Φ</td><td>Cl</td><td>ίίτ</td><td></td><td>9 fi</td><td>ABOUT</td><td> 9</td>

<td>'pi</td><td></td><td></td><td></td><td></td><td>$ —Y</td><td></td><td>Yy</td><td></td>

<td>No. Ex.</td><td>OO</td><td>OO ł — 4</td><td>□ O OO</td><td> 00</td><td>ABOUT Ot »—1</td><td>about</td><td>CS Ol »-K</td><td>m Oi t— +</td>

PL 204 281 B1

121

<td>S. WITH about d rt Q</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>+ WITH + 2</td><td></td><td> 431.04</td><td> 400.98</td><td>443.06 M + Na</td><td>AXIS about about TT</td><td>» σ \ ττ Axis TT</td><td>About G3 r- Ψ £ 3</td><td> 483.04</td>

<td>Time retention / method</td><td>1.86 Method B</td><td>1.75 Method B</td><td>1.65 Method B</td><td>1.82 Method B</td><td>1.64 Method B</td><td>1.95 Method B</td><td>2.05 Method B</td><td>1.72 Method B</td>

<td>Out- connected mass part.</td><td> 473.80</td><td>ABOUT ABOUT rC Tf</td><td>ABOUT rC D \ Ϊ * ΡΠ</td><td> 421.00 ;</td><td>ABOUT about oi r-</td><td> 495.00 ¹</td><td>ABOUT ui SD TT</td><td>ABOUT about r * S o. o Tf</td>

<td>Look</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Scheme reaction</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support J.</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - permanent medium</td>

<td>m 0 &lt;</td><td>AT fi</td><td>AT fi</td><td> 0</td><td>AT fi</td><td>fi</td><td>ABOUT fi</td><td>Q fi</td><td>ABOUT 0 X</td>

<td>M. and</td><td>ffi about</td><td> -4</td><td>about</td><td></td><td> ?</td><td>n li. AT OT about</td><td>χ.</td><td>Bl ε about about about AND</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>No. For,</td><td> 194</td><td> 195</td><td>about □&gt; * —T</td><td> 197</td><td> 198 1</td><td>ABOUT, axis</td><td>d about PM</td><td>5 CM</td>

122

PL 204 281 B1

<td>NMR data</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>+ and + 2</td><td></td><td>Ό rt ό £ “2</td><td></td><td> 431.04</td><td> 409.07</td><td> 463.04</td><td></td><td> 423.10</td><td></td><td> 492.91</td><td>431.04 M + Na</td><td>442.04 M + Na</td>

<td>Time retention / method</td><td></td><td>1.91 Method B</td><td></td><td>1.77 Method B</td><td>1.79 Method B</td><td>1.81 Method B</td><td></td><td>1.86 Method B</td><td></td><td>1.88 Method B</td><td>1.78 Method B</td><td>1.58 Method B</td>

<td>Out- connected mass part.</td><td></td><td> 463.80</td><td></td><td> 430.90</td><td>ABOUT about Oh about -d-</td><td> 462.90</td><td></td><td> 423.00</td><td></td><td> 491.80</td><td> 409.00</td><td>Oh Oh 'Ί *</td>

<td>Look</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Scheme reaction</td><td colspan="2">1 - on a solid support</td><td></td><td>and - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td></td><td>1 - on a solid support</td><td></td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td>

<td>from</td><td></td><td>ABOUT fi</td><td></td><td>AT 0 X</td><td>AT fi</td><td>fi</td><td></td><td>ABOUT 0 X</td><td></td><td>fi</td><td>0 X</td><td>fi</td>

<td>and ΓΝ from</td><td>about.</td><td>γ</td><td>AT</td><td>AT.</td><td>fi</td><td>fi</td><td></td><td></td><td>AT.</td><td>fc. α</td><td>fi</td><td></td>

<td>South</td><td></td><td> &gt;</td><td></td><td> »</td><td></td><td> £—</td><td></td><td> 1</td><td></td><td>~ y.</td><td></td><td> ^0“</td>

<td>and N t Z fi.</td><td></td><td> 202</td><td></td><td> 203</td><td> 204</td><td> 205</td><td></td><td> 206</td><td></td><td> 207</td><td>o. o about</td><td> 209</td>

PL 204 281 B1

123

<td>NMR data</td><td></td><td></td><td></td><td colspan="2"></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CS</td><td>fS</td><td></td><td>r-</td><td>Axis</td><td>Axis "</td><td> ©</td><td>es</td>

<td>B</td><td>°. WITH</td><td>ABOUT</td><td> ©</td><td></td><td> ©</td><td> ©</td><td>UNTIL</td><td> ©</td><td>ł — ł</td>

<td> +</td><td>r * T</td><td>♦ —ł</td><td>cn</td><td></td><td>vi</td><td>AND</td><td>OO · +</td><td></td><td>ΓΑ</td>

<td> 2</td><td> £2</td><td> 48</td><td> 45</td><td></td><td>AND * 3 *</td><td>AND</td><td>pp</td><td>o. o T.</td><td> ©</td>

<td></td><td>ca</td><td>m</td><td>ffl</td><td></td><td>ffi</td><td> 33</td><td>CQ</td><td> 33</td><td>. CQ</td>

<td>· —Ϊ Λ «'ΰ” α 8 = st U 3 y</td><td rowspan="2">1.56 Method 1</td><td>1.87 method</td><td>1.76 method</td><td></td><td>« —T Ό ABOUT -4 O</td><td>1.91 method</td><td>1.82 method</td><td>1.80 method</td><td>1.600 method</td>

<td>e ε</td><td> 2</td><td> 2</td><td></td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td>

<td>• ii S ** &gt; ·, Oc§ pj *</td><td rowspan="2"> 344.90</td><td>ABOUT Axis ©</td><td> 0.90</td><td></td><td> 5.00</td><td> 5.00</td><td> 7.40</td><td> 0.90</td><td>© AXIS rs</td>

<td>£ ΰ E -3</td><td>DOWN</td><td>en</td><td></td><td> 45</td><td>ł — t AND</td><td>T.</td><td>o. o -3-</td><td> ©</td>

<td>Ό,</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>ar</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>o. o</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> £</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Scheme reaction</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>03 c t—¹</td><td>permanent medium</td><td>1 - on a solid support</td><td>-1 1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td>

<td></td><td>ABOUT</td><td>ABOUT</td><td> 5</td><td></td><td>ABOUT</td><td>' about</td><td>ABOUT</td><td> 3</td><td>about</td>

<td> 74</td><td> &lt;5</td><td>d</td><td> &lt;5</td><td></td><td> (5</td><td>about</td><td>about</td><td> &lt;5</td><td>about</td>

<td></td><td></td><td> /=⁷</td><td> )—'</td><td></td><td></td><td></td><td></td><td></td><td> )—</td>

<td></td><td></td><td>fi.</td><td></td><td> 1</td><td>c</td><td>fi</td><td>fi</td><td>fi</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>AND</td><td></td><td></td><td rowspan="2">Y</td>

<td></td><td></td><td>LOAM</td><td></td><td></td><td>a&gt;</td><td>y</td><td></td><td>m</td>

<td></td><td></td><td> 1</td><td>IR Ji-</td><td>E.</td><td>E.</td><td>T.</td><td>about.</td><td>AT.</td><td> /</td>

<td></td><td>II</td><td></td><td>ΤΎ</td><td></td><td>iPr</td><td></td><td>ΊΠ</td><td>yy "</td><td> \</td>

<td>Ti</td><td>WITH</td><td>_QJU</td><td>T.</td><td></td><td>y</td><td>T.</td><td></td><td>jy</td><td></td>

<td></td><td></td><td>about</td><td></td><td></td><td>T.</td><td>ΐί ^ Ί</td><td></td><td> 1</td><td></td>

<td></td><td>τλ.</td><td>at</td><td></td><td></td><td> 1</td><td></td><td></td><td>L.</td><td> /</td>

<td></td><td></td><td> “·</td><td></td><td></td><td></td><td>L0</td><td>TG</td><td>V</td><td> 9</td>

<td> ..... ...,</td><td> ? .</td><td>and_,</td><td>e—.</td><td>and</td><td></td><td>and-.</td><td>Wed-X</td><td>Wed -.</td><td>Ś-V</td>

<td></td><td> ?— \</td><td></td><td>c \</td><td></td><td></td><td>c</td><td></td><td>c \ _</td><td>&lt;T \</td>

<td>those</td><td></td><td></td><td></td><td></td><td></td><td></td><td> /</td><td></td><td> /-</td>

<td>UN</td><td>about</td><td></td><td>CS</td><td></td><td>m</td><td>Tt</td><td>AND</td><td>\about</td><td>F-</td>

<td rowspan="2">from £</td><td></td><td></td><td></td><td></td><td></td><td></td><td>τ — H.</td><td></td><td></td>

<td>cs</td><td>ts</td><td>&lt;N</td><td></td><td>CS</td><td>CS</td><td>CS</td><td>es</td><td>es</td>

124

PL 204 281 B1

<td>NMR data</td><td></td><td></td><td></td><td></td><td> -</td><td></td><td></td>

<td>+ K. + s</td><td>s Tt</td><td> 471.00</td><td> 453.03</td><td>About nj ® 5 c? + 32</td><td> 5 £ 2</td><td>s rS »N Tl-</td><td> 453.05</td>

<td>Time retention / method</td><td>1.78 Method B</td><td>1.78 Method B</td><td>1.75 Method B</td><td>1.85 'Method B</td><td>1.87 Method B</td><td>1.62 Method B</td><td>m «-S 2</td>

<td>Out- connected mass part.</td><td> 429.40</td><td> 1 448.90</td><td> 430.90</td><td> 480.90</td><td> 445.00</td><td> 453.00</td><td> 453.00</td>

<td>Look</td><td></td><td></td><td></td><td> -</td><td></td><td></td><td></td>

<td>Scheme reaction</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td>

<td>en oi</td><td>fi</td><td>fi</td><td>fi</td><td>L&gt; fi</td><td>ABOUT P.</td><td>0 fi</td><td> 5 ,0</td>

<td>ΓΊ AXIS</td><td>AND</td><td>F.</td><td>'fi</td><td>V</td><td>AND</td><td>□ AjO</td><td>yO-⁷¹about</td>

<td>AXIS</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>U ΰ z £</td><td> 218</td><td>ABOUT\ Γ4</td><td>ABOUT tM es</td><td>**** cS es</td><td> -1 222 1</td><td> 223</td><td> 224</td>

PL 204 281 B1

125 α:

Z (U c

all a

<img file="PL204281B1_D0123.tif" />

126

PL 204 281 B1

<td>NMR data</td><td></td><td>&lt;sx S every X xP 2 t «» a - - a oo p A ^N χ ii. - about O _- 2 -5 - in “Sp -0 χ £ ί awp - pg r 2 n »a - d JI o xA a Jl - en about P. R cs R o - 2 »a £ Β» 8ί 3 'E' 1 ® 2222o “(SnArr®''® ie a 7“ eg * a - Χχ Γ * p “&gt; TT R-1 ł—«</td><td>•To me*?* 4 X κ m * pn R 'ΙΛ η X is o =&gt; t. - c 4 -, i 4 o, - .E. ό O - R 5? i / -, A 5w = ?? ® A 3 spal ji -. a Ω τί Ί &lt;- {X 'Ά i »- ace R -P. “P 2-0 O0R®4RX ARX ​​oo - · XX Ib-. · *</td><td></td><td></td><td></td>

<td>+ and + s</td><td>CN CB 07 Z CSC + $ 2</td><td>+ 2 * '—X</td><td>+ u ° M &lt;ri + 00</td><td> 530.99</td><td> 417.07</td><td> 467.06</td>

<td>Time retention / method</td><td>1.78 Method B</td><td>1.91 min Method F</td><td>2.13 min Method F</td><td>1.92 | Method B . and</td><td>1.61 Method B</td><td>1.62 Method B</td>

<td>Out- connected mass part.</td><td> 447.40</td><td> 419.11</td><td> 462.10</td><td> 530.92 !</td><td> 416.93</td><td>ABOUT\ axis about about TT</td>

<td>Look</td><td></td><td>white precipitate</td><td>white precipitate _____ 1</td><td>and white and precipitate</td><td>white precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>1 - on a solid support</td><td>1 - Method A</td><td>1 - Method A</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>1 - on a solid support</td>

<td>□ ί</td><td>ABOUT and⁵</td><td>ABOUT fi</td><td>d</td><td>ABOUT 0 fi</td><td>AT , 0</td><td>ABOUT fi</td>

<td>no Di</td><td>&lt;0 Cl</td><td>g.</td><td>n AT. ABOUT ^ 5</td><td>n rt UU Ύ</td><td>.j</td><td>x about about</td>

<td> «!</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>No. Ex.</td><td> 233</td><td> 234</td><td> 235</td><td>Ό m CN</td><td> 237</td><td>DOWN m ΓΊ</td>

PL 204 281 B1

127

<td>NMR data</td><td></td><td></td><td>_ &lt;—I O ir&gt; oo · ZŁ N k (N _vol csi ki S β "42- 'f' -i K - rt from. ® 7? £? * 7 / ν '43 g 353 A CfT 42-T-^- f Sf Qkii — 53 · £ o - 'cf- A Q -i * A © W “F M ^M. Ή'Ζχ * · '' · ^ 5Γό s'® '</td><td>τίί7 -.45 2--77 - p: CCi '-'►S T 2.5 ro f ”g AND II iX2 ® ® 7? a 5 eó fij ^ -as 4 K 09 ^ 53 'l Ki 2 AS ® 53 Si '⁰ 53 ®'S · ® -r , - © Es x; \ o - o - -e xS 5 from _-4i A tt \ = c -. n "¢ -4, ^ 0 + 40 ^ 7 0 ^ - m * _fc ►. »Om * oo_N i, - ^ And o</td>

<td> + + 2</td><td>oo et With β + SS</td><td> 396.01</td><td> 592.39</td><td> 648.43</td>

<td>Time retention / method</td><td> 1.62</td><td> 1.13</td><td>1.69 min Method A</td><td>1 1.88 min Method A</td>

<td>Out- connected mass part.</td><td> 379.13</td><td> 395.91</td><td> 592.29</td><td> cont AT YO</td>

<td>Look</td><td>white precipitate</td><td>white precipitate</td><td>amber- new glassy mass</td><td>1 amber- new glassy mass</td>

<td>Scheme reaction</td><td>1 - on a solid support</td><td>1 - on a solid support</td><td>OO</td><td> »</td>

<td>South</td><td>ABOUT fi</td><td>AT fi</td><td>0 X</td><td>fi</td>

<td>CJ Pi</td><td>X</td><td>fi</td><td>0-Z \</td><td>&gt; \ y X,) 0</td>

<td>ei</td><td>$ ~ y</td><td>alive.</td><td></td><td>alive</td>

<td>uyz £</td><td> 239</td><td> 240</td><td>1 — Vol 3.</td><td> ! 242</td>

128

PL 204 281 B1

<img file="PL204281B1_D0124.tif" />

PL 204 281 B1

129

<img file="PL204281B1_D0125.tif" />

130

PL 204 281 B1

<td>NMR data</td><td>X. AE cr. E. ! 3 Π 'S and Ξ - 0 £ * £ fc-E 7 * £ Ito ^M. B x fi δ © 1- EH £ P £ ay © η «η 2-2 jl f- i. £ x = x3§ ~; -Ss | ^ | ~ 5 £ 25? 2 5 ° ~ O t. - * » «X -z, .T:" ^ "S« * » ®Α ^ 2 £ ® £ ®</td><td>XX © 4&gt; c? «N X S Js ^ χ “Ξ ~ Ξ · £ 5 xC '^,_' ^volN'7'SiE Ό ffi * E 2. ΪΪ^s§ ffi E. ^v s © ^ © E -42.43 - 'oA a? ® - ΓΧ hT \ d -o A w * x ΰ Ώ -m S '-Ol -Ś® § e T ^^ b'— s? 2 “- '- cm »- θ '_T" o Μ 1 E ~ l2 s ffi G Η Λ N 'ώ &lt;&gt; · £&gt; * - &lt;3-</td><td>r- OAS - A x t 'S ll. n 5 ® p £ toPiprAA ^ SCTA 5? χϊ »'\ -E -— ® E i-; fi | t »B - £ -7 ff? §1? Κ Β'ΕχΑ 2 «en cm cm xu ό m *“ f H Aoah? 3eihp_sU «5 g * 1 2 ~ fi g U χΗ ^ ΠΕτχ ga“ pi75ⁿ.S? « Ι ^ ΡηΛ — τ® ξ B s. -⁰⁵ . Μ N Μ X. a ^ BA ^ annołEB - 4P- CN fN B- - Ν 'πΊ - - m</td>

<td>+ and + s</td><td> 479.02</td><td> 474.2</td><td> 479.07</td>

<td>Time retention / method</td><td>1.18nun Method B</td><td>1.92min Method B</td><td>2.01 min Method B</td>

<td>Out- connected mass part.</td><td> 479.05</td><td>and 474.03</td><td>and 482.00</td>

<td>Look</td><td>. yellow precipitate</td><td>beige precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>CM</td><td>CM</td><td>&lt;O</td>

<td>Id</td><td>δ P.</td><td>ABOUT fi</td><td>ϋ fi</td>

<td>C4</td><td>d</td><td>&lt;r ^</td><td>\ about / -with \ = o (/</td>

<td>ói</td><td></td><td></td><td></td>

<td>No. Ex.</td><td>CN 'fl- is</td><td> 250</td><td> 251</td>

PL 204 281 B1

131

<td>NMR data</td><td>"A" Ί j-τ " - OS ό s5 d? · —Ś ef® 3 | -iP &lt;SH c rs ffl ^1-1 opa_j ΙΞ ®Ρχ3 «ζ-οί p = O pT 1 ^ 0 er-ss ^ Ssśjis . ih p * · 5 = 3 ΡΞ. 0 0 11 · * p&gt; τ— '. ęn | as eP-3 | ifiog Sf 7®P.§7® a »? AAA r &lt;&amp; 6A «£ 4 - A</td><td>what M ht 0. &lt;? §Ϊ3 &lt;· 8 ^S..2S_-2 ^ = .- 0-7 s 5:. P here A S 0 8 χ4 E s £ P r- 9.3-K 3 WHAT Zr Up -. t * a N 43 00⁰ en υΡΐ'ί .'- 'Ήν-ΐ'ϊ-ρ' '-¹ t 8 £ 22A AZ} “a £ ó | T a B'3 5 A fi A 00 - _ =, -ρ'Ρν p&gt; es a 3 T .2 A ® Γ4 V'Ί T rm A o &lt;&lt;s- A - &lt;- A</td><td>0 Lł ζ μ · P 7 β-χ a ee S ^ -Sisplj wo \ i? - ~ 0 0 &lt;|| »X ~ £ 2α^ξ s-ssb £ Ze 2? 3f Zi SS ω 2.aa e.2 5? ^ j Q "i ©" Β 'ί · H U! 0 P · τί ® - n Χ-Α 7 '-' T 67 °! B 3 ej w A £ 3 ό 53&gt; n -^m 57 2 £ * 3 O s? ° and A 3 ZSS _-X u-&gt; p— ra »* 'B_!gP7 3s nf - &lt;&gt; WW «-Μ —i Z&gt; OA</td>

<td>ΐα 4- 2</td><td> 467.2</td><td> 481.2</td><td> 439.05</td>

<td>Time retention / method</td><td>1.92 min Method A</td><td>1.81 min Method A</td><td>1.20 Method B</td>

<td>Out- connected mass part.</td><td>00 0 SD ABOUT TT</td><td>481.01 and AND</td><td> 438.98</td>

<td>Look</td><td>white precipitate</td><td>white precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>1- Method A</td><td>1- Method A</td><td> 0</td>

<td>«* • 1 and</td><td>δ 0 Ά</td><td>0 . 0 X</td><td>5 P.</td>

<td>PI Bi</td><td>ω τ</td><td>ω 0 0 L&gt;. 0Λ s</td><td></td>

<td>and</td><td>ί-η, _</td><td>$ ~ y ~</td><td>^and&gt; </td>

<td>«- * N Z £</td><td> 252</td><td> 253</td><td>• e «4Π CS</td>

132

PL 204 281 B1

<img file="PL204281B1_D0126.tif" />

PL 204 281 B1

133

<img file="PL204281B1_D0127.tif" />

134

PL 204 281 B1

<td rowspan="2">□ i 3 WITH &lt;u c THIS Q</td><td rowspan="2">m S. this about about IN) Ł fn ABOUT 8 eS «</td><td rowspan="2">ABOUT WHAT 1! IN TT -σ S_x CN • X Oh from n and* CN •about</td><td rowspan="2">S? 50 * r- © Vl from B and CN TD on * r</td><td rowspan="2">6.52 &lt;s, 1H), 4.45 (s, 1H), 4.16 (dd, 1H, J = 5.2,9.8), 4.12 (d, 1H, J =</td><td rowspan="2">* 5 h tA **&gt; 00 O ł_J · ł-i Χί-β R tt -σ " * - * '^ F- * £ 3 II g E- X^N. ro o. Ξ . ł — 1 TO Ό ** ^ 2 CN RU ę * c? «* 9 ** 'f</td><td rowspan="2">n? . “&lt; II and" Axis ABOUT £ CT) J3 about about CN</td><td rowspan="2">£ s © 1 IN) l · - © and m E. &lt;n rn * T. ABOUT</td><td rowspan="2">S. o. o x about χ-ΐ. Γ * s © ΓΙ and m * © ^ j- r- © S?</td><td rowspan="2">r ~ X 11 s and" m</td><td rowspan="2">m c \ What 'ν' © about V) —1 □ 8 and</td><td rowspan="2">r— axis cont Π and¹fN -about s- ^ · CN wi r- ' sq from 13 &gt; » and CN</td><td rowspan="2">© · * -. OS —Γ · ws t Os 2 © «A ro u“ r ~ .a. li cn A ^ TS-. a ^^ 5 ^ 5 (N Ό -a- a 2, η Ξ ^ £ ζ-8 cU - * »o £&gt; - Xsc + -2 a ii S- ag &lt;c In 4, o, ύ aa cn w&gt; w »_ · —r * 4 OS n ** ^ · 4 IA rU d A2- 11 S- -</td><td rowspan="2">2.92 (m, 2H), 1.80-2.00 (m, 3H), 1.67 (d, 1H, 7 = 13), 1.05-1.40 (m,</td><td colspan="2">and cn Ό in - ' 5 o ® sS</td>

<td>and © o. o about' 1 IN) ©</td><td>H- &lt; HM m ό " N_ o. o SD © P. d II</td>

<td></td><td></td><td></td><td></td><td></td><td>m</td><td></td><td></td><td></td><td></td><td></td><td></td><td>* y</td><td></td><td></td><td></td>

<td>and</td><td></td><td></td><td></td><td></td><td>CN</td><td></td><td></td><td></td><td></td><td></td><td></td><td>CN</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>Axis</td><td></td><td></td><td></td><td></td><td></td><td></td><td>wi</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>00 wi</td><td></td><td></td><td></td><td></td><td></td><td></td><td>in&gt; Ό</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>q &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td>a &lt;</td><td></td><td></td><td></td>

<td>«'5” ane 2 d 3 a 52 E.</td><td></td><td></td><td></td><td></td><td>G T3 by 2 OS u - 2</td><td></td><td></td><td></td><td></td><td></td><td></td><td>9 This C -3 so o OO . 4) - 2</td><td></td><td></td><td></td>

<td>and 2 «J</td><td></td><td></td><td></td><td></td><td>OO</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>&gt;&gt; O ce S *</td><td></td><td></td><td></td><td></td><td>from</td><td></td><td></td><td></td><td></td><td></td><td></td><td>'T</td><td></td><td></td><td></td>

<td>£ ds 8</td><td></td><td></td><td></td><td></td><td>00 wi</td><td></td><td></td><td></td><td></td><td></td><td></td><td>* n wi</td><td></td><td></td><td></td>

<td> *3</td><td></td><td></td><td></td><td></td><td>&gt; \ * c .2 "</td><td></td><td></td><td></td><td></td><td></td><td></td><td>2? ^ TO £</td><td></td><td></td><td></td>

<td> £</td><td></td><td></td><td></td><td></td><td>X o</td><td></td><td></td><td></td><td></td><td></td><td></td><td>X o</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>THIS ' -</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>E 'σ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>δ -M - = 2</td><td></td><td></td><td></td><td></td><td>r ~</td><td></td><td></td><td></td><td></td><td></td><td></td><td>r-</td><td></td><td></td><td></td>

<td>at 52 V&gt; *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>about</td><td></td><td></td><td></td><td></td><td></td><td></td><td>G.</td><td></td><td></td><td></td>

<td> 1*1</td><td></td><td></td><td></td><td></td><td>&lt;H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>PS</td><td></td><td></td><td></td><td></td><td>IN</td><td></td><td></td><td></td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td colspan="2">X</td><td></td><td></td><td></td><td></td><td></td><td></td><td>• K</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>U- u.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Q</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td colspan="3">^ŁV.</td><td></td><td></td><td></td><td></td><td></td><td></td><td>H.</td><td></td><td></td><td></td>

<td rowspan="2">&lt;N PS</td><td></td><td></td><td></td><td>V</td><td>2X</td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">M. zx o = ^ about</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td colspan="2">ο = ς</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>rJT-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>PS</td><td colspan="9">iy</td><td colspan="6">Hy</td>

<td>CN</td><td></td><td></td><td></td><td></td><td>about</td><td></td><td></td><td></td><td></td><td></td><td></td><td>_r</td><td></td><td></td><td></td>

<td>from £</td><td></td><td></td><td></td><td></td><td>SO CN</td><td></td><td></td><td></td><td></td><td></td><td></td><td>\about CN</td><td></td><td></td><td></td>

PL 204 281 B1

135

<img file="PL204281B1_D0128.tif" />

136

PL 204 281 B1

<img file="PL204281B1_D0129.tif" />

PL 204 281 B1

137

<img file="PL204281B1_D0130.tif" />

138

PL 204 281 B1

<td>NMR data</td><td>Jfffi © ΓΝ 'XN r o. o. Ά · Γ&gt; ^ &lt;O θ ' «- T3“ 2§ffiffi- © 3ti ffiT o 2 2ffi ir- ^ TS Q Ό C-. ^H. 'About VI fi -J «S 3 -ffi x 3J- a ffi 27« 2 · « gs? ω a η T £ -o ΣΗ w</td><td>τ T? ". * ►τΊ M 'κ _T © 03 -— Μ S. what T 2, ^ - 52 n © «ffi AND 75 ffi C? © .5 S X3 u E3 r ~ S 2 2 ri ffi oo -I ffi -or? - 2 ffi χ © = Ί ffi * 3-ffi £ ffi3 £ ffi2 n!? S 3^M. ^ ° - © £ 3 ffi - II m ffi Pj 7 rś * 2S 5 -3- &lt;a '«^ ST^N.ST 1ASg®® © ^ -ga ffi η Y u- «ffi γ</td><td>r-. © -M ffi iu M # Ξ X ^rt ·. Ί pC · «, &lt;N. * * 7 P -¹⁰ ffi ⁰⁴ _r m p CS ffi «and ffi fi- ffi -ffi ό - ffi -σ χ 2 -o - ^ ii - = r, x © Τ 'E ffi T 7 Ot' — Κχόο — ιο II ΓΟ © «- &lt;ffi« x _ί 2 jx »3 ° i '' i ffi ffi U ffi Y b 2. ^ c— - 'm d TT fsj J * —- * &lt;. | · ^ 3ΐ ^ Ci J— ni - "JX ffi \ D 2 ffi" 5 ffiOi ffi 3-o 2 η - ffi ". ffi © «χ ffi -a °° ·. Y x ® Ή lr ffi— · »II ffi -. —And ό</td>

<td>+ ffi + 2</td><td> 482.18</td><td> 523.40</td><td> 437.13</td>

<td>Time retention / method</td><td>1.31 min Method A</td><td>1.30 min Method A</td><td>1.43 min Method B</td>

<td>Out- connected mass part.</td><td> 482.05</td><td>m cm * n</td><td>\ABOUT about\ kO m • * r</td>

<td>Look</td><td>transparent clean glassy mass</td><td>white precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td> 00</td><td>ABOUT\</td><td>ABOUT ł- “ł</td>

<td>ΓΠ those</td><td>fi</td><td>at 0 X</td><td>□ fi</td>

<td>«Ν those</td><td>\ about { and zz d</td><td>&lt;AĄry 0 ' 1</td><td>y = o 0 /</td>

<td>Βί</td><td>^ -y</td><td>Sy_</td><td>$ -y</td>

<td>UN from £</td><td> 271</td><td> 272</td><td>m CM</td>

PL 204 281 B1

139

<img file="PL204281B1_D0131.tif" />

140

PL 204 281 B1

<td>NMR data</td><td>si ' 8 "ifAęf co and II £ 5 SO ΐ ¢ 0 ώ AA -c * 7 O aO - 1-ł Ό O - £ -SOo-oJlfcC- ^ SriSZ □ IΎ. »© - Y“ Α3®® · = £ 92 ^ - Ο, Κ cd «'“' m * _Β · » N S-ΓΠ N. • r JS jY ą a AO © S fc. Bf S_sρί “Χ ^ * ^&gt;? 3 · --§ f STols ^ - ^ B« &amp; £ a σζ-Τ g '«a £</td><td>&lt;95 - i®Zo E "ts" · χ _ χ *&gt; j "5_-: D 1-1 7¹ F- K r_ oo σι \ Ξ »''“ ii ^ r- 5βϊ T rs PG yi * \ s® A □ r- ⁰⁰ - "· 'A ® -¹ · ££ —Γ G - II. -SB da · ^. 'ίίχ? - ™ 2 S-Ss Z »IM _ Dl» s ΓΟ » Ł_. Ł- • «^ ι — Μ-ΙΟί-.ΓΓί'ΰ ®ĆS'e5 ri5- ©</td><td>* -5 © * JF Ό £ 2 vo * fh SJ Ρβό c? . --Tf G f · * * θ '© —r. S? O 'żS 2Λ “Υ_Ξ“®ο $« 7? "N. 12.. Ί i-. S h £ © ST ° e SX _-W η o '' o X * © 5 II H g ​​- a 5 © βϊ * ·. · —1 1—4 FQ Al __T l IU CS *. *. a® ^ -42 © o ric * Tr_-R - »Z: '' 'x W · pci S? «. &gt; _4 About © □ &lt;Y Ό '' r-Γ O * ° O II Υ ^ 5ξ £ 5ορ _&gt; os © n nj © o ό g κ «2” s χΞ · S i $ ^M. CS -r ~ ° * i ⁰⁵ r &lt;«ra © L X x ffl S 33 EE - G II c Cr¹ - ρη</td>

<td>+ and + 2</td><td>m A τ — d AND</td><td>8 οί © AND</td><td>F. © AXIS T. AND</td>

<td>Time retention / method</td><td>1.47 min Method A</td><td>2.44 min Method C</td><td>2.76 min Method C</td>

<td>- 3 e c3 8 * £ S £ ΰ</td><td>ABOUT © AND A,</td><td>\about © jy © AND</td><td>2 oi ** AND</td>

<td>CU) £</td><td>beige foam</td><td> -4? .3 8 X) o</td><td>⁷³.5 this XO -</td>

<td>Scheme reaction</td><td>Ch</td><td>r-</td><td>F ~</td>

<td>Λ K.</td><td>ABOUT 0 Y</td><td>5 fi</td><td>fi</td>

<td>as</td><td>about h</td><td>Y P.</td><td>Y Y</td>

<td>~ ai</td><td></td><td>Y-</td><td></td>

<td>U Ń Z £</td><td>r * ·. f- CS</td><td>What r * rs</td><td>Axis Γ- CS</td>

PL 204 281 B1

141

Time

<img file="PL204281B1_D0132.tif" />

142

PL 204 281 B1

<img file="PL204281B1_D0133.tif" />

PL 204 281 B1

143

<td>NMR data</td><td>«E * r R OO -E ± K g x 2; s; - = igS-2 £ 1 T3 £ ² £ E S ^ .d "R En £ £ S? E &lt;£ ^_g'2 yoi «η. . βο_about· 8 ”χΖΈ2ιι ® ?? 2 u E 'R—' -'JL * n -e; -, ZP m .p 'ρ ko ^ 5 U— «Ό LX -Λ" Ζ p rn Xtr óxB Ć / l · 'wt - Ć' ^ n</td><td>[£ &lt;11 - v, r SS x ^ -2. uarp j. t- pp J 'p &lt;3 &lt;»* 00 Γ * -, -T 'p, ca «-Γ CM —r Ό_Λ -_r Ό B -p —i _ u Ss ^ 'ER A - £? * “&gt; A tn -Ί λο a-Ε 0 5 d 0 4 -rt 3 ® § Rp &lt;d χΛ. bottom - S? i. J *. v5- -rf a -da v&gt; »n -a «PeoaRRinpO U pil x» i&gt; E ~ A 6 ”« * £ x K ae; ii K 55 &lt;Ώ _ »tn * j u- CN OO nH tJ- · W '* CS * ”r 7 2 a S «2S0 ^ .a" E &lt;e.g. Xc * τι o "- Η • π cw -&gt; to TF - 'sS- m</td><td>2 &amp; -a -, 44 * e.g. A ^ 2 ^ “d“ S⁰⁰ pm 2A from ®? x “£«&gt; ® tAę £ Ai ηp d ffl ⁰⁰ e&gt;^M. ρ by 4 5 Π Buijrfi g ^ ru 5 aa - • η K Ό »·. 55 Jp P 25 2K B - r? -Ό a - R 2-0. y 2d - £ o^sp O - - * a. x yr p O £ 2 ni-§ td BZ p * ° W, p tq -R -'RT c; n g004 = SSx4 § £ - ^^ - Se * From CN Λλ ⁰³ ΥΊ y- &lt;m K χΕΕ ^^ Ε gd</td>

<td>ΐΰ s</td><td>sp r-4 V » m</td><td>SP cn »N • e</td><td>m ts ΓΠ axis</td>

<td>Time retention / method</td><td>Β ^&lt;B 3 Ό 2 mo ES</td><td>a &lt; '3 Π O -. o = *? about - s</td><td> 3 &lt; □ ^rtS Ό tri O CS - s</td>

<td>-Λ «« about S3 CS ' £ se ΰ</td><td>1— * *about TT in</td><td>X about H. V) TT</td><td>r- about H.</td>

<td>Sat £</td><td>η T3 3 g XO</td><td>i&gt; -! ^ 3 .'as °</td><td>.a S. X o</td>

<td>Scheme reaction</td><td>r-</td><td>rq + * d</td><td>v--</td>

<td>and R¹</td><td>about fi</td><td>t? 0 fi</td><td>δ -0</td>

<td>PJ oi</td><td>fi P.</td><td>\ 1 = ) about about</td><td>P.</td>

<td>Bi</td><td></td><td> /</td><td></td>

<td>* 7 Ń Z £</td><td>about in ΓΜ</td><td>Γρ 00 CM</td><td>0O 00 Ρ</td>

144

PL 204 281 B1

<img file="PL204281B1_D0134.tif" />

PL 204 281 B1

145

<img file="PL204281B1_D0135.tif" />

146

PL 204 281 B1

<td>NMR data</td><td>this i— A -i · A 33 S kjTS ^ .ss-f 2to 3; \ o tn ®^1-1A Λ BJ -O t- o - «35» 5 “I ^ = 33 ItEfitii g ». 5 - 2 * * - af-SlSA ^ S</td><td>0, - -? · Ύ ££ 5 "a 33 0 ffl 8 n 8 jj.^N U u £; c ri m 2 2to η je 11 '-'osia ^ 2ίΰ2 »Ί- i« x every 33 'To- Χο-: £ .-. M- ^ Oi-otU ^^ g 0-0 ^ 2 -a: S 5 c? «S. ^m ”Ϊ g-iS-SS '* iS® StoJOgSffiOi-ioS 33 A „-AlfAtoKAf - Jl &amp; h-&gt; MA ΓΑ CM C&gt; * -s</td><td>3 S? "-To - S ~ - 2 'n^-1 oi 2 e η Βτ? §43-β · 77 · ^ “A $ -gw 2ui 0 m 2-ς § »ło CjU U P | -os5i ^ Xe -sM ^ Sg - ^^ gA § τ ”x Μ®” p ϊ then r - ^ - 1 a_r N-th n -χυΈ-Αχ '* “-ŚS ^rt about^H. 0 £ ⁰ST? - - -ot U “7 A ® 5Ϊ ua- ~ SR 2 A ® A aaw - || .St — Ό—&gt; Mi -.- «Kimm</td>

<td>£ page + s</td><td> 558.10</td><td> 508.07</td><td> 524.09</td>

<td>Time retention / method</td><td>1.62 min Method E</td><td>1.49 min Method E</td><td>1.46 min Method E</td>

<td>Out- connected mass part.</td><td> 558.14 1</td><td> 508.08</td><td> 524.08</td>

<td>Look</td><td>white Powder</td><td>white and powder</td><td>whitish precipitate</td>

<td>Scheme reaction</td><td></td><td> -</td><td></td>

<td>cont</td><td>ϋ 0 X</td><td>0 Behind X</td><td>0 x ^</td>

<td>South</td><td>&lt;Ł £</td><td>^rAbout "x</td><td>about</td>

<td>* cont</td><td>? -y</td><td></td><td></td>

<td>£ Ś With Oh</td><td>* n CN CN</td><td> 296</td><td> 297</td>

PL 204 281 B1

147

Scheme

<img file="PL204281B1_D0136.tif" />

148

PL 204 281 B1

<img file="PL204281B1_D0137.tif" />

PL 204 281 B1

149

<td>NMR data</td><td>§5 £ J35J 2 gaf® 8 ua £ ® 7Sf = _E.-3- gp®3 T-oS ^ apgpg S. ^^ 3 ^ 3 ^ 7? * -¹ —R ό oo 'μ γί p- §0i | i®5 ^ _&gt; r— And r? a ό. r J3 s &lt;*&gt; m 3 Χ-Κ oTPmS ^ ^c -ae -a śa'K3 Z "cs - oo. '2χ · Γ TT in rs H? -, - Τ'ΙΒνΤΚ'ΠΊ ^ A ^ .SA \ d SAA ^ S-ł - to</td><td>/ -X. about * " &lt;N fP T3 and l »fP? what X a - ii ub * p »“ »Ś^N.ę? s a S τ3 EE u&gt; c cn m 0 irj up —J * c 0 “r ^ S? j · ** ° Ό - c ·. _ś ^ £ -e £ ™ ® gs? Ss? ®A δ-Γ3 £ 20® Ś-Z JS γί ui 0 r * a ^ 3 «3 B and 0 a ® - 0 1 — I 4-l -RH 0</td><td>? pp " «« «Ο, II^r5 j. ”ci _x7 2! 0 = ppó æs g bye 0 c? s * g ts &lt;τ cn a p3. S · Π ci Ć ^M.. ΐ¹ 'C' P 0 s- * ab ® cc a 0 - o - 0 m ts —i ^m 'S «sr&gt; lA ζ-ζ g .p cs u η κ in E Q 2 ^s t Ξ 0 κ » u " _μ-ό τ as— ap a s- ρί &lt;N _aboutand ^j . ^ ς ^_π'\ = · © 1β2, ρε £ ρ&gt; ο With fN r ^ cn y-ι £ j a-ri ^ T a η τ -5 - About and © || About me 00</td>

<td>+ and S</td><td>about rn © \ TT</td><td>Ό m c * 3 this</td><td>Axis ABOUT r- ^ 06 -</td>

<td>ril</td><td>cc f * - Λ ' tn td rn o * - * Tj&gt; 2</td><td>p &lt; '3 cd Η Ό a " 0 ~ 2</td><td>B &lt; * 3 &lt;0 £ Ό. σ&gt; 2 -a- ii - 2</td>

<td>&gt;, § s &amp; £ ΰ E 3</td><td>t * - about rn c? x v</td><td>m tr&gt;</td><td>r- 00 tT</td>

<td>Look</td><td>2 - ° 2 C (Λ = o Ui X</td><td>X? 3 .s S j = O</td><td> &gt;&gt; ⁷³.5 5 x&gt; O</td>

<td>re £ v * here χ rt op &amp; c * -</td><td>about</td><td>h-</td><td>P ~</td>

<td>TeJ</td><td>about P.</td><td>P '</td><td>0 P.</td>

<td>CS and</td><td>ΛΡ p</td><td>$ 0 .. P</td><td>vol P.</td>

<td>and</td><td>WITH-.</td><td> ^0_.</td><td></td>

<td>* fc- N Z £</td><td>Tf ABOUT m</td><td>ŁQ ABOUT</td><td>VO α m</td>

150

PL 204 281 B1

<td>NMR data</td><td>►t * en ti &amp; a &lt;n &lt;n jg -, a rd Ί oo »£ ^mN j- ⁿ XS kf a A χ. . ® ffl .A _B S? 4i a * X »2 ° 42." fi £ oa «= 'rs A £ A x £ - A a ^ Ms ^ soo - § - ° a pi tM V eTt-Γ- § ± νη -σ Λ M cs δ 6 ό 2 * νΧ 'Ο ~ -Γ Ν Ρ * S ΐ. ®? Ε Ε AA Α r-¹ Α Χτ 42 -— &lt;- β</td><td>• fl XI WA 2? X - p ^ r- i ° iaa £ X Ex^M. «'O * CM JM ł — H _T -. Sgjf§^E... ££ = · 31? S? JS§ $ gy ^Λ ~ 02 a - A am 33 oi -fES 'SEcNrtrNrnaES gS3 £ ® £ ~ 2 2. °° T - rd ° ł W gEH^J.x “.00 Ρ = 3 ·? 5Η ? SsX35ji§X</td><td>00 Nov _- &lt;£ NA 5 c -i ^ r- ~ Tt A '-'Ci' Ώ x X Μ w 3 5? N £ x A Ol “EeK2 £ H ©⁶⁰ A fi A - Β oo χ JX2A &lt;Suś U * 0j in "o HS in K_ο . at&gt; χ^M. A Ε BA «śiiSH ρ x fi cs a © c - '» -' ?? ? SdP-.5 ^ K XxA - -w A S "CN Ml". X _ fi £ · »A 3 ε s ε e - ł— 'x-&gt; * -&gt; Ό&gt; · _- · · ~ _χ to m</td>

<td>+ K. + 2</td><td> 444.04</td><td> 495.14</td><td> 535.29</td>

<td>Time retention / method</td><td>1.28 min Method Β</td><td>1.31 inin Method A</td><td>1.34 ruins Method A 1</td>

<td>Out- connected mass part.</td><td> 444.03</td><td> 495.04</td><td> 535.11</td>

<td>Look</td><td>transparent clear Oil</td><td>beige foam</td><td>beige foam</td>

<td>Scheme reaction</td><td>1- Method A</td><td>en cm</td><td>en CM</td>

<td>d Pfi</td><td>0 0 X.</td><td>σ fi</td><td>ABOUT 0 X.</td>

<td>n Those</td><td>\. with- .0</td><td>—Fi Ή ZI 0</td><td>ABOUT —With o M ' zx 0 \.</td>

<td>P4</td><td>d</td><td></td><td></td>

<td>No. Ex.</td><td> 307</td><td>What about en</td><td> 309</td>

PL 204 281 B1

151

<img file="PL204281B1_D0138.tif" />

152

PL 204 281 B1

<img file="PL204281B1_D0139.tif" />

PL 204 281 B1

153

<img file="PL204281B1_D0140.tif" />

154

PL 204 281 B1

<img file="PL204281B1_D0141.tif" />

PL 204 281 B1

155

<img file="PL204281B1_D0142.tif" />

156

PL 204 281 B1

<img file="PL204281B1_D0143.tif" />

PL 204 281 B1

157

<img file="PL204281B1_D0144.tif" />

158

PL 204 281 B1

<td>NMR data</td><td>-and.-. in 3 " O · * Ό -JS S CC ffi ·, - irr^Q 4 " W ^ °°^and&lt;4d ^ 2 i ' g 2-f 4 a ® a 2-f S g- - - hey Λ ^N rm -e _- 2 r'S ^^: SS-</td><td>&lt;N ~ X i r - m _rX ^ 2 &lt;© τ ® 3 τ ® S «- -a \ s · '-re ó ES Κ '—'ΣΣ -OB 2 ^M. 2 ™ c- -^Q Ss? 2 e tJ M S- &lt;»T. '⁵iSąa ^ p 4 ^ 0 -. and © * · &lt;Ą K u * -. oo wf _S ii ® ® ? ό x &lt;j ε ε ZW m - oo tn is Β X Ά f »1 n ir¹ ci- p- ιϋ, - «a- -» j- -rt -</td><td>ABOUT £ α £ γ · 3 ^ £ About 2-4 WOO? ΓQ T5 «-&gt; a -; -; x4r-: «aa J2 X r, _S MM, AT! \ 1 * t θ '/ “S § 4.3.3 ο »s-, + 5 s &lt;ce Ό w 'f · - ^ Εί^Λ.! η * · - ~ Ξ? 3 and £ 2 £ - 3 p X CN CN HM&gt; | WS hM _P X - ίο C ® SLpi Su</td><td>g - - &lt;Ό t— - O r— P - it r? aa - oo “oo S ME'ś-i ° H S es ™ on O 5 73 Ή N- “-l .St 4 φ ^ - this “S &lt;o S r- oo - from a Ξ ^ Λ ”ΒΪΕ. ®4 £ =&gt; 44 ^ £ SiSBgSs 5 "· · 3 χ &lt;x E From «NXN&gt; ΧΌ τ -X n“ ”E and¹³ SiU Λ 4 4 RX</td>

<td>+ and + 2</td><td>+ , b ° 1 '</td><td>«Ot ah</td><td>4 * c? © Ż Os ± ⁰⁰ 2 * &amp;</td><td>+ gs</td>

<td>Retention time / method</td><td>1.58 Method G.</td><td>1.43 Method G.</td><td>1.72 Method G.</td><td>1.54 Method G.</td>

<td>Out- connected mass part.</td><td>7— &lt; © r- THIS</td><td>OO * about cn CN &lt;</td><td>r- © X X</td><td>ABOUT\ © X ΙΛ</td>

<td>Look</td><td>&gt; 7- Ό 3 2? X o</td><td>&gt; 7 -a .2 " Xi o</td><td>3 8 XI O</td><td>&gt; Λ Ό © TO \ OW · WELL</td>

<td>Scheme reaction</td><td>AXIS at&gt; 4</td><td> AXIS</td><td>Axis</td><td>Axis mH</td>

<td>PS</td><td>δ and⁵</td><td>δ fi</td><td>δ '0 X</td><td>ABOUT fi</td>

<td>CM</td><td>n X about H. about ABOUT</td><td>with ABOUT</td><td>in AT- ABOUT</td><td>X &amp; at</td>

<td>PS</td><td>&gt; —U</td><td>\ ł</td><td>LOAM.</td><td>He's alive at.</td>

<td colspan="2"> ££ 1 £</td><td>X m rn</td><td>cn m</td><td>o. o m cn</td>

PL 204 281 B1

159

<img file="PL204281B1_D0145.tif" />

160

PL 204 281 B1

<img file="PL204281B1_D0146.tif" />

PL 204 281 B1

161

<img file="PL204281B1_D0147.tif" />

162

PL 204 281 B1

<img file="PL204281B1_D0148.tif" />

PL 204 281 B1

163

<img file="PL204281B1_D0149.tif" />

164

PL 204 281 B1

<td rowspan="2">those 2 2 at s Μ Q</td><td rowspan="2">WITH CM 'ABOUT* fi k © «0 at 8 «M * 2 and</td><td rowspan="2">WHAT 'T. f * i ! -: ffir) X TC o N. CM - jfśgg ffi T £ g cm r-. -. - m r-w 37? ^ «. ® ffi2T u-1 Tt _βOl rZ eo * 7 pA £ \ What ; o. o_ΛΛ3Α2</td><td rowspan="2">ABOUT ffi 3 3 l-H » kO in T— &lt; Sf »—1 K.</td><td rowspan="2">kO Oi WHAT £ 2 ABOUT about m Λ ABOUT and ί</td><td rowspan="2">11 Si CM f about k © r ^ fi ^ OO AT ffi CM</td><td rowspan="2">those V? 1! ffi CM fiS Ό Ό ę r-- s from What t — H</td><td rowspan="2">«Γ II • fi to ffi 2 = 4 4 35? 7 * ¹¹^ • 5 ffi ffi 33 CM »j.«. and— Ό Ό _D ^^ cM CM OO Τί * fi fi tT r- * n ffi ffi vS From r-</td><td rowspan="2">ΓΠ 11 * - » ffi * -P '• —ν' o. o * —L fi £ CM 3 U1 ffi fi *</td><td colspan="2">ST F * E. m * o. o about ς » 3 = s</td><td rowspan="2">fi k © l&gt; ca 't? ffi s ABOUT ABOUT ffi AT 6 and</td><td rowspan="2">fi DOWN II si CM s CM fi s fi from AT si CM T3</td><td rowspan="2">-3 - - Pffi o ffi a - bo CM -^- _f-l • o »3tr ^ ½¾ XV) KO S 2 p £ II S II 5 3 £ 3® td © 'dd&gt; 7 ffi Oj -' Τ 3® '3fn οβ X5—&gt; «h 'T« -' t ~ tó nj- 11</td><td rowspan="2">lH, J =&gt; 3.6), 1.92-2.08 (m, 1H), 1.55</td><td rowspan="2">ffi those M. about ffi ml 1 U-w ffi ffl k © vT</td><td rowspan="2">o. o e © 1 8 about cn n l3 ABOUT about. those 2 2 ffi</td><td rowspan="2">II si CM ABOUT • fi fil &lt;n fif 00 AT s si CM ^ Ś-</td><td rowspan="2">ii m 'U r- ffi ffi vó - fi * κ ^ CM 3g3 £ s'4 11 2 «M- · - uL» K 5? u-3 ffi ffi se f &lt;m oo -2 co - rn 2ϊ μ Ό L CM J 'm * r- · -' ^ r approx . About TT Ό τ 7 * II 3xfT 3 “5s5</td><td rowspan="2">3 o. o TT ABOUT ffi s? 3 * r&gt; o. o 1 about tfi</td><td rowspan="2">s rfi</td>

<td>m in* ABOUT fi ffi</td><td>ABOUT ITi WHAT ffi 1 “l</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>about</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> +</td><td></td><td>Vł</td><td></td><td></td><td></td><td></td><td>kf&gt;</td><td></td><td></td><td></td><td></td><td></td><td>oo 5</td><td></td><td></td><td></td><td></td><td>CM</td><td></td><td></td>

<td>ffi</td><td></td><td>o. o</td><td></td><td></td><td></td><td></td><td>ł — t</td><td></td><td></td><td></td><td></td><td></td><td>ffi -2</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> +</td><td></td><td>CM</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">£ ώ 4ł- Ł&gt; fi</td><td></td><td></td><td></td><td></td><td>e * 5</td><td></td><td></td>

<td> 2 </td><td></td><td>fi</td><td></td><td></td><td></td><td></td><td>• Φ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 3</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>~ eB S3 'ΰ ”£ 5 oo _rN fi tt</td><td></td><td>« .3 cd s 33 £ 2</td><td></td><td></td><td></td><td></td><td>«Ffi fi -3 &lt;© o</td><td></td><td></td><td></td><td></td><td></td><td>fi ^m* 3 fi S 33 at 2</td><td></td><td></td><td></td><td></td><td>fi ^ma fi fi ffi fi</td><td></td><td></td>

<td>l&gt; ą a</td><td></td><td>him</td><td></td><td></td><td></td><td></td><td>06 ffi</td><td></td><td></td><td></td><td></td><td></td><td>GO ©</td><td></td><td></td><td></td><td></td><td>What</td><td></td><td></td>

<td>ug</td><td></td><td> 2</td><td></td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td></td><td></td><td> - 2</td><td></td><td></td><td></td><td></td><td>• ^ s</td><td></td><td></td>

<td rowspan="2">• Λ ® nj X</td><td></td><td>ko</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>c *</td><td></td><td></td><td></td><td></td><td>about</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>fi</td><td></td><td></td><td></td><td></td><td></td><td>ABOUT\</td><td></td><td></td><td></td><td></td><td>fi</td><td></td><td></td>

<td>axis'</td><td></td><td>CM</td><td></td><td></td><td></td><td></td><td>k ©</td><td></td><td></td><td></td><td></td><td></td><td>k © '</td><td></td><td></td><td></td><td></td><td>CM</td><td></td><td></td>

<td>£ 8 E 8</td><td></td><td>U-ϊ fi *</td><td></td><td></td><td></td><td></td><td>ΜΊ fi</td><td></td><td></td><td></td><td></td><td></td><td>U3 fi^-</td><td></td><td></td><td></td><td></td><td>fi fi-</td><td></td><td></td>

<td>'cl 00</td><td></td><td> &gt;? 2 5?</td><td></td><td></td><td></td><td></td><td rowspan="2">Sfi Ό 'ΐί fi .2 OT X o</td><td></td><td></td><td></td><td></td><td></td><td>±? 33 2 S.</td><td></td><td></td><td></td><td></td><td> .2 3</td><td></td><td></td>

<td> 5-. £</td><td></td><td>JS O</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>42 O</td><td></td><td></td><td></td><td></td><td>X o</td><td></td><td></td>

<td> ·</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>cd * - *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>E 7</td><td></td><td></td><td></td><td></td><td></td><td></td><td> 00</td><td></td><td></td><td></td><td></td><td></td><td>OO</td><td></td><td></td><td></td><td></td><td> ¢0</td><td></td><td></td>

<td>at 42 • fi £</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>T—</td><td></td><td></td>

<td>□ K CZ3</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td>about</td><td></td><td></td><td></td><td></td><td></td><td>ABOUT</td><td></td><td></td><td></td><td></td><td>AT _ /</td><td></td><td></td>

<td> 1*1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>about</td><td></td><td></td>

<td>those</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td><td> \=/</td><td></td><td></td>

<td></td><td></td><td>Y</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Y</td><td></td><td></td><td></td><td></td><td>'T</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Φ</td><td></td><td></td><td></td><td></td><td></td><td>and;</td><td></td><td></td><td></td><td></td><td>X</td><td></td><td></td>

<td></td><td></td><td> «-</td><td></td><td></td><td></td><td></td><td>E. &lt;M</td><td></td><td></td><td></td><td></td><td></td><td>about</td><td></td><td></td><td></td><td></td><td>N ABOUT</td><td></td><td></td>

<td></td><td></td><td>UL A — U.</td><td></td><td></td><td></td><td></td><td>ABOUT</td><td></td><td></td><td></td><td></td><td></td><td> \</td><td></td><td></td><td></td><td></td><td rowspan="2">at</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>about</td><td></td><td></td><td></td><td></td><td></td><td> /</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>n</td><td></td><td>ΖΛ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2"> ¢3</td><td></td><td></td><td></td><td></td><td>&lt;ΓΆ</td><td></td><td></td>

<td>those</td><td></td><td> \ /</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> \ - /</td><td></td><td></td>

<td></td><td></td><td> £</td><td></td><td></td><td></td><td></td><td>ę</td><td></td><td></td><td></td><td></td><td></td><td>ę</td><td></td><td></td><td></td><td></td><td>f</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> ?__</td><td></td><td></td><td></td><td></td><td></td><td>and_.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>ffi</td><td></td><td>£ _. 0-LL</td><td></td><td></td><td></td><td></td><td>&lt; UL</td><td></td><td></td><td></td><td></td><td></td><td>( AT-</td><td></td><td></td><td></td><td></td><td>&lt; AT.</td><td></td><td></td>

<td>£ N</td><td></td><td> »—1 '</td><td></td><td></td><td></td><td></td><td>ΓΜ</td><td></td><td></td><td></td><td></td><td></td><td>ΡΠ</td><td></td><td></td><td></td><td></td><td>d-</td><td></td><td></td>

<td> 2 £</td><td></td><td>Ό Pfi</td><td></td><td></td><td></td><td></td><td>k © m</td><td></td><td></td><td></td><td></td><td></td><td>k © m</td><td></td><td></td><td></td><td></td><td>ffi</td><td></td><td></td>

PL 204 281 B1

165

<td>NMR data</td><td>OO _ O _Λ_i rf hH C ex3 mS oS ^ oSE⁰⁰ --Γ · ~ -Γ p SS³S- · * saaga MP 2 - PRR § oS £ ę? S a Ω ffl R® ni Rp 'T * O \ £ xxt xxA §3Ε * £ ϊa p \ χ “'Tx aa rf aa 5 a r * t- o- * - m 01- *</td><td>- 5? »2 χ Si aa« -o £ - House * " Ν ή ή, ς »n $ a £ ί33 &lt;£ £^ν. ~ _ £ χρ⁵έ: 2α 5 a * £ 4 £ ϊΓ7Γο &amp; 4SSfg-4 IgigSfff v * ~ · —tm a "ig aA f r⁴ Λ o- -sS-re cn</td><td>- "-M-" aV £ p. 2 R '' m s7 ^ pEp QO r P * Os O * “in rA eT · - P «XPX OX iK 4 2 K p 2es m ts § £ § £ £ &amp; £ Rp R p R g £ x &lt;e £ Z Ν Γ * Ca a ® g¹ ffi jr * r- m is pi</td><td>about - p_ ΡΊ - x MA XE a “2-t -R · * . A -Ng d 2 'Ck aa £ 'stick _-c X ^ 2-: a&gt; £ a ΰκ ^ Πι '⁵'qax&gt; a rf U ra * 7® R h- &lt;eo «1 7? * χί^r o §a ^ ° l. £ E RS &lt;π σ '" »Ϊ5 Sś?</td>

<td>+ and + s</td><td>; « 04 DOWN * Λ</td><td>σ \. cut about. v&gt;</td><td>about pq uń ABOUT\ ΙΛ</td><td>vol about ΓΜ SP Ti- m</td>

<td>Time retention / method</td><td>ϋ P4 • 9 ^ΛR Ό Ł -2 -d * ϋ E 2</td><td>CU S. b £ X 1</td><td>'9 TO c -a cs 2 Tf (U E 2</td><td>-. here '3 TO C Ό W - £ 5 m oh - s</td>

<td>Out- connected mass part.</td><td>fS about vi 6Φ «Λ</td><td>Ό ABOUT uS σ \</td><td>so about wS AXIS * n</td><td>Ό ABOUT and· m</td>

<td>Look</td><td>£ -u WHAT IS • τ- ^Μ.2 st AND</td><td>THIS Ό ΧΛ NO</td><td>&gt; L X&gt; in . JD O</td><td>Ό Λ ^ΛO ςΛ TO ° C ps - · - « ^at '3</td>

<td>Scheme reaction</td><td>3 - * Εΐ N * X £ w — i</td><td>3 TO N&gt; T3 N £ E</td><td>§ &lt;r η N * T3 X Ξ r — 1</td><td>= T. x £ in — 1</td>

<td>m PS</td><td>E5</td><td>B 0 fi</td><td>□ 0 fi</td><td>5 fi</td>

<td>Cd Ρί</td><td>about fi</td><td>b ? fi</td><td>b fi</td><td>about ?</td>

<td>PS</td><td>AT-</td><td>£ ~ \ Λ &gt; fr-lŁ H-</td><td>LOAM</td><td>Ib</td>

<td>Z £</td><td>V * i Ό m</td><td>&lt;P Sp m</td><td>5 m</td><td>00 Sp m</td>

Time

166

PL 204 281 B1

<img file="PL204281B1_D0150.tif" />

PL 204 281 B1

167

<td>NMR data</td><td>• σ TU .. (3733 35 i? I Hundred ^M. 43 o- ° .ς With saw '²-® T.KJ TT X? p_AT N Γ- K 'Ig μ "2 &lt;rj 5 -O -i - S to S? 2 □ '-'. B £ © η g - ϋ-Ό S .Sn -2 - .f 2 this ⁱⁿ¹ T.⁴ -τ ' ^m te 43 r-: co -Kf tl in -'Λ S - ii&gt; T. 2 -s ά - f _7 * “* ⁱⁿ * T? 1 ”2g £ 2 ^ £ 5 g £ 53ίί £</td><td>. - 22 2 A oi - &lt;D \ A 0 f li ^ 2 o κι ffl ^ra ~ -7? 3C oc? T 53E C. ^M. K Ξ LWW Q 'c' Xt. - 5 S. H * 3 2 * T eS ef to® -S § f - g »5 ae A '-'o ®' -'ΧΕΊ X. -v&gt; ιη-ΡΙΧ ffi B«. f li A 33 a - (SKHjia-KÓ</td><td>20 't? ślsfgj. X f- π ~ 2 gga 2- aj to · -&gt; '-' «OA ΤΓ - ± · rq x; £ -r-2 _ ' _S&gt; PR is you ux -. E ϋ^M. K- 5 Xo. -. ^ = 5 TJ-_ΐ ~ * 4Sg to STS O 43 * s? A Ki SC X O -Ν'AA m * 75 XA 2 ° ShXS^m b. fhMgssjs cc aa V b □</td><td>ε n -,. © .-— X 33 lA Ł * ΓΠ X o UA -o TA 2 &lt;=. 2 - • ii wa Ό aft-; a 'TCB “-a £? tS --c 2.55 ^. ^ 3i3 - Ξto y X "* 7 e ^ c-iss s^s.^and.'s3 § 22- ° t · '® a ® is aa 35 g - ta r- o- -. -</td>

<td>+ SC + s</td><td>β es o. o Those</td><td>04 Ol axis irj</td><td>about* »—4 ABOUT Vk</td><td>0 Oh "ABOUT 2Γ</td>

<td>Time retention / method</td><td>1.40 min Method A</td><td>1.17 min Method A</td><td>- &lt; '3 ¢ 0 £ Ό at 2 1 — and U - s</td><td>and ^ώand about Ot + - &lt; ~ 2</td>

<td>Out- connected mass part.</td><td>1 — i about ooh Ch 2 ±</td><td>00 about Ob N m</td><td>about about bC m</td><td>σ \ &gt; n 21-</td>

<td>Look</td><td>amber- new glassy mass</td><td>amber- new glassy mass</td><td>1 and amber- new glassy mass j 1</td><td>&gt; η * Π * 5 x&gt; 0</td>

<td>Scheme reaction</td><td>DOWN 03 and "H</td><td>TO. AFTER ł — 4</td><td>DOWN oo '</td><td>DOWN</td>

<td>Dd</td><td>δ fi</td><td>δ fi</td><td>δ X</td><td>δ 0 X</td>

<td>N ai</td><td>about</td><td>and Laws —-i V</td><td>about and</td><td></td>

<td>AXIS</td><td>at.</td><td>tk</td><td>LOAM.</td><td> t ~ \ -LL</td>

<td>UN from £</td><td>m Γ * e * ł</td><td>r *</td><td>U&gt; r— m</td><td>Ό about- m</td>

168

PL 204 281 B1

<td>NMR data</td><td>Γ b? rf -A «fix" SB x (C - m © - "Aa« Ί &lt;n 4 · 3-T® TχΕ οι ^1-1 tsx&gt; ES gCisiis · * s- U fs 2J ao £ p2 A® A x SEfi »i§” fi 2 o \ * - * λΊΓ ό "A Γ * &lt;z * * - * ©</td><td>AE te ~, gx £ es ν-Ά 33 A _- what S - Ort “vxC i_sk χ «· χ Οι XI -ΧΤ O t— _-1? 33 x 5 is £ 3- £ - them - &lt;5 ΟΊ 1 cg E _E&gt; 1 £ 3 XS, "&gt; y&gt; t&gt; 5?&gt; QC .M om χό 42.cn S fiS-® id x and EMAA 7 δ¹®¹ E.</td><td>in, un 5 i * rs r ** 'Ά A B x «AA - i-χΝ - A 2 S £ - °° ⁿ dT sS * «5 8 u &lt;XX Γ- '2 A o “uA“, η&gt; - Q * “» fl * -. ό Z OO s - * _ CM ® £ AAfiS</td><td>jis. . · P Si ί · ώ «ο o 27 h- ^ oi rf A“ P “_:- T OO XI ® ® © X X 2e? 2RE is 3b £ 22 rei A - · B^- 5 gSS ^ s SgE-iST . B XI M Ol TT ę - X CN AA g .2.3 «η- B © XI X CN X aba β ne - from C- u * and tj- - &lt;</td><td>x £ E N i ^ -1-1 £ A fi fi - «? 2 W Ol VA £ A - AK cn a52 ^ óx "Fi® £ 22" 5S m A -^-1 BE HPSjfS.s In. τ "Π« ri, _! · «Π * Z3 ΓΜ SO o so 2 t — i OS N &lt;* &lt; a == »n κ tH Kj -ef Tj- -x</td>

<td>+ B + Σ</td><td>tó —1 5 ® +</td><td>S \ © * Λ fl</td><td>3 oi © fl</td><td>AXIS axis ABOUT Tf</td><td>so Axis vi iO TP</td>

<td>Time retention / method</td><td>1.65 min Method E</td><td>• 3 ps 2 Ό 5 *ABOUT ~ S</td><td>- ABOUT • 3 co HIM 'mo “Ί«</td><td>Those ⁰³• a ce 6 'Τ 0 Ώ Έ - S</td><td>£ and ® • 3 cd E +3 ABOUT-. ABOUT And o - s</td>

<td>Out- connected mass part.</td><td>Axis DOWN fl fl</td><td>PM AXIS © in fl *</td><td>\ D Axis WHAT \ D fl</td><td>in Axis fl * '• P fl-</td><td>* ri S £&gt; TT</td>

<td>Look</td><td>ti Xi O</td><td>_ £? ό 3 S -C o</td><td>* n «P Xi o</td><td>&gt;&gt; Ό 3 8 X: O</td><td>^ 23 «8 X) o</td>

<td>Scheme reaction</td><td>rs ΓΜ</td><td>o. o</td><td>o. o l- ^</td><td>OO</td><td>o. o l-4</td>

<td>d</td><td>5 0 X.</td><td>fi</td><td>-p</td><td>about fi</td><td>ABOUT 0 X.</td>

<td>ct oi</td><td>with about rirv</td><td></td><td>with_vol 2*'^r .«· :^r</td><td></td><td></td>

<td> 34</td><td>AT-</td><td>\-at.</td><td>\-AT.</td><td>Ib</td><td>LOAM</td>

<td>No. Ex.</td><td>t- r * en</td><td>o. o t * en</td><td>Axis r- Π</td><td>© oO n</td><td>00 en.</td>

PL 204 281 B1

169

<img file="PL204281B1_D0151.tif" />

170

PL 204 281 B1

<td>NMR data</td><td>. , -c 5 a £ a ' and vo Pj 7P CM g 5 == a ..Sm'— rA YS'® 3 ^ 8 ΪΥ ~ -. &lt;Χ =^Ν 2 22 £ —¹⁰ . How much 2 a τ Ύ j® gd i&gt; - r-jg F- *_about,and Χ -, - ζίη £} ~ grnP ^ rn ^ ooOr-SiP</td><td>_and-iśh &lt;1 CM —ι β * -^with ,-and - CM C "* d- vp. o ffl FGF -, _ς o Y ba «μ τΛ WHAT ™ °! gh W © li m · —-pi *&gt; Ή · °. On - o - 5 a^-2 -3 · - 'oc tn ^N in B ΓΎ&gt; to © * ^RWELL .ai &amp; SiSS</td><td>© Γ- Tl- _ A . o ® Ύ j —— ** rY cn a aj3 *. «Ί ώ sby _ £ s * % P^S.-JSs fi g Ώ 5 &lt;! RG | p ^ -^s. £ i Cfi i ►Ή cn ZN - F j</td><td>-® 1 _L £ ςί rs Ό aa ^ .- - OT ~ yY o © tss 5 * Ί B. * £ In OO 5a ώ About all £ J r? 8 £ -3s · gs * -: - § p. Ϊ Z © £ rs</td>

<td>+ and + 2</td><td>© cM cY cM AND</td><td>'' t AXIS AND AND</td><td>«· 'S' § 2,</td><td>© r * Ti-</td>

<td>Time retention / method</td><td>fi ^IN-3 « g Ό UP TO 2 cm ω ύ Σ</td><td>.5 " E -S &gt; n O ό γ; - 2</td><td>c ® Έ m E Ό Take Fr. Ώ u - 2</td><td>e ⁰³-fi you S Ό OO O u ~ 2</td>

<td>Out- connected mass part.</td><td>CD ABOUT rY CM AND</td><td>What about © Ό AND</td><td>«- ^ ABOUT\ ooh F ~ .</td><td>© Axis ABOUT\ © TT</td>

<td>Look</td><td>orange awake precipitate</td><td>&gt; 1 £ 'Ο o you NS ŁJ 0 X</td><td>&gt; · X3 X efl Ό S. •WELL</td><td>&gt;&gt; T3 5s in X o</td>

<td>Scheme reaction</td><td>iC OO ł — i</td><td>iH OO * ł — 4</td><td>OO</td><td>00 l-H</td>

<td>ΓΊ Ρί</td><td>ΰ 0 Y</td><td>ABOUT fi</td><td>about fi</td><td>about fi</td>

<td>M. 05</td><td>b vol</td><td>Q Ł fi</td><td>Ό</td><td>AT</td>

<td>ai</td><td>bu</td><td>fi-</td><td>y — u. Ili</td><td>Fa y — u- LOAM</td>

<td>No. Ex.</td><td>F- OO en</td><td>o. o o. o en</td><td>Axis o. o m</td><td>© Axis m</td>

PL 204 281 B1

171

<img file="PL204281B1_D0152.tif" />

172

PL 204 281 B1

<td>NMR data</td><td>"--Ϊ CS -C p S "'ifa— II tf 3 S ¢ 5 CS Χ2-® 2 s-® g PA g -od jg g 2 - g ^ fa ^ Sp ^ p IgP ^ -TAPA -B «Ζΐ.Β Bo gi dp μ - P s 3 ό 1 A - oa 2- σ_ffi and τ T &lt;2nd da - C4 r * Κ »\ D s— 'T ± - &lt;</td><td>ri-p «S g, £ b £ p iTfePE κ« 5 pA S-4 p ^ a tc s z &lt;s □ rs £ V © ος ao fi ΡχΓ £ 5¾ a £ spa .Tl 8) ® - About g¹ rf O - A ° ^ _T st- ? as a ^ ś ^ -u - S - a r- ffi r-p 2 A S4 3 a ti ^ a £ “-gS? s 2P rs pn o-</td><td>»6 £ § £ 2 ^ 7? P PtfśSgdP £ SsnS-SaB? QN r- K 'jo -r OPA at * · * i_ “« i Γ4 PP ~ §.R £ A a “^ AS 5 £ oZ AP - (Si 57 P 2Xś | £££ § £ «δ“ 5ί33 ^ ίι</td>

<td>+ and 4- 2</td><td> 502.25</td><td> 515.27</td><td> 483.98</td>

<td>Time retention / method</td><td>1.17 min. Method A</td><td>1.21min Method A</td><td>1 (21 min Method A</td>

<td>Out- connected mass part.</td><td> 501.98</td><td> 515.02</td><td> 483.98</td>

<td>Look</td><td>amber- new glassy mass</td><td>1 amber- new glassy mass</td><td>amber- new glassy mass</td>

<td>Scheme reaction</td><td> 18,8</td><td> 18,8</td><td>OO o. o V — 4</td>

<td></td><td>about P.</td><td>ABOUT P.</td><td>δ P.</td>

<td>ΓΊ CC</td><td>about 0</td><td>pp</td><td>ό</td>

<td>and</td><td>P.</td><td>at_</td><td>LL-</td>

<td>No. Ex.</td><td>m Axis m</td><td> 396</td><td>r * axis m</td>

PL 204 281 B1

173

<img file="PL204281B1_D0153.tif" />

174

PL 204 281 B1

<td>NMR data</td><td>.. "M mb ^ £ ^ £ 2- t A4 £ 4^tnsft j S - p &lt;-e ”. 4 ? 4 n and U = M 4c &lt;ro a 0Q Ch ™ O * 3 “μ. χ; about Y “- rn Β 'κ iS “£ td 5 j τ '¥ £ pa ή η a AAS £, R - -</td><td>. β Tl —- χ- a ££ CN X ° θ CT&gt; Ό • © · xx r-, - * Sy £ a &lt;s £ A4 £ 4 ^ sP Sa '^s-4 «5 ^ x 4 4 ~ a z o. o. _th 7¹Τν-, Ρ-χιη XX, 2 here 5 sq &amp;_and- Pd 1? -3 £ ° x; R 4 ς? gs ^ s Ta ^N^ a bT ^ T £ Ϊ ΙτΑ ^ οΝχηΜίη</td><td>N £ - S® M ~ ££ s? £ Wed n S »i - int -ABOUT . ώ τ g. ir, Ąoó S ►χ '-' Ξ- S'® '-' 1 SxSn ΐ w7— | 2L HH μ-1 W&gt; JL PN^M. - -ci - d ~ -a ^ a W &lt;N 'un x ro m -' ; ta Ργν χ- ^ γί .t S tU £ fU N ~ ττ τ^Μ£ 4. . ε ® 1§ ^ A £ S | SBT “K δ τ ° ΐ β</td>

<td>+ X + 2</td><td>M. cN (No. THIS^-ir&gt;</td><td>oh wi in&gt; ν »</td><td>DOWN and— &lt; «Ν WHAT &lt;JO</td>

<td>Time retention / method</td><td>_e and this' E -g * M, O - Ή w -. 2</td><td>Of the Jagiellonian University • S «3 d τί WO 5 TT u 2</td><td>, E s -3 mo « . 2</td>

<td>Out- connected mass part.</td><td>r * © in . this- Vł</td><td>CN rH inj WO Ti</td><td>-at © CN m * n</td>

<td>Look</td><td>¹ - THIS c-5 ti C Mli _ABOUT ΧΛ Μ Ό EQ to -Si E? * ri - g.</td><td>r 2 2 P Λ i (5 &lt;2 c Q «λ THIS IS THIS NO. Oo about-</td><td>1 • - THIS by 5 t? - □ S ΐ o 15 «) group 42 S -N _about - Cl</td>

<td>Scheme reaction</td><td>—M 3</td><td>1— &lt; ABOUT &lt;N</td><td>OO HM</td>

<td>Di</td><td>δ 0</td><td>about 4</td><td>d d</td>

<td>Customs Pi</td><td>ABOUT 1 p about</td><td>ABOUT ? about</td><td>about l,.</td>

<td>oi</td><td>ϋ-</td><td>ϋ-</td><td>at.</td>

<td>, No- Ex.</td><td>CN © * $ -</td><td>What about THIS.</td><td>about 3-</td>

PL 204 281 B1

175

<td>1 IX s WITH V c THIS</td><td>x £ a ® «5 7 4 o - so _ * e S * 'JP p3 ® Έ? toT 5? SB gb-SS i p-. ^m- - -¾ cx O tok '^ tr »x £ ca _ -ΙΛ YYR 5 &lt;3 2nx x »gsSr-jN ^ B &lt;** * · u- * £&gt; &lt;S p ^ '-⁴e3 45 * ° J3 ° θ X * Σ3 p</td><td>about x "ł XB _ffi Ν Ό E, _ 5 χ mg * c-4 245 R τ no, SRBXA s £ = 43 «E χ £ 2S ^ S 2 A ^ lo OR d ffi 4&gt; X1 node £ J3 R p | o £ d ​​E »i £ - E a Λ s £ 2</td><td>- χΕ K ® K 43 X x - E ^Μ. § 3 M 2x 2 "A —i S OA Λ1 Ί 7 αΊ. "Α · * g \« =&gt; ° 1ρ 5 a ρ r £ 2ρ X ζϊ ρ g¹ta ρ - -R g „R 5 Ό Z? W Χ-Λρ £ &lt;* η ό 2 3ι S. S Α 2 R Ο ^ Χ 5Ζ a Τ as ® ° 3 ί ΰπ Λ r * &lt;77 κ m -77</td><td>'0A g' huh? a-THEO 'N 4_V Kl II ^ 4 K. n- p RRC? R s · ».j- R" JSI ^ B □ tSbA ^ g Ω AC? X «n 2 o \ oa 2 a _ · Β b \ e ££ g R Hj. a ΙΛ. a Sf £ xg'm - p A ρ X 2-a</td>

<td>£ + s</td><td>Axis tn TT k&gt;</td><td>ABOUT 1 — Ł What V » K.</td><td>CM Η Ό K.</td><td>AXIS rn S-</td>

<td>Time retention / method</td><td>IN '3 g r? ~ γ * ί ι&gt; - s</td><td>rt ⁱⁿ-A THIS g Ό S. ²X here - s</td><td>U · § Λ g £ £ r ** S q&gt;. E 2</td><td>a « 5 IT ii ^ 3 Well § i</td>

<td>XS w * w * Sk o 8 &amp; pi § E ΰ</td><td>Ki ABOUT K. AT K.</td><td>about about about Kus κ</td><td>'φ - about en S £&gt; K.</td><td>s: those</td>

<td>Look</td><td>, Έ i ° £ Λ «* P ”^ 'C Ν</td><td>- 3 £ Ή 'V λε α' fi Ν 2 hl o CU</td><td>'Ć 2 t¹-about Sauce E g O ru</td><td>ό 3-, N WO Ν NO R ° CU</td>

<td>Scheme reaction</td><td>«Γ '—1</td><td>•THIS 60 •THIS</td><td>What</td><td>P. K] O c _;»That's 3 p4 *. E. -D ° ogs x 5 O THIS</td>

<td>n ai</td><td>δ fi</td><td>V 0 fi</td><td>about.</td><td>AT &lt;^d</td>

<td>^rx</td><td>h vol</td><td>about fi THIS</td><td>b &lt; pT *</td><td>fi</td>

<td>~ ai</td><td>THIS</td><td>*&gt; this</td><td>^ A- ". Ili</td><td>THIS</td>

<td>, Ń £ £</td><td>KI about ΤΓ</td><td>S © about TT</td><td>s T.</td><td>• TO about</td>

176

PL 204 281 B1

<td>NMR data</td><td>£ I- rP AO— ' ® SΓ ± - »S 5 ^. © &lt;© (J \ D ffi «—'U"^{4 m}cd N ** * -C iais ^ S'®. £ sf £ u · d- £ T p r. A ΓΝΛ O-Tf</td><td>-at 5? . ® PSig-, Ρ aw gsfSSłiSi ώ Ή * A * .s oo 43 □ - ts XO © gza Pm &lt;= a W d tg ® a'pZ3 ^ O!;. 2 hS ffi «&lt;= 2 2 -r »5 '~^&gt;In the Civil Code * £ «S * * 25 2 - cs no 2 in SC X CC - T</td><td>• β Ίί „- TT ts © j about ^M. - &lt;£ J3 —— -PS SSsp® P §Sffi »-P8 8- words P et ~ f II g5 S 5 JL Sui Ξ. eX ® a Pm χτPPs «a 'ta τ ws ΐ rn r- - tt - OA</td><td>in 0 &gt;, τ ± m X 0 £ u · zX £ - CS μ m ę - ^ - a S ζ&gt;¹⁰ ; joó X “P m _ S5% - £ ° PS? ŚSTdgj ^ AP S - -&gt; P&gt; -5. B O BO - Μ 'Λ * U 2. * 0Q 33 ro --ί.'Ο ΐ MS A. Μ Ό r- - fcj Ό Q Μ T3 OS “O 3 'ΐ M ·. u - &lt; ® pp PP-5 p</td>

<td>- +. and + 2</td><td>ch τη Tt - T.</td><td>R CS »N</td><td>3 UP CS ΙΛ</td><td> 428.13</td>

<td>Time retention / method</td><td>0.993 min Method B</td><td>1.44 min : Method B</td><td>138 min Method B</td><td>1.39 min and Method B</td>

<td>Out- connected mass part.</td><td>Tf σ \ CS τΓ T.</td><td> 512.04</td><td> 525.08 1</td><td>427.87 and</td>

<td>&gt; cii) &gt;. £</td><td>transparent clear Oil</td><td>amber- new glassy mass</td><td>amber- new glassy mass</td><td>white precipitate</td>

<td>Scheme reaction</td><td>18.10, condition chap. 5</td><td> 20,8</td><td>IN? 0 CS</td><td>OO</td>

<td> □5</td><td>P.</td><td>□ P.</td><td>3 P.</td><td>3 P.</td>

<td>M. Pi</td><td>P.</td><td>about T.</td><td> 0</td><td>2 ABOUT</td>

<td>Ps</td><td>LOAM</td><td></td><td></td><td>&gt; —Ii. LOAM</td>

<td>at N Z £</td><td>Oi ABOUT</td><td>about 1-4 TT</td><td>1 “4 W4 'Φ</td><td>CS »—4 Tf</td>

PL 204 281 B1

177

<img file="PL204281B1_D0154.tif" />

178

PL 204 281 B1

<img file="PL204281B1_D0155.tif" />

PL 204 281 B1

179

<td>OZ ι ϋ R ηί Ο</td><td>OO _n v * ~&gt; H. r ··. _. £ fi C * &lt;- ^ 3-7 £ 35 as 7 11 K kfi 2 C? Fi S ts X i- 3 1 -. S 72 3® τ a^s d 5? 3 £ 2 ^ 772-.2, ^ 3 q 7 3 &lt;* g »g * Bś ° ^ 7K3 £ =? 1 Β ^ 4πρ2 «γ -j SA Eri _r 'A 33 * ^ 5 »? H ffi ~ fi ffi ϊ 3o -ne \ dn 3 «</td><td>«- g? 11 3 - 00 2 ffi -&gt; X ® _ -3 £ II 3® xjn 7. £ S £ ^ 2 £ = - «®S PS4 «s'-x £ ® fi es χ | Μ S, 11 3g X £ 3« 7SQSxo £ ® ^ 7 ^ ® 3 2, _ !? - t XH Ϊ fi «* gftf ^ gSOSfi ^ 3-7 j £ a 3-2. &lt;? Ξ v -⁰ AND X &lt;s «. «« «- X. Ba ”^ -3 ^ 7ίί7Κ 2n 4&gt; O e— &lt;fi fi - '« - *' ffi</td><td>3. 00 E. p «^ K - / ^ oS ρ 11 3 ^ 11 5, 3 0« ~ = 2 x-&gt; -? x ^ '^ SgSf 3 -tfffi sS-π "X 2. ° £ “n £ 3&gt; * n - P / g E -. 77 ^ rn ^ «fi o ^; o £&gt; A oó 3 =&gt; ® g * n 0 ni% - &lt;n I Λ». ^ 1 | _andY 0 ffi ffi^M. «32 xó3 3« 3SS32 ^ 33</td>

<td>+ ffi + S.</td><td>\ D r * i from CM ΙΓ »</td><td>ffi ffi vś m</td><td>r * . ł — H § fi</td>

<td>Time retention / method</td><td>a &lt; '3 rt ¢ - * a «0 m ay - 2</td><td>fi &lt; Ξ = p -a M? ABOUT &lt;o ΰ - S.</td><td>.a &lt; 3 «3 c Ό what o * © d&gt; - 2</td>

<td>.Λ 52 nj X 7.5 ί &amp;? 8 ε p</td><td>CM DOWN CM Ufi</td><td>WHAT 0 • ń * n</td><td>0 D ABOUT and © fi</td>

<td>Look</td><td>&gt; i Ό ™ 8 JO O</td><td>3 .2 ot x 0</td><td>3 = J. &lt;rt cd -S OT X 0</td>

<td>Scheme reaction</td><td>r-</td><td>r</td><td></td>

<td>ΠΊ ffi</td><td>ϋ fi</td><td>0 0 X</td><td>σ fi</td>

<td>ΓΊ ffi</td><td>about &gt; ° P.</td><td>0 ) = o P.</td><td>/ 0 Yo P.</td>

<td>ffi</td><td></td><td>alive</td><td>£ —y_</td>

<td>No. Ex.</td><td>fi fi </td><td>3 fi</td><td>cM fi</td>

180

PL 204 281 B1

<img file="PL204281B1_D0156.tif" />

PL 204 281 B1

181

<img file="PL204281B1_D0157.tif" />

182

PL 204 281 B1

<img file="PL204281B1_D0158.tif" />

PL 204 281 B1

183

<img file="PL204281B1_D0159.tif" />

184

PL 204 281 B1

<img file="PL204281B1_D0160.tif" />

PL 204 281 B1

185

<img file="PL204281B1_D0161.tif" />

186

PL 204 281 B1

<td>NMR data</td><td>OO _nS r- OA * tC mm ® tjsS £ 2.β- 'St. S CN yj V, N &lt;n O. _ n 1 = .1- Eg »rj - * 2. A ** t-¹ A 'β -' '«Λ Β χη? Μ 3 · 1'i 5? “G £ η χ ® - β ά d Ιίί ^ Ρϊιίί S £ f 3α '0αTb e?</td><td>* uT ·. χ-&gt;. pi 3. «B A Ε _Λ§ ϊ &lt;5 h * l 3 ^ i55s'Sś®^s- U tf «ν '",.^1-1 η I EAχχ- ^ ΑΚΒΕ «χΗΗ ™ g-« £ n r-. Μ * ° XXX © 2S ^ £ B- ' © X ^{M 1/1} ESS ^M. X KSf? ΑΒΓ'ξ'ξΑδ '?</td><td>r- 't? E _X "AB" Β'χ'Ε - · Χιο © ΐχ, ® gen £ i&gt; 'R ffi U 2 - s ”o \ «□ ęr sS © 3 * Λ ^ 5^όu S -1— * o tt S χ B ŁS.CIJJfJ' — X. °! B © in I II co B © ►7 * ° * 2 1 (Νχ'η.χχ'χχΑ. ? btsx®®'Jb 1X i fi23i-śg Π ώ 2 · ® t C g C b ® a ® rf '£ 3 ”A</td>

<td>+ B + s</td><td> 512.24</td><td> 525.23</td><td> 471.12</td>

<td>Time retention / method</td><td>1.36 min Method A</td><td>1.35 min Method A</td><td>1.74 min Method A</td>

<td>Out- connected mass part.</td><td> 512.04</td><td> 525.08</td><td>£ ABOUT Γ * fl *</td>

<td>Look</td><td>amber- new glassy mass 1 and.</td><td>amber- new glassy mass</td><td>amber- new glassy mass</td>

<td>Scheme, reaction</td><td>DOWN</td><td>o. o</td><td>1- Method A.</td>

<td>d C4</td><td>ABOUT 0 X</td><td>5 fi</td><td>AT fi</td>

<td>ΓΝ oi</td><td>H.</td><td>and</td><td>yp-⁷d</td>

<td>this</td><td>S-y_</td><td>$ -y</td><td>$ ~ y-</td>

<td>i-5 Ń £ 2</td><td>© fl fl *</td><td> 441</td><td>03 fl * fl *</td>

PL 204 281 B1

187

<img file="PL204281B1_D0162.tif" />

188

PL 204 281 B1

<td>NMR data</td><td>. © CM from — Μ Ό “- _ _“ τΤ - k, about - . .. XP 't -¹»= ŁS_about:l; ~ 1- ^ 5_S.-AE o- t ~ - ii «language Φ GF &lt;ol ~ 2 S &lt;bo oo «Ό2ΙΙ Ξ —A Λ a mt S. * i O ° O - "CM -e- a χ · »£ ω c? Hna 2 “33S9 5? 3. ZNrnmOO - NX ►ri -jr £ Ώ “and F“ - £ S r³ So r- -&gt; 3 · • 'J · U · es m</td><td>5 ”m . - -r _j at ~ -⁰³ θ '“G— ~ -Mt ° ó °° ~ e £ S? 5 TT oAA ^ ffSSA 2® ^ Ξ'Ξ- '! ^ £ Ybb- nSSb&gt; to 2, ± CM © ΖΓ 2Γ Ή CM ", o - "r- Ό o Ges m §B® -Só £ 5ϊ · ο · 3 · 5 -Bts-i za oi o- © ass 533 T3 - «η £ 3“ -T £ -Gr-roGS-Ar-</td><td>II F-4 4-1 *&gt; 7 S4 «. and «33 At CM Os Q _n , —1 3 mn 2. and foa — A® d 5ί and »j-. 3fY «PSR-ir □ 7tieA23 ~ A es m es es \ d 1 Β'2-ό * _-E - ZO CO «- A«, e-S a -3- ^ a ώ&gt; nga «% X- F- OO ** 3 * &lt;* -&gt;</td>

<td>K. + 2</td><td>+ r and CM 5:00 2γ</td><td>+ CM Ah oi + W1 2</td><td> 443.05</td>

<td>Time retention / method</td><td>1.53 m Method F</td><td>1.59 m Method G.</td><td>1.74 m Method A</td>

<td>Out- connected mass part.</td><td> 417.09</td><td> 458.12</td><td> 442.90</td>

<td>Look</td><td>whitish precipitate</td><td>whitish precipitate</td><td>whitish precipitate</td>

<td>Scheme reaction</td><td>OO</td><td>OO</td><td> 0©</td>

<td>en AXIS</td><td>about fi</td><td>about 0 Y</td><td>ϋ 0 Y</td>

<td>M. Pi</td><td>with at</td><td>about</td><td>about E. ABOUT \ = o about</td>

<td>'oi</td><td>t ..... \ _</td><td>£ lllll \ _</td><td>b</td>

<td>No. Ex.</td><td> 446</td><td> 447</td><td>DOWN Tf TT</td>

PL 204 281 B1

189

<img file="PL204281B1_D0163.tif" />

190

PL 204 281 B1

<img file="PL204281B1_D0164.tif" />

PL 204 281 B1

191

<img file="PL204281B1_D0165.tif" />

192

PL 204 281 B1

<img file="PL204281B1_D0166.tif" />

PL 204 281 B1

193

<img file="PL204281B1_D0167.tif" />

194

PL 204 281 B1

<img file="PL204281B1_D0168.tif" />

PL 204 281 B1

195

<img file="PL204281B1_D0169.tif" />

196

PL 204 281 B1

<img file="PL204281B1_D0170.tif" />

PL 204 281 B1

197

<td>NMR data</td><td>Χ-ο -. what WOH »In« 3 and 3 A »'-χϊ χ &amp; „Li“ A Mt II r ~ Aj · iT &lt;-A * »* - _i “S ° 0 s Ξ is y p4 · α is HT B7Xs? £ 5¾ to-A -e to ^ 773 £ BS ί B jl ti5 T ji. 2 Z (2 AX - oi ĆU VI Ό - 2 II M Ćirr - N - &lt;</td><td>• v ° £ CN 2Γ. Γ- Tj * ° ⁰⁰ X cs χ cs * - * CS gR ^ ci-Js 2 r ~ tt AA 2-: Χιό ~ o ^ ​​2 X ΧΓΜ-ιη ©; | A Ή χ yr * χ7 S 5- κι Μ &lt;ff Μ T KI KI % ^ s-Ms-Se From what r&gt;, n&gt; c - in r- mn α cn rs -&gt; \ OS · 'ri 3-'</td><td>&gt; o ~ X 1 £ ϊδ?⁰'Λη to 43 and PX A is Ó c ° l 335® ^. = 2-7- WAW 3 · 5Τ b ϊ ^ αΧακΜα »® · -υ K- g&gt; -e κ3 K, w 3 = b; iś "xś3 © ii-iS ^ esS ^ s · 2 5605 ^m 3 2k! - g With t- o oo r- -ą_λ_K. OO OO ΓΝ X RCS ^ tEC C ir¹ r- Ό as- * 4 * C * J 'i' m CS rs O</td>

<td>+ ae + s</td><td>K.⁴^ to ® S + . S. s ^ *</td><td> 456.20</td><td> 519.23</td>

<td>Time retention / method</td><td>1.72 min Method D</td><td>0.99 min Method A</td><td>1.12 min Method A</td>

<td>Out- connected mass part.</td><td> 460.93</td><td> 455.93</td><td> 519.04</td>

<td>Look</td><td>White foam</td><td>transparent clear Oil</td><td>transparent clear Oil</td>

<td>Scheme reaction</td><td>CM</td><td>r-</td><td>r-</td>

<td>1 * 1 Pi</td><td>about fi</td><td>3 fi</td><td>ϋ 0 X</td>

<td>es cont</td><td>AND about about</td><td>of the Penal Code X P.</td><td> ^^ΝΥΥΊ 0</td>

<td>'ρί</td><td>$ -X WITH^-0· Ik</td><td>κ \-at.</td><td>Y — IL</td>

<td>No. Ex.</td><td> 476</td><td> 477</td><td> 478</td>

198

PL 204 281 B1

<img file="PL204281B1_D0171.tif" />

PL 204 281 B1

199

<td>NMR data</td><td>-xn - 12® r-4 xa «Ο x A ba χ XA r ι-M CN AM Tf pi « II “XR Ξ S 33 '-sa A 1 RO ΓΓί' -χ '*“ · " ⁴ . o * g PA o "®" orru χ as -&gt; QSa '^ a ~' * =&gt; x 2 npa -r ^ - a , -C. ^m this " * §XS'-if &amp; A £ = ea because R r Zn "iowo &lt;7 0 \ P rf ± 2 M n- ui w-ι 2 M</td><td>e? °° tO O , &lt;n CJ S E &lt;every r-5 s ^ - x »Il * 7 O Γ-l ° 9 p »am tri A 00 ¹⁰ 72 «A -" J, - || -Ha .- E cf, τ χ-, a MA ^K. x2m has X ę X es _Q B © ti X “R g2x £ R \ OC?₌m § OO M OJ TT O 5 »§, ci AA UiiDiri C iz- Λ Ρ Ν Ό 2 AR Em M Π S? . C? Ch * &lt;ΧΓ AR Ω en K Róż · £ Ξ7 * “A r ”7“ x23 ^ 5 j |! 73 7 ^ n -o 2 £ s * ŚERa - “s R ^ £ R z N t&gt;, (Ν n;&gt; χ ^ζ ; in Bd2śeS3S ^ S</td><td>ζ-ϊ, T3 OEA cn from «β p ai, &amp; amas £ gP ^ r-iMmmASS 5. _. · »C ψ Ά 'Ί © ZS ba r σ&gt; A o E. A a ^ S-ooAmaR - s -O © A - * X -R “ SRAt xa g MA TAXA νη M © - s'5? W-tO? . 4 \ o «- 50 0. «Ί W - m u. _R R t-&gt; © S £ 17 22 * ​​R Ci With rsóctoX0 νι;&gt; &lt;; a χΑ aaag ®. aa "CJ-r— · η, 4- - 2 m —1 m</td>

<td>+ and + s</td><td> 447.06</td><td>A z s +</td><td> 470.15</td>

<td>Time retention / method</td><td>1.39 min Method B</td><td>1.34 min Method B</td><td>1.40 mht and 1 1 ; Method B</td>

<td>Out- connected mass part.</td><td> 446.86</td><td> 455.94</td><td>! and 469.97</td>

<td>Look</td><td>yellow precipitate</td><td>white precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>this</td><td>this</td><td>this</td>

<td>ti P5</td><td>about fi</td><td>3 0 fi</td><td>0 fi</td>

<td>ΓΜ this </td><td>about \ = o</td><td>&gt; Ϊ2 P.</td><td>/ -with \ = D ABOUT</td>

<td>Ćz</td><td>AT-</td><td>fi</td><td>b</td>

<td>No. Ex.</td><td>CN DOWN TT</td><td> 483</td><td> 484</td>

200

PL 204 281 B1

<img file="PL204281B1_D0172.tif" />

PL 204 281 B1

201

<td>NMR data</td><td>nj a κ τ and 3 _N , NX - s M -o Ή Hf “oi ® b £ 3 1— 'i «' W) (| 3. π S -B iS! -M g u? £ 4 «^^and Ξ Q eJ X Ε Ή ₌Λ η A x O II - £ + 3 ϊ 4 ^ £ rs £ 2 $ CN -X Λχ'ΰ ^ Z - · X «it, o - C.II - St - cn 0-7</td><td>t— ⁱⁿ —- Lo * * ·. _Λr- '»ŚK ^ Β e ~ £ 4 aa .if --5-42. - ? ^&gt; Ps'd 44 xt- oo a —to oa · 8 “Ϊ-3 ^ ί · '£ ε; ι; _x ^ CN ««. 4 yy ON S ~ ~ k- 2 © "WJ X 7 u · 4 X. 4 - U Φ 3 »? «7 A 4 X «ο _Λη X tA b *} Pu-; at *. and rir-oir, «- n, N -</td><td> 2? —¹ ~—¹ - by σ. r-^andSP2g4®4 j '“-dear_s-and^m - d 3 χ χ c, χγΏϊτΓ8 ^ λ * Π ^ U CN «0 ^M. CM *? &lt;N U &lt;Ń _- ta - cn it O Β 3βθ ^ * Π ci 4 4 o cs &lt;N rn 4 “. , 2 + TO * τ ± · —ζ κ'ί ^ εώερε g - r- oo ~ TO- &lt;N</td>

<td>+ and + 2</td><td> 488.34</td><td> 504.41</td><td>this* X 00 THIS*</td>

<td>Time retention / method</td><td>1.63 min Method D</td><td>1.40 min Method A</td><td>AND- 1.27 min Method B</td>

<td>Out- connected mass part.</td><td> 487.96</td><td>X Axis H. © wi</td><td> 485.97</td>

<td>Look</td><td>white precipitate . and</td><td>whitish precipitate</td><td>white precipitate</td>

<td>Scheme reaction</td><td>X</td><td>X</td><td>X</td>

<td>oi</td><td>about fi</td><td>about fi</td><td>about fi</td>

<td>CM ©</td><td>-with</td><td>\ about $ 12 \ = o about</td><td>\ about $ xz \ = o about</td>

<td>oi</td><td>w- \ y —— u- at_</td><td>XL</td><td>Λ</td>

<td>No. Ex. -1</td><td>00 o. o THIS</td><td>Axis 00 THIS*</td><td>© Axis THIS*</td>

202

PL 204 281 B1

<img file="PL204281B1_D0173.tif" />

PL 204 281 B1

203

<td>NMR data</td><td>cS H - fi © u. Γ ^ · g »PW 1! r- r ~ 'hu ffi - S cj ₌· t- i M «X A- - -tf s 3 p κ ° =. (7X - £ "M mm O S-iąs ~ P &amp; gpS g - T m £ g =! s O g&gt; i "'M o« ~ m 7 § * j £ ś2- d &lt;t ri ii N u S § Si r- jXL ^&gt; i_l ​​_r rn O TT rs rj O Hj rt «B r ~« Nl [&lt;s N ri 3</td><td>L. '-'s " Ie -D ^J. ✓—% _ Λ ii _ PP _T fu -e £ Ax $ d £ Ps. ^ And pPP · ^ w® εχ 5 ® S _r (X ^ '- * d -' -a · 'j P g - Tl », —7 π X c ffl * §Gii '3 -iP®KS «S ^ x5. ^ ίΡ'ά ^ ζ-3 u jf '^ - ^ S'S^{o. o}7^l'S.^,^^r3. 7 -τ Ό ΊΤ⁵ - \ q1 jjj, 2 xq&gt; pg ^ ffi *? - £ Z · - ć * 5 X: _ ί-s. · - * e&gt; fc - · - 'h »CO I — 1 l / Γ W' ν- 'ΓΝ r- *' i '</td><td>Kp.gi. , | ~ fShSŚMS ^ o '-' ns &lt;_p u '^and° ** ie * iC ό £ X, About £? Λ m -X p^M. - cm gS ^ SstfE £ 2 Z Γ4 rt ^ rŁ Λ &lt;r&gt; τ-f- ιλ β, ^ " X¹ 2ί * - and «Ll r- -j- 3</td>

<td>+ and + 2</td><td>•-and Φ pi * n</td><td>uO at oC V *</td><td>Ό thigh m «Ί</td>

<td>W 'ΓΓ * O 5 ii at</td><td>g co '2 C T3 S 2 - 2</td><td>d ⁰³'g &lt;3 p 1 M 1&gt; - 2</td><td>"&lt;C 3« 3 C TJ Λ 2 un,&gt; - 2</td>

<td>$ 1 i &gt; ssa</td><td>r- AXIS ABOUT\ Buy</td><td>ł — Ϊ about cK 10 in</td><td>□&gt; \ n - Γ * Ί V)</td>

<td>Look</td><td>&gt; p £ TO «sn PS '^Λ.5 st Lo</td><td>Λ 32S -2 °</td><td>&gt; 4 TQ XI o</td>

<td>^s V Ł&gt; X x?! Cj v IN</td><td>Ό</td><td>\about</td><td>V3</td>

<td>r * i aS</td><td>at P.</td><td>5 P.</td><td>V P.</td>

<td>Π K.</td><td>•-with y = o 0 /</td><td>q xz S = o 0 /</td><td>\ about iZ V = Q ABOUT</td>

<td> ¢4</td><td>£ - about 4 * ł AT-</td><td>^έΡ at-</td><td>h at LOAM</td>

<td>and with £</td><td>in C&gt; S 1</td><td>UD</td><td>r- CN * d-</td>

204