8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments

The present invention relates to novel substituted xanthines of general formula

<img file="RS52142B_D0001.tif" />

to their tautomers, stereoisomers, mixtures, their prodrugs and their salts, and in particular to their pharmaceutically acceptable salts with inorganic or organic acids or bases having valuable pharmacological properties, and in particular inhibiting effect on the activity of the enzyme dipeptidylpeptidase - IV (DPP-IV), to obtain them, their use for the prevention or treatment of diseases and conditions associated with increased DPP-IV activity or the ability to prevent or alleviate them by reducing DPP-IV activity, and in particular type I or type II diabetes mellitus, to pharmaceutical compositions containing a compound of general formula (I) or pharmaceutically acceptable salts thereof, as well as methods for its preparation.

In the upper formula I

R¹ denotes a 4-methoxy-1-naphthylmethyl group,

2-quinolinylmethyl, 4-quinolinylmethyl or 6-quinolinylmethyl group,

1-isoquinolinylmethyl, 3-methyl-1-isoquinolinylmethyl, 4-methyl-1-isoquinolinylmethyl or 3-isoquinolinylmethyl group or

2-quinazolinylmethyl, 4-methyl-2-quinazolinylmethyl or 4-quinazolinylmethyl group,

R² denotes a methyl group and

R³ denotes a 2-buten-1-yl or 2-butin-1-yl group,

52142 Β their tautomers, enantiomers, diastereomers, mixtures thereof and their salts.

The following compounds of general formula I are particularly preferred:

(1) 1 - [(quinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - ((R) -3-amino-piperidin-1-yl) - xanthine, (2) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - ((S) -3-amino-piperidine -1-yl) xanthine, (3) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - (R) - 3-Amino-piperidin-1-yl) -xanthine, (4) 1 - [(4-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - ((S) -3-amino-piperidin-1-yl) -xanthine, (5) 1 - [(4-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - ((R) -3-aminopiperidin-1-yl) ) - xanthine, (6) 1 - [(4-methoxy-naphthalen-1-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (S) -3-aminopiperidine - 1-yl) xanthine, (7) 1 - [(4-methoxy-naphthalen-1-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - (R) - 3-Amino-piperidin-1-yl) -xanthine, (S) 1 - [(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - (3- (R) -Amino-piperidin-1-yl) -xanthine, as well as tautomers, enantiomers, diastereomers, their mixtures and their salts.

According to the invention the compounds of the general formula I are obtained by methods known per se, for example by the following methods:

a) by reacting a compound of general formula

52142 Β

<img file="RS52142B_D0002.tif" />

R² where

R¹ to R³ are defined as above and

WITH¹ means a separable group, such as a halogen atom, a substituted hydroxy, mercapto, sulfinyl, sulfonyl or sulfonyloxy group, such as a chlorine or bromine atom, a methanesulfonyl or methanesulfonyloxy group, its enantiomers or its 3-aminopiperidine salts.

Suitably the reaction is carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, optionally in the presence of an inorganic or tertiary organic base, e.g. sodium carbonate, potassium carbonate or potassium hydroxide, tertiary organic bases, e.g. triethylamine, or in the presence of N-ethyl-diisopropylamine (Hinig's base), these organic bases being able to serve both as a solvent and optionally in the presence of a reaction accelerator, such as an alkali metal halide or a palladium-based catalyst, at temperatures between - 20 and 180 ° C, but preferably at temperatures between -10 and 120 ° C. However, the reaction can also be carried out without solvent or with an excess of 3-aminopiperidine.

b) separating the protecting group from the compounds of general formula

<img file="RS52142B_D0003.tif" />

R²

52142 Β where R¹, R² and R³ defined as above.

Terc. the butyloxycarbonyl group is preferably separated by acid treatment, such as trifluoroacetic acid or hydrochloric acid, or by treatment with bromotrimethylsilane or iodotrimethylsilane, optionally using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, methanol, methanol or methanol. ° C.

In the reactions described above, all reaction groups present such as carboxy, amino, alkylamino or imino groups during the reaction may be protected by conventional protecting groups which are separated again after the reaction.

For example, the protecting group for the carboxy group may be trimethylsilyl, methyl, ethyl, tert. butyl, benzyl or tetrahydropyranyl groups and protecting groups for amino, alkylamino or imino groups may be formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert. butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, and additionally, for the amino group, a phthalyl group.

Each protective shredder used is then subsequently separated, for example, by hydrolysis in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

However, the benzyl, methoxybenzyl or benzyloxycarbonyl groups are separated, for example, hydrogenolytically, e.g. hydrogen in the presence of a catalyst, such as palladium / activated carbon, in a suitable solvent, such as methanol, ethanol, ethyl acetate or ice-cold acetic acid, optionally with the addition of an acid, such as hydrochloric acid, at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C, and with hydrogen under a pressure of 1 to 7 bar, but preferably 3 to 5 bar. However, the 2,4-dimethoxybenzyl group is best separated in trifluoroacetic acid in the presence of anisole.

52142 Β

Terc. butyl or tert. the butyloxycarbonyl group is preferably separated by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The trifluoroacetyl group is preferably separated by treatment with an acid, such as hydrochloric acid, optionally in the presence of a solvent, such as acetic acid, at temperatures between 50 and 120 ° C, or by treatment with a sodium hydroxide solution, optionally in the presence of a solvent, such as tetrahydrofuran. at temperatures between 0 and 50 ° C.

The phthalyl group is preferably separated in the presence of a hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine, in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane, at temperatures between 20 and 50 ° C.

In addition, the obtained compounds of general formula I can be separated into their enantiomers and / or diastereomers, as mentioned above. Thus, for example, cis / trans mixtures may be separated into their cis and trans isomers, and compounds with at least one optically active carbon atom may. separate into their enantiomers.

Thus, for example, cis / trans mixtures can be separated by chromatography into their cis and trans isomers, while the resulting compounds of general formula I appearing as racemates can be separated by methods known as such (cf. Allinger NL and Eliel EL in Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971) to their optical antipodes, and compounds of general formula I with at least 2 asymmetric carbon atoms can be separated into their diastereomers based on their physicochemical differences using methods known as such, e.g. by chromatography and / or fractional crystallization, and, if these compounds are obtained in the form of racemates, then they can later be separated into the aforementioned enantiomers.

The enantiomers are preferably separated by separation by column chromatography on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance to form salts or derivatives such as e.g. esters or amides with a racemic compound, in particular acids and activated derivatives or their alcohols, and by separation

52142 Β mixtures of diastereomeric salts or derivatives thus obtained, e.g. based on differences in their solubility, while free antipodes can be isolated from pure diastereomeric salts or derivatives by the action of suitable reagents. Optically active acids in general use are e.g. D - and L - forms of tartaric acid or dibenzoyltartaric acid, di - o - tolylvic acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. The optically active alcohols may be, for example, (+) or (-) - menthol, and the optically active acyl group in the amides, for example, may be (+) - or (-) menthyloxycarbonyl.

In addition, the compounds of formula I can be converted into their salts, in particular for pharmaceutical use into pharmaceutically acceptable salts with inorganic or organic acids. Acids that can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumic acid, amber acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds of general formulas II to IV used as starting materials are either known from the literature or can be obtained by methods known from the literature (cf. Examples I to LXXI).

As described above, the compounds of general formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular an inhibitory effect on the enzyme DPP-IV.

The biological properties of the new compounds were examined as follows:

The ability of substances and their corresponding salts to inhibit DPP - IV activity can be demonstrated in a test using an extract of human colon cancer cell line Caco - 2 as a source of DPP - IV. Cell differentiation to induce DPP IV expression was performed as described in Reiher et al. in an article entitled Increased expression of intestinal cell line Caco - 2, which was published in Proc. Natl. Acad. Sci. Vol.

90, pp. 5757 - 5761 (1993). Cell extract was obtained from cells dissolved in buffer (10 mM Tris HCl, 0.15 M NaCl, 0.04 thi aprotinin, 0.5% Nonidet - P40, pH 8.0) by centrifugation at 35,000 g for 30 minutes at 4 ° C to remove cell debris. ).

The DPP - IV test was performed as follows:

52142 Β μΐ of substrate solution (AFC; AFC is amido - 4 - trifluoromethylcoumarin), final concentration 100 μΜ, was placed in cme microtiter plates. 20 μΐ of assay buffer (final concentrations of 50 mM Tris HCl pH 7.8, 50 mM NaCl, 1% DMSO) was added dropwise. The reaction was started by adding 30 μΐ of dissolved Caco - 2 protein (final concentration 0.14 pg of protein per well). The test substances tested are usually added pre-diluted to 20 μΐ, and the amount of test buffer is then reduced accordingly. The reaction was performed at room temperature, incubating for 60 minutes. Fluorescence was then measured in a Victor 1420 Multilabel Counter, the excitation wavelength was 405 nm, and the emission wavelength was 535 nm. Calibration readings (corresponding to 0% activity) were performed on mixtures without any Caco - 2 proteins (appropriate amount replaced with test buffer), while control values ​​(corresponding to 100% activity) were obtained in mixtures without added substances. The efficacy of the test substances, expressed through IC50 values, was calculated from dose / activity curves consisting of 11 measured points in each case. The following results were obtained:

<td>Compound (Example no.)</td><td>Inhibition of DPP - IV IC50 [nM]</td>

<td> 2(52)</td><td> 9</td>

<td> 2(80)</td><td> 1</td>

<td> 2(129)</td><td> 3</td>

<td> 2(130)</td><td> 3</td>

<td> 2(131)</td><td> 3</td>

<td> 2(132)</td><td> 1</td>

<td> 2(137)</td><td> 13</td>

<td> 2(138)</td><td> 8</td>

<td> 2(142)</td><td> 1</td>

The compounds obtained according to the invention are well tolerated, for example in the case where 10 mg / kg of the compound of Example 2 (80) given to rats orally no changes in animal behavior could be observed.

52142 Β

In terms of their ability to inhibit DPP - IV activity, the compounds of general formula I according to the invention and their corresponding pharmaceutically acceptable salts are suitable for the treatment of any condition or disease which may be affected by inhibition of DPP - IV activity. Therefore, it can be expected that the compounds according to the invention will be suitable for the prevention or treatment of diseases or conditions such as type 1 and type 2 diabetes mellitus, diabetic complications (such as e.g. retinopathy, nephropathy or neuropathy), metabolic acidosis or ketosis, reactive hypoglycaemia, insulin resistance, metabolic syndrome, dyslipidemia of various origins, arthritis, atherosclerosis and related diseases, obesity, allograft transplantation and calcitonin-induced osteoporosis. In addition, these substances are able to prevent the degeneration of B-cells, such as e.g. apoptosis or necrosis of pancreatic cells. These substances are also suitable for improving or restoring the functions of pancreatic cells as well as for increasing the number and size of B - pancreatic cells. In addition, based on the role of glucagon-like peptides (Glucagon - Like Peptides), such as e.g. GLP -1 and GLP - 2 and their connections with DPP - IV inhibition, it is probable that the compounds according to the invention are suitable for achieving, inter alia, a sedative or calming effect, as well as having a beneficial effect on catabolic conditions after surgery or on hormonal response to stress or reduced mortality or morbidity after myocardial infarction. They are also suitable for the treatment of all conditions associated with the above-mentioned effects and mediated by GLP-1 or GLP-2. The compounds of the invention may also be used as diuretics or antihypertensive agents and are suitable for the prevention and treatment of acute renal failure. Furthermore, the compounds according to the invention can be used for the treatment of inflammatory diseases of the respiratory tract. They are also suitable for the prevention and treatment of chronic inflammatory bowel diseases such as e.g. irritable bowel syndrome, abbr. IBS), Crohn's disease or ulcerative colitis, as well as pancreatitis. It is also likely that they can be used for all types of damage or worsening of the gastrointestinal tract, such as colitis and enteritis. It is also expected that DPP-IV inhibitors, and therefore the compounds of the invention, may be used in the treatment of sterility or to improve fertility in humans and mammals, especially when sterility is associated with insulin resistance or polycystic ovary syndrome. On the other hand, these substances are suitable for regulating sperm motility and can therefore be used as male contraceptives. These substances can also be used to treat growth hormone deficiencies that are related to small growth, and can also be used in all cases where growth hormones can be used. The compounds according to the invention are also suitable, due to their inhibitory effect on DPP - IV, for the treatment of various

52142 Β autoimmune diseases, such as e.g. rheumatoid arthritis, multiple sclerosis, thyroiditis, Bazedow's disease, etc. They can also be used to treat viral diseases and also, for example, in HIV infections, to stimulate blood production, in benign prostatic hyperplasia, gingivitis, as well as in the treatment of neuronal defects and neurodegenerative diseases, such as Alzheimer's disease. The described compounds can also be used in the treatment of tumors, in particular for modifying tumor invasiveness and also in metastases; examples of this are their use in the treatment of T-cell lymphoma, acute lymphoblastic leukemia, pancreatic cell tumors, basal cell tumors and breast tumors. Other indications are stroke, ischemia of various origins, Parkinson's disease and migraine. In addition, other indications include follicles and epidermal hyperkeratosis, increased keratinocyte production, psoriasis, encephalomyelitis, glomerulonephritis, lipodystrophy, as well as psychosomatic, depressive and neuropsychiatric diseases of all kinds.

The compounds according to the invention can also be used together with other active substances. Therapeutic reagents suitable for such combinations include, for example, antidiabetics such as metformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), pioglitazone. GI262570) and antagonists, PPAR-gamma / alpha modulators (eg KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), other DPPIV inhibitors, alpha2 antagonists, insulin and insulin analogs, GLP -1 and GLP -1 analogs (e.g. exendin - 4) or amylin. Also, SGLT2 inhibitors such as T-1095, protein tyrosine phosphatase 1 inhibitors, substances that affect the uncontrolled production of glucose in the liver, such as e.g. glucose-6-phosphatase or fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase, glucagon receptor antagonists and phosphoenol pyruvate carboxykinase inhibitors, glycogen synthase kinase or pyruvate dehydrokinase inhibitors, H-lowering reagents (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimib) or cholesterol resorption inhibitors, such as, for example, ezetimibe, bile acid-binding substances, such as cholestyramine, inhibitors of biliary acid transport from bile, HDL-raising compounds, such as CETP inhibitors, or ABCl regulators, or active substances for the treatment of obesity, such as e.g. sibutramine or tetrahydrolipostatin, dexfenfluramine, axokin, cannabinoid1 receptor antagonists, MCH-1 receptor antagonists, MC4 receptor agonists,

52142 Β agon5 or ΝΠΥ2 or β antagonists₃ - agonists, such as SB-418790 or AD-9677, as well as 5HT2c receptor agonists.

It is also possible to combine these compounds with drugs for the treatment of high blood pressure, such as e.g. AII antagonists or ACE inhibitors, diuretics, β-blockers, Ca antagonists, etc., or combinations thereof.

Accordingly, the doses required to achieve such effects are, intravenously, 1 to 100 mg, preferably 1 to 30 mg, and orally 1 to 1000 mg, preferably 1 to 100 mg, in both cases 1 to 4 times daily. To this end, the compounds of the formula I obtained according to the invention, optionally mixed with other active substances, can be incorporated together with one or more customary carriers and / or solvents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, Emunic acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol glycolloxymethyl alcohol, propylene alcohol substances, such as paraffin or suitable mixtures thereof, in conventional galenic preparations, such as plain or coated tablets, capsules, powders, solutions or suppositories.

The following examples are intended to illustrate the invention:

Preparation of starting compounds:

Example I

1,3 - dimethyl - 7 - (2,6 - dicyano - benzyl) - 8 - bromo - xanthine

A mixture of 555 mg of 8-bromoteophlin and 0.39 ml of Hing base in 9 ml of N, N-dimethylformamide was mixed with 600 mg of 2-bromomethyl-isophthalonitrile and stirred overnight at room temperature. For processing, the reaction mixture was poured into water. The precipitate formed was filtered off with suction, washed with water and dried.

Yield: 686 mg (83% of theory)

52142 Β

Rf value 0.56 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 399,401 [M + H]⁺

The following compounds were prepared analogously to Example I:

(1) 3-methyl-7- (3-methyl-2-buten-1-yl) -8-chloro-xanthine

Mass spectrum (ESI⁺): m / z = 269,271 [M + H]⁺ (2) 3-methyl-7- (2-cyano-benzyl) -8-chloro-xanthine

Mass spectrum (ESI⁺): m / z = 316, 318 [M + H]⁺ (3) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2-butyn-1-yl) -8-bromo-xanthine

Mass spectrum (ESI⁺): m / z = 415,417 [M + H]⁺ (4) 3-methyl-7 - [(2-trimethylsilanyl-ethoxy) methyl] -8-bromo-xanthine (Performed in the presence of potassium carbonate)

Mass spectrum (ESI⁺): m / z = 375,377 [M + H]⁺ (5) 3-methyl-7- (3-methyl-2-buten-1-yl) -8-bromo-xanthine

Mass spectrum (ESI⁺): m / z = 313,315 [M + H]⁺ (6) 3-methyl-7- (2,3-dimethyl-2-buten-1-yl) -8-bromo-xanthine

RfValue: 0.43 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI⁺): m / z = 327, 329 [M + H]⁺ (7) 3-methyl-7- (2-butyn-1-yl) -8-bromo-xanthine

Rf value: 0.72 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m / z = 297/299 [M + H]⁺ (8) 3 - methyl - 7 - ((E) -2 - buten - 1 - yl) - 8 - bromo - xanthine (Product contaminated with approx. 10 - 20% of Z compound)

R_f value: 0.55 (silica gel, cyclohexane / ethyl acetate / methanol = 6: 3: 1)

Mass spectrum (ESI⁺): m / z = 299,301 [M + H]⁺ (9) 3-methyl-7 - [(1-cyclopenten-1-yl) methyl] -8-bromo-xanthine

52142 Β

Mass spectrum (ESI⁺): m / z = 325,327 [M + H]⁺ (10) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7 - [(1-cyclopenten-1-yl) methyl] -8-bromo xanthine

Mass spectrum (ESI⁺): m / z = 443, 445 [M + H]⁺ (11) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- ((E) -2-buten-1-yl) -8-bromo-xanthine (the product contains approximately 25% Z isomer)

Mass spectrum (ESI⁺): m / z = 417,419 [M + H]⁺ (12) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2-methyl-allyl) -8-bromo-xanthine

R_f value: 0.71 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 417, 419 [M + H]⁺ (13) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (3-bromo-allyl) -8-bromo-xanthine

R_f value: 0.68 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 481,483,485 [M + H]⁺ (14) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7 - [(furan-2-yl) methyl] -8-bromo-xanthine

R_f value: 0.60 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI +): m / z = 443.445 [M + H]⁺ (15) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2-chloro-allyl) -8-bromo-xanthine

Rf value: 0.77 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 437,439,441 [M + H]⁺ (16) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- ((Z) -2-methyl-2-buten-1-yl) -8-bromo xanthine

Rf value: 0.77 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 431,433 [M + H]⁺ (17) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- ((E) -2-methyl-2-buten-1-yl) -8-bromo xanthine

Rf value: 0.77 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 431, 433 [M + H]⁺

52142 Β (18) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (1-phenylsulfanyl-butyl) -8-bromo-xanthine R_f value: 0.83 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 527,529 [M + H]⁺ (19) 3-Methyl-7- (3-methyl-1-phenylsulfanyl-butyl) -8-bromo-xanthine [[(1-chloro-3-methyl-butyl) sulfanyl] -benzene used as starting material is obtained by chlorination of [(3-methyl-butyl) sulfanyl] -benzene with N-chloro-succinimide to carbon tetrachloride)

Rf value: 0.38 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 423.425 [M + H]⁺ (20) 1,3 - dimethyl - 7- (2 - bromo - benzyl) - 8 - chloro - xanthine

R_f value: 0.50 (silica gel, cyclohexane / ethyl acetate = 1: 1) (21) 1,3-dimethyl -7- (2-chloro-benzyl) -8-chloro-xanthine

R_f value: 0.50 (silica gel, cyclohexane / ethyl acetate = 1: 1) (22) 3 - cyclopropyl -7- (2-butyn-1-yl) -8-bromo-xanthine

Rf value: 0.45 (prepared plate for reverse-phase TLC (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass spectrum (ESI⁺): m / z = 223/225 [M + H]⁺

Example II

1- (2- (2 - [(ethoxycarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8-GZ - (tert Butyloxycarbonylamino) -piperidin-1-yl] -xanthine mg ethyl bromoacetate was added to a mixture of 200 mg 1- [2- (2-hydroxy-phenyl) -2-oxo ethyl] -3-methyl-7- (3-methyl- 2 - buten - 1 - yl) - 8 - [3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine and 63 mg of potassium carbonate in 3 ml of N, N-dimethylformamide. The reaction mixture was stirred for five hours at room temperature. For processing, it was mixed with water and the precipitate formed was filtered off with suction, washed with water and dried for three hours at 80 ° C in a rack dryer.

Yield: 216 mg (94% of theory)

Mass spectrum (ESI⁺): m / z = 653 [M + H]⁺

52142 Β

The following compounds were prepared analogously to Example II:

(1) 1- (2- (2 - [(aminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-

- buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m / z = 624 [M + H]⁺ (2) 1- (2 - (3 - [(methylsulfanyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [ 3- (tert. Butyloxycarbonylamino) -piperidin-1-yl] -xanthine RfValue: 0.20 (silica gel, cyclohexane / ethyl acetate = 6: 4)

Mass spectrum (ESI⁺): m / z = 627 [M + H]⁺ (3) 1- (2- (3 - [(ethoxycarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-

- buten-1-yl) -8- (3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.50 (silica gel, cyclohexane / ethyl acetate = 3: 7) (4) 1- (2- (2- (methylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl -7 - (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (ESI)⁺): m / z = 638 [M + H]⁺ (5) 1- (2 - (2 - [(dimethylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3) - (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (ESI)⁺): m / z = 652 [M + H]⁺ (6) 1- (2- (3- (3- (methoxycarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-

- buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m / z = 639 [M + H]⁺ (7) 1- (2- (2- (ethylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl -7- (2butin -1-11) -8 - ((7 ^ -3) - (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (ESI)⁺): m / z = 636 [M + H]⁺ (8) 1- (2- (2 - [(methylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (1-cyclopenten-1-yl) methyl] -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] xanthine

Mass spectrum (ESI⁺): m / z = 650 [M + H]⁺

52142 Β (9) 1- (2- (2 - [(methylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2butin-1-yl) -8 - [3- (tert butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 622 [M + H]⁺ (10) 1- (2- (2 - [(aminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2-butyne)

- yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 608 [M + H]⁺ (11) 1- (2- (2 - [(methoxycarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2butin-1-yl) -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (ESI)⁺): m / z = 623 [M + H]⁺ (12) 1- (2- (2 - [(isopropyloxycarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8 - [ 3 - (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m / z = 667 [M + H]⁺ (13) 1- (2- (2 - [(methylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2butin-1-yl) -8 - [(N - 3) - (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (ESI)⁺): m / z = 622 [M + H]⁺ (14) 1- (2- (2 - [(methylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (E) -

- buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (product contains some Z isomers)

Rf value: 0.35 (silica gel, cyclohexane / ethyl acetate / methanol = 5: 4: 1)

Mass spectrum (ESI⁺): m / z = 624 [M + H]⁺ (15) 1- (2- (2 - [(ethylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2butin-1-yl) -8 - [(5) - 3 - (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (ESI)⁺): m / z = 636 [M + H]⁺ (16) 1- (2- (2 - [(methylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2butin-1-yl) -8 - [(5) - 3 - (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (ESI +): m / z = 622 [M + H]⁺

52142 N (17) 1- (2- (2- [(methoxycarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m / z = 639 [M + H]⁺ (18) 1- (2- (2- (methylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8 - [( 5) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] xanthine

Mass spectrum (ESI +): m / z = 638 [M + H]⁺ (19) 2- (2-acetyl-phenoxy) -N-ethyl-acetamide

Mass spectrum (ESI⁺): m / z = 222 [M + H]⁺ (20) 1- (2- (2- (1-methoxycarbonyl-ethoxy) -phenyl] -2-oxo-ethyl} -3-methyl-7- (2butin-1-yl) -8- [3- (tert Butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (EST): m / z = 637 [M + H]⁺ (21) 1- (2- (2- (1-aminocarbonyl-ethoxy) -phenyl] -2-oxo-ethyl} -3-methyl-7- (2butin-1-yl) -8- [3- (tert Butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (ESI)⁺): m / z = 622 [M + H]⁺ (22) 2- (2-acetyl-phenoxy) -N-methyl-acetamide

Mass spectrum (ESI +): m / z = 208 [M + H]⁺ (23) 1- (2- (2- (2-oxo-propoxy) -phenyl] -2-oxo-ethyl} -3-methyl-7- (2-butyn-1-yl) 8- [3 - ( tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 607 [M + H]⁺ (24) 1- (2- (2- (1-ethoxycarbonyl-1-methyl-ethoxy) -phenyl] -2-oxo-ethyl} -3-methyl-7- (2-butin-1-yl) -8- (3- (tert-butoxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (ESI)⁺): m / z = 665 [M + H]⁺ (25) 1- (2- (2-cyanomethoxy-phenyl] -2-oxo-ethyl} -3-methyl-7- (2-butyn-1-yl) -8- (3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 590 [M + H]⁺

52142 26 (26) 1- (2- (2 - [(methylsulfanyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2-butyn-1-yl) -8- [3- ( tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 611 [M + H]⁺ (27) 1 - {[2- (tert-butylcarbonyl) -benzofuran-3-ylmethyl} -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1 - yl] - xanthine (Formed as the main product when 1 - [2 - (2 - hydroxy - phenyl) - 2 - oxo - ethyl] - 3 - methyl - 7 (2 - butin -1 - yl) - 8 - (3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine reacts with 1-chloro-3,3-dimethyl-butane-2-one)

Mass spectrum (ESI⁺): m / z = 631 [M + H]⁺

Example III

- [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8 - [3- (tert-butyloxycarbonylamino) -piperidine -1 - ill - xanthine

1.30 g 3 - terc. butyloxycarbonylamino-piperidine was added to a mixture of 2.51 g of 1- [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8-chloro xanthine and 880 mg of sodium carbonate in 8 ml of dimethylsulfoxide. The reaction mixture was stirred at 60 ° C for 18 hours. For processing, it is mixed with water and a precipitate is formed

V filtered by suction. The solid crude product was dissolved in ethyl acetate, and the solution was dried over magnesium sulfate and evaporated. The residue from the flask was chromatographed on a silica gel column with cyclohexane / ethyl acetate (10: 1 to 1: 1) as eluent. Yield: 2.56 g (91% of theory)

Mass spectrum (ESI⁺): m / z = 567 [M + H]⁺

The following compounds were prepared analogously to Example III:

(1) 3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 433 [M + H]⁺ (2) 1- (1-methyl-2-oxo-2-phenyl-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3 (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 565 [M + H]⁺

52142 Β (3) 3-methyl-7- (2-cyano-benzyl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.90 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI '): m / z = 478 [M - H] (4) 1 - methyl - 3 - [(methoxycarbonyl) methyl] -7- (2 - cyano - benzyl) - 8 - [3 - (tert butyloxycarbonyl-amino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 552 [M + H]⁺ (5) 1-methyl-3-cyanomethyl-7- (2-cyano-benzyl) -8- [3- (tert.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 519 [M + H]⁺ (6) 1-methyl-3- (2-propyn-1-yl) -7- (2-cyano-benzyl) -8- [3- (tert.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ES1⁺): m / z = 518 [M + H]⁺ (7) 1- [2- (3-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3 (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf Value: 0.25 (silica gel, cyclohexane / ethyl acetate / methanol = 7: 2: 1)

Mass spectrum (ESI +): m / z = 596 [M + H]⁺ (8) 1-methyl-3- (2-propene-1-yl) -7- (2-cyano-benzyl) -8- [3- (tert.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 520 [M + H]⁺ (9) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] - xanthine

Mass spectrum (ESI⁺): m / z = 535 [M + H]⁺ (10) 1- [2- (2-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.52 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m / z = 596 [M + H]⁺

52142 11 (11) 1-methyl-3-phenyl-7- (2-cyano-benzyl) -8- [3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 556 [M + N]⁺ (12) 1- [2- (2-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8 [(S) -3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 596 [M + H]⁺ (13) 1 - [(quinolin-4-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1 - yl] - xanthine mixed with 1 - [(1,4 - dihydroquinolin - 4 - yl) methyl] -3 - methyl - 7 - ((3 - methyl - 2 - buten - 1 - yl) - 8 - [3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.62 (silica gel, ethyl acetate) (14) 1 - ({4 - oxo - 3 - [(2 - trimethylsilanyl - ethoxy) methyl] - 3,4 - dihydro - phthalazin - 1 - yl} methyl) - 3-methyl -7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine (Made with potassium carbonate in the presence of a Hinig base)

Rf value: 0.27 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m / z = 720 (M + HR) (15) 1 - [(isoquinolin-3-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8 - [ 3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.31 (silica gel, ethyl acetate / petroleum ether = 7: 3)

Mass spectrum (ESI⁺): m / z = 574 [M + H]⁺ (16) 1 - [(3-methyl-4-oxo-3,4-dihydro-phthalazin-1-yl) methyl] -3-methyl-7- (3-methyl 2-buten-1-yl) -8 - [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.45 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 95: 5)

Mass spectrum (ESI⁺): m / z = 605 [M + H]⁺

52142 17 (17) 3-methyl-7- (2,3-dimethyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine (Made with potassium carbonate)

Rf value: 0.42 (silica gel, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m / z = 447 [M + H]⁺ (18) 3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Made with potassium carbonate)

Melting point: 235 - 237 ° C

Mass spectrum (ESI⁺): m / z = 417 [M + H]⁺ (19) 1 - [(quinolin-4-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] - xanthine (Made with potassium carbonate)

Rf Value: 0.36 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m / z = 558 [M + H]⁺ (20) 1 - [(isoquinolin-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] - xanthine (Made with potassium carbonate)

Rf value: 0.71 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m / z = 558 [M + H]⁺ (21) 1 - [(isoquinoline -1 -11) methyl] -3 - methyl - 7 - ((E) -2-buten-1-yl) - 8 - [3- (tert-butyloxycarbonylamino) -piperidine -1 - yl] - xanthine (Made with potassium carbonate; product contains approx. 20% Z isomer)

R_f value: 0.24 (silica gel, ethyl acetate / petroleum ether = 1: 1)

Mass spectrum (ESI⁺): m / z = 560 [M + H]⁺ (22) 3-methyl-7- (2-butyn-1-yl) -8 - [(N-3- (tert-butyloxycarbonylamino) -piperidine 1 -11] -xanthine (Made with potassium carbonate)

52142 Β

R_f value 0.64 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m / z = 417 [M + H]⁺ (23) 3-methyl-7- (2-butyn-1-yl) -8 - [(S) -3- (tert-butyloxycarbonylamino) -piperidin 1-yl] -xanthine (Made with potassium carbonate)

R_f value 0.64 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m / z = 417 [M + H]⁺ (24) 3-methyl-7- ((E) -2-buten-1-yl) -8 - [(S) -3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine (the product contains approx. 15% Z isomer)

Rf value: 0.35 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m / z = 419 [M + H]⁺ (25) 3-methyl-7 - ((E) -2-buten-1-yl) -8 - [(.A) -3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine (the product contains approx. 15% Z isomer)

R_f value: 0.35 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m / z = 419 [M + H]⁴ (26) 1- [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butin-1-yl) -8- [SL) -3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 551 [M + H]⁺ (27) 1- [2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7 - [(1-cyclopenten-1-yl) methyl] -

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 578 [M + H]⁺ (28) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7 - [(1-cyclopenten-1-yl) methyl] -8- [3- (tert-butyloxycarbonylamino) -piperidine -1 - il] - xanthine

Mass spectrum (ESI⁺): m / z = 563 [M + H]⁺

52142 Β (29) 1- [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7 - [(1-cyclopenten-1-yl) methyl] -8- [3- (tert butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 579 [M + H]⁺ (30) 1-methyl-3-isopropyl-7- (2-cyano-benzyl) -8- [3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 522 [M + H]⁺ (31) 1- [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 551 [M + H]⁺ (32) 1- [2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- (E) -2-buten-1-yl) -8- [3- (terc) butyloxycarbonylamino) -piperidin-1-yl] -xanthine (product contains approx. 10% Z isomer)

Rf value: 0.20 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m / z = 552 [M + H]⁺ (33) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- ((E) -2-buten-1-yl) -8- [3- (tert.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine (product contains approx. 25% Z isomer)

Mass spectrum (ESI⁺): m / z = 537 [M + H]⁺ (34) 1- [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8 - [(7j) -3- (tert butyloxycarbonylamino) - piperidin-1-yl] -xanthine (35) 1- [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- ((E) -2-butene - 1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (the product contains some Z isomers)

Rf Value: 0.30 (silica gel, cyclohexane / ethyl acetate = 4: 6)

Mass spectrum (ESI⁺): m / z = 553 [M + H]⁺ (36) 1- [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8 - [(S) -3 - (tert) butyloxycarbonylamino) -piperidin-1-yl] -xanthine

52142 Β

Mass spectrum (ESI⁺): m / z = 551 [M + H]⁺ (37) 1- [2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Rf value: 0.50 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 550 [M + H]⁺ (38) 1- [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -

- [(S) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 567 [M + H]⁺ (39) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2-butyn-1-yl) -8 - [(7t) -3- (tert-butyloxycarbonylamino) -piperidine- 1 - yl] - xanthine

Mass spectrum (ESI⁺): m / z = 535 [M + H]⁺ (40) 1-methyl-3 - [(2-trimethylsilanyl-ethoxy) methyl] -7- (2-cyano-benzyl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 610 [M + H]⁺ (41) 3-Methyl-7- (2-butyn-1-yl) -8 - [(S) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Made with potassium carbonate)

Rf value: 0.52 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m / z = 417 [M + H]⁺ (42) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2-methyl-allyl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.46 (silica gel, methylene chloride / methanol = 95; 5) (43) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (3-bromo-allyl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.22 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 601, 603 [M + H]⁺

52142 Β (44) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7 - [(furan-2-yl) methyl] -8- [3- (tert-butyloxycarbonylamino) -piperidine-1- il] - xanthine

Rf value: 0.41 (silica gel, methylene chloride / methanol = 95: 5) (45) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2-chloro-allyl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.49 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 557,559 [M + H]⁺ (46) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2-butyn-1-yl) -8 - [(S) -3- (tert.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 535 [M + H]⁺ (47) 1- [2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- ((E) -2-buten-1-yl) - 8- [(5) 3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.40 (silica gel, cyclohexane / ethyl acetate = 4: 6)

Mass spectrum (ESI⁺): m / z = 552 [M + H]⁺ (48) 1- [2- (2-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- ((E) -2-butene -1-11) -8- [(A) -

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.50 (silica gel, cyclohexane / ethyl acetate = 1: 2) (49) 1 - [2- (2-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (E) - 2 - buten - 1 - yl) - 8- [(S) -

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 582 [M + H]⁺ (50) 1- [2- (2-nitro-3-methoxy phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum (ESI)⁺): m / z = 626 [M + H]⁺ (51) 1- (2- (2-oxo-3 - [(2-trimethylsilanyl-ethoxy) methyl] -2,3-dihydro-benzooxazol 7-yl} -2-oxo-ethyl) -3-methyl-7 - (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 738 [M + H]⁺

52142 52 (52) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- ((Z) -2-methyl-2-buten-1-yl) -8- [3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.48 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 551 [M + H]⁺ (53) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- ((E) -2-methyl-2-buten-1-yl) -8- [3 (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 551 [M + H]⁺ (54) 1- (2- {2-oxo-3 - [(2-trimethylsilanyl-ethoxy) methyl] -2,3-dihydro-benzooxazol 4-yl} -2-oxo-ethyl) -3-methyl-7 - (2-butyn-1-yl) -8- [3- (tert.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.40 (silica gel, petroleum ether / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺&gt; ): m / z = 722 [M + H]⁺ (55) 1- [2- (2,2-difluoro-benzo [1,3] dioxol-4-yl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) - 8 - [(7t) -3 - (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m / z = 615 [M + H]⁺ (56) 1- [2- (2,2-difluoro-benzo [1,3] dioxol-4-yl) -2-oxo-ethyl] -3-methyl-7- (2butin-1-yl) -8 - [(5) -3 - (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m / z = 615 [M + H]⁺ (57) 1 - [(1-methyl-1H-indol-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1-yl] -xanthine

Rf value: 0.80 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 560 [M + H]⁺ (58) 1 - [(quinolin-3-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] - xanthine

R_f value: 0.50 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m / z = 558 [M + H]⁺

52142 59 (59) 1 - {[1 - (tert. Butyloxycarbonylamino) - 1H-indol-2-ylmethyl} -3 - methyl-7- (2butin-1-yl) - 8 - [3- (tert. Butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Rf value: 0.40 (silica gel, petroleum ether / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m / z = 646 [M + H]⁺ (60) 1 - [(2-methyl-1 - [(2-trimethylsilanyl-ethoxy) methyl] -1H-benzoimidazol-5-yl) methyl] 3-methyl-7- (2-butyn-1-yl) - 8 - [[3- (tert-butyloxycarbonylamino) -piperidin-1-yl] xanthine [mixed with 1 - [(2-methyl-3 - [(2-trimethylsilanyl-ethoxy) methyl] -3H-benzoimidazol-5-yl) methyl] - 3 - methyl -7- (2-butyn-1-yl) -8 - [3- (tert.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine)

R_f value: 0.15 (silica gel, ethyl acetate)

Mass spectrum (ESI +): m / z = 691 [M + H]⁺ (61) 1- [2- (quinolin-8-yl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Rf value: 0.35 (silica gel, methylene chloride / methanol = 95: 5)

Ma ss spectrum (ESI⁺): m / z = 586 [M + H]⁺ (62) 1 - [(1 - [(2-trimethylsilanyl-ethoxy) methyl] -1H-benzoimidazol-5-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- [3 - (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine [mixed with 1 - [(3 - [(2-trimethylsilanyl-ethoxy) methyl] -377-benzoimidazol-5-yl) methyl] 3-methyl-7 - (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] xanthine)

Rf value: 0.23 (siEka gel, ethyl acetate)

Mass spectrum (ESI⁺): m / z = 677 [M + H]⁺ (63) 1 - [(pyrazolo [1,5-aipyridin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1-yl] -xanthine

Rf value: 0.46 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 547 [M + H]⁺ (64) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- ((E) -1-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Rf value: 0.48 (silica gel, methylene chloride / methanol = 95: 5)

52142 Β

Mass spectrum (ESI⁺): m / z = 537 [M + H]⁺ (65) 1- (2 - [1- (tert-butyloxycarbonyl) -1H-indol-7-yl] -2-oxo-ethyl} -3-methyl-7- (2-butin-1-yl) -8 - [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.38 (silica gel, petroleum ether / ethyl acetate = 1: 1) (66) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (3-methyl-1) - buten-1-yl) -8- [(L) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.40 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 588 [M + H]⁺ (67) 1,3-dimethyl-7- (2-bromo-benzyl) -8- [3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine

Rf value: 0.40 (silica gel, cyclohexane / ethyl acetate = 1: 1) (68) 1,3 - dimethyl -7- (2-chloro-benzyl) -8- [3- (tert-butyloxycarbonylamino) piperidine-1 - il] - xanthine

R_f value: 0.42 (silica gel, cyclohexane / ethyl acetate = 1: 1) (69) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-cyano-benzyl) - 8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 635 [M + H]⁺

Rf value: 0.40 (silica gel, cyclohexane / ethyl acetate = 3: 7) (70) 3 - cyclopropyl -7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine 1 - il] - xanthine

Mass spectrum (ESI⁺): m / z = 443 [M + H]⁺

Rf value: 0.70 (silica gel, ethyl acetate) (71) 3-cyclopropyl -7- (2-butyn-1-yl) -8 - [([0 - 3 - (tert-butyloxycarbonylamino) piperidin-1-yl]) - xanthine

Rf value: 0.35 (reverse phase TLC prepared plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass spectrum (ESI⁺): m / z = 443 [M + H]⁴·

52142 Β (72) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-chloro-benzyl) -8 - ((7'-3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 644, 646 [M + H]⁺

Rf value: 0.39 (silica gel, cyclohexane / ethyl acetate = 1: 1) (73) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-bromo-benzyl) -8 - [(N- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 644,646 [M + H]⁺ (74) 1 - [(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-chloro-benzyl) -8 - [(7t) -3 (tert-butyloxycarbonylamino) -piperidine - 1 - yl] - xanthine

It is obtained by reaction with (4-methyl-quinazolin-2-yl) -methyl chloride and 3-methyl-7- (2-chlorobenzyl) -8-bromo-xanthine, followed by reaction with (7t) -3- (tert-butyloxycarbonylamino) - piperidine

Mass spectrum (ESI⁺): m / z = 645,647 [M + H]⁺ (75) 1- (4-phenyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-chloro-benzyl) -8 - ((N- (tert-butyloxycarbonylamino) -piperidine- 1 - yl] - xanthine

Obtained by reaction with (4-phenyl-quinazolin-2-yl) -methyl chloride and 3-methyl-7- (2-chlorobenzyl) -8-bromo-xanthine, followed by reaction with (7t) -3- (tert-butyloxycarbonylamino) - piperidine

Mass spectrum (ESI⁺): m / z = 707.709 [M + H]⁺

Example IV

1- (2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8 chloro-xanthine

Obtained by treating 1- (2- (2-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl 2-buten-1-yl) -8-chloro-xanthine with boron tribromide in methylene chloride The desired product is contaminated with about 20% 1 - [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-bromo-3-methyl-butyl) - 8 - chloro - xanthine.

Mass spectrum (ESI⁺): m / z = 403,405 [M + H]⁺

52142 Β

The following compounds were prepared analogously to Example IV:

(1) 1- (2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8-bromo xanthine (the product is contaminated with approx. 20% 1- [2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-bromo-2-buten-1-yl) -8-bromo-xanthine)

Mass spectrum (ESI⁺): m / z = 431,433 [M + H]⁺ (2) 1- (2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7 - ((1-cyclopenten-1-yl) methyl] -

- bromo - xanthine

Mass spectrum (ESI⁺): m / z = 459,461 [M + H]⁺ (3) 1- (2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (E) -2-buten-1-yl) -8 bromo-xanthine (product contains some Z isomers)

Rf value: 0.60 (silica gel, cyclohexane / ethyl acetate = 4: 6)

Mass spectrum (ESI⁺): m / z = 433,435 [M + H]⁺ (4) 1- (2- (2-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8-bromo-xanthine)

Mass spectrum (ESI⁺): m / z = 447,449 [M + H]⁺

Example V

1- (2- (2-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8 chloro-xanthine

1.71 g of 2-bromo-1- (2-methoxy-phenyl) -ethanone were added to a mixture of 2.00 g of 3-methyl-7- (3-methyl-2-buten-1-yl) -8-chloro-xanthine and 1.38 mg of potassium carbonate. in 15 ml of N, N dimethylformamide. The reaction mixture was stirred for eight hours at room temperature. After treatment with water, the crude product was purified by column chromatography on silica gel with cyclohexane / ethyl acetate (8: 1 to 8: 1) as eluent.

Yield: 2.61 g (84% of theory)

Mass spectrum (ESI⁺): m / z = 417,419 [M + H]⁺

52142 Β

The following compounds were prepared analogously to Example V:

(1) 1- (2- (3-hydroxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8 [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine (reaction performed with 2-bromo--1- [3- (tert-butyldimethylsilanyloxy-phenyl] ethanone)

Rf Value: 0.40 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m / z = 567 [M + H]⁺ (2) 1- (1-methyl-2-oxo-2-phenyl-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8 chloro-xanthine

Mass spectrum (ESI⁺): m / z = 401,403 [M + H]⁺ (3) 1- (2-cyano-ethyl) -3-methyl-7- (2-cyano-benzyl) -8-chloro-xanthine

Mass spectrum (ESI⁺): m / z = 391,393 [M + Na]⁺ (4) 1- (2-phenoxy-ethyl) -3-methyl-7- (2-cyano-benzyl) -8- [3- (tert.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.90 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI⁺): m / z = 600 [M + H]⁺ (5) 1- (2-phenyl-2-oxo-ethyl) -3 - [(2-trimethylsilanyl-ethoxy) methyl] -7- (3-methyl-2-buten-1-yl) -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 667 [M + H]⁺ (6) 1- (2-methoxy-ethyl) -3-methyl-7- (2-cyano-benzyl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.90 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI⁺): m / z = 538 [M + H]⁺ (7) 1 - methyl -3- (2-trimethylsilanyl-ethoxy) methyl] -7- (2-cyano-benzyl) -xanthine

Rf value: 0.60 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m / z = 412 [M + H]⁺

52142 Β (8) 1- [2- (3-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-butene -1-11) -8chloro-xanthine

Rf value: 0.40 (silica gel, cyclohexane / ethyl acetate / methanol = 7: 2: 1)

Mass spectrum (ESI⁺): m / z = 432, 434 [M + H]⁺ (9) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7 - [(2-trimethylsilanyl-ethoxy) methyl] -8-bromo xanthine

Mass spectrum (ESI⁺): m / z = 493,495 [M + H]⁺ (10) 1- [2- (2-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8 chloro-xanthine

R_fvalue: 0.64 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m / z = 432,434 [M + H]⁺ (11) 1- [2- (2-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-butene-11) -8-bromo-xanthine

Mass spectrum (ESI⁺): m / z = 476,478 [M + H]⁺ (12) 1 - [(quinolin-2-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1 - il] - xanthine

R_f value: 0.45 (silica gel, ethyl acetate / petroleum ether = 7: 3)

Mass spectrum (ESI⁺): m / z = 574 [M + H]⁺ (13) 1 - [(2-oxo-2H-chromen-4-yl) methyl] -3-methyl-7- (3-methyl-2-butene-11) -8 [3- (tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine (starting material 4-bromomethyl-chromene-2-one was obtained analogously to Kimura et al., Chem. Farm. Bull. 1982,30,552 - 558.)

Rf value: 0.52 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 591 [M + H]⁺ (14) 1 - [(1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl) methyl] -3-methyl-7- (3-methyl-

- buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.54 (silica gel, methylene chloride / methanol = 95: 5)

52142 Β

Mass spectrum (ESI⁺): m / z = 604 [M + H]⁺ (15) 1 - [(quinazolin-4-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine-1) - il] - xanthine

Melting point: 195 - 197 ° C

Mass spectrum (ESI⁺): m / z = 575 [M + H]⁺ (16) 1 - [(5-methyl-3-phenyl-isoxazol-4-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.40 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 604 [M+H]⁺ (17) 1 - [(3-phenyl - [1,2,4] oxadiazol-5-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.18 (silica gel, petroleum ether / ethyl acetate = 2: 1)

Mass spectrum (ESI⁺): m/z = 591 [M+H]⁺ (18) 1 - [(4-phenyl-pyridin-2-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Rf value: 0.53 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 600 [M+H]⁺ (19) 1 - [(5-phenyl-pyridin-2-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Rf value: 0.73 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 600 [M+H]⁺ (20) 1- [2- (3-methylsulfanyl-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine

Rf value: 0.43 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 597 [M+H]⁺ (21) 1- [2- (3-methoxycarbonyl-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

52142 Β (Made in N - methylpyrrolidin - 2 - one at 60 ° C)

R_f value: 0.27 (silica gel, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m/z = 609 [M+H]⁺ (22) 1 - [2 - (2 - ethoxycarbonyl - phenyl) - 2 - oxo - ethyl] - 3 - methyl -7- (3- methyl - 2 - buten -

- yl) - 8 - [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Made in N-methylpyrrolidin-2-one at 60 ° C)

Rf Value: 0.35 (silica gel, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m/z = 623 [M+H]⁺ (23) 1- [2- (2,6-dimethoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert. butyloxycarbonylamino) - piperidin-1-yl] -xanthine (Made in N-methylpyrrolidin-2-one at 60 ° C)

Rf value: 0.53 (silica gel, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m/z= 611 [M+H]⁺ (24) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2,3-dimethyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine (Made in N-methylpyrrolidin-2-one at 60 ° C)

Rf value: 0.38 (silica gel, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m/z= 565 [M+H]⁺ (25) 1- ((E) -3-phenyl-allyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine - 1 - yl] - xanthine

Rf value: 0.54 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 95: 5: 0.1)

Mass spectrum (ESI⁺): m/z = 549 [M+H]⁺ (26) 1 - [(1-benzo [Z&gt;] thiophen-3-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.75 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 579 [M+H]⁺

52142 Β (27) 1 - {[1 - (terc. Butiloksikarbonil) - indol - 3 - il] metil} - 3 - metil-7- (3- metil- 2 buten -1 - il) - 8 - [3 - ( terc. butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Rf value: 0.61 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI⁺); m/z = 662 [M+H]⁺ (28) 1 - [(biphenyl-4-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1 - il] - xanthine

Rf value: 0.68 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 599 [M+H]⁺ (29) 1 - [(1-naphthyl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.83 (silica gel, ethyl acetate / petroleum ether = 4: 1)

Mass spectrum (ESI⁺): m/z = 557 [M+H]⁺ (30) 1 - [(1 - methyl - 2 - okso -1,2 - dihidro - hinolin - 4 - il) methyl] - 3 - methyl -7- (2- butin 1 - il) - 8 - [3 - (terc. butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Rf value: 0.25 (silica gel, ethyl acetate / petroleum ether = 4: 1)

Mass spectrum (ESI⁺): m/z = 588 [M+H]⁺ (31) 1- (2-cyclohexyl-2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3 (tert-butyloxycarbonylamino) -piperidine -1 - il] - xanthine

Melting point: 163 - 165 ° C

Mass spectrum (ESI⁺): m/z = 557 [M+H]⁺ (32) 1- (3,3-dimethyl-2-oxo-butyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8 - [3- (tert-butyloxycarbonylamino) -piperidine -1-yl] -xanthine

Rf value: 0.95 (silica gel, ethyl acetate / petroleum ether = 4: 1)

Mass spectrum (ESI⁺): m/z = 531 [M+H]⁺ (33) 1 - [(hinazolin - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

R_f value: 0.40 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 559 [M+H]⁺

52142 Β (34) 1 - [(2 - metil- naftalen -1 - il) metil] - 3 - metil-7- (2- butin -1 - il) - 8 - [3- (terc. Butiloksikarbonilamino) - piperidin - 1 - il] - ksantin

Rf value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z= 571 [M+H]⁺ (35) 1 - [(5 - nitro - isoquinoline -1 - il) methyl] - 3 - methyl-7- (3- methyl - 2 - butene -1 - il) - 8 - [3 - (terc. Butyloxycarbonylamino) - piperidine -1 - il] - xanthine

Rf value: 0.54 (silica gel, methylene chloride / methanol = 95: 5) (36) 1- (2-dimethylamino-2-oxo-ethyl) -3-methyl-7- (3-methyl-2-butene -1 - yl) - 8 - [3 (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.23 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z= 518 [M+H]⁺ (37) 1- [2- (piperidin-1-yl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.44 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 558 [M+H]⁺ (38) 1 - [(2- methyl-1 - oxo -1,2 - dihydro - isoquinoline - 4 - il) methyl] -7- (2- butin - 1 - il) -

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.25 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 588 [M+H]⁺ (39) 1 - [(2 - methyl -1 - oxo -1, 2 - dihydro - isoquinoline - 4 - il) methyl] -7- (3- methyl - 2 butene -1 - il) - 8 - [3 - (terc. butyloxycarbonilamino) - piperidine -1 - il] - xanthine

Rf value: 0.30 (siEka gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z= 604 [M+H]⁺ (40) 1 - [(2-methoxy-naphthalen-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine-1 - il] - xanthine

Rf value: 0.75 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z= 587 [M+H]⁺

52142 Β (41) 1 - [(4- metoksi - naftalen -1 - il) metil] - 3 - metil -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin - 1 - il] - ksantin

R_f value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 587 [M+H]⁺ (42) 1 - [(3 - methyl - isoquinoline -1 - il) methyl] - 3 - methyl-7- (2- butin -1 - il) - 8 - [3 - (terc. Butyloxycarbonilamino) - piperidine -1 - il] - xanthine

R_f value: 0.56 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 572 [M+H]⁺ (43) 1- [2- (2,3-dimethoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- ( tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.83 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 611 [M+H]⁺ (44) 1 - [(5 - nitro - naphthalen -1 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf value: 0.78 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 602 [M+H]⁺ (45) 1- [2- (pyrrolidin-1-yl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.39 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 544 [M+H]⁺ (46) 1 - [(4 - methyl - isoquinoline -1 - il) methyl] - 3 methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butyloxycarbonilamino) - piperidine -1 - il] - xanthine

Rf value: 0.56 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 572 [M+H]⁺ (47) 1 - [(2-naphthyl) methyl] -3-methyl 7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.78 (silica gel, ethyl acetate)

52142 Β

Mass spectrum (ESI⁺): m/z = 557 [M+H]⁺ (48) 1-cyanomethyl-3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine

Rf value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 456 [M+H]⁺ (49) 1 - [(hinolin - 6 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Rf value: 0.40 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 558 [M+H]⁺ (50) 1 - [(3-methoxy-naphthalen-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine-1 - il] - xanthine

Rf value: 0.83 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 587 [M+H]⁺ (51) 1- [2- (2,3-dihydro-benzo [4] dioxin-5-yl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) - 8 - [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Rf value: 0.38 (silica gel, ethyl acetate / petroleum ether = 1: 1)

Mass spectrum (ESI⁺): m/z = 609 [M+H]⁺ (52) 1- [2- (3-methyl-2-oxo-2,3-dihydro-benzooxazol-7-yl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-butene) -1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Made with potassium tert-butoxide in dimethylsulfoxide)

R_f value: 0.48 (silica gel, ethyl acetate / petroleum ether = 2: 1)

Mass spectrum (ESI⁺): m/z = 622 [M+H]⁺ (53) 1 - [2 - (benzo [1,3] dioxol - 4 - yl) - 2 - oxo - ethyl] - 3 - methyl - 7 - (3 - methyl - 2 - buten -

- il) - 8 - [3 - (terc. butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Mass spectrum (ESI⁺): m/z = 595 [M+H]⁺

52142 Β (54) 1 - [(hinazolin - 2 - il) metil] - 3 - metil -7- (2- booty-1 - il) - 8 - [(79 - 3 - (terc.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m / z = 559 [M + HJ + (55) 1 - [(hinazolin- 2 - il) metil] - 3 - metil-7- (2- butin-1 - il) - 8 - [(5) - 3 - (terc.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z= 559 [M+H]⁺ (56) 1 - [(hinazolin - 2 - il) methyl] - 3 - methyl- 7 - ((E) - 2 - buten -1 - il) - 8 - [(5) - 3 - (terc.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine (product contains approx. 15% Z isomer)

R_f value: 0.30 (silica gel, ethyl acetate / cyclohexane = 8: 2)

Mass spectrum (ESI⁺): m/z= 561 [M+H]⁺ (57) 1 - [(hinazolin - 2 - il) methyl] - 3 - methyl - 7 - ((E) - 2 - buten -1 - il) - 8 - [(79 - 3 - (terc.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine (product contains approx. 15% Z isomer)

R_f value: 0.30 (silica gel, ethyl acetate / cyclohexane = 8: 2)

Mass spectrum (ESI⁺): m/z= 561 [M+H]⁺ (58) 1 - [(3 - methyl- izohinolin -1 - il) methyl] - 3 - methyl- 7 - ((E) - 2 - butene -1 - il) - 8 - [(79 -

- (tert. butyloxycarbonylamino) - piperidin-1-yl] -xanthine (product contains approx. 17% Z isomer)

R_f value: 0.58 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z= 574 [M+H]⁺ (59) 1 - [(3-methyl-izohinolin- 1-yl) methyl] - З-теШ-7- ((E) - 2-buten-1-yl) - 8 - [(S) -

- (tert. butyloxycarbonylamino) - piperidin-1-yl] -xanthine (product contains approx. 17% Z isomer)

Rf value: 0.58 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 574 [M+H]⁺ (60) 1 - [2 - (2 - methoxy - phenyl) - 2 - oxo - ethyl] - 3 - methyl -7- (2- butin -1 - province) - 8 - bromo xanthine

52142 Β

Mass spectrum (ESI⁺): m/z = 445,447 [M+H]⁺ (61) 1- [2- (2-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7 - [(1-cyclopenten-1-yl) methyl] 8-bromo-xanthine

Mass spectrum (ESI⁺): m/z = 488,490 [M+H]⁺ (62) 1- (2- (2-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7 - [(1-cyclopenten-1-yl) methyl] -8-bromo-xanthine)

Mass spectrum (ESI⁺): m/z = 473,475 [M+H]⁺ (63) 1 - [(isochinoline -1 - il) methyl] - 3 - [(methoxycarbonyl) rnetil] -7- (3- methyl - 2 - butene -

- il) - 8 - [3 - (terc. butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Rf value: 0.35 (silica gel, methylene chloride / methanol = 95: 5) (64) 1 - [2- (2-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (E) - 2-buten-1-yl) -8 bromo-xanthine (product contains approx. 10% Z isomer)

R_f value: 0.60 (silica gel, cyclohexane / ethyl acetate = 4: 6)

Mass spectrum (ESI⁺): m/z = 462,464 [M+H]⁺ (65) 1- [2- (2-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (E) -2-butene -1-11) -8bromo-xanthine (product contains some Z isomer)

Rf value: 0.30 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 447,449 [M+H]⁺ (66) 1 - [2 - (2 - nitro - phenyl) - 2 - oxo - ethyl] - 3 - methyl -7- (2- butin -1 - province) - 8 - bromo xanthine

Rf value: 0.77 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 460,462 [M+H]⁺ (67) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- ((E) -2-buten-1-yl) -8 - [(R) -3- (tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine (product contains approx. 20% Z isomer)

52142 Β

Mass spectrum (ESI⁺): m/z = 537 [M+H]⁺ (68) 1- [2- (2-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) 8-bromo-xanthine

Mass spectrum (ESI⁺): m/z = 461,463 [M+H]⁺ (69) 1- (2- phenyl - 2 - oxo - ethyl) - 3 - methyl -7- (2- butin -1 - province) - 8 - bromo - xanthine

R_f value: 0.61 (silica gel, cyclohexane / ethyl acetate = 4: 6) (70) 1 - (2 - {2 - [(ethylaminocarbonyl) methoxy] - phenyl} - 2 - oxo - ethyl) - 3 - methyl - 7 - (E) -

2-Buten-1-yl) -8- (CA) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (product contains approx. 17% Z isomer)

Mass spectrum (ESI⁺): m/z= 638 [M+H]⁺ (71) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- ((E) -2-buten-1-yl) -8 - [(S) -3- (tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine (product contains approx. 18% Z isomer)

R_fvalue: 0.35 (silica gel, cyclohexane / ethyl acetate = 6: 4)

Mass spectrum (ESI⁺): m/z = 537 [M+H]⁺ (72) 1- [2- (2-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8 - [(S) -3 - (tert) butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.60 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 580 [M+H]⁺ (73) 1 - [(3 - methyl- izohinolin -1 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [(5) - 3- (terc. Butyloxycarbonylamino) - piperidine -1 - il] - xanthine

Rf value: 0.52 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 572 [M+H]⁺ (74) 1 - [(3 - methyl- izohinolin -1 - il) methyl] - 3 - methyl-7- (2- butin -1 - il) - 8 - [(7? - 3- (terc. Butyloxycarbonylamino) - piperidine -1 - il] - xanthine

Mass spectrum (ESI⁺): m/z = 572 [M+H]⁺

52142 Β (75) 1 - [(4- metil- izohinolin -1 - il) metil] - 3 - metil-7- (2- butin-1 - il) - 8 - [(5) - 3 (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Mass spectrum (ESI⁺): m/z= 572 [M+H]⁺ (76) 1 - [(4- methyl- izohinolin -1 - il) methyl] - 3 - methyl-7- (2- butin -1 - il) - 8 - [(73 - 3 (terc. Butyloxycarbonilamino)) - piperidin -1 - il] - xanthine

Mass spectrum (ESI⁺): m/z = 572 [M+H]⁺ (77) 1 - [(4-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- ((E) -2-buten-1-yl) -8 - [(S) 3 - (tert butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.52 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 574 [M+H]⁺ (78) 1 - [(4-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- ((E) -2-buten-1-yl) -8 - [(73 3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.52 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 574 [M + HJ + (79) 1 - [2 - (2,3 - dihydro - benzo [1,4] dioxin - 5 - yl) - 2 - oxo - ethyl] - 3 - methyl - 7- (2butin -1 - province) - 8 - [(73 - 3 - (trans. Butyloxycarbonylamino) - piperidine -1 - province] - xanthine R_f value: 0.18 (silica gel, ethyl acetate / petroleum ether = 1: 1)

Mass spectrum (ESI⁺): m/z= 593 [M+H]⁺ (80) 1- [2- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -2-oxo-ethyl] -3-methyl-7- (2-butin-1-yl) -8 - [(5) -3 - (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m/z = 593 [M+H]⁺ (81) 1 - [(4-methoxy-naphthalen-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8 - [(S) -3 (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Rf value: 0.56 (silica gel, petroleum ether / ethyl acetate = 1: 2)

Mass spectrum (ESI⁺): m/z = 587 [M+H]⁺ (82) 1 - [(4-methoxy-naphthalen-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8 - [(73-3 (tert-butyloxycarbonylamino) -piperidine -1-yl] -xanthine

52142 Β

Mass spectrum (ESI⁺): m/z = 587 [M+H]⁺ (83) 1 - [2 - (benzo [l, 3] dioksol - 4 - il) - 2 - okso - etil] - 3 - metil -7- (2- booty -l-il) -8- [(Л ) - 3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

R_f value: 0.86 (silica gel, ethyl acetate / petroleum ether = 4: 1)

Mass spectrum (ESI⁺): m/z= 579 [M+H]⁺ (84) 1- [2- (benzo [1,3] dioxol-4-yl) -2-oxo-ethyl] -3-methyl-7- (2-butyne-11) -8- [(5) ) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.86 (silica gel, ethyl acetate / petroleum ether = 4: 1)

Mass spectrum (ESI⁺): m/z = 579 [M+H]⁺ (85) 1 - [(4 - methyl- hinazolin - 2 - il) methyl] - 3 - methyl - 7 - (2 - butin -1 - il) - 8 - [(5) - 3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf value: 0.48 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 573 [M + HJ + (86) 1 - [(4 - metil- hinazolin - 2 - il) metil] - 3 - metil -7- (2- booty -1 - il) - 8 - [ (A) - 3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Rf value: 0.48 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m / z = 573 [M + N]⁺ (87) 1- [2- (3-methyl-2-oxo-2,3-dihydro-benzooxazol-4-yl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-butene) -1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.50 (silica gel, petroleum ether / ethyl acetate = 1: 2)

Mass spectrum (ESI⁺): m/z = 622 [M+H]⁺ (88) 1- (2 - {2 - [(ethylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (E) -

- buten-1-yl) -8 - [(5) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m/z = 638 [M+H]⁺

52142 89 (89) 1- (2- (2 - [(methylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- ((E) 2-buten-1-yl) -8- [(A) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m/z = 624 [M+H]⁺ (90) 1- (2- (2 - [(methylaminocarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- ((E) 2-buten-1-yl) -8- ( (S) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m/z = 624 [M+H]⁺ (91) 1 - [2 - (2 - nitro - phenyl) - 2 - oxo - ethyl] - 3 - methyl -7- (2- butin -1 - yl) - 8 - (СЛ) - 3 (trans. Butyloxycarbonylamino ) - piperidin -1 - province] - xanthine

R_f value: 0.60 (silica gel, methylene chloride / methanol = 95: 5) (92) 1- (2- (2-nitro-3-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- 3-methyl-2-buten-1-yl) -8-bromo-xanthine

Mass spectrum (ESI⁺): m/z = 506,508 [M+H]⁺ (93) 1- (4-dimethylamino-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine-1- il] - xanthine (Performed in the presence of cesium carbonate)

Rf value: 0.40 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z= 602 [M+H]⁺ (94) 1- (2- (2-oxo -3- (2-trimethylsilanyl-ethoxy) methyl] -2,3-dihydro-benzooxazole -

- yl} -2-oxo-ethyl) -3-methyl -7- (3-methyl-2-butene-11) -8-bromo-xanthine

R_f value: 0.75 (silica gel, ethyl acetate / petroleum ether = 1: 1)

Mass spectrum (ESI⁺): m/z = 618,620 [M+H]⁺ (95) 1 - ((imidazo [l, 2 - ajpiridin - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - (3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf value: 0.44 (silica gel, methylene chloride / methanol = 95: 5)

52142 Β

Mass spectrum (ESI⁺): m/z= 547 [M+H]⁺ (96) 1 - [(hinoksalin - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonil - amino) - piperidin -1 - il ] - ksantin

R_f value: 0.50 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 559 [M+H]⁺ (97) 1 - [2 - (1,3 - dimethyl - 2 - oxo - 2,3 - dihydro - 1H - benzoimidazole - 4 - yl) - 2 - oxo ethyl] - 3 - methyl -7- (2- butin -1 - province) - 8 - [3 - (trans. Butyloxycarbonylamino) - piperidine -1 province] - xanthine

R_f value: 0.50 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 619 [M+H]⁺ (98) 1 - [(hinoksalin - 6 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

R_f value: 0.35 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 559 [M+H]⁺ (99) 1- (2- (2-oxo-3 - [(2-trimethylsilanyl-ethoxy) methyl] -2,3-dihydro-benzooxazole -

- yl} -2-oxo-ethyl) -3-methyl -7- (2-booty-1-yl) -8-bromo-xanthine

R_f value: 0.30 (silica gel, petroleum ether / ethyl acetate = 2: 1)

Mass spectrum (ESI '): m / z = 600, 602 [M - H] (100) 1 - [(3-methyl-quinoxalin-2-yl) methyl] -3-methyl-7- (2-butyne - 1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.44 (silica gel, petroleum ether / ethyl acetate = 1: 2)

Mass spectrum (ESI⁺): m/z = 573 [M+H]⁺ (101) 1 - [(3 - phenyl - isochinoline -1 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butyloxycarbonilamino) - piperidin -1 - il] - xanthine

Rf value: 0.85 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 634 [M+H]⁺

52142 B (102) 1 - [(3,4 - dimethyl - isoquinoline-1 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butyloxycarbonilamino) - piperidin -1 - il] - xanthine

Rf value: 0.60 (silica gel, ethyl acetate / methanol = 3: 1)

Mass spectrum (ESI⁺): m/z = 586 [M+H]⁺ (103) 1 - [(benzofuran - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - [(7 ^ - 3 - (terc. Butil oksikarbonilamino) - piperidin -1 - the] - ksantin

Mass spectrum (ESI⁺): m/z = 547 [M+H]⁺ (104) 1 - {[4 - ((morpholin-4-yl) -quinazolin-2-ylmethyl} -3-methyl-7- (2-butyn-1-yl) -8 [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine (performed in the presence of cesium carbonate)

Rf value: 0.28 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 644 [M+H]⁺ (105) 1 - {[4 - ((piperidin-1-yl) -quinazolin-2-yl] methyl} -3-methyl-7- (2-butyn-1-yl) -8 [3- (tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine (Performed in the presence of cesium carbonate)

Rf value: 0.35 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 642 [M+H]⁺ (106) 1- ({4- [4 - (tert-butyloxycarbonyl) -piperazin-1-yl] -quinazolin-2-ylmethyl) -3-methyl-7- (2-butyn-1-yl) -8 - [ 3- (tert-butyloxycarbonylamino) -piperidin-1-yl] xanthine (Performed in the presence of cesium carbonate)

R_f value: 0.50 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 743 [M+H]⁺ (107) 1 - {[4 - ((pyrrolidin-1-yl) -quinazolin-2-yl] methyl} -3-methyl-7- (2-butyn-1-yl) -8 [3- (tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine (Performed in the presence of cesium carbonate)

R_f value: 0.59 (silica gel, ethyl acetate / methanol / conc. aqueous ammonia solution = 95: 5: 0.1)

Mass spectrum (ESI⁺): m/z = 628 [M+H]⁺

52142 108 (108) 1- (2- (1-ethoxycarbonyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl) -2-oxo-ethyl] -3-methyl-7- ( 2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) piperidin-1-yl] -xanthine

R_f value: 0.25 (silica gel, petroleum ether / ethyl acetate = 1: 2)

Mass spectrum (ESI⁺): m/z = 677 (M+H]⁺ (109) 1- (4-cyano-naphthalen-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8 - [(N, N- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

R_f value: 0.77 (silica gel, methylene chloride / methanol / conc. aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 582 [M+H]⁺ (110) 1 - [(imidazofl, 2-a] pyridin-3-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 547 (M+H]⁺ (111) 1 - ((8- metil- imidazo [l, 2 - ajpiridin- 2 - il) metil] - 3 -metil -7- (2- booty -1 - il) -

- (3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.25 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 561 [M+H]⁺ (112) 1 - ((8- metoksi - hinolin - 5 - il) methyl] - 3 - methyl- 7- (2 - butin -1 - il) - 8- (3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf value: 0.60 (silica gel, ethyl acetate / methanol = 9: 1)

Mass spectrum (ESI⁺): m/z = 588 [M+H]⁺ (113) 1 - ((5- metoksi - hinolin - 8 - il) methyl] - 3 - methyl-7- (2- butin-1 - il) - 8- [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf value: 0.40 (silica gel, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m/z = 588 [M+H]⁺ (114) 1 - ((4- phenyl- hinazolin- 2 - il) methyl] - 3 - methyl-7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

52142 Β

Mass spectrum (ESI⁺): m/z = 635 [M+H]⁺ (115) 1 - ((7- metil - imidazo [l, 2 - ajpiridin - 2 - il) metil] - 3 - metil-7- (2- booty -1 - il) -

- (3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.50 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 561 [M+H]⁺ (116) 1- (2-Oxo-4-phenyl-butyl) -3-methyl-7- (2-butyn-1-yl) -8 - [(N- (3- (tert-butyloxycarbonylamino) -piperidine- 1 - yl] - xanthine

Mass spectrum (ESI⁺): m/z = 563 (M+H]⁺ (117) 1- (2- (2-oxo-1,3-bis - [(2-trimethylsilanyl-ethoxy) methyl] -2,3-dihydro-177-benzoimidazol-4-yl} -2-oxo-ethyl) - 3-methyl-7- (2-butyn-1-yl) -8- (3- (tert-butyloxy-carbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.50 (silica gel, ethyl acetate / petroleum ether = 1: 1)

Mass spectrum (ESI⁺): m/z= 851 [M+H]⁺ (118) 1- (3-difluoromethyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8 - [3- (tert-butyloxycarbonylamino) -piperidine-1- yl] - xanthine (by-product of the reaction of 3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxy carbonylamino) -piperidin-1-yl] -xanthine with 1-chloromethyl-3- trifluoromethyl -3,4-dihydro-isoquinoline)

Rf Value: 0.75 (aluminum oxide, petroleum ether / ethyl acetate = 1: 2)

Mass spectrum (ESI⁺): m/z = 608 [M+H]⁺ (119) 1- [2- (2,2-difluoro-benzo [1,3] dioxol-4-yl) -2-oxo-ethyl] -3-methyl-7- (2butin-1-yl) -8-bromo - xanthine

Mass spectrum (ESI⁺): m/z= 495,497 (M+H]⁺ (120) 1 - ((3- metil - imidazo [l, 2 - ajpiridin - 2 - il) metil] - 3 - metil -7- (2- booty -1 - il) -

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.50 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 561 (M+H]⁺

52142 121 (121) 1 - [(5-methyl-imidazo [1,2-pyridin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.50 (silica gel, methylene chloride / methanol / conc. aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 561 [M+H]⁺ (122) 1 - [(6 - metil - imidazo [l, 2 - ajpiridin - 2 - il) metil] - 3 - metil -7- (2- booty -1 - il) -

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.10 (silica gel, ethyl acetate / methanol = 98: 2)

Mass spectrum (ESI⁺): m/z = 561 [M+H]⁺ (123) 1 - [(3 - benzil - imidazo [l, 2 - a] piridin - 2 - il) metil] - 3 - metil -7- (2- booty -1 - il) -

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.60 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 637 [M+H]⁺ (124) 1 - [(4 - izopropil - hinazolin - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

R_f value: 0.50 (silica gel, ethyl acetate / petroleum ether = 8: 2)

Mass spectrum (ESI⁺): m/z = 601 [M+H]⁺ (125) 1 - [(2, 3 - dihidro - benzo [l, 4] dioksin - 6- il) metil] - 3 - metil -7- (2- booty -1 - il) -

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.53 (silica gel, ethyl acetate / petroleum ether = 3: 2) (126) 1 - [(3-phenyl-imidazo [1,2-aipyridin-2-yl) methyl] -3-methyl-7- 2-Butin-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.50 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 623 [M+H]⁺ (127) 1- [2- (naphthalen-1-yl] -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Rf value: 0.54 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESP): m / z = 585 [M + H]⁺

52142 B (128) 1 - [(5 - methoxy - isoquinoline - 8 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butyloxycarbonilamino) - piperidine - 1 - il] - xanthine

Rf value: 0.50 (silica gel, ethyl acetate / methanol = 24: 1)

Mass spectrum (ESI⁺): m/z = 588 [M+H]⁺ (129) 1 - [(3-difluoromethyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8 - [3 (tert-butyloxycarbonylamino) -piperidine-1- yl] -xanthine 3-methyl -7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine with 1-chloromethyl-3-reaction trifluoromethyl-3,4-dihydro-isoquinoline)

Rf value: 0.75 (aluminum oxide, petroleum ether / ethyl acetate = 1: 2)

Mass spectrum (ESI⁺): m/z = 608 [M+H]⁺ (130) 1 - {[1- (1-cyano-1-methyl-ethyl) -isoquinolin-3-yl] methyl} -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rfvrednost: 0.75 (silika gel, etil acetat)

Mass spectrum (ESI⁺): m/z = 625 [M+H]⁺ (132) 1-Methoxycarbonylmethyl-3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonyl-amino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 489 [M+H]⁺ (133) 1 - [(4 - phenyl - hinazolin - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [(75 - 3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Mass spectrum (ESI⁺): m/z = 635 [M+H]⁺ (134) 1 - [(2,3-dimethyl-quinoxalin-6-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1 - yl] - xanthine (Performed in the presence of cesium carbonate)

R_f value: 0.40 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 587 [M+H]⁺

52142 Β (135) 1 - [(4 - fenil- hinazolin- 2 - il) metil] - 3 - metil -7- (2- butin -1 - il) - 8 - [(5) - 3 - (terc. Butiloksikarbonilamino ) - piperidin -1 - il] - ksantin

Rf value: 0.55 (silica gel, ethyl acetate / petroleum ether = 8: 2)

Mass spectrum (ESI⁺): m/z = 635 [M+H]⁺ (136) 1 - [2 - (hinolin - 8 - il) - 2 - okso - ethyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - bromine ksantin

R_f value: 0.55 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 466,468 [M+H]⁺ (137) 1 - [(3,4 - dimethyl - 6, 7 - dihidro - 5H- [2] pirindin -1 - the) methyl] - 3 - methyl-7- (2butin -1 - the) - 8 - [ 3 - (terc.Butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.65 (aluminum oxide, ethyl acetate / petroleum ether = 3: 1)

Mass spectrum (ESI⁺): m/z = 576 [M+H]⁺ (138) 1 - [(3,4-dimethyl-5,6,7,8-tetrahydro-isoquinolin-1-yl) methyl] -3-methyl-7- (2butin-1-yl) -8- [3 - (tert. butyloxycarbonylamino) - piperidin-1-yl] -xanthine Rf Value: 0.40 (aluminum oxide, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m/z = 590 [M+H]⁺ (139) 1 - {2 - [1 - (terc. Butiloksikarbonil) - 1H- indol - 4 - il] - 2 - okso - ethyl} - 3 - methyl - 7 - (2 - butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Rf value: 0.55 (silica gel, petroleum ether / ethyl acetate = 1: 2)

Mass spectrum (ESI⁺): m/z = 674 [M+H]⁺ (140) 1 - [(1 - methyl - 2 - oxo -1,2 - dihydro - hinolin - 6 - yl) methyl] - 3 - methyl -7- (2- butin -

- il) - 8 - [3 - (terc. butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Mass spectrum (EI): m / z = 587 [M]⁺ (141) 1- ({1 - [(2-trimethylsilanyl-ethoxy) methyl] -2-oxo-1,2-dihydro-quinolin-6-yl} methyl) -3-methyl-7- (2-butyne -1) - yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin 1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 704 [M+H]⁺

52142 Β (142) 1 - [(2,3,8 - trimetil - hinoksalin - 6 - il) metil] - 3 - metil-7- (2- butin-1 - il) - 8 - [3 (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Mass spectrum (ESI⁺): m/z = 601 [M+H]⁺ (143) 1 - [(8 - methyl - hinoksalin - 6 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Mass spectrum (ESI⁺): m/z = 573 [M+H]⁺ (144) 1 - [(4 - methyl - phthalazin -1 - il) methyl] - 3 - methyl -7- (2- butin-1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

R_f value: 0.65 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI⁺): m/z= 573 [M+H]⁺ (145) 1 - [(4 - bromo - 3 - methoxy - isoquinoline -1 - il) methyl] - 3 - methyl-7- (2- butin-1 - il) 8 - [3 - (terc. Butyloxycarbonilamino) - piperidin -1 - il] - xanthine

Rf value: 0.65 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 666, 668 [M+H]⁺ (146) 1 - [(4-difluoromethoxy-naphthalen-1-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - [(Jt) -3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

R_{ value: 0.80 (silica gel, methylene chloride / methanol / conc. aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 623 [M+H]⁺ (147) 1 - {2 - [1 - (terc. Butiloksikarbonil) - 1J7- indol - 7 - il] - 2 - okso - etil} - 3 - metil - 7 (2 - booty -l-il) -8- bromo - ksantine

R_f value: 0.83 (silica gel, methylene chloride / methanol = 95: 5) (148) 1 - [(E) -3- (2-nitro-phenyl) -2-propene-1-yl] -3-methyl-7- (2-butyn-1-yl) -8-

V t

S3 - (tert-butyloxycarbonylamino) -piperidin-1-ylC-xanthine

Mass spectrum (ESI⁺): m/z = 578 [M+H]⁺ (149) 1 - ((E) - 3 - pentafluorophenyl - 2 - propen -1 - il) - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbomlamino) - piperidin -1 - the] - ksantin

52142 Β

Mass spectrum (ESI⁺): m/z = 623 [M+H]⁺ (150) 1 - [(4 - nitro - naphthalen -1 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [(A) - 3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf value: 0.41 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 602 [M+H]⁺ (151) 1 - [(benzooksazol - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

R_f value: 0.40 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m/z = 548 [M+H]⁺ (152) 1 - [(5 - nitro - benzooksazol - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf Value: 0.50 (silica gel, cyclohexane / ethyl acetate / methanol = 5: 4: 1)

Mass spectrum (ESI⁺): m/z = 593 [M+H]⁺ (153) 1 - [(3 - methyl - isoquinoline -1 - il) methyl] - 3 - methyl -7- (3- methyl -1 - butene-1 - il) - 8 bromo - xanthine

Rf value: 0.65 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 468,470 [M+H]⁺ (154) 1 - [(hinolin - 7 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonil - amino) - piperidin -1 - il ] - ksantin

Mass spectrum (ESI⁺): m/z = 558 [M+H]⁺ (155) 1 - [([1,5] naftiridin - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc.Butyloxycarbonylamino) -piperidin-1-the] -xanthine

Mass spectrum (ESI⁺): m/z = 559 [M+H]⁺ (156) 1 - [(8 - methyl - hinoksalin- 6- il) methyl] - 3- methyl-7- (2- butin -1 - il) - 8- [(Л) - 3 (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf value: 0.45 (silica gel, methylene chloride / methanol = 19: 1)

Mass spectrum (ESI⁺): m/z = 573 [M+H]⁺ (157) 1 - [(2, 3,8 - trimethyl - hinoksalin - 6 - il) methyl] - 3 - methyl -7- (2- butin -l-il) -8- [СЛ) - 3 - (terc . butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Rf value: 0.32 (silica gel, methylene chloride / methanol = 96: 4)

52142 Β

Mass spectrum (ESI⁺): m/z = 601 [M+H]⁺ (158) 1 - [([1, 6] naphthyridin - 5 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin - 1 - the] - ksantin

Rf value: 0.20 (silica gel, ethyl acetate / methanol = 98: 2)

Mass spectrum (ESI⁺): m/z = 559 [M+H]⁺ (159) 1 - [([1,8] naftiridin - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin - 1 - the] - ksantin

Rf value: 0.12 (silica gel, ethyl acetate / methanol = 98: 2)

Mass spectrum (ESI⁺): m/z = 559 [M+H]⁺ (160) 1 - [(4 - fluoro - naphthalen -1 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [(Jt) - 3 (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf value: 0.47 (silica gel, petroleum ether / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 575 [M+H]⁺ (161) 1 - [([1, 5] naftiridin - 2 - il) metil] - 3 - metil -7- (2-butin -1 - il) - 8 - [(7t) - 3 - (terc. Butiloksikarbonilamino ) - piperidin -1 - il] - ksantin

Rf value: 0.39 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 559 [M+H]⁺ (162) 1 - [2 - (3 - metil - 2 - okso - 2,3 - dihidro - benzooksazol - 4 - il) - 2 - okso - etil] - 3 metil -7- (2- butin -1 - il ) - 8 - [(7t) - 3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] ksantin

Rf value: 0.60 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 606 [M+H]⁺ (163) 1 - [(8-phenyl-quinoxalin-6-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8 - [(L) -3 (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

R_f value: 0.48 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESF): m / z = 356 [M + H]⁺ (164) 1 - [([1, 5] naphthyridine - 4- il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [(7 ^ - 3 - (terc. Butiloksikarbonilamino ) - piperidin -1 - the] - ksantin

52142 Β

R_f value: 0.25 (silica gel, ethyl acetate / petroleum ether = 4: 1)

Mass spectrum (ESI⁺): m/z = 559 [M+H]⁺ (165) 1 - ((E) - 3 - pentafluorophenyl - alyl) - 3 - methyl -7- (2- butin -1 - il) - 8 - [(70 - 3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Mass spectrum (ESI⁺): m/z = 623 [M+H]⁺ (166) 1 - [(E) - 3 - (2 - trifluorometil- fenil) - alil] - 3 - metil -7- (2- booty -1 - it) - 8 - [(70 -

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 601 [M+H]⁺ (167) 1 - [(E) - 3 - (3 - trifluorometil- fenil) - alil] - 3 - metil-7- (2- booty -1 - it) - 8 - [(70 -

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 601 [M+H]⁺ (168) 1 - [(E) - 3 - (4 - trifluorometil- fenil) - alil] - 3 - metil-7- (2- booty -1 - it) - 8 - [(70 -

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 601 [M+H]⁺ (169) 1 - [(3 - trifluoromethyl - isoquinoline -1 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [(70 - 3 - (terc. Butyloxycarbonylamino)) - piperidin -1 - il] - xanthine

Rf Value: 0.68 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m/z = 626 [M+H]⁺ (170) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-cyano-benzyl) -8-chloro-xanthine (171) 1 - [(3-difluoromethyl-isoquinoline) -1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8 [(70-3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.38 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 608 [M+H]⁺ (172) 1 - [(4 - chloro - 3 - methoxy - isoquinoline -1 - il) methyl] - 3 - methyl -7- (2-butin-1 - il) -

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

52142 Β

Rf value: 0.65 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI +): m / z = 622.624 [M + H]⁺ (173) 1 - [(4-ethoxy-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine-1 - il] - xanthine

R_f value: 0.25 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 603 [M+H]⁺ (174) 1 - [(4-isopropyloxy-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine-1) - il] - xanthine

R_f value: 0.40 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 617 [M+H]⁺ (175) 1 - [(2 - methyl - benzothiazol - 6 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8- [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

R_f value: 0.56 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 578 [M+H]⁺ (176) 1 - [(3-phenyl-isohinolin-1 - il) methyl] - 3 - methyl- 7 - (2- butin-1 - il) - 8- [(73 - 3- (terc. Butyloxycarbonylamino)) - piperidin -1 - il] - xanthine

R_f value: 0.75 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 634 [M+H]⁺ (177) 1 - [(4 - feniloksi - hinazolin - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8- [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

R_f value: 0.35 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 651 [M+H]⁺ (178) 1 - [(4-phenyl-quinazolin-2-yl) methyl] -3-cyclopropyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine-1 - il] - xanthine

R_f value: 0.45 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 661 [M+H]⁺

52142 Β (179) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-cyclopropyl-7- (2-butyn-1-yl) -8- [3 (tert-butyloxycarbonylamino) -piperidine-1 - il] - xanthine

Rf value: 0.50 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z= 598 [M+H]⁺ (180) 1- [2- (3-difluoromethoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8 [(N, -3- (tert.). butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.77 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 601 [M+H]⁺ (181) 1 - [(2 - phenyl - hinazolin- 4 - il) methyl] - 3 - methyl-7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf value: 0.65 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 635 [M+H]⁺ (182) 1- [2- (2-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1-yl] -xanthine

Rf value: 0.57 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z= 565 [M+H]⁺ (183) 1- [2- (3-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2- butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Rf value: 0.63 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 565 [M+H]⁺ (184) 1- [2- (3-trifluoromethoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8 [(79-3- (tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine

Rf value: 0.64 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 619 [M+H]⁺ (185) 1 - [2 - (biphenyl - 2 - il) - 2 - okso - ethyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [(79 3 (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

Rf value: 0.70 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 611 [M+H]⁺

52142 Β (186) 1- [2- (bifenil-3-il) - 2-okso-etil] - 3-metil-7 - (2-butin-1 -il) -8 - ((79-3 (terc.). butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Rf value: 0.75 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 611 [M+H]⁺ (187) 1- [2- (3-Isopropyloxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyne-11-yl) -8 [(79-3 - (tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine

R_f value: 0.66 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 593 [M+H]⁺ (188) 1 - [(3 - methyl - isoquinoline -1 - il) methyl] - 3 - cyclopropyl -7- (2- butin -1 - il) - 8 - [(79 -

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.50 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 598 [M+H]⁺ (189) 1 - [(4- fenil - hinazolin - 2 - il) metil] - 3 - ciklopropil -7- (2- booty -1 - il) - 8 - [(79 -

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.50 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 661 [M+H]⁺ (190) 1 - [(4-cyano-naphthalen-1-yl) methyl] -3-cyclopropyl-7- (2-butyn-1-yl) -8 - [(79)

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.75 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 608 [M+H]⁺ (191) 1 - [2 - (2 - phenyloxy - phenyl) - 2 - oxo - ethyl] - 3 - methyl -7- (2- butin -1-11) -8 - ((79-

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.85 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 627 [M+H]⁺ (192) 1- (2- (3-ethoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8 - [[79-3 - tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine

R_f value: 0.72 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 579 [M+H]⁺

52142 19 (193) 1- [2- (3-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8 - [(7i) -3 - (tert butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.67 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 565 [M+H]⁺ (194) 1- [2- (2-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butin-1-yl) -8 - [(N - 3 - tert. butyloxycarbonylamino) -piperidin-1-yl) -xanthine

Rf value: 0.57 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 565 [M+H]⁺ (195) 1 - [(3 - methyl - isohinoline -1 - il) methyl] - 3 - methyl -7- (2- chloro - benzyl) - 8 - bromo xanthine (196) 1 - [(3 - methyl - isohinoline -1 - il) methyl] - 3 - methyl-7- (2- bromo - benzyl) - 8 - [(7 ^ - 3 (terc. Butyloxycarbonilamino) - piperidin -1 - il] - xanthine (197) 1 - [ (1,2,3,4 - tetrahiđro - phenanthiridine - 6 - il) methyl] - 3 - methyl -7- (2- butin-1 - il) -

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.55 (silica gel, ethyl acetate / petroleum ether = 2: 1)

Mass spectrum (ESI⁺): m/z = 612 [M+H]⁺

FirstVI

- (2 - {3 - [(methanesulfinyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert butyloxycarbonylamino) -piperidin-1-yl] -xanthine

U solution 402 mg 1- (2 - {3 - [(methylsulfanyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7 (3-methyl-2-buten-1-yl) -8- [3 - [(tert-Butyloxycarbonylamino) -piperidin-1-yl] xanthine in 10 ml of hexafluoroisopropanol was added 0.15 ml of a 35% solution of hydrogen peroxide. The reaction mixture was stirred for half an hour at room temperature. Then 5 ml of 10% sodium thiosulfate solution was added. The aqueous phase was extracted twice with 5 ml of methylene chloride. The combined extracts were dried over sodium sulfate and evaporated. The yellow residue was purified by column chromatography on silica gel with cyclohexane / ethyl acetate / methanol (5: 4: 1) as eluent.

Yield: 299 mg (73% of theory)

52142 Β

Rf value: 0.28 (silica gel, cyclohexane / ethyl acetate / methanol = 5: 4: 1)

Mass spectrum (ESI⁺): m/z = 643 [M+H]⁺

The following compounds were prepared analogously to Example VI:

(1) 1- [2- (3-methanesulfinyl-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value 0.05 (silica gel, ethyl acetate / cyclohexane = 3: 1)

Mass spectrum (ESI⁺): m/z = 613 [M+H]⁺ (2) 1- (2- (2 - [(methanesulfinyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert) butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 627 [M+H]⁺

FirstVII

- [((2-trimethylsilanyl-ethoxy) methyl] -7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

236 μΐ 1,8-diazabicyclo [5.4.0] undec-7-ene was added dropwise to 630 mg of 7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine-1 - yl] - xanthine in 11 ml of acetonitrile. The solution was stirred for two hours at room temperature and then the acetonitrile was distilled off in vacuo. The residue from the flask was taken up in 11 ml of N, N - dimethylformamide and mixed with 258 mg (2 - trimethylsilanyl - ethoxy) of methyl chloride. The reaction mixture was stirred at 120 ° C for three hours. Water was added for processing, the precipitate formed was filtered off and taken up in ethyl acetate. The solution was dried over magnesium sulfate, evaporated and chromatographed on a silica gel column with cyclohexane / ethyl acetate / methanol (6: 1: 0 to 0: 5: 1) as eluent.

Yield: 435 mg (53% of theory)

Mass spectrum (ESI⁺): m/z = 549 [M+H]⁺

The following compounds were prepared analogously to Example VII:

(1) 3 - [(2 - trimethylsilanyl - ethoxy) methyl] - 7 - (2 - cyano - benzyl) - xanthine Mass spectrum (ESI): m / z = 396 [M - H] '

52142 Β (2) 3 - [(methoxycarbonyl) methyl] -7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.31 (silica gel, methylene chloride / methanol / conc. aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 491 [M+H]⁺

First VIII

- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] xanthine

510 mg potassium tert. butoxide was added to 2.32 g of 2 - [[3- (tert. butyloxycarbonylamino) piperidin-1-yl] -3- (3-methyl-2-buten-1-yl) -4-ethoxycarbonyl-5 {[(ethoxycarbonylamino) carbonylamino } - 377- imidazole in 35 ml of ethanol. The yellow solution was refluxed for five hours. After cooling to room temperature, it was diluted with methylene chloride. The organic phase was washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The crude product was purified by column chromatography on silica gel with methylene chloride / methanol / conc. with methanolic ammonia solution (95: 5: 1 to 90: 10: 1) as eluent.

Yield: 630 mg (35% of theory)

R_f value: 0.24 (silica gel, methylene chloride / methanol / conc. aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 419 [M+H]⁺

First IX

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -3- (3-methyl-2-buten-1-yl) -4-ethoxycarbonyl-5 -1 [(ethoxycarbonylamino) carbonylaminol-377-imidazole

2.97 ml of ethyl isocyanatoformate was added to 4.00 g of 2 - [3- (tert-butyloxycarbonylamino) piperidin-1-yl] -3- (3-methyl-2-buten-1-yl) -4-ethoxycarbonyl-5-amino- 377imidazole in 90 ml of 1,2 - dimethoxyethane and a light brown solution were heated overnight at 120 ° C in an oil bath. Then another 0.6 ml of ethyl isocyanatoformate was added and heating was continued for another four hours. For work-up, the reaction mixture was mixed with saturated potassium carbonate solution and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, evaporated and purified on a silica gel column with methylene chloride / methanol / conc. with methanolic ammonia solution (98: 2: 1 to 90: 10: 1) as eluent.

52142 Β

Yield: 2.27 g (45% of theory)

Rf value: 0.29 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 537 [M+H]⁺

First X

- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -3- (3-methyl-2-buten-1-yl) -4-ethoxycarbonyl-5-amino-ZN-imidazole

Obtained by refluxing cyanimino - [N- (3-methyl-2-buten-1-yl) -N- (ethoxycarbonylmethyl) -amino] - [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -methane with sodium in ethanol.

R_f value: 0.26 (aluminum oxide, ethyl acetate / petroleum ether = 8: 2)

Mass spectrum (ESI⁺): m/z = 422 [M+H]⁺

RgJtegH!

Cyanimino -1N - (3-methyl-2-butene -1-yl) -N- (ethoxycarbonylmethyl) -amino] - [3 (tert-butyloxycarbonylamino) -piperidine -1-yl-methane

Obtained by reacting cyanimino - [N - (3 - methyl - 2 - buten - 1 - yl) - N - (ethoxycarbonylmethyl) amino] - phenyloxy - methane with 3 - (tert. Butyloxycarbonylamino) piperidine in the presence of potassium carbonate in N, N - dimethylformamide at room temperature.

Rf value: 0.10 (silica gel, petroleum ether / ethyl acetate = 6: 4)

Mass spectrum (ESI⁺): m/z = 422 [M+H]⁺

RptegHP

Cyanimino - [N- (3-methyl-2-buten-1-yl) -N-fetoxycarbonylmethyl) -amino] phenyloxy-methane

It is obtained by reacting cyanimino - ((ethoxycarbonylmethyl) amino] - phenyloxy - methane with 1 bromo - 3 - methyl - 2 - butene in the presence of potassium carbonate in acetone at room temperature.

R_f value: 0.70 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 316 [M+H]⁺

РНтегХШ

52142 Β

Ciianimino - [(ethoxycarbonylmethylaminol - phenyloxy - methane

It is obtained by reacting diphenylcyanocarbonimidate with ethyl aminoacetate hydrochloride in the presence of triethylamine in isopropanol at room temperature (analogous to R. Besse et al., Tetrahedron 1990, 46, 7803-7812).

Rf value: 0.73 (silica gel, petroleum ether / ethyl acetate = 8: 2)

Mass spectrum (ESI⁺): m/z = 248 [M+H]⁺

Primer XIV

- methyl - 3 - [(methoxycarbonyl) methyl] -7- (2-cyano-benzyl) -8-chloro-xanthine Obtained by the reaction of 1-methyl-7- (2-cyano-benzyl) -8-chloro-xanthine with methyl bromoacetate in the presence of potassium carbonate in N, N - dimethylformamide at room temperature.

Rf value: 0.80 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI⁺): ш/z = 388,390 [M+H]⁺

The following compounds were prepared analogously to Example XIV:

(1) 1-methyl-3-cyanomethyl-7- (2-cyano-benzyl) -8-chloro-xanthine

Mass spectrum (ESI⁺): m/z = 355,357 [M+H]⁺ (2) 1 - methyl -3- (2-propyn-1-yl) - 7- (2-cyano-benzyl) -8-chloro-xanthine

Rf value: 0.80 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 354, 356 [M+H]⁺ (3) 1 - methyl -3- (2-propene-1-yl) - 7- (2-cyano-benzyl) -8-chloro-xanthine

Rf value: 0.90 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 356,358 [M+H]⁺ (4) 1- (2-phenyl-2-oxo-ethyl) -3-cyanomethyl-7- (3-methyl 2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine-1- il] - xanthine

Rf value: 0.78 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 576 [M+H]⁺ (5) 1-methyl-3-isopropyl-7- (2-cyano-benzyl) -8-chloro-xanthine

52142 Β

Mass spectrum (ESI⁺): m/z = 358,360 [M+H]⁺

FirstXV

- methyl -7- (2-cyano-benzyl) -8-chloro-xanthine

It is obtained by treating 1 - methyl - 3 - [(2 - trimethylsilanyl - ethoxy) methyl] - 7 - (2 - cyano benzyl) - 8 - chloro - xanthine with trifluoroacetic acid in methylene chloride at room temperature.

Rf value: 0.50 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI⁺): m/z = 316,318 [M+H]⁺

The following compounds were prepared analogously to Example XV:

(1) 1- (2-phenyl-2-oxo-ethyl) -3-methyl-8-bromo-xanthine

Rf value: 0.26 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI '): m / z = 361.363 [M - H] (2) 1 - [(4 - oxo - 3,4 - dihydro - phthalazin - 1 - yl) methyl] -3 - methyl - 7 - 3-methyl-2-buten 1-yl) -8- (3-amino-piperidin-1-yl) -xanthine (Since the compound still contains impurities that cannot be removed by chromatography, the material is again converted to a derivative with protected BOC and then purified by chromatography, cf. Ex. XXV (1).)

Mass spectrum (ESI⁺): m/z = 491 [M+H]⁺

FirstXVI

- methyl -3 - ((2-trimethylsilanyl-ethoxy) methyl -7- (2-cyano-benzyl) -8-chloro-xanthine Obtained by chlorination of 1-methyl-3 - [(2-trimethylsilanyl-ethoxy) methyl] - 7- (2-cyano benzyl) -xanthine with N-chlorosuccinimide in dichloroethane at reflux.

Mass spectrum (EI): m / z = 445.447 [M]⁺

RgJtegHUP

7- (2-cyano-benzyl) -xanthine

They were obtained by treating 16.68 g of 2-amino -7- (2-cyano-benzyl) -1,7-dihydro-purine-6 ​​one with 17.00 g of sodium nitrite in a mixture of 375 ml of conc. acetic acid, 84 ml of water and 5.2 ml of conc. hydrochloric acid at 50 ° C.

Yield: 8.46 g (50% of theory)

52142 Β

Mass spectrum (ESI⁺): m/z = 268 [M+H]⁺

First XVIII

- amino -7-(2- ciiano - benzil) -1.7 - dihidro - purin - 6 - on

Obtained by reacting 20.00 g of guanosine hydrate with 22.54 g of 2-cyano-benzyl bromide in dimethylsulfoxide at 60 ° C, followed by treatment with 57 ml of conc. hydrochloric acid. Yield: 18.00 g (97% of theory)

Mass spectrum (ESI⁺): m/z = 267 [M+H]⁺

First XIX

- {2 - [3 - (2 - oxo - imidazolidin -1 - yl) - phenyl] - 2 - oxo - ethyl} - 3 - methyl -7- (3- methyl -

- buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Obtained by treating 1- (2- (3 - {[(2-chloro-ethylamino) carbonyl] amino } - phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine with potassium tert. butoxide in N, N · dimethylformamide at room temperature.

R_f value: 0.50 (silica gel, methylene chloride / methanol = 9: 1)

РгJтегХХ

- [2- (3 - {N (2-chloro-ethylamino) carbonyl] amino} -phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- GZ - (tert, butyloxycarbonylamino) - piperidin-1-xanthine

Obtained by the reaction of 221 mg of 1- (2- (3-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert butyloxycarbonylamino) - piperidin-1 - yl] - xanthine with 60 μΐ of 2 - chloroethyl isocyanate in 3 ml of methylene chloride at room temperature.

Yield: 163 mg (64% of theory)

R_f value: 0.20 (silica gel, cyclohexane / ethyl acetate / methanol = 6: 3: 1)

Mass spectrum (ESI⁺): m/z = 671, 673 [M+H]⁺

The following compounds were prepared analogously to Example XX:

(1) 1- (2- (2 - {[(ethoxycarbonylamino) carbonyl] amino} -phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-butene-11) - 8- (3- (tert. Butyloxycarbonylamino) -piperidin-1-yl] xanthine (Performed in N, N-dimethylformamide at 30 ° C)

52142 Β

R_f value: 0.26 (silica gel, cyclohexane / ethyl acetate = 4: 6)

Mass spectrum (ESI⁺): m/z = 681 [M+H]⁺

RpsheghXX!

1- (2- (3-amino-phenyl) -2-oxo-ethyl-3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3- (tert-butyloxycarbonylamino) -piperidine -1 - ill - xanthine

Obtained by treating 1- (2- (3-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert. butoxycarbonylamino) -piperidin-1-yl] -xanthine with iron powder in a mixture of ethanol, water and ice-cold acetic acid (80:25:10) at 100 ° C.

Rf value: 0.55 (silica gel, cyclohexane / ethyl acetate / methanol / conc. Aqueous ammonia solution = 50: 30: 20: 1)

Mass spectrum (ESI⁺): m/z = 566 [M+H]⁺

The following compounds were prepared analogously to Example XXI:

(1) 1- (2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8 [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 566 [M+H]⁺ (2) 1- (2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8 [(5) -3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 566 [M+H]⁺ (3) 1 - [(5 - amino - isohinolin -1 - il) methyl] - 3 - methyl - 7 - (3 - methyl - 2 - butene -1 - il) - 8 [3 - (terc. Butyloxycarbonilamino) - piperidin -1 - il] - xanthine

R_f value: 0.22 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m / z = 589 [M + H] + (4) 1- (2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7 - [(1-cyclopenten-1-yl) methyl] 8 - bromo - xanthine

Mass spectrum (ESI⁺): m/z = 458,460 [M+H]⁺ (5) 1- (2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- ((E) -2-buten-1-yl) -8-bromo-xanthine)

52142 Β (product contains approx. 10% Z isomer)

R_f value: 0.55 (silica gel, cyclohexane / ethyl acetate = 4: 6)

Mass spectrum (ESI⁺): m/z = 432, 434 [M+H]⁺ (6) 1 - [2 - (2 - amino - phenyl) - 2 - okso - ethyl] - 3 - methyl - 7 - (2 - butin -1 - il) - 8 - bromine ksantin

R_f value: 0.50 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 430,432 [M+H]⁺ (7) 1- [2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- ((E) -2-buten-1-yl) -8 - [(75 3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI +): m / z = 552 [M + H]⁺ (8) 1- [2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- ((E) -2-buten-1-yl) -8 - [(S) -

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 552 [M+HJ⁺ (9) 1- [2- (2-amino-3-methoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.82 (silica gel, ethyl acetate / petroleum ether = 4: 1)

Mass spectrum (ESI⁺): m/z = 596 [M+H]⁺

FirstXXII

1- (2-12-phenylcarbonylamino] -phenyl) -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-butene 1-11) -8- (3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Obtained by the reaction of 248 mg of 1- [2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert butyloxycarbonylamino) - piperidin-1-yl] -xanthine with 40 μΐ of propionic acid chloride in the presence of 60 μΐ of pyridine in N, N-dimethylformamide at 80 ° C.

Yield: 168 mg (62% of theory)

Rf value: 0.55 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m/z = 622 [M+H]⁺

The following compounds were prepared analogously to Example XXII:

52142 N (1) 1- ({5 - [(methoxycarbonyl) methylamino] -isoquinolin-1-yl} methyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- ( tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Made with methyl bromoacetate and potassium carbonate)

Rf value: 0.42 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 661 [M+H]⁺ (2) 1- [2- (2-acetylamino-phenyl) -2-oxo-ethyl] -3-methyl-7- (E) -2-buten-1-yl) -8 [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine (product contains approx. 10% Z isomer)

Mass spectrum (ESI⁺): m/z = 594 [M+H]⁺ (3) 1- (2 - {2 - [(isopropylcarbonyl) amino] -phenyl} -2-oxo-ethyl) -3-methyl-7- ((E) -2-buten-1-yl) -8 - [ 3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (product contains approx. 10% Z isomer)

Mass spectrum (ESI⁺): m/z = 622 [M+H]⁺ (4) 1- [2- (2-acetylamino-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) 8- [(S) -3 - (tert. butyloxycarbonylamino) - piperidin-1-yl] - xanthine

Rf value: 0.50 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m/z = 608 [M+H]⁺ (5) 1- [2- (2-acetylamino-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1-yl] -xanthine

Rf value: 0.34 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m/z = 592 [M+H]⁺ (6) 1- (2- (2- [(isopropylcarbonyl) amino] - phenyl} - 2 - oxo - ethyl) - 3 - methyl -7- (3- methyl -

- buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.25 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z= 636 [M+H]⁺ (7) 1- (2- (2- [(isopropylcarbonyl) amino] - phenyl} - 2 - oxo - ethyl) - 3 - methyl -7- (2- butin -

- il) - 8 - [3 - (terc. butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Rf value: 0.44 (silica gel, methylene chloride / methanol = 95: 5)

52142 Β

Mass spectrum (ESI⁺): m/z = 620 [M+H]⁺ (8) 1- (2- (2-acetylamino-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyne-1-11) -8 - ((6) -

- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.34 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m/z = 592 [M+H]⁺ (9) 1 - (2 - {2 - [(isopropylcarbonyl) amino] - phenyl} - 2 - oxo - ethyl) - 3 - methyl -7- (2- butin -

- il) - 8- [(6) - 3 - (terc. butiloksikarbonilamino) - piperidin-1 - il] - ksantin

R_f value: 0.44 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 620 [M+H]⁺ (10) 1- (2- (2- [(methoxycarbonyl) amino] - phenyl} - 2 - oxo - ethyl) - 3 - methyl - 7 - (3 - methyl -

- buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Performed in acetonitrile at 55 ° C)

Rf value: 0.25 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 624 [M+H]⁺ (11) 1- (2- (2 - [(isopropylcarbonyl) amino] -phenyl) -2-oxo-ethyl) -3-methyl-7- ((E) -2-buten-1-yl) -8 - [ (S) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Performed in acetonitrile at 65 ° C)

Rf value: 0.50 (silica gel, cyclohexane / ethyl acetate / isopropanol = 14: 3: 3)

Mass spectrum (ESI⁺): m/z = 622 [M+H]⁺ (12) 1- (2- (2- (ethylcarbonyl) amino] -phenyl} -2-oxo-ethyl) -3-methyl-7- ((E) -2-buten 1-yl) -8 - [ (7) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 608 [M+H]⁺ (13) 1- (2- (2-acetylamino-phenyl) -2-oxo-ethyl] -3-methyl-7- (E) -2-buten-1-yl) -8 [(7) -3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 594 [M+H]⁺ (14) 1- (2- (2-acetylamino-phenyl) -2-oxo-ethyl] -3-methyl-7- (E) -2-buten-1-yl) -8 [(6) -3 - (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

52142 Β

R_f value: 0.28 (silica gel, cyclohexane / ethyl acetate / isopropanol = 8: 1: 1)

Mass spectrum (ESI⁺): m/z = 594 [M+H]⁺ (15) 1- (2- (2- [(isopropylcarbonyl) amino] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2-butyne 1-11) -8- (75) - 3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.90 (silica gel, methylene chloride / methanol = 9: 1) (16) 1- (2- (2- (isopropylcarbonyl) amino] -phenyl} -2-oxo-ethyl) -3-methyl-7- ((E) -2 Buten-1-yl) -8 - [((5-3- (tert-butyloxycarbonylamino) -piperidin-1-yl]) - xanthine (Performed in 1,2-dichloroethane at 45 ° C)

R_f value: 0.30 (silica gel, cyclohexane / ethyl acetate / isopropanol = 8: 1: 1)

Mass spectrum (ESI⁺): m/z = 622 [M+H]⁺ (17) 1- (2- (2 - [(ethylcarbonyl) amino] -phenyl} -2-oxo-ethyl) -3-methyl-7- ((E) -2-butene 1-11) -8- (S) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.48 (silica gel, cyclohexane / ethyl acetate / isopropanol = 14: 3: 3) Mass spectrum⁺): m/z = 608 [M+H]⁺ (18) 1- (2- (2 - [(ethylcarbonyl) amino] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2-butyn-1-yl) -8 - [(7 ^) - 3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Mass spectrum⁺): m/z = 606 [M+H]⁺ (19) 1- (2- (2 - [(ethylcarbonyl) amino] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2-butyn-1-yl) -8 - [(5) - 3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.22 (silica gel, methylene chloride / methanol = 95: 5) (20) 1- (2- (2- (phenylcarbonyl) amino] -phenyl} -2-oxo-ethyl) -3-methyl-7 - ((E) -2 buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.55 (silica gel, cyclohexane / ethyl acetate / isopropanol = 14: 3: 3)

Mass spectrum (ESI⁺): m/z = 656 [M+H]⁺ (21) 1- (2- (2 - ((cyclopropylcarbonyl) amino] -phenyl} -2-oxo-ethyl) -3-methyl-7 - (((1cyclopenten-1-yl) methyl] -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] xanthine

52142 Β (Performed with Hinig base and 4-dimethylamino-pyridine in methylene chloride)

Rf value: 0.60 (silica gel, methylene chloride / methanol = 18: 1)

Primer XXIII

1- (2-13-Chromoxycarbonibmethoxy-phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3-amino-piperidin-1-yl) ) - xanthine

Obtained by treating 1- (2 - {3 - [(methoxycarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8 - [ 3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine with trifluoroacetic acid in methylene chloride at room temperature. Mass spectrum (ESI⁺): m/z = 539 [M+H]⁺

The following compounds were prepared analogously to Example XXIII:

(1) 1- (2- (2 - [(methoxycarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (3-methyl 2-buten-1-yl) -8- ( 3-amino-piperidin-1-yl) -xanthine

Mass spectrum (ESI⁺): m/z = 539 [M+H]⁺

FirstXXIV

- methyl - 3 - phenyl -7- (2-cyano-benzyl) -8-chloro-xanthine

A mixture of 829 mg of 1-methyl-7- (2-cyano-benzyl) -8-chloro-xanthine, 640 mg of phenylboronic acid, 509 mg of anhydrous copper acetate and 0.43 ml of pyridine in 20 ml of methylene chloride was stirred for four days at room temperature in in the presence of 100 mg of molecules o

4A sieves. Then another 320 mg of phenylbonemic acid was added, and the reaction mixture was stirred for another day at room temperature. For work-up, the mixture was filtered through talc and washed with ethyl acetate. The filtrate was evaporated and chromatographed on a silica gel column with cyclohexane / ethyl acetate (7: 3 to 1: 1) as eluent.

Yield: 142 mg (14% of theory)

Mass spectrum (ESI⁺): m/z = 392,394 [M+H]⁺

Primer XXV

- ((2-phenyl-2-oxo-ethyl) -7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonyl-amino) -piperidin-1-yl-xanthine)

52142 Β

Obtained by reacting 1- (2-phenyl-2-oxo-ethyl) -7- (3-methyl-2-buten-1-yl) -8- (3 amino-piperidin-1-yl) -xanthine with di- tert. butyl pyrocarbonate in the presence of a Hinig base in methylene chloride at room temperature.

Rf value: 0.27 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

The following compounds were prepared analogously to Example XXV:

(1) 1 - [(4-oxo-3,4-dihydro-phthalazin-1-yl) methyl] -3-methyl-7- (3-methyl-2-butene -

- il) - 8 - [3 - (terc. butiloksikarbonil - amino) - piperidin -1 - il] - ksantin

Rf value: 0.27 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 591 [M+H]⁺ (2) 7-acetyl -1 - (tert. Butyloksikarbonyl) - 1H- indole

Rf value: 0.82 (silica gel, methylene chloride / petroleum ether / ethyl acetate = 5: 4: 1)

Mass spectrum (ESI⁺): m/z = 260 [M+H]⁺

РпшегХХУ!

- Г (quinolin-4-dimethyl-3-methyl -7- (3-methyl-2-buten-1-yl) -8-chloroxanthine 1 [(1,4-dihydro-quinolin-4-yl) nonethyl] 3-methyl -7- (3-methyl-2-buten-1-yl) -8-chloroxanthine

To a mixture of 510 mg (quinolin-4-yl) -methanol and (1,4-dihydro-quinolin-4-yl) -methanol (see Ex. XXVII) was added 830 mg of 3-methyl-7- (3-methyl-2 - buten-1-yl) -8- chloro-xanthine and 1.25 g of triphenylphosphine in 25 ml of tetrahydrofuran. The reaction mixture was mixed with 0.92 ml of diethyl azodicarboxylate and stirred overnight at room temperature. It was then evaporated and chromatographed on a silica gel column with ethyl acetate / petroleum ether (7: 3 to 0: 1) as eluent. A mixture of quinoline and 1,4 - dihydro - quinoline compounds was obtained. Yield: 660 mg (52% of theory)

Rf value: 0.60 (silica gel, ethyl acetate / petroleum ether = 7: 3)

The following compounds were obtained analogously to Example XXVI:

(1) 1- ({4-oxo-3 - [(2-trimethylsilanyl-ethoxy) methyl] -3,4-dihydro-phthalazin-1-yl} methyl) -3-methyl-7- (3-methyl-2 - buten-1-yl) -8-chloro-xanthine

Rf value: 0.85 (silica gel, methylene chloride / methanol = 95: 5)

52142 Β

Mass spectrum (ESI⁺): m/z = 557,559 [M+H]⁺ (2) 1 - [(izohinolin - 3 - il) methyl] - 3 - methyl -7- (3- methyl - 2 - butene -1 - il) - 8 - chloro xanthine

Melting point: 194 - 195 ° C

Mass spectrum (ESI⁺): m/z = 410,412 [M+H]⁺ (3) 1 - [(3-methyl-4-oxo-3,4-dihydro-phthalazin-1-yl) methyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8 - chloro - xanthine

R_f value: 0.66 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 441,443 [M+H]⁺ (4) 1 - [(quinolin-4-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-bromo-xanthine (Made with potassium carbonate)

Rf value: 0.45 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 438,440 [M+H]⁺ (5) 1 - [(izohinolin -1 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - bromo - xanthine

Rf value: 0.78 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 438,440 [M+H]⁺ (6) 1 - [(4 - dimethylamino - naphthalen -1 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - the] - ksantin

R_f value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 600 [M+H]⁺ (7) 1 - [(isoquinolin-1-yl) methyl] -3-methyl-7 - ((E) -2-buten-1-yl) -8-bromo-xanthine (the product contains approximately 20% of the Z isomer )

Rf value: 0.71 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 440,442 [M+H]⁺ (8) 1 - [(1 - metil - indol - 2 - il) metil] - 3 - metil -7- (2- booty -1 - il) - 8 - bromo ksantin

Rf value: 0.95 (silica gel, methylene chloride / methanol = 95: 5)

52142 Β

Mass spectrum (ESI⁺): m/z = 440, 442 [M+H]⁺ (9) 1 - [(hinolin - 3 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - bromine - ksantin

Reflection: 0.55 (silika gel, etil acetat / petrol etar = 8: 2)

Mass spectrum (ESI⁺): m/z = 438,440 [M+H]⁺ (10) 1 - {[1- (tert-butyloxycarbonylamino) -1H-indol-2-ylmethyl} -3-methyl-7- (2butin-1-yl) -8-bromo-xanthine

R_f value: 0.74 (silica gel, petroleum ether / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 526,528 [M+H]⁺ (11) 1- ({2-methyl-1 - [(2-trimethylsilanyl-ethoxy) methyl] -1H-benzoimidazol-5-yl} methyl) -3-methyl-7- (2-butyn-1-yl) - 8-bromo-xanthine (mixed with 1- ({2-methyl 3 - [(2-trimethylsilanyl-ethoxy) methyl] -3H-benzoimidazol-5-yl} methyl) -3-methyl-7- (2butin-1) -yl) -8-bromo-xanthine)

Mass spectrum (ESI⁺): m/z = 571,573 [M+H]⁺ (12) 1 - [(1 - [(2-trimethylsilanyl-ethoxy) methyl] -17H-benzoimidazol-5-yl) methyl] -3-methyl 7- (2-butyne-11-yl) -8-bromo - xanthine (mixed with 1 - [(3 - [(2-trimethylsilanyl ethoxy) methyl] -3H-benzoimidazol-5-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8 - xanthine bromine)

Rf value: 0.50 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 557,559 [M+H]⁺ (13) 1 - [(pyrazolo [1,5-a] pyridin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-bromo xanthine

Rf value: 0.35 (silica gel, petroleum ether / ethyl acetate = 1: 2)

Mass spectrum (ESI⁺): m/z = 427,429 [M+HJ+

Primer XXVII (Quinolin-4-yl) -methanol and (1,4-dihydro-quinolin-4-yl) -methanol

A solution of 1.00 g of methyl quinoline - 4 - carboxylate in 15 ml of diethyl ether was added dropwise at 0 ° C to a suspension of 222 mg of lithium aluminum hydride in 5 ml of diethyl ether. After 1.5 hours, water was carefully added dropwise to the reaction mixture, then mixed with methylene chloride and

52142 Β is filtered by suction through a glass fiber filter. The aqueous phase was extracted with methylene chloride, and the combined organic phases were dried over magnesium sulfate and evaporated. According to^!H - NMR gave a mixture of quinoline and 1,4 - dihydro quinoline compounds as a yellow oil which was further reacted without any further purification.

Yield: 530 mg (62% of theory)

Rf value: 0.63 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 161 [Ml+H]⁺ i 163 [M2+H]⁺

The following compounds were prepared analogously to Example XXVII:

(1) {2-methyl-1 - [(2-trimethylsilanyl-ethoxy) methyl] -1H-benzoimidazol-5-yl} -methanol (mixed with {2-methyl-3 - [(2-trimethylsilanyl-ethoxy) methyl] ] - 3H-benzoimidazole-5-yl} methanol)

Mass spectrum (ESI⁺): m/z = 293 [M+H]⁺ (2) (2,3,8 - trimethyl - hinoksalin - 6 - il) - methanol

Rf value: 0.45 (silica gel, petroleum ether / ethyl acetate = 1: 2)

Mass spectrum (ESI⁺): m/z = 203 [M+H]⁺ (3) (8 - methyl - hinoksalin - 6 - il) - methanol

Rf value: 0.18 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 175 [M+H]⁺ (4) (E) -3-Pentafluorophenyl-2-propene-1-ol (Made with diisobutylaluminum hydride in toluene)

Mass spectrum (EI): m / z = 224 [M]⁺ (5) (E) -3- (2- (trifluoromethyl-phenyl) -2-propene-1-ol (Made with diisobutylaluminum hydride in toluene) (6) (E) -3- (3-Trifluoromethyl-phenyl) -2 - propene -1 - ol (Made with diisobutylaluminum hydride in toluene)

Mass spectrum (EI): m / z = 202 [M]⁺

52142 Β (7) (Ε) -3- (4-trifluoromethyl-phenyl) -2-propene-1-ol (Made with diisobutylaluminum hydride in toluene)

primer 28

- hydroxymethyl - 2 - [(2 - trimethylsilanyl- ethoxypmetill - 2H- phthalazine -1 - on

Obtained by treating methyl 4 - oxo - 3 - [(2 - trimethylsilanyl - ethoxy) methyl] - 3,4 - dihydro phthalazine - 1 - carboxylate with sodium borohydride in tetrahydrofuran at 40 ° C.

Rf value: 0.55 (silica gel, cyclohexane / ethyl acetate 1: 1)

Mass spectrum (ESI⁺): m/z = 307 [M+H]⁺

The following compounds were prepared analogously to Example XXVIII:

(1) (3,4-Dimethyl-isoquinolin-1-yl) -methanol (Made with lithium borohydride in tetrahydrofuran)

Rf value: 0.35 (silica gel, petroleum ether / ethyl acetate = 2: 1)

Mass spectrum (EST): m / z = 188 [M + H]⁺ (2) (3-methyl-imidazo [1,2-a] pyridin-2-yl) -methanol (Made with lithium borohydride in tetrahydrofuran)

Rf value: 0.48 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z= 163 [M+H]⁺ (3) (3,4-Dimethyl-6,7-dihydro-5H- [2] pyridin-1-yl) -methanol (Made with Ethium borohydride in tetrahydrofuran)

Rf value: 0.40 (aluminum oxide, petroleum ether / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 178 [M+H]⁺ (4) (3,4-Dimethyl-5,6,6,7,8-tetrahydro-isoquinolin-1-yl) -methanol (Made with lithium borohydride in tetrahydrofuran)

Rf value: 0.45 (aluminum oxide, petroleum ether / ethyl acetate = 3: 1)

Mass spectrum (ESI⁺): m/z = 192 [M+H]⁺ (5) 6 - hydroxymethyl -1, 2, 3,4 - tetrahydro - phenanthridine

52142 Β (Performed with lithium borohydride in tetrahydrofuran at room temperature)

Rf value: 0.40 (silica gel, petroleum ether / ethyl acetate = 2: 1)

Mass spectrum (ESI⁺): m/z = 214 [M+H]⁺

Primer XXIX

Methyl 4-oxo-3 - [(2-trimethylsilanyl-ethoxy) methyl-1,3,4-dihydro-phthalazine-1-carboxylate

They are obtained by reacting methyl 4 - oxo - 3,4 - dihydro - phthalazine - 1 - carboxylate with (2 trimethylsilanyl - ethoxy) methyl chloride in the presence of a Hinig base in methylene chloride at room temperature.

Rf value: 0.75 (silica gel, cyclohexane / ethyl acetate 6: 4)

Mass spectrum (ESI⁺): m/z = 335 [M+H]⁺

The following compounds were prepared analogously to Example XXIX:

(1) 7-acetyl-3 - [(2-trimethylsilanyl-ethoxy) methyl] -ZN-benzooxazol-2-one

Mass spectrum (ESI⁺): m/z = 308 [M+H]⁺ (2) 4-acetyl-3 - [(2-trimethylsilanyl-ethoxy) methyl] -3 / 7-benzooxazol-2-one

Rf value: 0.87 (silica gel, methylene chloride / methanol = 99: 1) (3) 4 - acetyl -1,3 - bis - [(2 - trimethylsilamlo - ethoxy) methyl] -1,3 - dihydro - benzoimidazole 2- on (Performed with potassium tert. butoxide in N, N - dimethylformamide)

Rf value: 0.90 (silica gel, petroleum ether / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 437 [M+H]⁺ (4) 6-methyl-1 - [(2-trimethylsilanyl-ethoxy) methyl] -1 / 7-quinolin-2-one

Rf value: 0.78 (silica gel, petroleum ether / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 290 [M+H]⁺ (5) methyl {2-methyl-1 - [(2-trimethylsilanyl-ethoxy) methyl] -benzoimidazol-5-yl} carboxylate (mixed with methyl {2-methyl-3 - [(2-trimethylsilanyl-ethoxy) methyl] - 3Hbenzoimidazole - 5 - yl} - carboxylate)

Mass spectrum (ESI⁺): m/z = 321 [M+H]⁺

52142 Β

Primer XXX

1- (2- (3-methanesulfonyl-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) 8- [3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

0.22 ml of a 35% solution of hydrogen peroxide and 20 mg of sodium tungstate was added to 500 mg of 1- [2- (3-methylsulfanyl-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-butene -1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine in 5 ml of methylene chloride. The reaction mixture was stirred overnight at room temperature and then 1 ml of methanol was added. After the next 48 hours, another 1.5 ml of 35% hydrogen peroxide solution was added, on top of a spatula of sodium tungstate and two drops of water. The next morning, according to thin layer chromatography, the oxidation was completed, and the reaction mixture was diluted with 50 ml of methylene chloride and washed twice with 30 ml of 10% sodium thiosulfate solution. The organic phase was dried over magnesium sulfate and evaporated, leaving a viscous resin which reacted further without any further purification.

Yield: 530 mg (100% of theory)

Rf value: 0.72 (silica gel, ethyl acetate) Mass spectrum⁺): m/z = 629 [M+H]⁺

primer 31

1- (2- (3-carboxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3-tert-butyloxycarbonylamino) -piperidine -1 - ill - xanthine

Obtained by treating 1- (2- (3-methoxycarbonyl-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine with a 3 M solution of sodium hydroxide in methanol at room temperature.

Rf value: 0.34 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI⁺): m/z = 595 [M+H]⁺

The following compounds were prepared analogously to Example XXXI:

(1) 1- (2- (2-carboxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- 3- [tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.49 (silica gel, methylene chloride / methanol = 9: 1) (2) 1- (2- (2-carboxymethoxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyne - 1-yl) -8- (3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

52142 Β (Made with 4 Μ solutions of potassium hydroxide in tetrahydrofuran)

Mass spectrum (ESI⁺): m/z = 609 [M+H]⁺ (3) 1- (2- (2-carboxymethylamino-phenyl) -2-oxo-ethyl] -3-methyl-7- (E) -2-buten-1-yl) -8 - [(79- 3- (tert. Butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Made with 4 M solution of potassium hydroxide in tetrahydrofuran) Rf value: 0.65 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m/z = 610 [M+H]⁺ (4) 1-carboxymethyl-3-methyl-7- (2-butyn-1-yl) -8- (3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mass spectrum (ESI⁺): m/z = 475 [M+H]⁺

primer 32

1- (2- (3- (methylaminocarbonyl) -phenyl-2-oxo-ethyl} -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine

Mixture 190 mg 1- (2- (3-carboxy-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine, 43 μΐ 40% aqueous methylamine solution, 103 mg O - (benzotriazol-1-yl) -N, N, N ', N' tetramethyluronium tetrayl fluoroborate, 43 mg N-hydroxybenzotriazole and 45 μΐ of triethylamine in 3 ml of tetrahydrofuran was stirred for eight hours at room temperature. For work-up, the reaction mixture was diluted with ethyl acetate and washed with water, 10% citric acid solution, 10% potassium carbonate solution and saturated sodium chloride solution. The organic phase was evaporated and chromatographed on a silica gel column with methylene chloride / methanol (98: 2 to 80:20) as eluent.

Yield: 173 mg (89% of theory)

R_f value: 0.30 (silica gel, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m/z = 608 [M+H]⁺

The following compounds were prepared analogously to Example XXXII:

(1) 1- (2- (3- (dimethylaminocarbonyl) -phenyl] -2-oxo-ethyl} -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- ( tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine Rf value: 0.28 (silica gel, methylene chloride / methanol = 20: 1) Mass spectrum⁺): m/z= 622 [M+H]⁺

52142 Β (2) 1- {2- [3- (morfolin - 4 - il - karbonil) - fenil] - 2 - okso - etil} - 3 - metil - 7 - (3 - metil -

- buten-1-yl) -8- (3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

R_f value: 0.30 (silica gel, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m/z = 664 [M+H]⁺ (3) 1- (2- (2- (dimethylaminocarbonyl) -phenyl] -2-oxo-ethyl} -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3- ( tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Rf value: 0.30 (silica gel, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m/z = 622 [M+H]⁺ (4) 1- (2- (2- (morpholine - 4 - yl - carbonyl) - phenyl] - 2 - oxo - ethyl} - 3 - methyl -7- (3- methyl -

- buten -l-il) -8- [3- (terc. butiloksikarbonilamino) - piperidin -1 - il] - ksantin

R_f value: 0.30 (silica gel, methylene chloride / methanol = 20: 1)

Mass spectrum (ESI⁺): m/z = 664 [M+H]⁺ (5) 1- (2- (2 - [(isopropylaminocarbonyl) methoxy] -phenyl) -2-oxo-ethyl) -3-methyl-7- (2butin-1-yl) -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Performed with Hinig base in N, N-dimethylformamide)

Mass spectrum (ESI⁺): m/z = 650 (M+H]⁺ (6) 1- (2 - (2 - [(ethylaminocarbonyl) methoxy] -phenyl) -2-oxo-ethyl) -3-methyl-7- (2butin-1-yl) -8- (3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Performed with Hinig base in N, N-dimethylformamide)

Mass spectrum (ESI⁺): m/z = 636 [M+H]⁺ (7) 1- (2- (2- (2-oxo-2- (pyrrolidin-1-yl) -ethoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7 (2-butyn-1) -yl) -8- (3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Performed with Hinig base in N, N-dimethylformamide)

Mass spectrum (ESI⁺): m/z = 662 [M+H]⁺ (8) 1- (2- (2- (2- (morpholin-4-yl) -2-oxo-ethoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7- (2-butyne. - 1-yl) -8- (3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine (Performed with Hinig base in N, N-dimethylformamide)

Mass spectrum (ESI⁺): m/z = 678 [M+H]⁺

52142 Β (9) 1 - (2 - {2 - [(metilaminokarbonil) metilamino] - fenil} - 2 - okso - etil) - 3 - metil - 7 ((E) - 2 - buten -1 - il) - 8 - [(.Л) - 3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] - *

xanthine

Rf value: 0.40 (silica gel, cyclohexane / ethyl acetate / methanol = 5: 4: 1)

Mass spectrum (ESI⁺): m/z = 623 [M+H]⁺ (10) 1 - [(2 - amino - phenylaminokarbonyl) methyl] - 3 - methyl-7- (2- butin -1 - il) - 8 - [3 (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

Rf Value: 0.40 (silica gel, cyclohexane / ethyl acetate / methanol = 5: 4: 1)

Mass spectrum (ESI⁺): m/z = 565 [M+H]⁺

primer 33

- chloromethyl - 4 - methyl - isoquinoline - hydrochloride

They are obtained by treating (4-methyl-isoquinolin-1-yl) -methanol with thionyl chloride in methylene chloride.

R_f value: 0.76 (silica gel, methylene chloride / methanol / conc. aqueous ammonia solution = 95: 5: 0.1)

Mass spectrum (ESI⁺): m/z = 192,194 [M+H]⁺

The following compounds were prepared analogously to Example XXXIII:

(1) 1 - chloromethyl - 3,4 - dimethyl - isoquinoline - hydrochloride

Rf value: 0.65 (silica gel, petroleum ether / ethyl acetate = 2: 1)

Mass spectrum (ESI⁺): m/z = 206, 208 [M+H]⁺ (2) 5 - Chloromethyl - 8 - methoxy - quinoline hydrochloride

Mass spectrum (ESI⁺): m/z = 208, 210 [M+H]⁺ (3) 8 - Chloromethyl - 5 - methoxy - quinoline hydrochloride

Mass spectrum (EI): m / z = 207, 209 [M]⁺ (4) 2-Chloromethyl-3-methyl-imidazo [1,2-a] pyridine hydrochloride

Rf value: 0.55 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Β 52142

Mass spectrum (ESI⁺): m/z = 181,183 [M+H]⁺ (5) 8 - chloromethyl - 5 - methoxy - isoquinoline - hydrochloride

Mass spectrum (ESI⁺): m / z = 208, 210 [M + H]⁺ (6) 1-Chloromethyl-3,4-dimethyl-6,7-dihydro-577- [2] pyridine hydrochloride

Rf value: 0.50 (aluminum oxide, petroleum ether / ethyl acetate = 10: 1)

Mass spectrum (ESI⁺): m/z = 196,198 [M+H]⁺ (7) 1 - chloromethyl - 3,4 - dimethyl - 5, 6,7, 8 - tetrahydro - isoquinoline - hydrochloride

Rf value: 0.50 (aluminum oxide, petroleum ether / ethyl acetate = 10: 1)

Mass spectrum (ESI⁺): m/z = 210,212 [M+H]⁺ (8) 6-Chloromethyl-2,3,3,8-trimethyl-quinoxaline hydrochloride

Mass spectrum (ESI⁺): m/z = 221,223 [M+H]⁺ (9) 6 - Chloromethyl - 8 - methyl - quinoxaline hydrochloride

Mass spectrum (ESI⁺): m/z = 193,195 [M+H]⁺ (10) 6 - Chloromethyl - 1,2,3,4 - tetrahydro - phenanthridine hydrochloride

R_f value: 0.50 (silica gel, petroleum ether / ethyl acetate = 5: 1)

Mass spectrum (ESI⁺): m/z = 232,234 [M+H]⁺

Primer XXXIV

1- (4-oxo-3,4-dihydro-quinazolin-2-ylmethyl-3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl- xanthine

0.5 ml of a 1 M solution of sodium methoxide in methanol was added dropwise to a solution of 428 mg of 1 cyanomethyl-3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) piperidin-1-yl] - xanthine in 3 ml of methanol at room temperature. After about 20 minutes, the resulting thick suspension was gently heated in a water bath and diluted with 2 mL of methanol. As soon as the iminoester formation reaction was complete according to thin layer chromatography, the reaction mixture was neutralized with 0.5 ml of a 1 M solution of ice-cold acetic acid in methanol and mixed with a 130 mg solution.

52142 Β anthranilic acid in 2 ml of methanol. A clear solution was formed by gentle heating, which was stirred for 2.5 hours at room temperature. The reaction mixture was then gently refluxed for about 3.5 hours. After standing overnight at room temperature, the methanol was distilled off, and the precipitate was mixed with cold water, filtered off with suction and dried. The crude product was suspended in 5 ml of methanol, heated slightly and, after cooling, filtered off with suction, washed with methanol and dried in a desiccator.

Yield: 302 mg (56% of theory)

R_f value: 0.55 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 575 [M+H]⁺

The following compounds were prepared analogously to Example XXXV:

(1) (4-difluoromethoxy-naphthalene-1-yl) -methanol

Rf Value: 0.33 (silica gel, cyclohexane / ethyl acetate = 6: 4)

Mass spectrum (ESI): m / z = 223 [M - H] '

PrimerXXXV (4 - dimethylamino - naphthalen -1 - il) - methanol

It was obtained by reduction of 4 - dimethylamino - naphthalene - 1 - carbaldehyde with sodium borohydride in an aqueous solution of tetrahydrofuran.

R_f value: 0.67 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Primer XXXVI

-bromo -1-(2.3-dihidro-benzoil, 41dioksin-5-il)-etanon

It was obtained by bromination of 1 - (2,3 - dihydro - benzo [1,4] dioxin - 5 - yl) - ethanone in methylene chloride while being slightly cooled in an ice bath. The dibromo compound formed as a by-product was isolated by column chromatography.

Mass spectrum (ESI⁺): m/z = 257,259 [M+H]⁺

Rf value: 0.92 (silica gel, methylene chloride)

The following compounds were prepared analogously to Example XXXVI:

52142 Β (1) 7- (2-bromo-acetyl) -3-methyl-37Λ benzooxazol-2-one (bromination was performed in dioxane at 40 ° C; the product was contaminated with approx. 20% dibromo compound)

Rf value: 0.44 (silica gel, petroleum ether / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 270,272 [M+H]⁺ (2) 1 - benzo [l, 3] dioksol - 4 - il - 2 - bromine - ethanon

Mass spectrum (ESI⁺): m/z = 243,245 [M+H]⁺

Rf value: 0.94 (silica gel, methylene chloride) (3) 2 - [2 - (2 - bromo - acetyl) - phenoxy] - N - ethyl - acetamide (bromination was performed with copper (II) bromide in dioxane)

Mass spectrum (ESI⁺): m/z = 300,302 [M+H]⁺ (4) 4-(2- bromo - acetil) - 3 - metil - 377- benzooksazol - 2 - on

Rf value: 0.67 (silica gel, methylene chloride / methanol = 99: 1)

Mass spectrum (ESI +): m / z = 270.272 [M + H]⁺ (5) 2- (2- (2-bromoacetyl) phenoxy] -N-methylacetamide

Mass spectrum (ESI⁺): m/z = 386,388 [M+H]⁺ (6) 7- (2-bromo-acetyl) -3 - [(2-trimethylsilanyl-ethoxy) methyl] -377-benzooxazol-2-one

R_f value: 0.84 (silica gel, methylene chloride / methanol = 99: 1)

Mass spectrum (ESI⁺): m/z = 384, 386 [M+H]⁺ (7) 4-(2- bromo - acetil) -1,3 - dimetil -1,3 - dihidro - benzoimidazol - 2 - on

Rf value: 0.38 (silica gel, ethyl acetate / petroleum ether = 1: 1)

Mass spectrum (ESI⁺): m / z = 283,285 [M + N]⁺ (8) 4- (2-bromo-acetyl) -3- (2-trimethylsilamlo-ethoxy) methyl] -3 / 7-benzooxazol-2-one Rf value: 0.82 (silica gel, methylene chloride / methanol = 99: 1) (9) 4- (2-bromo-acetyl) -1-ethoxycarbonyl-3-methyl-1,3-dihydro-benzoimidazol-2-one

52142 Β

R_fvalue: 0.39 (silica gel, petroleum ether / ethyl acetate = 2: 1)

Mass spectrum (ESI⁺): m/z = 341,343 [M+H]⁺ (10) 2 - bromine -1 - (2,2 - difluoro - benzo [l, 3] dioksol - 4 - il) - etanon

Mass spectrum (ESI '): m / z = 277.279 [M - H]'

Primer XXXVII (2,3-dihydro-benzofl, 41-dioxin-5-yl) -ethanone

It is obtained by reacting 1 - (2,3 - dihydroxy - phenyl) - ethanone with 1,2 - dibromoethane in the presence of potassium carbonate in N, N - dimethylformamide at 100 ° C.

R_f value: 0.43 (silica gel, ethyl acetate / petroleum ether = 1: 4)

Mass spectrum (ESI⁺): m/z = 179 [M+H]⁺

primer 38

1- (3-methyl-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1-yl] -xanthine

Obtained by the reaction of 1- (4-oxo-3,4-dihydro-quinazolin-2-yl) methyl] -3-methyl-7- (2butin-1-yl) -8- (3- (tert-butyloxycarbonylamino) - piperidin-1-yl] -xanthine with methyl iodide in the presence of potassium carbonate in N, N-dimethylformamide at room temperature Rf value: 0.50 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 589 [M+H]⁺

The following compounds were prepared analogously to Example XXXVIII:

(1) 7 - acetyl - 3 - methyl - ZN - benzooxazol - 2 - one (methylation was performed in the presence of sodium carbonate in methanol)

Rf value: 0.46 (silica gel, petroleum ether / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 192 (M+H]⁺ (2) 4 - acetyl - 3 - methyl - ZN - benzooxazol - 2 - one (methylation was performed in the presence of sodium carbonate in methanol at reflux)

R_f value: 0.67 (silica gel, methylene chloride / methanol = 99: 1)

Mass spectrum (ESI⁺): m/z = 192 [M+H]⁺

52142 Β (3) 4 - acetyl -1,3 - dimethyl -1,3 - dihydro - benzoimidazol - 2 - one (Performed in the presence of potassium tert - butoxide)

Reference: 0.40 (silika gel, etil acetat / petrol etar = 2: 1)

Mass spectrum (ESI⁺): m/z = 205 [M+H]⁺ (4) 4 - acetyl -1 - ethoxycarbonyl - 3 - methyl -1,3 - dihydro - benzoimidazole - 2 - ten

R_f value: 0.23 (silica gel, petroleum ether / ethyl acetate = 2: 1)

Mass spectrum (ESI⁺): m/z = 263 [M+H]⁺ (5) 1 - [(1 - methyl - 1H- benzoimidazol - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 (terc. Butiloksikarbonilamino) - piperidin - 1 - the] - ksantin

Mass spectrum (ESI⁺): m/z = 561 [M+H]⁺ (6) 1 - {[1- (2-cyano-ethyl) -1H-benzoimidazol-2-ylmethyl} -3-methyl-7- (2-butyn-1-yl) -8 - [3- (tert-butyloxycarbonylamino) ) - piperidin-1-yl] -xanthine

R_fvalue: 0.50 (silica gel, cyclohexane / ethyl acetate / methanol = 5: 4: 1)

Mass spectrum (ESI⁺): m/z = 600 [M+H]⁺ (7) 1 - ({1 - [(methylaminokarbonyl) methyl] - 1H - benzoimidazol - 2 - the} methyl) - 3 - methyl - 7 (2 - butin -1 - the) - 8 - [3 - (terc. butiloksikarbonilamino) - piperidin -1 - il] - ksantin

R_f value: 0.45 (silica gel, cyclohexane / ethyl acetate / methanol = 5: 4: 1)

Mass spectrum (ESI⁺): m/z = 618 [M+H]⁺ (8) 1 - [(1 - benzyl - 1H - benzoimidazol - 2 - il) methyl] - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 (terc. Butiloksikarbonilamino) - piperidin - 1 - the] - ksantin

Rf Value: 0.50 (silica gel, cyclohexane / ethyl acetate / methanol = 5: 4: 1)

Mass spectrum (ESI⁺): m/z = 637 [M+H]⁺

Primer XXXIX

- [2- (2-cyanomethylamino-phenyl) -2-oxo-ethyl-3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine - 1 - ill - xanthine

Obtained by the reaction of 1- [2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-2-buten-1-yl) -8- [3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine with

52142 Β paraformaldehyde and potassium cyanide in the presence of zinc chloride in ice-cold acetic acid at 40 ° C.

Rf value: 0.45 (silica gel, cyclohexane / ethyl acetate = 3: 7)

Mass spectrum (ESI⁺): m/z = 605 [M+H]⁺

PrimerXL

- [2 - (2 - amino - phenyl - 2 - oxo - ethyl - 3 - methyl - 7 - (2 - butyn - 1 - yl) - 8 - [(5) -3 - ((tert. Butyloxycarbonylamino) - piperidine - 1 - yl] - xanthine

Obtained by reduction of 1- [2- (2-nitro-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8 - [(S) -3- (tert. butyloxycarbonylamino) -piperidin-1-yl] -xanthine with sodium dithionite in a mixture of methylglycol and water (2: 1) at 100 ° C.

R_f value: 0.34 (silica gel, methylene chloride / methanol = 95: 5)

The following compounds were prepared analogously to Example XL:

(1) 1- [2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- (2-butyn-1-yl) -8 - [(.Л) -3 (tert butyloxycarbonylamino) -piperidin -1-yl] -xanthine

Rf value: 0.50 (silica gel, cyclohexane / ethyl acetate = 4: 6)

PrimerXLI - chloromethyl-4-methyl-hinazolin

It was obtained by treating 2.95 g of 2 - chloromethyl - 4 - methyl - quinazoline - 3 - oxide with 6 ml of phosphorus trichloride in 150 ml of chloroform at reflux.

Yield: 1.75 g (57% of theory)

Rf Value: 0.81 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 193,195 [M+H]⁺

PrimerXLII

- chloromethyl-4-dimethylamino-hinazoline

A freshly prepared solution of 202 mg of dimethylamine in 3.2 ml of tetrahydrofuran was added dropwise to 500 mg of 4-chloro-2-chloromethyl-quinazoline in 5 ml of tetrahydrofuran while cooling in an ice bath. The reaction mixture was then stirred for another 3.5 hours while cooling in an ice bath and then for another 30 minutes at room temperature.

52142 Β

The solvent was then lightly distilled off using a rotary evaporator, and the precipitate was taken up in methylene chloride. The solution was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated. The solid precipitate was mixed with a small third. butyl methyl ether, then filtered off with suction, washed with petroleum ether and dried in vacuo. Yield: 323 mg (62% of theory)

Rf value: 0.60 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 222,224 [M+H]⁺

The following compounds were prepared analogously to Example XLII:

(1) 2 - chloromethyl - 4 - (morpholin - 4 - il) - hinazolin

R_f value: 0.50 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 264,266 [M+H]⁺ (2) 2 - chloromethyl - 4 - (piperidin -1 - il) - hinazolin

Rf value: 0.70 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 262,264 [M+H]⁺ (3) 4 - [4 - (tert. Butyloksikarbonyl) -piperazin-1-yl] -2-hloromethyl-hinazolin

R_f value: 0.57 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 363,365 [M+H]⁺ (4) 2 - chloromethyl - 4 - (pyrolidin -1 - il) - hinazolin

Rf value: 0.50 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 248,250 [M+H]⁺ (5) 2 - chloromethyl - 4 - ethoxy - quinazoline (reaction was performed with sodium ethoxide in ethanol at room temperature.) Rf value: 0.50 (silica gel, cyclohexane / ethyl acetate = 3: 1)

Mass spectrum (ESI⁺): m/z = 223,225 [M+H]⁺ (6) 2 - chloromethyl - 4 - isopropyloxy - quinazoline (reaction was performed with sodium isopropoxide in isopropanol at room temperature.) Rf value: 0.70 (silica gel, cyclohexane / ethyl acetate = 3: 1)

Mass spectrum (ESI⁺): m/z = 237,239 [M+H]⁺

52142 Β (7) 2 - chloromethyl - 4 - phenyloxy - quinazoline (reaction was performed with sodium hydride and phenol in tetrahydrofuran at room temperature.)

Rf value: 0.65 (silica gel, cyclohexane / ethyl acetate = 3: 1)

Mass spectrum (ESI⁺): m/z = 271,273 [M+H]⁺

PrimerXLIII

- (2 - {2 - [(ethoxycarbonyl) methylamino] - phenyl} -2 - oxo - ethyl) - 3 - methyl - 7 - ((E) -2 buten-1-yl) - 8 - GZ - (tert. Butyloxycarbonylamino) -piperidin-1-yl] -xanthine A solution of 110 μL of ethyl diazoacetate in 0.5 ml of toluene was added dropwise to 531 mg of 1- [2- (2-amino-phenyl) -2-oxo-ethyl] -3-methyl-7- (E) -2 - buten - 1 - yl) - 8 - [3- (terc.

butyloxycarbonylamino) -piperidin-1-yl] -xanthine and 10 mg of methyl trioxorenium in 4.5 ml of toluene at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 15 hours. Then approx. 5 mg of methyl trioxorenium and 20 [mu] L of ethyl diazoacetate, and the reaction mixture was heated at 50 [deg.] C. for two hours. After cooling to room temperature, another 5 mg of methyl trioxorenium and 20 [mu] L of ethyl diazoacetate were added. After another 16 hours at room temperature, the reaction mixture was mixed with 5 ml of conc. aqueous ammonia solution, well shaken and added to the Extrelut package. After 15 min it was washed with 200 ml of methylene chloride. The methylene chloride solution was evaporated and chromatographed on a silica gel column with cyclohexane / ethyl acetate / isopropanol (8: 2: 0 to 8: 1: 1) as eluent.

Yield: 220 mg (36% of theory)

Rf value: 0.40 (silica gel, cyclohexane / ethyl acetate = 1: 1) Mass spectrum⁺): m/z = 638 [M+H]⁺

PrimerXLIV

- [(2-cyano-benzofuran-3-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl-xanthine

Mixture 215 mg 1- (2- (2-cyanomethoxy-phenyl] -2-oxo-ethyl} -3-methyl-7- (2-butyn 1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidine -1-yl] -xanthine and 244 mg of cesium carbonate in 4 ml of N, N-dimethylformamide were stirred for two hours at 50 [deg.] C. and then for another three hours at 70 [deg.] C. The reaction mixture was mixed with water for processing and the precipitate formed was filtered off with suction and dried.

Yield: 130 mg (62% of theory)

52142 Β

Mass spectrum (ESI⁺): m/z = 572 [M+H]⁺

PrimerXLV

- [2 - (3 - methyl - 2 - oxo - 2,3 - dihydro -177- benzoimidazole - 4 - yl) - 2 - oxo - ethyl] - 3 methyl -7- (2- butin -1 - yl) - 8 - [3 - (trans. Butyloxycarbonylamino) - piperidin -1 - yl] xanthine

Obtained by treating 1- [2- (1-ethoxycarbonyl-3-methyl-2-oxo-2,3-dihydro-177-benzoimidazol-4-yl) -2-oxo-ethyl] -3-methyl-7- (2- butin-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine with a 1N solution of sodium hydroxide in methanol at room temperature.

R_f value: 0.36 (silica gel, ethyl acetate) Mass spectrum⁺): m/z = 605 [M+H]⁺

PrimcrXLVI

- acetil -1 - etoksikarbonil -1.3 - dihidro - benzoimidazol - 2 - on

5.29 g of diethyldicarbonate and 611 mg of dimethylaminopyridine were added to 1.50 g of 1- (2,3-diamino-phenyl) -ethanone in 75 ml of methylene chloride. The reaction mixture was stirred for three hours at room temperature, then another 100 mg of dimethylaminopyridine and 1 ml of diethyldicarbonate were added, and the mixture was stirred for another 20 hours at room temperature. For work-up, the reaction mixture was diluted with methylene chloride, washed with 2 N citric acid solution as well as saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over magnesium sulfate and evaporated. The residue was chromatographed on a silica gel column with petroleum ether / ethyl acetate (3: 1 to 1: 2) as eluent. The desired product is mixed with a little terc. butyl methyl ether, filtered off with suction, washed with a little ethyl acetate and tert. butyl methyl ether and dried.

Yield: 900 mg (36% of theory)

Rf value: 0.15 (silica gel, petroleum ether / ethyl acetate = 2: 1) Mass spectrum⁺): m/z = 249 [M+H]⁺

First XLVII

- [(4 - amino - hinazolin - 2 - il) methyl] - 3 - methyl - 7 - (2 - butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

501 1 mg of cyanomethyl-3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine was added to a mixture of 17 mg of potassium tert.

52142 Β butoxide in 10 ml of methanol. After a short heating with stirring, a clear solution was formed, and after about 20 minutes according to thin layer chromatography, the nitrile mainly reacted to form an immunoester. Then 206 mg of 2 - amino - benzamidine hydrochloride was added and the reaction mixture was refluxed for four hours. After cooling to room temperature, the precipitate formed was filtered off with suction, washed with methanol and dried. Yield: 143 mg (23% of theory)

Rf value: 0.15 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z = 574 [M+H]⁺

First XLVIII

- ((2 - phenyl - 2 - oxo - ethyl) -3 - methyl - 7 - ((S) -2 - buten - 1 - yl) - 8 - [3- (tert. Butyloxycarbonylamino) - piperidin - 1 - yl - xanthine

150 mg 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine was hydrogenated in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol in the presence of 30 mg of 5 wt% palladium on activated carbon (contaminated with quinoline) at room temperature, until the predicted amount of hydrogen was consumed. The mixture was then added to the top of the activated carbon spatula, and it was filtered off with suction. The filtrate was evaporated and the crude product was purified by column chromatography on silica gel with cyclohexane / ethyl acetate (7: 3 to 4: 6). Yield: 120 mg (85% of theory)

Rf value: 0.40 (silica gel, cyclohexane / ethyl acetate = 4: 6)

Mass spectrum (ESI⁺): m/z = 537 [M+H]⁺

PrimerXLIX

- hydroxymethyl - 5 - methoxy - hinolin

148 mg of sodium hydride (ca. 60% in mineral oil) was added at once to a solution of 640 mg of 8 - hydroxymethyl - quinolin - 5 - ol in N, N - dimethylformamide while cooling in an ice bath, and the reaction mixture was warmed slightly to room temperature. After gas formation was complete, 230 μΐ of methyl iodide was added dropwise while cooling in an ice bath, and then the reaction mixture was stirred for approx. for another two hours at room temperature. For processing, it was poured into ice-cold water, saturated with sodium chloride and extracted with a mixture of diethyl ether and ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The rest from

52142 Β The balloon was triturated with petroleum ether and the clarified liquid was drained. The crude product was purified on a silica gel column with ethyl acetate as eluent.

Yield: 470 mg (68% of theory)

Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum⁺): m/z= 190 [M+H]⁺

The following compounds were prepared analogously to Example XLIX:

(1) 8 - hydroxymethyl - 5 - methoxy - isohinoline

Rf value: 0.40 (silica gel, methylene chloride / methanol = 10: 1)

Mass spectrum (ESI⁺): m/z = 190 [M+H]⁺

First L

- hydroxymethyl - hinolin - 5 - ol

3.40 g of quinoline - 5 - ol is mixed with 8 ml of conc. hydrochloric acid and 8 ml of 37% formalin solution during cooling in an ice bath. The hydrogen chloride gas was then purged through the reaction mixture for about two hours, while the temperature rose slowly. The reaction mixture was first stirred overnight with cooling in an ice bath, then at room temperature, and then evaporated in vacuo. The residue from the flask was taken up in water, covered with a layer of diethyl ether and adjusted to pH 10 during cooling in an ice bath, then vigorously mixed with dilute ammonia solution. After stirring vigorously for two hours at room temperature, the organic phase was separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue from the flask was chromatographed on a silica gel column with methylene chloride / methanol (20: 1) as eluent.

Yield: 660 mg (16% of theory)

Mass spectrum (ESI⁺): m/z= 176 [M+H]⁺

The following compounds were prepared analogously to Example L:

(1) 8 - hydroxymethyl - isoquinoline - 5 - ol

Rf value: 0.50 (silica gel, methylene chloride / methanol = 5: 1)

Mass spectrum (ESI⁺): m/z= 176 [M+H]⁺

52142 Β

Example LI

1 - ((2-cyclopropyl-quinazolin-4-ylmethyl-3-methyl-7 - (1-cyclopentene-1-ylmethyl-8 [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine

Mixture of 250 mg 1- (2- (2- (cyclopropylcarbonyl) amino] -phenyl} -2-oxo-ethyl) -3-methyl 7 - ((1-cyclopenten-1-yl) methyl] -8- (3 - (tert-butyloxycarbonylamino) -piperidin-1-yl] xanthine and 7.5 ml of ethanol ammonia solution (6 M) were heated in a balloon at 150 [deg.] C. For work-up, the reaction mixture was evaporated and chromatographed on a silica gel column with methylene chloride / methanol (100: 0 to 70:30) as eluent. The contaminated fraction was evaporated and re-purified by reverse phase column HPLC with water / acetonitrile / trifluoroacetic acid (65: 15: 0.08 to 0: 100: 0.1) as eluent. The product fractions were evaporated, made basic with dilute sodium hydroxide solution and extracted with methylene chloride. The combined extracts were dried over magnesium sulfate and evaporated.

Yield: 40 mg (14% of theory)

R_f value: 0.40 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 627 (M+H]⁺

Example LII

- (2 - bromo - acethyl) -1.3 - bis - [(2 - trimethylsilanyl - ethoxyl methyl-1,3 - dihydro benzoimidazole - 2 - on

520 mg of 2 - pyrrolidinone - hydrotribromide and 89 mg of 2 - pyrrolidinone were added to 420 mg of 4 acetyl -1,3 - bis - ((2 - trimethylsilanyl - ethoxy) methyl] -1,3 - dihydro - benzoimidazol - 2 - one in 5 ml of tetrahydrofuran under argon The reaction mixture was refluxed for two hours and then filtered off with suction while still warm.The filter cake was washed with tetrahydrofuran and the filtrate was evaporated so that 660 mg of a tan solid remained. It was mixed with a little methanol, filtered off with suction, washed with some methanol and dried. The crude product was further used in the reactions without any further purification.

Yield: 430 mg (87% of theory)

Rf value: 0.23 (silica gel, petroleum ether / ethyl acetate = 9: 1)

Mass spectrum (EI): m / z = 514, 516 [M]⁺

The following compounds were prepared analogously to Example LII:

(1) 7 - (2-bromo-acetyl) -1 - (tert. Butyloksikarbon.il) -177- indole

52142 Β

R_f value: 0.33 (silica gel, petroleum ether / ethyl acetate = 9: 1)

Mass spectrum (ESI⁺): m/z = 338,340 [M+H]⁺ (2) 2 - bromo -1 - (3 - isopropyloxy - phenyl) - ethanone (Made with phenyltrimethylammonium tribromide in methylene chloride)

Rf value: 0.39 (silica gel, cyclohexane / ethyl acetate = 9: 1) (3) 2 - bromo -1 - (3 - difluoromethoxy - phenyl) - ethanone (Made with phenyltrimethylammonium tribromide in methylene chloride)

Rf value: 0.24 (prepared plate for reverse - phase TLC (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Example LIII

Methyl 3 - methyl - imidazori. 2 - alpyridine - 2 - carboxylate

A mixture of 1.91 g of 2-aminopyridine and 4.40 g of methyl 3-bromo-2-oxo-butyrate in 40 ml of ethanol was refluxed for 6 hours and then allowed to stand for 2 days at room temperature. The solvent was distilled off using a rotary evaporator and the crude product was purified by column chromatography on silica gel with a solution of methylene chloride / methanol / methanol ammonia (95: 4: 1 to 90: 9: 1) as eluent. 560 mg of ethyl ester were isolated as a by-product.

Yield: 2.09 g (54% of theory)

Rf value: 0.20 (silica gel, methylene chloride / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 191 [M+H]⁺

Primer LIV

- chloromethyl - 4 - isopropyl - quinazoline

Dry, hydrogen chloride gas was purged through a solution of 2.86 g of 1- (2-amino-phenyl) -2-methyl-propan-1-one and 1.33 ml of chloroacetonitrile in 14 ml of dioxane with stirring at room temperature for approx. five o'clock. The dioxane was then largely distilled off in a vacuum formed by a water jet. The honey-like precipitate was mixed with ice-cold water and the resulting solution was made basic with a saturated solution of potassium carbonate during cooling in an ice bath. The precipitate was filtered off with suction, washed with water and dried. The crude product was purified by column chromatography on silica gel with petroleum ether / methylene chloride (8: 2 to 0: 1) as eluent.

52142 Β

Yield: 1.80 g (58% of theory)

R_f value: 0.30 (silica gel, methylene chloride / petroleum ether = 1: 1)

Mass spectrum (ESI⁺): m/z = 221,223 [M+H]⁺

Example LV

- chloromethyl - 3 - trifluoromethyl - 3.4 - dihydro - isohinoline

530 mg of N- (1-benzyl-2,2,2-trifluoro-ethyl) -2-chloro-acetamide (obtained by reacting 1-benzyl-2,2,2-trifluoro-ethylamine with chloroacetyl chloride in the presence of triethylamine) and 0.74 ml of phosphorus oxychloride was added to 4.00 g of polyphosphomic acid. The viscous mixture was stirred at 130 ° C for 1.5 hours. For work-up, the reaction mixture was cooled and mixed with ice-cold water, stirred vigorously for ten minutes and filtered off with suction. The filter cake was dissolved in ethyl acetate and the solution was dried over magnesium sulfate, evaporated to give a white solid.

Yield: 415 mg (84% of theory)

Rf value: 0.55 (aluminum oxide, petroleum ether / ethyl acetate = 10: 1)

Mass spectrum (ESI⁺): m/z = 248,250 [M+H]⁺

The following compound was obtained analogously to Example LV:

(1) 1 - Methyl - 3 - trifluoromethyl - 3,4 - dihydro - isoquinoline (starting material N- (1 - benzyl - 2,2,2 - trifluoro - ethyl) - acetamide was obtained by reaction of 1 - benzyl - 2,2 , 2 - trifluoro - ethylamine with acetic anhydride.)

First LVI

- bromomethyl -1 - (1 - ciiano -1 - methyl - ethyl) - isochinoline

A mixture of 375 mg of 1- (1-cyano-1-methyl-ethyl) -3-methyl-isoquinoline and 321 mg of N-bromosuccinimide in 5 ml of carbon tetrachloride was mixed with 2.2-azoisobutanoic acid on top of a spatula of dinitrile and refluxed for about six hours. The cooled reaction mixture was filtered and evaporated. The residue from the flask was further used in the reactions without any further purification.

R_f value: 0.70 (silica gel, cyclohexane / ethyl acetate = 3: 1)

The following compounds were prepared analogously to Example LVI:

52142 B (1) 6 - bromomethyl -1 - [(2- trimethylsilanyl - ethoxy) methyl] - 1H- quinoline - 2 - on (2) 1 - bromomethyl - 4 - bromo - 3 - methoxy - isohinoline (3) 2 - bromomethyl - [1,5] naftiridin

Mass spectrum (ESI +): m / z = 223.225 [M + H] + (4) 5-bromomethyl - [1,6] naphthyridine

R_f value: 0.48 (silica gel, ethyl acetate / methanol = 98: 2) (5) 7 - bromomethyl - 5 - phenyl - quinoxaline

R_f value: 0.85 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 299, 301 [M+H]⁺ (6) 4 - bromometil - [1, 5]naftiridin

Rf value: 0.56 (silica gel, methylene chloride / ethyl acetate = 7: 3)

Mass spectrum (ESI⁺): m/z = 223,225 [M+H]⁺ (7) 1 - bromomethyl - 3 - trifluoromethyl - isochinoline

Mass spectrum (ESI⁺): m/z = 290,292 [M+H]⁺ (8) 1 - bromomethyl - 3 - difluoromethyl - isochinoline

Mass spectrum (ESI⁺): m/z = 272,274 [M+H]⁺ (9) 1 - bromomethyl - 4 - chloro - 3 - methoxy - isohinoline

Primer LVII

- (1 - ciiano -1 - methyl - ethyl) - 3 - methyl - isohinoline

3.30 g of 2,2 - azoisobutanoic acid dinitrile are added to 1.60 g of 3 - methyl - isoquinoline - N oxide in 30 ml of toluene. The reaction mixture was stirred at 85 ° C for six hours, then allowed to stand at room temperature for two days. For work-up, the reaction mixture was extracted with 20% hydrochloric acid. The combined aqueous phases were diluted with methylene chloride, made basic with saturated potassium solution.

52142 Β carbonates while cooled in an ice bath and extracted with methylene chloride. The mixed methylene chloride extracts were dried over magnesium sulfate and evaporated. The residue was chromatographed on a silica gel column with cyclohexane as eluent. Yield: 375 mg (18% of theory)

Mass spectrum (ESI⁺): m/z = 211 [M+H]⁺

Rf value: 0.75 (silica gel, cyclohexane / ethyl acetate = 3: 1)

Primer LVIII

- (2-cyanoimino-2-phenyl-ethyl) -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -Diperidin-1-yl] -xanthine / Z - mixture)

0.48 ml of a 1M solution of titanium tetrachloride in methylene chloride was added dropwise to 244 mg of 1- (2-phenyl-2-oxo-ethyl) -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert .

butyloxycarbonylamino) -piperidin-1-yl] -xanthine in 7 ml of methylene chloride. Then 88 μΐ 1,3 - bis (trimethylsilyl) carbodiimide was added and the mixture was stirred for four hours at room temperature. For work-up, the reaction mixture was diluted with methylene chloride and poured into ice-cold water. The organic phase was washed with 0.5 N citric acid, dried over magnesium sulfate and evaporated. The crude product was purified by column chromatography on silica gel with methylene chloride / methanol (98: 2 to 95: 5) as eluent. Yield: 206 mg (97% of theory)

Mass spectrum (ESI ': m / z = 557 [M - H])

R_f value: 0.16 (silica gel, cyclohexane / ethyl acetate = 1: 1)

First LIX

- Г (1Н - benzoimidazol - 2 - iDmetill - 3 - methyl -7- (2- butin -1 - il) - 8 - [3 - (terc. Butiloksikarbonilamino) - piperidin -1 - il] - ksantin

350 mg 1 - [(2-amino-phenylaminocarbonyl) methyl] -3-methyl -7- (2-butyn-1-yl) -8 - [3 (tert-butoxycarbonylamino) -piperidin-1-yl] -xanthine was refluxed in 3 ml of ice-cold acetic acid for two hours. The reaction mixture was then evaporated, the residue from the flask was mixed with 5 ml of 1M sodium hydroxide solution and washed with methylene chloride. The aqueous phase was then acidified with 1 M hydrochloric acid and extracted with methylene chloride. The combined extracts were evaporated and chromatographed on a silica gel column with cyclohexane / ethyl acetate / methanol (6: 4: 0 to 5: 4: 1) as eluent.

Yield: 250 mg (74% of theory)

Mass spectrum (ESI⁺): m/z = 547 [M+H]⁺

52142 Β

Primer LX

Ethyl 3,4 - dimethyl - 6,7 - dihydro - 577- [2] pyridine -1 - carboxylate

Obtained by treating 1.16 g of ethyl 3,4-dimethyl-4a - (pyrrolidin-1-yl) -5,6,7,7a tetrahydro-4a77- [2] pyridine-1-carboxylate with 1.08 g of 70% 3-chloro- perbenzoic acid in 50 ml of methylene chloride at room temperature.

Yield: 850 mg (97% of theory)

Rf value: 0.30 (aluminum oxide, petroleum ether / ethyl acetate = 5: 1)

Mass spectrum (ESI⁺): m/z = 220 [M+H]⁺

The following compounds were prepared analogously to Example LX:

(1) ethyl 3,4 - dimethyl - 5, 6, 7, 8 - tetrahydro - isoquinoline -1 - carboxylate

Rf value: 0.35 (aluminum oxide, petroleum ether / ethyl acetate = 5: 1)

Mass spectrum (ESI⁺): m/z = 234 [M+H]⁺

First LXI

Ethyl 3.4 - dimethyl - 4a - (pyrrolidine -1 - yl) - 5.6. 7,7a - tetrahydro - 4a77- ffipyridine -1 carboxylate

Obtained by reacting 2.50 g of ethyl 5,6-dimethyl - [1,2,4] triazine - 3 - carboxylate with 2.74 g of 1 (cyclopenten - 1 - yl) - pyrrolidine in 25 ml of chloroform at room temperature.

Yield: 3.00 g (75% of theory)

R_f value: 0.60 (aluminum oxide, petroleum ether / ethyl acetate = 5: 1)

Mass spectrum (ESI⁺): m/z = 291 [M+H]⁺

The following compounds were prepared analogously to Example LXI:

(1) ethyl 3,4 - dimethyl - 4a - (pyrrolidine -1 - il) - 4a, 5, 6, 7, 8, 8a - hexahydro - isoquinoline -1 carboxylate

Rf value: 0.60 (aluminum oxide, petroleum ether / ethyl acetate = 5: 1)

Mass spectrum (ESI⁺): m/z = 305 [M+H]⁺

First LXII

Methyl 2, 3, 8 - trimethyl - hinoxaline - 6 - carboxylate

Β 52142

Obtained by reacting 1.60 g of methyl 3,4-diamino-5-methyl-benzoate with 0.86 ml of diacetyl in a mixture of water and ethanol at reflux.

Yield: 1.53 g (80% of theory)

R_f value: 0.63 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 231 [M+H]⁺

The following compounds were prepared analogously to Example LXII:

(1) methyl 8 - methyl - quinoxaline - 6 - carboxylate (reaction was performed with glyoxal in water.)

Rf value: 0.55 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Mass spectrum (ESI⁺): m/z = 203 [M+H]⁺ (2) 5 - bromo - 7 - methyl - quinoxaline (reaction performed with glyoxal in a water / ethanol mixture.)

Rf value: 0.75 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 223, 225 [M+H]⁺

FirstUIII

Metil 3.4 - diamino - 5 - metil - benzoat

It is obtained by reduction of methyl 3 - nitro - 4 - amino - 5 - methyl - benzoate under a hydrogen partial pressure of 50 psi in the presence of Raney nickel in methanol at room temperature. Rf value: 0.40 (silica gel, tert. Butyl methyl ether)

First LXIV

Metil 3 - nitro - 4 - amino - 5 - metil - benzoat

It is obtained by treating 3 - nitro - 4 - acetylamino - 5 - methyl - benzoic acid with hydrogen chloride in a gaseous state in methanol at room temperature and subsequent heating at reflux.

Mass spectrum (ESI⁺): m/z = 211 [M+H]⁺

R_f value: 0.75 (silica gel, tert. butyl methyl ether / acetic acid = 99: 1)

Example LXV

52142 Β

1- (2-Phenyl-2-oxo-ethyl) -3-methyl-7 - ((E) · 1-buten-1-yl) -8-bromo-xanthine 0.13 ml of a 35% solution of hydrogen peroxide was added in 290 mg 1 - (2 - phenyl - 2 - oxo - ethyl) 3 - methyl - 7 - (1 - phenylsulfanyl - butyl) - 8 - bromo - xanthine in 6 ml of hexafluoroisopropanol. The reaction mixture was stirred for one hour at room temperature, diluted with methylene chloride and washed with sodium thiosulfate solution. The organic phase was dried over magnesium sulfate and evaporated. The residue from the flask was taken up in 6 ml of toluene and refluxed for eight hours. The toluene was then distilled off in vacuo and the crude product was purified on a silica gel column with methylene chloride / methanol (100: 0 to 95: 5) as eluent.

Yield: 104 mg (45% of theory)

Rf value: 0.61 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum (ESI⁺): m/z = 417,419 [M+H]⁺

The following compounds were prepared analogously to Example LXV:

(1) 3 - metil -7-(3- metil -1 - buten -1 - П) - 8 - bromo - ksantin R_f value: 0.24 (silica gel, methylene chloride / methanol = 95: 5) Mass spectrum⁺): m/z = 313,315 [M+H]⁺

Primer LXVI

- methanesulfonyloxymethyl - 4 - difluoromethoxy - naphthalene

They are obtained by reacting (4 - difluoromethoxy - naphthalen - 1 - yl) - methanol with methanesulfonic acid chloride in methylene chloride in the presence of triethylamine.

The following compounds were prepared analogously to Example LXVI:

(1) (E) -1-methanesulfonyloxy-3- (2-nitro-phenyl) -2-propene (2) (E) -1-methanesulfonyloxy-3-pentafluorophenyl-2-propene (3) (E) -1 - methanesulfonyloxy-3- (2-trifluoromethyl-phenyl) -2-propene (4) (E) -1-methanesulfonyloxy-3- (3-trifluoromethyl-phenyl) -2-propene

100

52142 B (5) (E) -1-methanesulfonyloxy-3- (4-trifluoromethyl-phenyl) -2-propene

FirstLKVII

- methyl - 5 - phenyl - hinoxaline

A mixture of 400 mg of 5 - bromo - 7 - methyl - quinoxaline, 244 mg of phenylboronic acid and 100 mg of tetrakis (triphenylphosphine) palladium in 12 ml of dioxane, 4 ml of methanol and 3.6 ml of 1M aqueous sodium carbonate solution was refluxed for three hours under argon. The reaction mixture was then evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate phase was separated, dried over magnesium sulfate and evaporated. The crude product was purified by column chromatography on silica gel with cyclohexane / ethyl acetate (85:15 to 70:30) as eluent.

Yield: 390 mg (66% of theory)

Rf value: 0.36 (silica gel, petroleum ether / ethyl acetate = 5: 1)

Mass spectrum (ESI⁺): m/z = 221 [M+H]⁺

First LXVIII

- methyl - 3 - trifluoromethyl - isohinoline

They are obtained by treating 905 mg of 1 - chloromethyl - 3 - trifluoromethyl - 3,4 - dihydro - isoquinoline with 420 mg of potassium tert. butoxide in 10 ml of tetrahydrofuran at room temperature. Yield: 755 mg (98% of theory)

Mass spectrum (ESI⁺): m/z = 212 [M+H]⁺

The following compounds were prepared analogously to Example LXVHI:

(1) 1 - methyl - 3 - difluoromethyl - isohinoline (dobija se od 1 - methyl - 3 - trifluoromethyl - 3,4 - dihydro - isochinoline)

Mass spectrum (ESI⁺): m/z = 194 [M+H]⁺

First LXIX

- chloro - 3 - methoxy -1 - methyl - isohinoline

They are obtained by treating 3 - methoxy - 1 - methyl - isoquinoline with sulfuryl chloride in methylene chloride.

Rf value: 0.30 (silica gel, cyclohexane)

Mass spectrum (ESI⁺): m/z = 208,210 [M+H]⁺

101

52142 Β

FirstLXX

- cyclopropyl - 8 - bromo - xanthine

They are obtained by reacting 3-cyclopropyl-xanthine with bromine in the presence of potassium carbonate in acetonitrile at 60 ° C.

Rf value: 0.65 (prepared plate for reverse - phase TLC (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass spectrum (ESI⁺): m/z = 271,273 [M+H]⁺

First LXXI

Ethyl 1.2, 3, 4 - tetrahydro - phenanthridine - 6 - yl - carboxylate

Analogous to the procedure described in Gonsalves et al. (Tetrahedron 1992, 48, 6821), solution

3.90 g of ethyl 5, 6,7, 8 - tetrahydro - benzo [1,2,4] triazine - 3 - carboxylate (Sagi et al., Heterocycles 1989, 29,2253) in 20 ml of dioxane was refluxed. Then, 8.22 g of anthranilic acid and 7.02 g of isoamyl nitrite, dissolved in 20 ml of dioxane each, were instilled simultaneously for 25 minutes through two dropping funnels. The reaction mixture was refluxed for a further 30 minutes. For work-up, the cooled dark brown reaction solution was diluted with 150 ml of diethyl ether, washed with 100 ml of 2 N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated. The brown, oily residue from the flask was chromatographed on a silica gel column with ethyl acetate / petroleum ether (20:80 to 50:50) as eluent. The resulting product was still partially contaminated, but was used in further reactions without any further purification.

Yield: 380 mg (8% of theory)

Rf value: 0.55 (silica gel, petroleum ether / ethyl acetate = 2: 1)

Mass spectrum (ESI⁺): m/z = 256 [M+H]⁺

Preparation of final compounds:

Primer 1

1,3-dimethyl-7- (2,6-dicyano-benzyl) -8- (3-amino-piperidin-1-yl) -xanthine

129 mg of 3 - amino - piperidine - dihydrochloride was added to a mixture of 298 mg of 1,3 - dimethyl - 7 - (2,6 - dicyano - benzyl) - 8 - bromo - xanthine and 420 mg of potassium carbonate in 9 ml of N, N dimethylfomiamide. The reaction mixture was stirred at 80 ° C for three hours. For processing, the mixture was diluted with methylene chloride and washed with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated. It is a raw product

102

52142 Β purified by column chromatography on silica gel with methylene chloride / methanol / conc. with methanolic ammonia solution (95: 5: 1 to 80: 20: 1) as eluent.

Yield: 43 mg (14% of theory)

Rf value: 0.67 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 80: 20: 1)

Mass spectrum (ESI⁺): m/z = 419 [M+H]⁺

The following compounds were prepared analogously to Example 1:

(1) 1- (2-cyano-ethyl) -3-methyl-7- (2-cyano-benzyl) -8- (3-amino-piperidin-1-yl) xanthine

Rf value: 0.35 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI⁺): m/z = 433 [M+H]⁺

Primer 2

1- (2- (2- (ethoxycarbonylmethoxy-phenyl) -2-oxo-ethyl) -3-methyl-7- (3-methyl-2-buten-1-yl) -8- (3-amino-piperidine- 1 - yl) - xanthine

Solution 209 mg 1- (2- (2 - [(ethoxycarbonyl) methoxy] -phenyl} -2-oxo-ethyl) -3-methyl-7 (3-methyl-2-buten-1-yl) -8 - ( 3- (tert-butyloxycarbonylamino) -piperidin-1-yl] xanthine in 4 ml of methylene chloride was mixed with 1 ml of trifluoroacetic acid and stirred for half an hour at room temperature. saturated potassium carbonate solution. The organic phase was dried, evaporated and chromatographed on a silica gel column with methylene chloride / methanol (1: 0 to 4: 1) as eluent.

Yield: 153 mg (87% of theory)

Mass spectrum (ESI⁺): m/z = 553 [M+H]⁺

The following compounds were prepared analogously to Example 2:

(52) 1- (quinolin-4-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino-piperidin-1-yl) -xanthine (Performed with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

103

52142 Β

R_f value: 0.52 (silica gel, methylene chloride / methanol / conc. aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 458 [M+H]⁺ (55) 1 - [(quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino-piperidin 1-yl) -xanthine (Completed with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.20 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 95: 5: 0.1)

Mass spectrum (ESI⁺): m/z = 459 [M+H]⁺ (63) 1 - [(isoquinolin-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino-piperidin 1-yl) -xanthine (Performed with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.42 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 458 [M+H]⁺ (64) 1 - [(4-methoxy-naphthalen-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino piperidin-1-yl) -xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.14 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 95: 5: 0.1)

Mass spectrum (ESI⁺): m/z = 487 [M+H]⁺ (65) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino piperidin-1-yl) -xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Melting point: 155 - 158 ° C

Mass spectrum (ESI⁺): m/z = 472 [M+H]⁺ (69) 1 - [(4 - methyl - izohinolin -1 - il) methyl] - 3 - methyl - 7 - (2 - butin -1 - il) - 8 - (3 - amino piperidin -1 - il) - ksantin

104

52142 Β (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.46 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 472 [M+H]⁺ (72) 1 - [(quinolin-6-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3-amino-piperidin-1-yl) -xanthine (Completed with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.15 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 95: 5: 0.1)

Mass spectrum (ESI⁺): m/z = 458 [M+H]⁺ (74) 1 - [(isoquinolin-1-yl) methyl] -3-methyl-7 - ((E) -2-buten-1-yl) -8- (3-amino piperidin-1-yl) -xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride; the product still contains approx. 20% Z isomer)

Rf value: 0.66 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 0.1)

Mass spectrum (ESI⁺): m/z = 460 [M+H]⁺ (80) 1 - [(quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8 - ((70-3-amino piperidin-1-yl) -xanthine ( Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Mass spectrum (ESI⁺): m/z = 459 [M+H]⁺ (81) 1 - [(quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (S) -3-amino piperidin-1-yl) -xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Mass spectrum (ESI⁺): m/z= 459 [M+H]⁺ (82) 1 - [(quinazolin-2-yl) methyl] -3-methyl-7 - ((E) -2-buten-1-yl) -8- (5) -3-amino piperidin-1- il) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride; the product still contains approx. 20% of the Z isomer)

105

52142 Β

R_f value: 0.12 (silica gel, methylene chloride / methanol / conc. aqueous ammonia solution = 95: 5: 0.1)

Mass spectrum (ESI⁺): m/z = 461 [M+H]⁺ (83) 1 - [(quinazolin - 2 - yl) methyl] -3 - methyl - 7 - ((E) - 2 - butene -1 - H) - 8 - ((A) -3 - amino piperidin -1 - il) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride; the product still contains approx. 15% Z isomer)

Rf value: 0.12 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 95: 5: 0.1)

Mass spectrum (ESI⁺): m/z = 461 [M+H]⁺ (84) 1 - [(3 - methyl - isoquinoline -1 - il) methyl] - 3 - methyl - 7 - ((E) - 2 - butene -1 - il) - 8 - ((A) -

- amino-piperidin-1-yl) -xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride; the product still contains approximately 17% Z isomer)

Rf value: 0.54 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 474 [M+H]⁺ (85) 1 - [(3 - methyl - isoquinoline -1 - il) methyl] - 3 - methyl- 7 - ((E) - 2 - butene -1 - il) - 8- ((S) -

- amino-piperidin-1-yl) -xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride; the product still contains approximately 17% Z isomer)

Rf value: 0.54 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 474 [M+H]⁺ (129) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (5) -3-amino-piperidin-1- il) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Melting point: 155 - 156.5 ° C

Mass spectrum (ESI⁺): m/z = 472 [M+H]⁺

106

52142 130 (130) 1 - [(3-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (R) -3-amino-piperidine-1 - yl) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.52 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 472 [M+H]⁺ (131) 1 - [(4-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (5) -3-amino-piperidin-1- il) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value 0.46 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 472 [M+H]⁺ (132) 1 - [(4-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (79-3 amino-piperidin-1-yl) ) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.46 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 472 [M+H]⁺ (133) 1 - [(4 - methyl - isoquinolin - 1 - yl) methyl] -3 - methyl - 7 - ((E) -2 - buten - 1 - yl) - 8 - ((5) 3 - amino - piperidin-1-yl) -xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.48 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 474 [M+H]⁺ (134) 1 - [(4-methyl-isoquinolin-1-yl) methyl] -3-methyl-7- ((E) -2-buten-1-yl) - 8 - (79 (3-amino-piperidine) -1 - yl) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

107

52142 Β

Melting point: 167.5 - 172 ° C

Mass spectrum (ESI⁺): m/z = 474 [M+H]⁺ (137) 1- (4-methoxy-naphthalen-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (5) -3-amino-piperidin-1- il) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.52 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 487 [M+H]⁺ (138) 1- (4-methoxy-naphthalen-1-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (L) -3-amino-piperidin 1-yl ) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.52 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90.10: 1)

Mass spectrum (ESI⁺): m/z = 487 [M+H]⁺ (141) 1- (4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (S) amino-piperidin-1-) il) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Rf value: 0.51 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 1)

Mass spectrum (ESI⁺): m/z = 473 [M+H]⁺ (142) 1- (4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (T-amino-piperidin-1-) il) - xanthine (Made with 5 - 6 M isopropanol solution of hydrochloric acid in methylene chloride)

Melting point: 198 - 202 ° C

Mass spectrum (ESI⁺): m/z = 473 [M+HJ+

First4

Coated tablets containing 75 mg of active substance The core of the tablet contains:

108

52142 Β

<td>active substance</td><td>75.0 mg</td>

<td>calcium phosphate</td><td>93.0 mg</td>

<td>corn starch</td><td>35.5 mg</td>

<td>polyvinylpyrrolidone</td><td>10.0 mg</td>

<td>hydroxypropylmethylceluloza</td><td>15.0 mg</td>

<td>magnesium stearate</td><td>1.5 mg 230.0 mg</td>

Preparation:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate. Castings with a diameter of 13 mm are made in a tableting machine, then rubbed through a sieve with openings of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tableting machine to obtain tablets of the desired shape.

Core weight: 230 mg mold: 9 mm, convex

The core of the tablets thus obtained is coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.

Tablet weight: 245 mg.

Primer 5

Tablets containing 100 mg of active substance

Composition:

tablet contains:

<td>active substance</td><td>100.0 mg</td>

<td>lactose</td><td>80.0 mg</td>

<td>corn starch</td><td>34.0 mg</td>

<td>polyvinylpyrrolidone</td><td>4.0 mg</td>

<td>magnesium stearate</td><td>2.0 me</td>

<td></td><td>220.0 mg</td>

Preparation procedure:

109

52142 Β

The active substance, lactose and starch are mixed together and evenly moistened with an aqueous solution of polyvinylpyrrolidone. After the moistened composition is sieved (sieve opening 2.0 mm) and dried in a rack dryer at 50 ° C, it is sieved again (sieve opening 1.5 mm) and lubricant is added to it. The finished mixture is compressed to obtain tablets.

Tablet weight: 220 mg

Diameter: 10 mm, biplane, flat on both sides and notched on one side.

Primer 6

Tablets containing 150 mg of active substance

Composition:

tablet contains:

<td>active substance</td><td>150.0 mg</td>

<td>lactose powder</td><td>89.0 mg</td>

<td>corn starch</td><td>40.0 mg</td>

<td>colloidal silica</td><td>10.0 mg</td>

<td>polyvinylpyrrolidone</td><td>10.0 mg</td>

<td>magnesium stearate</td><td>1.0 mg 300.0 mg</td>

Preparation:

The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous solution of polyvinylpyrrolidone and then passed through a sieve with a mesh size of 1.5 mm. The granules, dried at 45 ° C, are again passed through the same sieve and mixed with the specified amount of magnesium stearate. Tablets are pressed from this mixture.

Tablet weight: 300 mg mold: 10 mm, flat

Primer 7

Hard gelatin capsules containing 150 mg of active substance capsule contains:

active substance corn starch (dried)

150.0 mg pribl. 80.0 mg

110 lactose (powder) magnesium stearate approx. 87.0 mg

3.0 mg pribl. 420.0 mg

Preparation:

The active substance is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed until homogenized using appropriate devices. The finished mixture is packed in hard gelatin capsules of size 1.

Capsule filling: approx. 320 mg

Capsule body: size 1 hard gelatin capsule.

Primer 8

Suppositories containing 150 mg of active substance of the suppository contain:

<td>active substance polyethylene glycol 1500 polyethylene glycol 6000 polyoxyethylene sorbitan monostearate</td><td>150.0 mg 550.0 mg 460.0 mg 840.0 mg 2,000.0 mg</td>

Preparation:

After the mass for suppositories melts, the active substance is homogeneously distributed in it, so the melted mass is poured into cooled molds.

Primer 9

A suspension containing 50 mg of active substance

100 ml suspension contains:

<td>active substance Na - with carboxymethylcellulose methyl p - hydroxybenzoate propyl p - hydroxybenzoate glucose glycerol 70% sorbitol solution</td><td>1.00 g 0.10 g 0.05 g 0.01 g 10.00 g 5.00 g 20.00 g</td>

111

52142 Β aroma 0.30 g dest. water ad 100 ml

Preparation:

The distilled water is heated to 70 ° C. Methyl and propyl p - hydroxybenzoates together with glycerol and sodium salt of carboxymethylcellulose with stirring dissolve in it. The solution is cooled to room temperature and the active substance is added and distributed homogeneously with stirring. After the sugar, a solution of sorbitol and aromas are added, they are dissolved, and air is removed from the suspension by stirring.

ml of solution contains 50 mg of active substance.

Primer 10

Ampoules containing 10 mg of active substance

Composition:

active substance 10.0 mg

0.01 N hydrochloric acid qs

doubly distilled water ad 2.0 ml

Preparation:

The active substance is dissolved in the required amount of 0.01 N HCl, made isotonic with common salt, sterile filtered and transferred into 2 ml ampoules.

Primer 11

Ampoules with 50 mg of active substance

Composition:

active substance 50.0 mg

0.01 N hydrochloric acid qs

doubly distilled water ad 10.0 ml

Preparation:

The active substance is dissolved in the required amount of 0.01 N HCl, made isotonic with common salt, sterile filtered and transferred into 2 ml ampoules.