2-Phenyl-substituited Imidazotriazinones as Phoshodiesterase Inhibitors

2-PHENYL-SUBSTITUTED IMIDASOTRIASINONE

The present invention relates to 2-phenyl-substituted imidazotriazinones, methods for their preparation and their use as medicaments, in particular as inhibitors of cGMP metabolizing phosphodiesterases.

Published Patent Application DE 2 811 780 describes imidazotriazines as bronchodilators with antispasmodic activity and cyclic adenosine monophosphate (cAMP-PDEs).

Inhibitory activity of PDE III and PDE IV metabolizing phosphodiesterases according to Beavo nomenclature. Phosphodiesterases metabolizing cyclic guanosine monophosphate (cGMP-PDEs, Beavo and Reifsnyder terminology (Trends in Pharmacol. Sci. 1990, 11, 150-155) PDE I, PDE II and PDE V) have not been described. Compounds having a sulfonamide group at the 2-position of the aryl are not claimed. In addition, FR 2 213 058, CH 594 671, DE 2 255 172, DE 2 364 076 and EP

0 009,384 imidazotriazinones, which do not have a substituent at the 2-position of the aryl radical, and are also said to be bronchodilators with cAMP-PDE inhibitory activity.

WO 94/28902 describes pyrazolopyrimidineones useful for treating impotence.

The compounds of the present invention are potent inhibitors of one or more phosphodiesterase metabolizing guanosine 3 ', 5'-monophosphate (cGMP-PDEs). According to the terminology of Beavo and Reifsnyder (Trends in Pharmacol. Sci., 1990, 11, 150-155), these phosphodiesterase isoenzymes are PDE I, PDE II and PDE V.

Increased cGMP concentrations may provide beneficial anti-aggregative, antithrombotic, anti-proliferative, antivasospastic, vasodilatory, natriuretic and diuretic effects. This may affect short- or long-term modulation of vascular and cardiac inotropy, pulse and cardiac conduction (JC Stoclet, T. Keravis, N. Komas, C. Kugnier, Exp. Invest. Drugs, 1995, 4 (11), 1081- 1100).

Accordingly, the invention relates to 2-phenyl-substituted imidazotriazinones of the general formula (I)

<img file="EE200000291A_D0001.tif" />

in what

R¹ is hydrogen or straight or branched alkyl up to four carbon atoms,

R² is a straight chain alkyl of up to four carbon atoms,

R³ and R⁴ are the same or different and each may be a hydrogen atom or a straight or branched alkenyl or alkoxy group having up to 8 carbon atoms or a straight or branched alkyl group having up to 10 carbon atoms, optionally mono- or polysubstituted with oxygen, which is selected from: trifluoromethyl, trifluoromethoxy, hydroxy, halo, carboxyl, benzyloxycarbonyl, straight or branched alkoxycarbonyl of up to 6 carbon atoms, and / or groups of the formulas -SO₃H,

- (A)_a-NR⁷R⁸, -O-CO-NR⁷'r⁸', -S (O)_b-R⁹, -P ( O) {OR¹⁰) (OR¹¹) ,

<img file="EE200000291A_D0002.tif" />

<img file="EE200000291A_D0003.tif" />

EE 200000291 Α wherein a and b are the same or different and can each be 0 or 1,

A is CO or SO₂,

R⁷, R⁷ , R⁸ and R⁸ are the same or different and each may be hydrogen or a cycloalkyl group having up to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, a 5- to 6-membered unsaturated, partially unsaturated or saturated heterocycle optionally fused with benzene; S, N and O, wherein the above ring systems are optionally mono- or poly-substituted with the same or different substituents selected from hydroxy, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, linear or branched alkoxy or alkoxycarbonyl of carbon atom, or - (SO₂)_c-NR¹²R¹³, where c is 0 or 1,

R¹² and R¹³ are the same or different and each may be hydrogen or straight or branched chain alkyl having up to 5 carbon atoms, or

R⁷, R⁷ , R⁸ and R⁸ is a linear or branched alkoxy group having up to 8 carbon atoms or a straight or branched alkyl group having up to 8 carbon atoms, optionally mono- or poly-substituted with the same or different substituents selected from hydroxyl, halogen, aryl of 6 to 10 carbon atoms, straight or alkoxy or alkoxycarbonyl of up to 6 carbon atoms in the chain, or - (CO) _d~ NR^uR¹⁵, in what

R¹⁴ and R¹⁵ are the same or different and each may be hydrogen or straight or branched alkyl up to 4 carbon atoms and d is 0 or 1, or

R⁷ and R⁸ and / or R⁷ and R⁸ together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain heteroatoms S and O or a group of formula -NR¹⁶, in what

R¹⁶ is a hydrogen atom, an aryl group of 6 to 10 carbon atoms, a benzyl group, a 5- to 7-membered aromatic or saturated heterocycle containing up to 3 heteroatoms selected from S, N and O optionally substituted with methyl20 or straight or branched Alkyl having 6 carbon atoms, optionally substituted with hydroxy,

R⁹ is an aryl of 6 to 10 carbon atoms or a straight or branched chain alkyl of up to 4 carbon atoms,

R¹⁰ and R¹¹ are the same or different and each may be hydrogen or straight or branched chain alkyl up to 4 carbon atoms, and / or above R³/ R⁴ said alkyl chain is optionally substituted with a cycloalkyl group of 3 to 8 carbon atoms, an aryl group of 6 to 10 carbon atoms or a 5- to 7-membered partially unsaturated, saturated or unsaturated heterocycle optionally fused to a benzene ring,

EE 200000291Α may contain up to 4 heteroatoms selected from S, N and O, or with the group -NR¹⁷, in what

R¹⁷ is hydrogen, hydroxy, formyl, trifluoromethyl, straight or branched acyl or alkoxy having up to 4 carbon atoms, or straight or branched alkyl having up to 6 carbon atoms, optionally mono- or polyio substituted with the same or different substituents selected from : hydroxy and straight or branched chain alkoxy of up to 6 carbon atoms, and wherein the aryl and heterocycle are optionally mono- or poly-substituted with the same or different substituents selected from nitro, halogen, -SO₃H, linear or branched alkyl of up to 6 carbon atoms or alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, and / or a group of formula -SO₂~ NR¹⁸R¹⁹, in what

R¹⁸ and R¹⁹ are the same or different and each may be hydrogen or straight or branched alkyl up to 6 carbon atoms and / or

R³ or R⁴ is a group of the formula -NR²⁰R²¹, in what

R²⁰ and R²¹ has the same meaning as R above¹⁸ and R¹⁹ and are the same as or different from them and / or

R³ or R⁴ is an adamantyl group or a group of formulas

<img file="EE200000291A_D0004.tif" />

or a cycloalkyl of 3 to 8 carbon atoms, an aryl of 6 to 10 carbon atoms or a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally fused benzene ring, which may contain up to 4 heteroatoms selected from S,

N and O or a group of the formula -NR²², in what

R²² has the same meaning as R above¹⁶ and is the same or different from or an acyl group having carboxyl, formyl or straight or branched chain up to 5 carbon atoms and wherein the cycloalkyl, aryl and / or heterocycle is optionally mono- or poly-substituted with the same or different substituents selected from: halogen, triazolyl, trifluoromethyl, trifluoromethoxy, carboxyl, straight or branched acyl or alkoxycarbonyl and nitro with up to 6 carbon atoms and / or groups of formula -SO₃H, -OR²³, (SO₂) _eNR²⁴R²⁵,

-P (O) (OR²⁶) (OR²⁷) where e is 0 or 1,

R²³ is a group of formula

SO

3 a cycloalkyl group having up to 7 carbon atoms or a hydrogen atom or a linear or branched alkyl group having up to 4 carbon atoms, optionally substituted with a cycloalkyl group having 3 to 7 carbon atoms, benzyloxy, tetrahydropyranyl, tetrahydrofuranoyl, straight or branched chain; -, benzyloxycarbonyl or phenyl which may itself be mono- or poly-substituted with the same or different substituents, which is selected from:

, Straight or branched chain alkoxy, hydroxy and halo of up to 4 carbon atoms, and / or alkyl optionally substituted by a group of the formula -CO-NR²⁸R²⁹ or -CO-R³⁰, in what

R²⁸ and R²⁹ are the same or different and each may be a hydrogen atom or a straight or branched alkyl group having up to 8 carbon atoms; or

R²⁸ and R²⁹ together with the nitrogen atom, form from 5 to

A 7-membered saturated heterocycle which may optionally contain a heteroatom S or O and

R³⁰ is phenyl or adamantyl,

R²⁴ and R²⁵ has the same meaning as R above¹⁸ and R¹⁹and are the same or different from them,

R²⁶ and R²⁷ has the same meaning as R above¹⁰ and R¹¹and are the same or different, and / or the cycloalkyl, aryl and / or heterocycle is optionally substituted with up to 6 straight or branched chain

EE 200000291 Α alkyl having carbon atoms optionally substituted with hydroxy, carboxyl, a 5- to 7-membered heterocycle containing up to 3 heteroatoms selected from S, N and O, or with the formulas -SO₂R³¹,

-P (O) (OR³²) (OR³³) or -NR³⁴R³⁵, in what

R³¹ is a hydrogen atom or has the same meaning as above R⁹ and is the same or different from it, io R³² and R³³ has the same meaning as R above¹⁰ and R¹¹ and are the same or different from them,

R³⁴ and R³⁵ are the same or different and each may be a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms, optionally substituted by a hydroxyl or straight or branched alkoxy group having up to 4 carbon atoms; or

R³⁴ and R³⁵ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may further contain a heteroatom selected from S and

O or a group of the formula -NR³⁶, in what

R³⁶ is hydrogen, hydroxy, straight or branched chain alkoxy of up to 7 carbon atoms, carbonyl or straight or branched chain of up to 5 carbon atoms, optionally substituted by hydroxy, or R³ and R⁴ together with the nitrogen atom, form a 5- to 7-membered unsaturated, saturated or partially unsaturated heterocycle optionally fused with a benzene ring and optionally containing up to 3 heteroatoms selected from S, N and O, or a group of formula -NR³⁷, in what

R³⁷ is hydrogen, hydroxy, formyl, trifluoromethyl, straight or branched acyl, alkoxy or alkoxycarbonyl having up to 4 carbon atoms, or straight or branched alkyl having up to 6 carbon atoms, optionally mono- or poly-substituted with the same or different substituents; which is selected from: hydroxy, trifluoromethyl, carboxyl, straight or branched chain alkoxy or alkoxycarbonyl of up to 6 carbon atoms, or with groups of formulas - (D) f-NR³⁸R³⁹, -CO (CH 2) _g-O-CO-R⁴⁰, -CO- (CH₂) _h~ OR⁴¹ or -P (O) (OR⁴²) (OR⁴³) in which g and h are the same or different and can each be 1, 2, 3 or 4 and f is 0 or 1,

D is a group of formula CO or SO₂,

R³⁸ and R³⁹ are the same or different and both have the same meaning as R above⁷ and R⁸,

R⁴⁰ is a straight or branched alkyl group having up to 6 carbon atoms,

R⁴¹ is a straight or branched alkyl group having up to 6 carbon atoms,

R⁴² and R⁴³ are the same or different and each may be a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, or

R³⁷ is a group of formula - (ΟΟ), - Ε, wherein i is 0 or 1,

E is a cycloalkyl or benzyl group of 3 to 7 carbon atoms, an aryl group of up to 10 carbon atoms, or a 5- to 6-membered aromatic heterocycle having 4 heteroatoms selected from S, N and 0, wherein the above ring system is optionally mono- or poly-substituted with the same or different substituents selected from nitro, halogen, SO₃H, straight or branched chain alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy having up to 6 carbon atoms, or a group of formula -SO₂NR⁴⁴R⁴⁵, in what

R⁴⁴ and R⁴⁵ is . having the same meaning as above R¹⁸ and R¹⁹ and are the same as or different from them, or

E is a group of formula

<img file="EE200000291A_D0005.tif" />

oh

<img file="EE200000291A_D0006.tif" />

I and R³ and R⁴ wherein the heterocycle formed with the nitrogen atom is optionally mono- or poly-substituted, if appropriate, with two or more substituents, the same or different, selected from hydroxy, formyl, carboxyl, straight or branched acyl or up to 6 carbon atoms. alkoxycarbonyl, nitro and groups of the formula -P (O) (OR⁴⁶) (OR⁴⁷),, = NR⁴⁸ or - (CO) jNR⁴⁹R⁵⁰ ,

<img file="EE200000291A_D0007.tif" />

o -

EE 200000291 Α in which

R⁴⁶ and R⁴⁷ has the same meaning as R above¹⁰ and R¹¹and are the same or different from them,

R⁴⁸ is hydroxy or straight or branched alkoxy of 5 to 4 carbon atoms, j is 0 or 1, and

R⁴⁹ and R⁴⁹ are the same or different and have the same meaning as R above¹⁴ and R¹⁵, and / or R³ and R⁴ optionally substituted with a linear or branched alkyl group of up to 6 carbon atoms, optionally mono- or poly-substituted with the same or different substituents selected from hydroxy, halo, carboxyl, 3 to 8 carbon atoms cycloalkyl or cycloalkoxy, linear or branched alkoxy or alkoxycarbonyl having up to 6 carbon atoms, or groups of formulas

-SO₃H, -NR⁵¹R⁵² or -P (O) (OR⁵³) (OR⁵⁴) , in what

R⁵¹ and R⁵² are the same or different and each may be hydrogen, phenyl, carboxyl, benzyl or straight or branched alkyl or alkoxy having up to 6 carbon atoms,

R⁵³ and R⁵⁴ are the same or different and have the same meaning as R above¹⁰ and R¹¹that is, and / or the alkyl group is optionally substituted with an aryl group of 6 to 10 carbon atoms, which itself may be mono- or poly-substituted with the same or different substituents selected from halo, hydroxy, straight or branched alkoxy of up to 6 carbon atoms -NR⁵¹'r⁵²', in what

EE 200000291Α

R⁵¹ and R⁵² has the same meaning as R above⁵¹ and R⁵²and are the same as or different from them and / or R³ and R⁴ wherein the heterocycle formed with the nitrogen atom is optionally substituted with an aryl group of 6 to 10 carbon atoms or a 5 to 7 membered saturated, partially unsaturated or unsaturated heterocycle containing up to 3 heteroatoms selected from: S, N and O, optionally also bonded via a nitrogen atom in which the ring system of this moiety may be substituted by a hydroxyl or straight or branched alkyl or alkoxy group of up to 6 carbon atoms, or

R³ and R⁴ together with the nitrogen atom form a group of the formula

<img file="EE200000291A_D0008.tif" />

CHfH₃

R⁵ and R⁶ are the same or different and each may be hydrogen, straight or branched alkyl or hydroxy having up to 6 carbon atoms or straight or branched alkoxy having up to 6 carbon atoms, and salts, hydrates, N-oxides and isomeric forms thereof.

The compounds of the present invention may exist in stereoisomeric forms which are attached as images and mirror images (enantiomers) or which are not linked as images and mirror images (diastereomers). The invention relates to both enantiomers and diastereomers and their respective mixtures. Racemic forms, such as diastereomers, can be separated into stereoisomerically pure constituents in a known manner.

Agents of the invention may also exist in the form of salts. Physiologically acceptable salts are preferred in the context of the invention.

Physiologically acceptable salts may include salts of the compounds of the invention with inorganic or organic acids. Salts with inorganic acids such as hydrochloric, hydrobromic, phosphoric or sulfuric acids, or salts with organic carboxylic or sulfonic acids such as acetic, maleic, fumaric, malic, citric, tartaric, lactic, benzoic, are preferred. - or with methanesulfonic, ethanesulfonic, phenylsulfonic, toluenesulfonic or naphthalenedisulfonic acid.

Physiologically acceptable salts may also be metal or ammonium salts of the compounds of the invention. Preferred are, for example, sodium, potassium, magnesium or calcium salts, as well as ammonium salts obtained with ammonia or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, l .

In the context of the invention, the benzene ring-fused heterocycle is optionally a saturated, partially unsaturated or unsaturated 5- to 7-membered heterocycle containing up to 4 heteroatoms S, N and O. Examples are azepine, diazepine, indolyl, isoquinolyl, quinolyl, benzo [b] thiophene, benzo [b] furanyl, pyridyl, thienyl, tetrahydrofuranyl, tetrahydropyranyl, furyl, pyrrolyl, thiazolyl , triazolyl, tetrazolyl, isoxazolyl, imidazolyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl or piperidinyl. Quinolyl, furyl, pyridyl, thienyl, piperidinyl,

EE 200000291Α pyrrolidinyl, piperazinyl, azepine, diazepine, thiazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl.

In the context of the invention, the linear or branched acyl group having 1 to 6 carbon atoms is, for example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. A linear or branched acyl group of from 10 to 4 carbon atoms is preferred. Acetyl and ethylcarbonyl are particularly preferred.

In the context of the invention, straight-chain or branched alkoxy having 1 to 6 or 1 to 4 carbon atoms is methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, pentoxy and hexoxy. Preferred are straight or branched chain alkoxy having 1 to 6, 1 to 4 or 1 to 3 carbon atoms.

Particular preference is given to straight or branched chain alkoxy having from 1 to 3 carbon atoms.

In the context of the invention, straight or branched chain alkoxycarbonyl groups having from 1 to 6 carbon atoms are, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. A branched or unbranched alkoxycarbonyl group having 1 to 4 carbon atoms is preferred. Particular preference is given to straight or branched chain alkoxycarbonyl of 1 to 3 carbon atoms.

In the context of the invention, linear or branched chain is 1 to

4 Alkyl groups having 1 to 6, 1 to 8 and 1 to 10 carbon atoms are, for example, methyl, ethyl, propyl, isopropyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Unbranched or branched alkyl groups having 1 to 3, 1 to 4 or 1 to 8 carbon atoms are preferred. Particular preference is given to straight or branched chain alkyl having 1 to 4 or 1 to 3 carbon atoms.

EE 200000291 Α

In the context of the invention, straight chain alkyl of up to 4 carbon atoms is, for example, methyl, ethyl, propyl and butyl.

(C₆-C_w) -aryl is an aromatic group having 6 to 10 carbon atoms. Preferred aryl groups are phenyl and naphthyl.

In the context of the invention, a cycloalkyl group having 3 to 8 or 3 to 7 carbon atoms is, for example, cyclopropyl, cyclopentyl, 10 cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

In the context of the invention, cycloalkyl15 oxy groups having 3 to 8 carbon atoms are, for example, cyclopropyloxy, cyclopentyloxy, cyclobutyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy. Cyclopropyloxy, cyclopentyloxy and cyclohexyloxy are preferred.

In the context of the invention, halogen is fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred.

In the context of the invention and depending on the above substituents, the 5- to 6-membered or 7-membered saturated heterocycle may additionally contain the heteroatoms S, N and O, for example morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or tetrahydrofuranyl. Morpholinyl, tetrahydropyranyl, piperidinyl and piperazinyl are preferred.

In the context of the invention, a 5- to 6-membered aromatic heterocycle containing from 3 to 4 heteroatoms selected from S, O and N is, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. . Pyridyl, pyrimidyl, pyridazinyl, furyl and thiazolyl are preferred.

EE 200000291 Α

In the context of the invention, a 5- to 6-membered heterocycle containing unsaturated, partially unsaturated and saturated 3 to 4 heteroatoms selected from S, O and N is, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrosyl, thiazolyl. , oxazolyl, imidazolyl, piperidinyl, piperazinyl or morpholinyl. Pyridyl, pyrimidyl, piperazinyl, pyridazinyl, morpholinyl, furyl and thiazolyl are preferred.

The compounds of the invention, in particular salts, may also exist as hydrates. Hydrates in the context of the invention are those compounds which contain water of crystallization. These compounds may contain one or more, typically 1 to 5 equivalents of water. Hydrates can be prepared, for example, by crystallizing the compound in water or in a solvent containing water.

According to the invention, the compounds of general formula (I) in which

R¹ is a straight or branched alkyl group having up to 3 carbon atoms,

R² is a straight chain alkyl of up to 3 carbon atoms, R³ and R⁴ are the same or different and each may be a hydrogen atom or a straight or branched alkenyl or alkoxy group having up to 6 carbon atoms or a straight or branched alkyl group having up to 8 carbon atoms, optionally mono- or tri-substituted with a carbon atom; which is selected from: hydroxy, fluoro, chloro, carboxyl, benzyloxycarbonyl, straight or branched alkoxycarbonyl of up to 5 carbon atoms, and / or groups of formula -SO₃H, - (A)_a-NR⁷R⁸, -O-CO-NR⁷'R⁸', -S (O)_bR⁹, —P (O) {OR¹⁰) (OR¹¹) ,

<img file="EE200000291A_D0009.tif" />

wherein a and b are the same or different and each may be 0 or 1,

A is CO or SO₂,

R⁷, R⁷ , R⁸ and R⁸ are the same or different and each may be hydrogen or cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl and pyridyl, wherein the above ring system is optionally mono- to tri-substituted with the same or different substituents : hydroxy, nitro, tri25 fluoromethyl, trifluoromethoxy, carboxyl, fluoro, chloro, straight or branched chain alkoxy or alkoxycarbonyl of up to 4 carbon atoms, or a group of the formula - (SO)₂) _c-NR¹²R¹³, where c is 0 or 1,

R¹² and R¹³ are the same or different and each may be a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, or

EE 200000291Α

R⁷, R⁷ , R⁸ and R⁸ is a straight or branched alkoxy group having up to 3 carbon atoms or a straight or branched chain alkyl group having up to 7 carbon atoms, optionally mono- or poly-substituted with the same or different substituents selected from hydroxyl, fluoro, chloro, phenyl, straight or branched alkoxy or alkoxycarbonyl of up to 4 carbon atoms in the chain, or a group of formula - (CO)_d-NR¹⁴R¹⁵, in what

R¹⁴ and R¹⁵ are the same or different and each may be hydrogen or straight or branched alkyl up to 3 carbon atoms and d is 0 or 1, or

R⁷ and R⁸ and / or R⁷ and R⁸ together with the nitrogen atom form a pyrrolidinyl, morpholinyl, piperidinyl or triazolyl group or a group of the formula

<img file="EE200000291A_D0010.tif" />

in what

R¹⁶ is hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or N-methylpiperazinyl or straight or branched chain alkyl of up to 5 carbon atoms, optionally substituted by hydroxy,

R⁹ is a straight or branched alkyl group having up to 3 carbon atoms,

R¹⁰ and R¹¹ are the same or different and each may be hydrogen or straight or branched chain alkyl up to 3 carbon atoms, io and / or above R³/ R⁴ the alkyl chain mentioned in Scheme I is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, quinolinyl, pyrrolidinyl, pyrimidyl, morpholinyl, furyl, piperidinyl, tetrahydrofuranyl, or

<img file="EE200000291A_D0011.tif" />

in what

R¹⁷ is hydrogen, hydroxy, formyl, trifluoromethyl, straight or branched acyl or alkoxy having up to 3 carbon atoms, or straight or branched alkyl having up to 4 carbon atoms, optionally mono- to tri25 substituted with the same or different substituents : hydroxy and straight or branched chain alkoxy of up to 4 carbon atoms, and wherein the phenyl and heterocycles are optionally mono-30 to trisubstituted with the same or different substituents selected from nitro, fluoro, chloro, -SO₃H, linear or branched alkyl having up to 4 carbon atoms or alkoxy and hydroxyl, and / or a group of formula -SO₂-NR¹⁸R¹⁹, in what

EE 200000291Α

R¹⁸ and R¹⁹ are the same or different and each may be hydrogen or straight or branched alkyl up to 4 carbon atoms, and / or

R³ and R⁴ is a group of the formula -NR²⁰R²¹, in what

R²⁰ and R²¹ has the same meaning as R above¹⁸ and R¹⁹io and are the same as or different from them, and / or

R³ and R⁴ is an adamantyl group or a group of formulas

<img file="EE200000291A_D0012.tif" />

or o

<img file="EE200000291A_D0013.tif" />

or is cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or a group of the formula

<img file="EE200000291A_D0014.tif" />

in what

EE 200000291 Α

R²² has the same meaning as R above¹⁶ and is the same or different, or an acyl group having a carboxylic, formyl or straight or branched chain of up to 3 carbon atoms, and wherein the cycloalkyl, phenyl and / or heterocycles are optionally mono- to tri-substituted with the same or different substituents: fluoro, chloro, triazolyl, trifluoromethyl, trifluoromethoxy, carboxylic, straight or branched acyl or alkoxycarbonyl of up to 5 carbon atoms, nitro, and / or groups of formula -SO₅H, -OR²³, (SO₂) _eNR²⁴R²⁵,

-P (O) (OR²⁶) (OR²⁷) where e is 0 or 1,

R²³ is a group of formula or

O is cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or cycloheptyl, hydrogen or straight or branched alkyl up to 4 carbon atoms, optionally substituted with cyclopropyl, cyclopentyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, or branched-chain alkoxy or alkoxycarbonyl, benzyloxycarbonyl or phenyl of up to 4 carbon atoms, which may itself be mono- or poly-substituted with the same or different substituents selected from the group consisting of linear or branched alkoxy, hydroxyl, fluoro and chloro of up to 3 carbon atoms, and / or wherein the alkyl is optionally substituted with a group of formula -CO-NR²⁸R²⁹ or -CO-R³⁰, in what

R²⁸ and R²⁹ are the same or different and each may be a hydrogen atom or a straight or branched alkyl group having up to 5 carbon atoms; or

R²⁸ and R²⁹ together with the nitrogen atom form a morpholinyl, pyrrolidinyl or piperidinyl group, and

R³⁰ is phenyl or adamantyl, io

R²⁴ and R²⁵ has the same meaning as R above¹⁸ and R¹⁹and are the same or different from them,

R²⁶ and R²⁷ has the same meaning as R above¹⁰ and R¹¹and are the same or different, and / or the cycloalkyl, phenyl and / or heterocycles are optionally substituted with straight or branched alkyl up to 4 carbon atoms, optionally substituted with hydroxyl, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or triazolyl, or groups of formula -SO₂R³¹, -P (O) {OR³²) (OR³³) or -NR³⁴R³⁵, in what

R³¹ has the same meaning as R above⁹ and it's the same or different,

R³² and R³³ has the same meaning as R above¹⁰ and R¹¹and are the same or different from them,

R³⁴ and R³⁵ are the same or different and each may be a hydrogen atom or a straight or branched alkyl group having up to 5 carbon atoms, optionally substituted by a hydroxyl or straight or branched alkoxy group having up to 3 carbon atoms, or

R³⁴ and R³⁵ together with the nitrogen atom form a morpholinyl, triazolyl or thiomorpholinyl group or a group of the formula

EE 200000291Α

<img file="EE200000291A_D0015.tif" />

in what

R³⁶ is hydrogen, hydroxy, straight or branched alkoxycarbonyl having up to 5 carbon atoms or straight or branched chain alkyl up to 4 carbon atoms, io being optionally substituted by hydroxy, or

R³ and R⁴ together with the nitrogen atom form a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl or group of the formula

NR in which

R³⁷ is hydrogen, hydroxy, formyl, trifluoromethyl, straight or branched acyl, alkoxy or alkoxycarbonyl of up to 4 carbon atoms, or straight or branched alkyl of up to 5 carbon atoms, optionally mono- to tri-substituted in the same or different positions which is selected from: hydroxy, trifluoromethyl, carboxyl, straight or branched chain alkoxy or alkoxycarbonyl of up to 4 carbon atoms, or with groups of formula - (D) f-NR³⁸R³⁹, -CO (CH 2) _g-O-CO-R⁴⁰, -CO- (CH.) _h-OR⁴¹ or -P (O) (OR⁴²) (OR⁴³) where g and h are the same or different and can each be 1, 2 or 3 and f is 0 or 1,

EE 200000291 Α

D is a group of formula CO or SO₂,

R³⁸ and R³⁹ are the same or different and both have the same meaning as R above⁷ and R⁸,

R⁴⁰ is a straight or branched alkyl group having up to 4 carbon atoms,

R⁴¹ is a straight or branched alkyl group having up to 4 carbon atoms,

R⁴² and R⁴³ are the same or different and each may be hydrogen or straight or branched chain alkyl having up to 3 carbon atoms, or

R³⁷ is a group of formula - (CO)_;-E, where i is 0 or 1,

E is cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, wherein the above ring systems are optionally mono- or di-substituted with the same or different substituents selected from nitro, fluoro, chloro, -SO 2 H, straight-chain or branched alkoxy, hydroxy, tri25 fluoromethyl and trifluoromethoxy having up to 4 carbon atoms, or a group of formula -SO₂~ NR⁴⁴R⁴⁵, in what

R⁴⁴ and R⁴⁵ has the same meaning as above

R¹⁸ and R¹⁹ and are the same as or different from them, or

E is a group of formula

<img file="EE200000291A_D0016.tif" />

/ \ or f \ - N \ _ / N-CH₃ —_O 'and R³ and R⁴ wherein the heterocycles formed with the nitrogen atom are optionally mono- to tri-substituted, optionally double, with the same or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, linear or branched Io to acyl or alkoxycarbonyl having up to 5 carbon atoms , nitro and groups of the formula -P (O) (OR⁴⁶) (OR⁴⁷),, = NR⁴⁸ or - (CO) jNR⁴⁹R⁵⁰, in what

R⁴⁶ and R⁴⁷ has the same meaning as R above¹⁰ and R¹¹and are the same or different from them,

R⁴⁸ is hydroxy or straight or branched chain alkoxy having 20 to 3 carbon atoms, j is 0 or 1, and

R⁴⁹ and R⁵⁰ are the same or different and both have the same meaning as R above¹⁴ and R¹⁵, and / or R³ and R⁴ wherein the heterocycles formed with the nitrogen atom are optionally substituted with straight or branched chain alkyl up to 5 carbon atoms, optionally mono- or poly-substituted with the same or different substituents selected from: hydroxy, fluoro, chloro, carboxyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, straight or branched chain alkoxy or alkoxycarbonyl of up to 4 carbon atoms, or with groups of the formula -SO₃H, -NR⁵¹R⁵² or -P (O) (OR⁵³) (OR⁵⁴) , in what

R⁵¹ and R⁵² are the same or different and each may be hydrogen, phenyl, carboxyl, benzyl or straight or branched alkyl or alkoxy having up to 4 carbon atoms,

R⁵³ and R⁵⁴ are the same or different and both have the same meaning as R above¹⁰ and Rⁿ, and / or alkyl is optionally substituted with phenyl, which itself may be mono- to tri-substituted with the same or different substituents selected from fluoro, chloro, hydroxy, straight or branched alkoxy of up to 4 carbon atoms, or a group of formula - NR⁵¹ R⁵² , in what

R⁵¹ and R⁵² has the same meaning as R above⁵¹ and R⁵²and are the same as or different from them and / or R³ and R⁴ wherein the heterocycles formed with the nitrogen atom are optionally substituted with phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl, optionally also bonded through a nitrogen atom in which the ring system of this moiety may itself be substituted by hydroxyl or straight or branched chain alkyl or alkoxy having up to 5 carbon atoms, or

R³ and R⁴ together with the nitrogen atom form a group of the formula

<img file="EE200000291A_D0017.tif" />

EE 200000291 Α

<img file="EE200000291A_D0018.tif" />

R⁵ and R⁶ are the same or different and each may be hydrogen, hydroxy or straight or branched alkoxy having up to 4 carbon atoms, and salts, N-oxides, hydrates, and isomeric forms thereof.

Particularly preferred according to the invention are compounds of formula (I) wherein

R¹ is a straight or branched alkyl group having up to 3 carbon atoms,

R² is a straight chain alkyl of up to 3 carbon atoms, R³ and R⁴ are the same or different and each may be a ve20 blue atom or a straight or branched alkenyl or alkoxy group having up to 4 carbon atoms, or a straight or branched alkyl group having up to 6 carbon atoms, the carbon chain of which is optionally interrupted by oxygen; with various substituents selected from: hydroxy, fluoro, chloro, carboxyl, straight or branched alkoxycarbonyl having up to 4 carbon atoms, and / or groups of formula -SO₃H, - (A)_a-NR⁷R⁸, -O-CO-NR^Z'R⁸', -S (O)_b~ R⁹, -P (O) {OR¹⁰) (OR¹¹) ,

<img file="EE200000291A_D0019.tif" />

EE 200000291Α

<img file="EE200000291A_D0020.tif" />

wherein a and b are the same or different and each may be 0 or 1,

A is CO or SO₂,

R⁷, R⁷ , R⁸ and R⁸ are the same or different and each may be hydrogen or cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl and pyridyl wherein the above ring systems are optionally mono- or di-substituted with the same or different substituents selected from hydroxy -, nitro, carboxyl, fluoro, chloro, straight or branched alkoxy or alkoxy20 carbonyl having up to 3 carbon atoms or a group of the formula - (SO₂) _c~ NR¹²R¹³, where c is 0 or 1,

R¹² and R¹³ are the same or different and each may be hydrogen or straight or branched alkyl having up to 3 carbon atoms, or

R⁷, R⁷ , R⁸ and R⁸ is a methoxy group or a straight or branched alkyl group having up to 6 carbon atoms optionally mono- or di-substituted with the same or different substituents selected from hydroxy, fluoro, chloro, phenyl, straight or branched alkoxy having up to 3 carbon atoms 35 - or alkoxycarbonyl, or - (CO) _d~ NR¹⁴R¹⁵, in what

R¹⁴ and R¹⁵and d is 0 is the same or different and each may be hydrogen or methyl or ethyl, or 1, or

R⁷ and R⁸ and / or R⁷ and R⁸ together with the nitrogen atom form a morpholinyl, piperidinyl or triazolyl group or a group of the formula

<img file="EE200000291A_D0021.tif" />

ch₃

<img file="EE200000291A_D0022.tif" />

oh

<img file="EE200000291A_D0023.tif" />

• R setting

R¹⁶ is hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or N-methylpiperazinyl, or straight or branched chain alkyl of up to 3 carbon atoms, optionally substituted by hydroxy,

R⁹ is methyl,

R¹⁰ and R¹¹ are the same or different and each may be hydrogen, methyl or ethyl, and / or R³/ R⁴ the alkyl chain mentioned in Scheme 1 is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, furyl or tetrahydrofuranyl or by a group of formula

EE 200000291 Α

<img file="EE200000291A_D0024.tif" />

'0 or setting

R¹⁷ is hydrogen, hydroxy, formyl, acetyl or alkoxy having up to 3 carbon atoms, or straight or branched chain alkyl having up to 3 carbon atoms, optionally mono- or di-substituted with the same or different substituents selected from hydroxy and straight or branched alkoxy of up to 3 carbon atoms in the chain, and wherein the phenyl and the heterocycles are optionally monosubstituted with the same or different substituents selected from: fluoro, chloro, -SO₃H, linear or branched alkyl or alkoxy having up to 3 carbon atoms and hydroxyl, and / or a group of formula -SO₂~ NR¹⁸R¹⁹, in what

R¹⁸ and R¹⁹ are the same or different and each may be hydrogen or straight or branched alkyl up to 3 carbon atoms, and / or

R³ or R⁴ is a group of the formula -NR²⁰R²¹, in what

R²⁰ and R²¹ has the same meaning as R above¹⁸ and R¹⁹and are the same as or different from them, and / or

R³ and R⁴ is an adamantyl group or a group of formula

EE 200000291 Α

<img file="EE200000291A_D0025.tif" />

or cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or groups of formulas

<img file="EE200000291A_D0026.tif" />

in what

R²² has the same meaning as R above¹⁶ and is the same or different or formyl or acetyl, and wherein the cycloalkyl, phenyl and / or heterocycles are optionally mono- or di-substituted with the same or different substituents selected from fluoro, chloro, triazolyl, carboxyl · -, a linear or branched acyl or alkoxycarbonyl group of up to 4 carbon atoms and a nitro group, and / or groups of the formula -SO₃H,

-OR²³, (SO₂) _eNR²⁴R²⁵, -P (O) {OR²⁶) (OR²⁷) where e is 0 or 1,

R²³ is a group of the formula or o is cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl, hydrogen or straight or branched chain alkyl up to 3 carbon atoms, optionally substituted with cyclopropyl, cyclohexyl, benzyloxy, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl, alkoxy or alkoxycarbonyl, benzyloxycarbonyl or phenyl which may itself be mono- or di-substituted with the same or different substituents, which is selected from the group consisting of methoxy, hydroxy, fluoro or chloro, and / or wherein the alkyl group is optionally substituted with a group -CO-NR²⁸R²⁹ or -CO-R³⁰, in what

R²⁸ and R²⁹ are the same or different and each may be a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms; or

R²⁸ and R²⁹ together with the nitrogen atom form a morpholinyl, pyrrolidinyl or piperidinyl group, and

R³⁰ is phenyl or adamantyl,

R²⁴ and R²⁵ has the same meaning as R above¹⁸ and R¹⁹and are the same or different from them,

R²⁶ and R²⁷ has the same meaning as R above¹⁰ and R¹¹and are the same or different from each other and / or the cycloalkyl, phenyl and / or heterocycles are optionally substituted with straight or branched chain up to

EE 200000291 Α alkyl having optionally substituted hydroxy, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl or groups of formula -SO₂R³¹, -P (O) {OR³²) (OR³³) or -NR³⁴R³⁵, in what

R³¹ is methyl,

R³² and R³³ has the same meaning as R above¹⁰ and R¹¹and are the same or different from them,

R³⁴ and R³⁵ are the same or different and each may be a hydrogen atom or a straight or branched alkyl group having up to 3 carbon atoms, optionally substituted with a hydroxyl or methoxy group; or

R³⁴ and R³⁵ together with the nitrogen atom form a morpholinyl, triazolyl or thiomorpholinyl group or a group of the formula

<img file="EE200000291A_D0027.tif" />

in what

R³⁶ is hydrogen, hydroxy, straight or branched alkoxycarbonyl having up to 3 carbon atoms or straight or branched chain alkyl up to 3 carbon atoms, optionally substituted with hydroxy, or

R³ and R⁴ together with the nitrogen atom form a morpholinyl, thiomorpholinyl, pyrrolidinyl or piperidinyl group or a group of the formula

<img file="EE200000291A_D0028.tif" />

in what

R³⁷ is hydrogen, hydroxy, formyl, straight or branched acyl, alkoxy or alkoxycarbonyl having up to 3 carbon atoms, or straight or branched alkyl having up to 4 carbon atoms, optionally mono- or di-substituted with the same or different substituents selected from : hydroxy, straight or branched alkoxy or alkoxycarbonyl of up to 3 carbon atoms, or groups of formulas

- (D) _f-NR³⁸R³⁹, -CO- (CH 2) gO-CO-R⁴⁰, -CO- (CH 2) _h~ OR⁴¹ or

-P (O) (OR⁴²) (OR⁴³) in which g and h are the same or different and can each be 1 or 2 and f is 0 or 1,

D is a group of formula CO or SO₂, _r3S j_R39 are the same or different and both have the same meaning as R above⁷ and R⁸,

R⁴⁰ is a straight or branched alkyl group having up to 3 carbon atoms,

R⁴¹ is a straight or branched alkyl group having up to 3 carbon atoms,

R⁴² and R⁴³ are the same or different and each may be hydrogen, methyl or ethyl, or

R³⁷ is a group of formula - (CO)₁--E, where i is 0 or 1,

E is cyclopentyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, wherein the above ring systems are optionally monosubstituted with the same or different substituents selected from nitro, fluoro, chloro, -SO₃H, straight or branched chain alkoxy and hydroxy with up to 3 carbon atoms, or a group of formula -SO₂~ NR⁴⁴R⁴⁵, in what

R⁴⁴ and R⁴⁵ has the same meaning as R above¹⁸ and R¹⁹ and are the same or different from them, io or

E is a group of formula

<img file="EE200000291A_D0029.tif" />

<img file="EE200000291A_D0030.tif" />

and R³ and R⁴ optionally mono- to tri-substituted, optionally double, with the same or different substituents selected from hydroxy, hydroxyl, formyl, carboxyl, straight or branched acyl or alkoxycarbonyl having up to 3 carbon atoms or groups of the formulas -P (O) (OR⁴⁶) (OR⁴⁷),, = NR⁴⁸ or - (CO) jNR⁴⁹R⁵⁰, in what

R⁴⁶ and R⁴⁷ has the same meaning as R above¹⁰ and R¹¹and are the same or different from them,

R⁴⁸ is hydroxy or methoxy, j is 0 or 1 and

R⁴⁹ and R⁵⁰ are the same or different and have the same meaning as R above¹⁴ and R¹⁵, and / or R³ and R⁴ wherein the heterocyclic ring formed with the nitrogen atom is optionally substituted by a linear or branched alkyl group of up to 4 carbon atoms, optionally mono- to tri-substituted with the same or different substituents: hydroxy, fluoro, chloro, carboxyl, cyclopropyl, cycloheptyl -, straight or branched chain alkoxy or alkoxycarbonyl of up to 3 carbon atoms, or with groups of the formula -SO₃H, -NR⁵¹R⁵² or -P (O) (OR⁵³) (OR⁵⁴) , in what

R⁵¹ and R⁵² are the same or different and each may be hydrogen, phenyl, carboxyl, benzyl or straight or branched alkyl or alkoxy having up to 3 carbon atoms,

R⁵³ and R⁵⁴ are the same or different and have the same meaning as R above¹⁰ and R¹¹and / or the alkyl group is optionally substituted with a phenyl group which may itself be mono- to di-substituted with the same or different substituents selected from the group consisting of fluoro, chloro, hydroxyl and methoxy, or a group of formula -NR⁵¹R⁵²', in what

R⁵¹ and R⁵² has the same meaning as R above⁵¹ and R⁵²and are the same as or different from them and / or R³ and R⁴ wherein the heterocycles formed with the nitrogen atom are optionally substituted with phenyl, pyridyl, piperidinyl, pyrrolidinyl, or tetrazolyl optionally also bonded through a nitrogen atom in which the ring systems of these moieties may be substituted with hydroxyl or straight or branched Alkyl or alkoxy having 3 carbon atoms, or

R³ and R⁴ together with the nitrogen atom form the groups of the formulas

EE 200000291Α

N—^J

CH₃ or

<img file="EE200000291A_D0031.tif" />

CHpH₃

R⁵ and R⁶ are the same or different and each may be hydrogen, hydroxy or straight or branched alkoxy having up to 3 carbon atoms, and salts, N-oxides, hydrates, and isomeric forms thereof.

Compounds of general formula (I) in which

R¹ is methyl or ethyl,

R² is ethyl or propyl,

R³ and R⁴ are the same or different and each may be a linear or branched al 25 alkyl group having up to 5 carbon atoms, optionally substituted up to twice by the same or different substituents: hydroxy and methoxy; or

R³ and R⁴ together with the nitrogen atom form a piperidinyl, morpholinyl or thiomorpholinyl group or a group of the formula

<img file="EE200000291A_D0032.tif" />

in what

EE 200000291 Α

R³⁷ is hydrogen, formyl, straight or branched acyl or alkoxycarbonyl having up to 3 carbon atoms, or straight or branched alkyl having up to 3 carbon atoms, optionally mono- or di-substituted with the same or different substituents selected from hydroxy, carboxyl, straight or branched chain alkoxy or alkoxycarbonyl of up to 3 carbon atoms, or groups of formulas - (D) _f-NR³⁸R³⁹ or -P (O) (OR⁴²) (OR⁴³) where f is 0 or 1,

D is a group of formula CO,

<td>R³⁸</td><td>and R³⁹to be</td><td>are the same hydrogen atom</td><td>or or</td><td colspan="2">different and methyl,</td><td>each</td><td>can</td>

<td>R⁴²</td><td>and R⁴³</td><td>are the same</td><td>or</td><td>different</td><td>and</td><td>each</td><td>can</td>

<td></td><td>to be</td><td>hydrogen atom,</td><td colspan="2">methyl or</td><td colspan="2">ethyl,</td><td></td>

oh

R³⁷ is cyclopentyl, and R³ and R⁴ optionally mono- or di-substituted, optionally double, with the same or different substituents selected from hydroxy, formyl, carboxyl, straight or branched acyl or alkoxycarbonyl having up to 3 carbon atoms; groups of formula -P (O) (OR⁴⁶) (OR⁴⁷) or - (CO) _;NR⁴⁹R⁵⁰, in what

R⁴⁶ and R⁴⁷ are the same or different and each may be hydrogen, methyl or ethyl, j is 0 or 1, and

EE 200000291 Α

R⁴⁹ and R⁵⁰ are the same or different and each may be hydrogen or methyl, and / or R³ and R⁴ wherein the heterocycles formed with the nitrogen atom are optionally substituted with a straight or branched alkyl group of up to 3 carbon atoms, optionally mono- or di-substituted with the same or different substituents selected from hydroxy and carboxyl, or with the formula -P ( O) (OR⁵³) (OR⁵⁴) , in what

R⁵³ and R⁵⁴ are the same or different and each may be hydrogen, methyl or ethyl, and / or R³ and R⁴ wherein the heterocycles formed with the nitrogen atom are optionally substituted by a pyrrolidinyl or piperidinyl group on the nitrogen atom,

R⁵ is a hydrogen atom and

R⁶ is an ethoxy or propoxy group, and salts, hydrates, N-oxides, and isomeric forms thereof.

Also very preferred are the compounds of general formula (I) according to the invention wherein R⁵ is a hydrogen atom and the groups R⁶ and -SO₂NR³R⁴ is at para to the phenyl ring.

Particularly preferred compounds are listed in Table A.

Table A

<img file="EE200000291A_D0033.tif" />

<img file="EE200000291A_D0034.tif" />

EE 200000291 Α

<img file="EE200000291A_D0035.tif" />

Structure

<img file="EE200000291A_D0036.tif" />

^C2^Hs CH₂-OH

EE 200000291 Α

<img file="EE200000291A_D0037.tif" />

The invention further relates to a process for the preparation of the compounds of the general formula (I) according to the invention, characterized in that the compounds of the general formula (II) or

<img file="EE200000291A_D0038.tif" />

o (II) wherein

R¹ and R² is as defined above and

L is a straight or branched alkyl group having up to 4 carbon atoms, modified with compounds of general formula (III)

<img file="EE200000291A_D0039.tif" />

(III), x HCl in which

R⁵ and R⁶ are as defined above, in a two-step reaction system of ethanol and phosphorus oxychlorochloride di / dichloroethane to give compounds of general formula (IV)

<img file="EE200000291A_D0040.tif" />

(IV) wherein

R¹, R², R⁵ and R⁶ is as defined above, which is reacted in the next step with chlorosulfonic acid to give compounds of general formula (V)

<img file="EE200000291A_D0041.tif" />

in what

R¹, R², R⁵ and R⁶ is as defined above which is finally reacted with the amines of general formula (VI) in an inert solvent

HN³R⁴ (VI) wherein

R³ and R⁴ is as defined above.

The method according to the invention can be illustrated using the following scheme as an example:

<img file="EE200000291A_D0042.tif" />

EE 200000291 Α n rn π

<img file="EE200000291A_D0043.tif" />

<img file="EE200000291A_D0044.tif" />

HCl

<img file="EE200000291A_D0045.tif" />

ethanol phosphorus oxychloride / dichloroethane

<img file="EE200000291A_D0046.tif" />

chlorosulfonic acid

<img file="EE200000291A_D0047.tif" />

Suitable solvents for the individual steps are conventional organic solvents which do not change under the reaction conditions.

These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions or halogenated hydrocarbons such as dichloromethane, dichloromethane, trichloromethane, or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. Mixtures of the above solvents may also be used. Ethanol in the first step and dichloroethane in the second step are particularly preferred.

The reaction temperature can be varied within a relatively wide range. The reaction is usually carried out at a temperature of -20 to 200 ° C, preferably 0 to 70 ° C.

The steps of the process of the invention are typically carried out at atmospheric pressure, although higher and lower pressures (e.g., 0.5 to 5 bar) may be used.

To obtain compounds of general formula (V), the reaction is carried out at a temperature between 0 ° C and room temperature and at atmospheric pressure.

The reaction with the amines of general formula (VI) is carried out in one of the aforementioned chlorinated hydrocarbons, preferably dichloromethane.

The reaction temperature can be varied within a relatively wide range. The reaction is usually carried out at a temperature of -20 to 200 ° C, preferably 0 ° C to room temperature.

The reaction is usually carried out at atmospheric pressure, although higher and lower pressures (e.g., 0.5 to 5 bar) may be used.

Some compounds of the general formula (II) are known or new and can be prepared by converting the compounds of the general formula (VII)

R²-CO-T (VII) wherein

R² is as defined above and

T is a halogen atom, preferably a chlorine atom, io first by reaction with compounds of general formula (VIII) (VIII),₂c nh₂ is setting

R¹ are as defined above in compounds of general formula (IX) (IX) in an inert solvent, optionally in the presence of a base and trimethylsilyl chloride,

R-CONH CO., LTD₂H setting

R¹ and R² is as defined above and finally reacting with a compound of formula (X) cr in an inert solvent, optionally in the presence of a base₂wherein L is as defined above.

Suitable solvents for the individual process steps are conventional organic solvents which do not change under the reaction conditions. These preferably include ethers such as

EE 200000291Α ethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloroethane or tetrachloroethyl; acetonitrile, acetone, dimethoxyethane or pyridine. Mixtures of the above solvents may also be used. Dichloromethane in the first step and tetrahydrofuran in the second step in the mixture of pyridine are particularly preferred.

Suitable bases are usually alkali metal hydrides or alkali metal alkoxides, such as sodium hydride or potassium tert-butoxide, or cyclic amines, such as piperidine, pyridine, dimethylaminopyridine or C 1 -C 6 alkyl amines, such as triethylamine. Triethylamine, pyridine and / or dimethylaminopyridine are preferred.

The base is usually used in an amount of 1 to 4 moles, preferably 1.2 to 3 moles, per 1 mole of the compound of formula (X).

The reaction temperature can usually vary within a relatively wide range. The reaction is usually carried out at a temperature of -20 to 200 ° C, preferably at a temperature of 0 to 100 ° C.

Compounds of general formulas (VII), (VIII), (IX) and (X) are known per se or may be prepared by conventional methods.

Compounds of general formula (III) may be prepared by compounds of general formula (XI)

CN (XI) wherein

EE 200000291Α

R⁵ and R⁶ reaction with ammonium chloride in toluene and trimethylaluminum / hexane in the presence of -20 ° C to room temperature, preferably 0 ° C and atmospheric pressure, and reaction of the resulting amidine, if necessary in situ, with hydrazine hydrate.

The compounds of general formula (XI) are known per se or may be prepared by conventional methods.

Some compounds of the general formula (IV) are known or are new. in which case they may be prepared by known methods [David R. Marshall, Chemistry and Industry, 2 May 1983, 331-335].

Compounds of general formula (V) are novel per se, but may be prepared from compounds of general formula (IV) according to Organikum, VEB Deutscher Verlag der Wissenschaften, Berlin 1974, 338-339.

The compounds of the general formula (I) according to the invention have an unexpectedly useful pharmacological activity spectrum.

They inhibit one or more cGMP metabolizing phospho-25 diesterases (PDE I, PDE II and PDE V). As a result, the concentration of cGMP is increased. The differential expression of phosphodiesterases in different cells, tissues, and organs, as well as the differential subcellular localization of these enzymes, together with the selective inhibitors of the invention, allow the selective targeting of various cGMP-regulated processes.

In addition, the compounds of the present invention enhance the activity of agents such as EDRF (endothelial relaxation factor), ANP (atrio35 peptide), nitrovasodilators and all other agents that increase cGMP concentrations in a manner different from phosphodiesterase inhibitors.

EE 200000291Α

Therefore, they can be used as medicaments for the treatment of cardiovascular disorders such as hypertension, neuronal hypertension, stable and unstable angina pectoris, peripheral and cardiac vasculopathies and arrhythmias; for the treatment of thromboembolic disorders and ischaemia such as myocardial infarction, heart attack, transient and ischemic attacks, angina pectoris and peripheral circulatory obstruction; to prevent restenosis after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA) and forced surgery. In addition, they may also be important in the treatment of cerebrovascular disorders. Due to their relaxing effect on smooth muscles, they are suitable for the treatment of disorders of the urogenital system such as prostate hypertrophy, urinary incontinence and especially erectile dysfunction and sexual dysfunction in women.

Phosphodiesterase (PDE) activity cGMP-stimulated PDE II, cGMP-inhibited PDE III, and cAMP20 specific PDE IV were isolated from porcine or bovine cardiac muscle. Ca.²⁺- calmodulin-stimulated PDE I was isolated from porcine aorta, porcine brain or preferably bovine aorta. cGMP-specific PDE V was obtained from porcine small intestine, porcine aorta, human platelets, and preferably from bovine aorta. Purified by anion exchange chromatography on MonoQ® Pharmacia M. Hoey and Miles D. Houslay in Biochemical Pharmacology, 1990, 40,

193-202 and by the method described by C. Lugman et al., Biochemical Pharmacology, 1986, 35, 1743-1751.

Enzyme activity is determined by using 100 ml assay mixture in 20 mM Tris / HCl pH 7.5 containing 5 mM MgCl₂, 0.1 mg / ml bovine serum albumin, and either 800 Bq [³H] cAMPd or [³H] cGMPd. The final concentration of these nucleotides is 10 *⁶ moles / l. The reaction was initiated by the addition of enzyme and the amount of enzyme is about 35% which converts about 50% of the substrate over a 30 minute incubation period. For testing cGMP-stimulated PDE II was used as substrate [³H] cAMPd and adjunct to EE 200000291 A 10 '⁶ moles / l of unlabeled cGMP. Test Tax Ca²⁺-calmodulin-dependent PDE I is added to the reaction mixture with 1 mM CaCl₂ and 0.1 mM calmodulin. The reaction is stopped by the addition of 100 ml of acetonitrile containing 1 mM cAMP and 1 mM AMP. 100 ml of the reaction mixture is separated by HPLC and the products obtained are quantified in real time using a continuous running scintillation counter. The concentration of the substance to be measured is the concentration at which the reaction rate is reduced by 50%. In addition, phosphodiesterase from Amersham io Life Science [³H] cAMP-SPA enzyme sample and phosphodiesterase [³H] cGMP-SPA enzyme sample. Tested according to the test manufacturer's protocol. PDE II activity was determined using [³H] cAMP-SPA and ens' were added to the reaction mixture to activate⁶ M cGMPd. To determine PDE I, 15 ′ was added to the reaction mixture.⁷ M calmodulin and 1 mM CaCl₂. PDE V was measured using [³H] cAMP-SPA sample.

Inhibition of phosphodiesterase in vitro

<td>The experiment</td><td>PDE-I</td><td>PDE-II</td><td>PDE-V</td>

<td>number</td><td>IC₅₀ (nM)</td><td>IC₅₀ (nM)</td><td>IC₅₀ (nM)</td>

<td> 16</td><td> 300</td><td> &gt; 1000</td><td> 2</td>

<td> 19</td><td> 200</td><td> &gt; 1000</td><td> 2</td>

<td> 20</td><td> 200</td><td> &gt; 1000</td><td> 2</td>

<td> 26</td><td> 100</td><td> &gt; 1000</td><td> 1</td>

<td> 27</td><td> 200</td><td> &gt; 1000</td><td> 3</td>

<td> 32</td><td> 100</td><td> &gt; 1000</td><td> 4</td>

<td> 260</td><td> 300</td><td> &gt; 1000</td><td> 10</td>

<td> 275</td><td> 50</td><td> &gt; 1000</td><td> 3</td>

<td> 338</td><td> 200</td><td> &gt; 1000</td><td> 5</td>

Typically, inhibition of one or more phosphodiesterases of this type will increase the concentration of cGMP. Thus, the compounds are of interest in any treatment where it is considered beneficial to increase cGMP levels.

EE 200000291Α

Cardiovascular effects were studied in SH rats and dogs. The agents were administered intravenously and orally.

The erectile stimulating effect was studied in awake rabbits (Naganuma H., Egashira T., Fuji J., Clinical and Experimental Pharmacology and Physiology 20, 177-183 (1993)).

The agents were administered intravenously, orally or parenterally.

The novel active compounds and their physiologically acceptable salts (e.g., hydrochlorides, maleate or lactates) may be converted, in a known manner, into conventional dosage forms such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inert, non-toxic pharmaceutically acceptable or solvents. In this case, the concentration of the therapeutically active agent in each dosage form should be from about 0.5% to about 90% by weight of the total weight of the mixture, i.e., in an amount sufficient to achieve the indicated dosage range.

The formulations are formulated, for example, by prolonging the release time of the active ingredient, using solvents and / or excipients, optionally emulsifiers and / or dispersing agents. When water is used as a solvent, organic solvents may be used as auxiliary solvents, if necessary.

It is administered by conventional means, preferably orally, transdermally or parenterally, for example, sublingually, buccally, intravenously, nasally, rectally or by inhalation.

For oral administration to humans, it is customary to administer doses of 0.001 to 50 mg / kg, preferably 0.01 to 20 mg / kg. For parenteral administration, such as nasal mucosa, buccal or inhalation, dosages of 0.001 to 0.5 mg / kg are customary.

EE 200000291 Α

Nevertheless, it may be necessary to adjust the above dosages, namely, depending on body weight or mode of administration, individual response to the drug, dosage form, and time or intervals of administration. Thus, in some cases, lower doses than the aforementioned minimum amounts can be handled, whereas in other cases the above-mentioned upper limit must be exceeded. For relatively large amounts, it may be advisable to divide them into multiple single doses throughout the day.

The compounds of the invention are also suitable for use in veterinary medicine. For use in veterinary medicine, the compounds or non-toxic salts thereof may be administered in a suitable dosage form according to standard veterinary practice. Depending on the species of animal being treated, the dosage may be determined by the veterinarian.

STARTING MATERIALS

Example IA

2-Butyrylaminopropionic acid

<img file="EE200000291A_D0048.tif" />

ch₃

22.27 g (250 mmol) of D, L-alanine and 55.66 (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane and the solution is cooled to 0 ° C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred for 1 hour at room temperature and 1 hour at 40 ° C. After cooling to -10 ° C, 26.64 g (250 mmol) of butyryl chloride is added dropwise and the resulting mixture is stirred at -10 ° C for 2 hours and at room temperature for one hour.

Under ice-cooling, 125 ml of water are added dropwise and the reaction mixture is stirred at room temperature for 15 minutes. The aqueous layer is evaporated to dryness, the residue triturated with acetone and the mother liquor filtered under vacuum. The solvent is removed and the residue is chromatographed. The product obtained is dissolved in 3N aqueous sodium hydroxide solution and the resulting solution is evaporated to dryness. The residue is dissolved in concentrated HCl and evaporated again to dryness. The residue is stirred with acetone, the precipitated solid is filtered off with suction and the solvent is removed under reduced pressure. 28.2 g (71%) of a viscous oil are obtained which crystallize over time.

200 MHz ¹1 H-NMR (DMSO-d₆0.84 (t, 3H), 1.22 (d, 3H), 1.50 (hex, 2H), 2.07 (t, 2H), 4.20 (quin, 1H), 8.09 ( d, 1H).

Example 2A

2-Butyrylaminobutanoic acid

<img file="EE200000291A_D0049.tif" />

²⁰ CH₃

25.78 g of 2-aminobutanoic acid (250 mmol) and 55.66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane and the solution is cooled to 0 ° C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred at room temperature for 1 hour and at 40 ° C for 1 hour. After cooling to -10 ° C, 26.64 g (250 mmol) of butyryl chloride is added dropwise, and the resulting mixture is stirred at -10 ° C for 2 hours and at room temperature for one hour.

Under ice-cooling, 125 ml of water are added dropwise and the reaction mixture is stirred at room temperature for 15 minutes. The organic layer is stirred with aqueous sodium hydroxide and the organic solvent is removed under reduced pressure. After acidification, the precipitated solid is re-mixed with water, washed twice with pet35 ether and dried under reduced pressure at 45 ° C. 29.1 g (67%) of a colorless solid are obtained.

EE 200000291 Α

200 MHz 1 H NMR (DMSO-d6)?₆0.88 (2t, 6H), 1.51 (quart, 2H), 1.65 (m, 2H), 2.09 (t, 2H), 4.10 (m, 1H), 8.01 ( d, 1H), 12.25 (s, m, 1H).

Example 3A

2-ethoxybenzonitrile

CH,

O

J

<img file="EE200000291A_D0050.tif" />

g (210 mmol) of 2-hydroxybenzonitrile is heated at reflux overnight with 87 g of potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled off under reduced pressure. 30.0 g (97%) of a colorless liquid are obtained.

200 MHz 1 H NMR (DMSO-d6)?₆1.48 (t, 3H), 4.15 (quart, 2H), 6.99 (dt, 2H), 7.51 (dt, 2H).

Example 4A

2-ethoxybenzamidine hydrochloride

<img file="EE200000291A_D0051.tif" />

C! H

21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml of toluene and the suspension is cooled to 0 ° C. 200 ml of a 2M solution of trimethylaluminum in hexane are added dropwise and the mixture is stirred at room temperature until gas evolution ceases. After addition of 29.44 g (200 mmol) of 2-ethoxybenzonitrile, the reaction mixture is stirred at 80 ° C (bath) overnight.

After cooling with ice, the resulting mixture is added to a suspension of 100 g of silica gel and 950 ml of chloroform and the mixture is stirred at room temperature 200000291 ° C for 30 minutes. The mixture is filtered under vacuum and the residue on the filter is washed with the same amount of methanol. The mother liquor is concentrated, the resulting residue is mixed with dichloromethane: methanol (9: 1), the solid is filtered off with suction and the mother liquor is concentrated. 30.4 g (76%) of a colorless solid are obtained.

200 MHz ¹1 H NMR (DMSO-d 6) 1.36 (t, 3H), 4.12 (quart, 2H), 7.10 (t, 1H), 7.21 (d, 1H), 7.52 (m, 2H) ), 9.30 (s, broad, 4H).

Example 5A

2-Propoxybenzonitrile

<img file="EE200000291A_D0052.tif" />

g (630 mL) of 2-hydroxybenzonitrile is heated at reflux with 174 g (1.26 mol) of potassium carbonate and 232.2 g (1.89 mol) of ethyl bromide in 1 L of acetone overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled off under reduced pressure.

Mp 89 ° C (0.7 mbar). Yield: 95.1 g (93.7%).

Example 6A

2-Propoxybenzamidine Hydrochloride

<img file="EE200000291A_D0053.tif" />

x HCl

21.41 g (400 mmol) of ammonium chloride are suspended in 400 ml of toluene and cooled to 0-5 ° C. 200 ml of a 2 M solution of triethyl aluminum in hexane are added dropwise and the mixture is stirred at room temperature until gas evolution ceases.

After addition of 32.2 g (200 mmol) of 2-propoxybenzonitrile, the reaction mixture is stirred at 80 ° C (bath) overnight. After cooling with ice, the resulting reaction mixture is added to a suspension of 300 g silica gel 200000291 A gel and 2.85 L of ice-cooled chloroform and the mixture is stirred for 30 minutes. The mixture is filtered under vacuum and the residue on the filter is washed with the same amount of methanol. The solvent is distilled off under reduced pressure, the residue is mixed with 500 ml of dichloromethane: methanol (9: 1), the solid is filtered off and the mother liquor is concentrated. The residue is stirred with light petroleum and filtered under vacuum. 22.3 g (52%) of product are obtained.

200 MHz ¹1 H-NMR (CD 3 OD) 1.05 (3H), 1.85 (sex, 2H), 4.1 (A, 2H), 7.0-7.2 (m, 2H), 7.50- 7.65 (m, 2H).

Example 7A

2-ethoxy-4-methoxybenzonitrile

<img file="EE200000291A_D0054.tif" />

30.0 g (201 mmol) of 2-hydroxy-4-methoxybenzonitrile are heated with 83.4 g (603 mmol) of potassium carbonate and 32.88 g (301 mmol) of bromomethane in 550 mL of acetone at reflux for 18 hours. After filtration, the solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel (cyclohexane / ethyl acetate 10: 1) to give 35.9 g of an oil.

R_f = 0.37 (3: 1 cyclohexane / ethyl acetate).

200 MHz ¹1 H-NMR (CDCl 3₃1.48 (t, 3H), 3.85 (s, 3H), 4.12 (quart, 2H), 6.46 (m, 2H), 7.48 (d, 1H).

Example 8A

2-ethoxy-4-methoxybenzamidine hydrochloride

<img file="EE200000291A_D0055.tif" />

6.98 g (130 mmol) of ammonium chloride are suspended in 150 ml of toluene and the suspension is cooled to 0 ° C.

70 ml of 2 M trimethylaluminum solution are added dropwise

EE 200000291 Α in hexane and stir at room temperature until gas evolution ceases. After addition of 11.56 g (65 mmol) of 2-ethoxy-4-methoxybenzonitrile, the reaction mixture is stirred at 80 ° C (bath) overnight.

After cooling with ice, the resulting reaction mixture is added to a suspension of 100 g of silica gel and 950 ml of dichloromethane, and the mixture is stirred at room temperature for 30 minutes. The mixture is filtered under vacuum and the residue on the filter is washed with the same amount of methanol. The mother liquor is concentrated, the resulting residue is mixed with dichloromethane / methanol (9: 1), the solid is filtered off with suction and the mother liquor is concentrated. The residue is stirred with light petroleum and filtered under vacuum. 7.95 g (50%) of a solid are obtained.

200 MHz ¹1 H-NMR (DMSO-d 1, 1.36 (t, 3H), 3.84 (s, 3H), 4.15 (quart, 2H), 6.71 (m, 2H), 7.53 (d, 1H ), 8.91 (s, broad, 3H).

Example 9A

2- (2-Ethoxyphenyl) -5,7-dimethyl-3H-imidazo [5,1-f], 2,41-triazin-4-one

<img file="EE200000291A_D0056.tif" />

24.4 g (0.186 mol) of N-acetyl-D, L-alanine are firstly introduced into 200 ml of anhydrous tetrahydrofuran and 45 ml of anhydrous pyridine and 0.5 g of 4-dimethylaminopyridine are added. The mixture is heated to reflux and added dropwise

51.85 g (0.372 mol) of ethyl oxalyl chloride. The mixture is refluxed for a further 90 minutes, cooled, poured into ice-water and extracted three times with ethyl acetate. The organic layer is dried over sodium sulfate, concentrated and dissolved in 62.5 mL of methanol. Adding

9th g of sodium bicarbonate, the mixture is stirred at reflux for 2.5 hours and filtered.

Under ice-cooling, a solution of 38.26 g (190.65 mmol) of 2-ethoxy-4-methoxybenzamidine hydrochloride in 250 ml of methanol is added dropwise to 9.54 g (190.65 mmol) of hydrazine hydrate and the resulting suspension is stirred at room temperature for another 30 minutes. To this reaction mixture is added the methanolic solution described above and the mixture is stirred in a bath at 70 ° C for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure.

The residue is dissolved in 250 ml of 1,2-dichloroethane, 32.1 ml (348 mmol) of phosphorus oxychloride are added dropwise and the mixture is refluxed for 2 hours. The mixture is cooled, concentrated, dissolved in a small amount of dichloromethane and stirred with diethyl ether, and the solid is filtered off with suction. After chromatography on silica gel (dichloromethane / methanol 95: 5), the solution is concentrated and the crystalline residue is stirred with diethyl ether. Yield 8.1 g (14.9% of theory).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.58 (t, 3H), 2.62 (s, 3H), 2.68 (s,

3H), 4.25 (q, 2H), 7.04 (d, 1H), 7.12 (t, 1H), 7.5 (dt, 1H), 8.19 (dd, 1H), 10, 02 (s, 1H).

Example 10A

2- (2-Ethoxyphenyl) -5-methyl-7-propyl-3H-imidazo [5,1-f] 25,1,2,41-triazin-4-one

<img file="EE200000291A_D0057.tif" />

7.16 g (45 mmol) of 2-butyrylaminopropionic acid and 10.67 g of pyridine are dissolved in 45 ml of THF and, after addition of DMAP with a spatula, are heated to reflux. 12.29 g (90 mmol) of ethyl oxalyl chloride are slowly added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate, the organic layer is dried over sodium sulfate and concentrated by rotary evaporation. The residue is dissolved in 15 ml of ethanol and refluxed with 2.15 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.

To a solution of 9.03 g (45 mmol) of 2-ethoxybenzamidine hydrochloride in 45 mL of methanol is added dropwise 2.25 g (45 mmol) of hydrazine hydrate under ice-cooling and the resulting suspension is stirred at io room temperature for a further 10 min. To this reaction mixture is added the ethanol solution described above and the mixture is stirred in a bath at 70 ° C for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure.

The residue obtained is dissolved in 60 ml of 1,2-dichloroethane, after which 7.5 ml of phosphorus oxychloride are added, the mixture is refluxed for 2 hours. The mixture is diluted with dichloromethane, neutralized with sodium bicarbonate solution and solid sodium bicarbonate. The organic layer is dried and the solvent removed under reduced pressure. Chromatograph with ethyl acetate and crystallize to give 4.00 g (28%) of a colorless solid.

R_f = 0.42 (95: 5 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.56 (t, 3H), 1.89 (hex, 2H), 2.67 (s, 3H), 3.00 (t, 2H), 4.26 ( quart, 2H), 7.05 (m, 2H), 7.50 (dt, 1H), 8.17 (dd, 1H), 10.00 (s, 1H).

Example 11A ³⁰ 2- (2-Propoxyphenyl) -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,4-triazin-4-one

<img file="EE200000291A_D0058.tif" />

EE 200000291 Α

7.16 g (45 mmol) of 2-butyrylaminopropionic acid and 10.67 g of pyridine are dissolved in 45 ml of THF and after the addition of the spatula dimethylaminopyridine is heated to reflux. 12.29 g (90 mmol) of ethyl oxalyl chloride are slowly added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate, the organic layer is dried over sodium sulfate and concentrated by rotary evaporation. The residue is dissolved in 15 ml of ethanol and refluxed with 2.15 g of sodium bicarbonate at reflux for 2.5 hours. The cooled solution is filtered.

To a solution of 9.66 g (45 mmol) of 2-propoxybenzamidine hydrochloride in 45 mL of ethanol is added dropwise 2.25 g (45 mmol) of hydrazine hydrate under ice-cooling and the resulting suspension is stirred at room temperature for a further 10 minutes. To this reaction mixture is added the ethanol solution described above and the mixture is stirred in a bath at 70 ° C for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure.

The residue is dissolved in 60 ml of 1,2-dichloroethane and, after the addition of 7.5 ml of phosphorus oxychloride, is refluxed for 2 hours. The mixture is diluted with dichloromethane, neutralized with sodium bicarbonate solution and solid sodium bicarbonate. The organic layer is dried and the solvent removed under reduced pressure. Crystallization from ethyl acetate gives 2.85 g (19.1%) of a yellow solid , and chromatographic purification of the mother liquor yields another 1.25 g (8.4%) of product.

R_f = 0.45 (95: 5 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃1.03 (t, 3H), 1.15 (t, 3H), 1.92 (m, 4H), 2.67 (s, 3H), 3.01 (t, 2H), 4.17 ( t, 2H), 7.09 (m, 2H), 7.50 (dt, 1H), 8.17 (dd, 1H), 10.02 (s, 1H).

EE 200000291 Α

Example 12A

2- (2-ethoxy-4-methoxyphenyl) -5-methyl-7-propyl-3H-imidazo [5,1-f] 1,2,2,4-pyridazole. triazine-4-one

<img file="EE200000291A_D0059.tif" />

5.50 g (34.8 mmol) of 2-butyrylaminopropionic acid and 8.19 g of pyridine are dissolved in 35 ml of tetrahydrofuran and, after addition of dimethylaminopyridine with a spatula, are heated to reflux. 9.43 g of isopropyl oxalyl chloride (69 mmol) are slowly added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate, the organic layer is dried over sodium sulfate and concentrated by rotary evaporation. The residue is dissolved in 11 ml of methanol and refluxed with 1.65 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.

To a solution of 7.95 g (34.5 mmol) of 2-ethoxy-4-methoxybenzamidine hydrochloride in 35 mL of ethanol is added dropwise 1.73 g (34.5 mmol) of hydrazine hydrate under ice-cooling and the resulting suspension is stirred at room temperature for a further 30 minutes. To this reaction mixture is added the methanolic solution described above and the mixture is stirred in a bath at 70 ° C for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure.

The residue is dissolved in 4 6 ml of 1,2-dichloroethane and after the addition of 5.74 ml of phosphorus oxychloride, the mixture is refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized with sodium bicarbonate solution and solid sodium bicarbonate. The organic layer is dried and the solvent removed under reduced pressure. Chromatograph

EE 200000291Α (dichloromethane / methanol 50: 1) to give 0.31 g (2.5%) of a solid.

R_f = 0.46 (dichloromethane / methanol 20: 1).

200 MHz ¹1 H-NMR (CDCl 3) 1.03 (t, 3H), 1.58 (t, 3H), 1.88 (m,

2H), 2.62 (s, 3H), 2.98 (t, 2H), 3.89 (s, 3H), 4.25 (quart,

2H), 6.54 (d, 1H), 6.67 (dd, 1H), 8.14 (d, 1H), 9.54 (s, 1H).

Example 13A

2- (2-Ethoxyphenyl) -5-ethyl-7-propyl-3H-imidazo [5,1-f] (1,2,4110 triazin-4-one

<img file="EE200000291A_D0060.tif" />

29.06 g (167.8 mmol) of 2-butyrylaminobutanoic acid and 39.76 g of pyridine are dissolved in 170 ml of tetrahydrofuran and, after the addition of the spatula dimethylaminopyridine, are heated to reflux. 45.81 g (335.5 mmol) of ethyl oxalyl chloride are slowly added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate, the organic layer is dried over sodium sulfate and concentrated by rotary evaporation. The residue is dissolved in 15 ml of methanol and half of the solution is heated under reflux with 7.96 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.

To a solution of 16.83 g (83.9 mmol) of 2-ethoxybenzamidine hydrochloride in 85 mL of ethanol are added dropwise 4.20 g (83.9 mmol) of hydrazine hydrate under ice-cooling and the resulting suspension is stirred at room temperature for a further 10 minutes. To this reaction mixture is added the methanolic solution described above and the mixture is stirred in a bath at 70 ° C for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between methylene chloride 200000291Α methane and water, the organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure.

The residue is dissolved in 112 ml of 1,2-dichloroethane and after the addition of 14 ml of phosphorus oxychloride, the mixture is heated to reflux for 2 hours. The mixture is diluted with dichloromethane and neutralized with sodium bicarbonate solution and solid sodium bicarbonate. The organic layer is dried and the solvent removed under reduced pressure. Chromatography (dichloromethane / methanol 50: 1) gives 3.69 g (12.4%) of a colorless solid.

R_f = 0.46 (dichloromethane / methanol 20: 1).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.32 (t, 3H), 1.57 (t, 3H), 1.94 (m,

8H), 3.03 (quart, 2H), 3.64 (quin, 1H), 4.27 (quart, 2H), 7.06 (d, 1H), 7.12 (t, 1H), 7, 50 (dt, 1H), 8.16 (dd, 1H), 9.91 (s,

IH).

Example 14A

4-Ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydro-imidazo [5,1-f] -1,2,41-triazin-2-yl) -benzenesulfonyl chloride

<img file="EE200000291A_D0061.tif" />

7.25 g (25.5 mmol) of 2- (2-ethoxyphenyl) 5,7-dimethyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one are first taken in ice-cooling. 26.74 g (0.23 mol) of chlorosulfonic acid are added.

The mixture is stirred at room temperature overnight and poured into ice-water, the crystals are filtered off with suction and dried in a vacuum desiccator. Yield 9.5 g (97% of theory).

200 MHz ¹1 H-NMR (DMSO-d₆) 1.32 (t, 3H), 2.63 (s, 3H), 2.73 (s,

3H), 4.13 (q, 2H), 7.15 (d, 1H), 7.77 (m, 2H), 12.5 (s, 1H).

EE 200000291 Α

Example 15A

4-Ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) -benzenesulfonyl chloride

<img file="EE200000291A_D0062.tif" />

To 3.83 ml of chlorosulfonic acid is slowly added 2.00 g (6.4 mmol) of 2- (2-ethoxyphenyl) -5-methyl-7-propyl-3H-imidazo [5.1f] [1,2] at 0 ° C. 4] triazin-4-one. The mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. 2.40 g (91%) of a colorless foam are obtained.

200 MHz ¹1 H-NMR (CDCl 3₃) 1.03 (t, 3H), 1.61 (t, 2H), 1.92 (hex, 2H), 2.67 (s, 3H), 3.10 (t, 2H), 4.42 ( quart, 2H), 7.27 (t,

1H), 8.20 (dd, 1H), 8.67 (d, 1H), 10.18 (s, 1H).

Example 16A

4-Propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazole 5,1-f] -1,2,4-triazin-2-yl) benzenesulfonyl chloride

<img file="EE200000291A_D0063.tif" />

To 5.13 ml of chlorosulfonic acid is slowly added 2.80 g (8.6 mmol) of 2- (2-propoxyphenyl) -5-methyl-7-propyl-3H-imidazo [5,1f] [1,2] at 0 ° C, 4] triazin-4-one. The reaction mixture is stirred at room temperature overnight and then poured into ice water and extracted with dichloromethane. 3.50 g (96%) of a colorless foam are obtained.

R_f = 0.49 (95: 5 dichloromethane / methanol).

200 MHz @ 1 H NMR (CDCl3₃1.03 (2t, 6H), 1.95 (m, 4H), 2.81 (s, 3H), 3.22 (t, 2H), 4.11 (t, 2H), 7.09 ( m, 1H), 8.06 (dd, 1H), 8.21 (m, 1H), 12.0 (s, 1H).

Example 17A

4-Ethoxy-2-methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f], 2,41-triazin-2-yl) -benzenesulfonyl chloride

<img file="EE200000291A_D0064.tif" />

i

Cl

To 0.54 mL of chlorosulfonic acid is slowly added 0.31 g (0.9 mmol) of 2- (2-ethoxy-4-methoxyphenyl) -5-methyl-7-propyl-3H-imidazo [5,1-f] at 0 ° C. ] [1,2,4] Triazin-4-one. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. 0.355 g (89%) of a colorless foam is obtained.

R_f = 0.50 (dichloromethane / methanol 20: 1).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.05 (t, 3H), 1.66 (t, 3H), 1.95 (m,

2H), 2.61 (s, 3H), 3.11 (t, 2H), 4.15 (s, 3H), 4.40 (quart, 2H), 6.65 (s, 1H), δ, 72 (s, 1H), 9.75 (s, 1H).

Example 18A

4-Ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazole³⁰ ,1 5,1-f1 (1,2,41 Triazin-2-yl) benzenesulfonyl chloride

CH_? O ^ -CH «AW

SO₂CI

CH

EE 200000291 Α

To 3.12 mL of chlorosulfonic acid is slowly added 1.70 g (5.21 mmol) of 2- (2-ethoxyphenyl) -5-ethyl-7-propyl-3 H -imidazo [5,1-f] [0] at 0 ° C. , 2,4] triazin-4-one. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. 2.10 g (94%) of a colorless foam are obtained.

400 MHz ¹1 H-NMR (CDCl₃) 1.03 (t, 3H), 1.35 (t, 3H), 1.62 (t, 3H), 1.92 (sex, 2H), 3.07 (quart, 2H), 3.12 ( t, 2H), 4.42 (quart, 2H), 7.38 (d, 1H), 8.19 (dd, 1H), 8.70 (d, 1H), 10.08 (s, broad, 1H) ).

Example 19A

Diethyl (4-piperidinylmethyl) phosphonate · “-^OC2^H5

C oc₂h₅

N

I

H

First, 2.11 g (528 mmol) of 60% sodium hydride in 50 ml of anhydrous tetrahydrofuran are added dropwise and 15.7 g (52.8 mmol) of diethyl methane diphosphonate are added dropwise. The mixture is stirred at room temperature for a further 30 minutes and then 10.1 g (52.8 mmol) of 1-benzyl-4-piperidone are added. The mixture is stirred for another hour at room temperature and for one hour at reflux, concentrated, stirred with water and extracted three times with dichloromethane, the organic layer is dried over sodium sulfate and concentrated. The residue is hydrogenated

50 ml of ethanol, 1.7 g of 10% palladium on carbon at room temperature and 3 bar. The catalyst is filtered off with suction and the filtrate is concentrated. Yield: 12.5 g (100% of theory). 400 MHz¹1 H-NMR (CDCl 3₃) 1.13 (m, 2H), 1.32 (t, 6H), 1.69 (dd,

2H), 1.74-1.95 (m, 4H), 2.62 (dt, 2H), 3.05 (m, 2H), 4.1 (m,

4H).

EE 200000291Α

Example 2OA

5-methyl-4-furoxanecarbaldehyde

<img file="EE200000291A_D0065.tif" />

Dissolve g (571 mmol) of crotonaldehyde in 80 ml of acetic acid and add a solution of 137 g (1.99 mol) of sodium nitrite in 300 ml of water at 0 ° C. The mixture is stirred at room temperature for 2 hours, diluted with 800 ml of water and extracted 3 times with dichloromethane. The organic layer is dried and chromatographed (cyclohexane / ethyl acetate) to give 13.8 g (18.9%) of 5-methyl-4-furoxanecarbaldehyde.

200 MHz ¹1 H-NMR (CDCl 3₃) 2.39 (s, 3H), 10.10 (s, 1H).

Example 21A

5-methyl-4-furoxanecarbonyl chloride

<img file="EE200000291A_D0066.tif" />

13.5 g (105 mmol) of 5-methyl-4-furoxanecarbaldehyde are dissolved in 200 ml of acetone and a solution of 16.86 g (168 mmol) of chromium trioxide in 120 ml of 2.2 M sulfuric acid is added dropwise at 0 ° C. The mixture is stirred at 10-15 ° C for 2 hours and then at room temperature overnight. Upon cooling, 100 ml of isopropanol are added dropwise and after 30 minutes the solvent is removed under reduced pressure. The aqueous layer is extracted 3 times with diethyl ether, the organic layer is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in 1 M sodium hydroxide solution and the solution is extracted 3 times with diethyl ether. The aqueous layer is acidified and extracted 3 times with diethyl ether. The organic layer is dried and the solvent removed under reduced pressure 200000291. The residue is stirred with light petroleum and filtered under vacuum.

6.92 g of the residue is heated with 10 ml of thionyl chloride in 20 ml of dichloromethane at reflux for 6 hours. The mixture is diluted with toluene, filtered and concentrated by rotary evaporation. The residue is redissolved in dichloromethane, stirred with 10 ml of thionyl chloride and heated at reflux for 48 hours. The solvent is removed under reduced pressure and the residue is distilled under reduced pressure. 2.00 g (25%) of colorless crystals are obtained.

200 MHz ¹1 H-NMR (CDCl 3) 2.41 (s).

Example 22A

1- (5-Methyl-4-furoxanecarbonyl) -4-tert-butyloxycarbonyl15-piperazine

<img file="EE200000291A_D0067.tif" />

2.75 g (14.7 mmol) of Boc-piperazine and 1.49 g of triethylamine are dissolved in 20 ml of dichloromethane and 2.00 g (12.3 mmol) of 5-methyl-4-furoxanecarbonyl chloride are stirred at 0 ° C in small intervals. The mixture is stirred at 0 ° C for 30 minutes and at room temperature for 2 hours, diluted with dichloromethane and washed with water. The solvent is removed under reduced pressure and the residue is purified by chromatography (cyclohexane / ethyl acetate). 3.33 g (87%) of 1- (5-methyl-4-furoxanecarbonyl) -4-tert-butyloxycarbonylpiperazine are obtained.

200 MHz ¹ 1 H-NMR (CDCl 3₃) 1.50 (s, 9H), 2.30 (s, 3H), 3.55 (m,

4H), 3.78 (m, 2H), 3.87 (m, 2H).

Example 23A

1- (5-methyl-4-furoxanecarbonyl) piperazine trifluoroacetate

<img file="EE200000291A_D0068.tif" />

3.12 g (10 mmol) of 1- (5-methyl-4-furoxanecarbonyl) -4-tert-butyloxycarbonylpiperazine are dissolved in 20 ml of dichloromethane and stirred at 0 ° C with 2 ml of trifluoroacetic acid. The mixture is allowed to warm to room temperature and stirred for 72 hours. After addition of 10 ml of ether, the precipitate is filtered off with suction and dried. 2.47 g (83%) of 1- (5-methyl-4-furoxanecarbonyl) piperazine trifluoroacetate are obtained.

200 MHZ ¹1 H-NMR (DMSO-d₆) 2.18 (s, 3H), 3.18 (m, 2H), 3.25 (m,

2H), 3.83 (m, 2H), 3.90 (m, 2H), 8.89 (s, broad, 2H).

EXAMPLES OF MANUFACTURE

Example 1

2- [2-Ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0069.tif" />

I

N

N

I ch₃

0.1 g (0.26 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydro-35 imidazo [5,1-f] [1,2,4] triazine-2 -yl) benzenesulfonyl chloride is dissolved in 10 ml of dichloromethane and cooled to 0 ° C. After the addition of DMAP with a spatula tip, 80 mg is added

EE 200000291Α (0.784 mmol) N-methylpiperazine and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic layer is washed with ammonium chloride solution and dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel (dichloromethane / methanol 9: 1).

Yield 40 mg (34.5% of theory).

Mass Spectrum: 447 (M + H) 284, 256, 224.

io Example 2

2- [2-Ethoxy-5- (4-hydroxyethyl-piperazine-1-sulfonyl) -phenyl] 15,7-dimethyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0070.tif" />

OH

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride, and 100 mg (0.784 mmol) of 4-hydroxypiperazine give 45 mg (36.1% of theory) of 230 [2-ethoxy-5- (4-hydroxyethyl-piperazine-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [ 5,1-f] [1,2,4] triazin-4-one. Mass Spectrum: 447 (M + H) 284, 256, 239.

Example 3

2- [2-Ethoxy-5- (4-hydroxypiperidine-1-sulfonyl) -phenyl] -5,8-dimethyl-3H-imidazor 5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0071.tif" />

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride, and 80 mg (0.784 mmol) of 4-hydroxypiperidine give 35 mg (29.8% of theory) of 2- [2-ethoxy-5- (4-hydroxypiperidine-1-sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [ 5,1-f] [1,2,4] triazin-4-one.

200 MHz ¹1 H-NMR (CDCl 3₃) 1.61 (t, 3H), 1.69 (m, 2H), 1.94 (m,

2H), 2.67 (s, 3H), 2.70 (s, 3H), 3.02 (m, 2H), 3.30 (m, 2H), 3.84 (m, 1H), 4, 37 (q, 2H), 7.18 (d, 1H), 7.90 (dd, 1H), 8.52 (d, 1H), 9.73 (s, 1H).

Example 4

2- [2-Ethoxy-5- (4-hydroxymethyl-piperidine-1-sulfonyl) -phenyl] -15,7-dimethyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0072.tif" />

OH

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride, and 90 mg (0.784 mmol) of 4-hydroxymethylpiperidine give 22 mg (18% of theory)

2- [2-Ethoxy-5- (4-hydroxymethyl-piperidine-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

200 MHz ¹1 H-NMR (CDCl 3) 1.38 (dt, 2H), 1.62 (t, 3H), 1.82 (dd,

2H), 2.35 (dt, 2H), 2.78 (s, 3H), 2.84 (s, 3H), 3.5 (d, 2H),

3.87 (d, 2H), 4.39 (q, 2H), 7.21 (d, 1H), 7.95 (dd, 1H), 8.51 (d, 1H), 10.03 (bs) , 1H).

Example 5

2- [2-Ethoxy-5- (3-hydroxy-pyrrolidine-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] η, 2,41-triazin-4-one

<img file="EE200000291A_D0073.tif" />

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) -benzenesulfonyl chloride and 70 mg (0.784 mmol) of 3-hydroxypyrrolidine gives 13 mg (11.1% of theory) of 2- [2-ethoxy-5- (3-hydroxypyrrolidine-1-sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

Mass Spectrum: 434 (M + H).

EE 200000291 Α

Example 6

4-Ethoxy-N-ethyl-N- (2-hydroxyethyl) -3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] -1,2,41-triazin-2-yl) benzenesulfonamide

<img file="EE200000291A_D0074.tif" />

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,715 dimethyl-4-oxo-3,4-dihydroimidazo [5,1f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride and 70 mg ( 0.784 mmol) of 2- (ethylamino) ethanol to give 23 mg (20.1% of theory) of 4-ethoxy-N-ethyl-N- (2-hydroxyethyl) -3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,11f] [1,2,4] triazin-2-yl) -benzenesulfonamide 20 di.

<td> 200</td><td>MHz</td><td>1 H-NMR</td><td>(CDCl₃) 1.2 (t,</td><td>3H),</td><td> 1,6</td><td>(t, 3H),</td><td> 2,17</td><td>(bs,</td><td>IH),</td>

<td> 2,69</td><td>(s,</td><td>3H),</td><td>2.75 (s, 3H),</td><td> 3,33</td><td>(m,</td><td>4H), 3.8</td><td>(t,</td><td>2H),</td><td> 4,36</td>

<td>(q,</td><td>2H),</td><td> 7,18</td><td>(d, 1H), 7.99</td><td>(dd,</td><td>IH),</td><td>8.6 (d,</td><td>IH),</td><td> 9,84</td><td>(bs,</td>

IH).

Example 7

N, N-Diethyl-4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydro-imidazo [5,1-f] [1,2,41-triazin-2-yl) -benzenesulfonamide

<img file="EE200000291A_D0075.tif" />

^h3C ^ / N ch₃

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride, and From 60 mg (0.784 mmol) of diethylamine, 21 mg (18.6% of theory) of N, N-diethyl-45 ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1- f] [1,2,4] Triazin-2-yl) -benzenesulfonamide.

200 MHz @ 1 H NMR (CDCl3₃) 1.18 (t, 6H), 1.61 (t, 3H), 2.68 (s, 3H), 2.72 (s, 3H), 3.29 (q, 4H), 4.35 ( q, 2H), 7.15 (d, 1H), 7.95 (dd, 1H), 8.58 (d, 1H), 9.8 (bs, 1H).

Example 8

2- [2-Ethoxy-5- (4- (2-pyrimidinyl) piperazine-1-sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] -1,2,41-triazine-4- Oh

<img file="EE200000291A_D0076.tif" />

ι

N

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride and 130 mg (0.784 mmol!) of 1- (230 pyrimidinyl) piperazine give 38 mg (28.2% of theory) of 2- [2-ethoxy-5- (4- (2-pyrimidinyl) piperazine-1-sulfonyl) phenyl ] -5,7-dimethyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

<td> 200</td><td>MHz 1 H-NMR</td><td>(CDCl₃) 1,</td><td>, 6 (t,</td><td>3H)</td><td>, 2.68 (s,</td><td>3H), 2, '</td><td>72 (s,</td><td>3H),</td>

<td> 35 3,12</td><td>(t, 4H),</td><td>3.96 (t,</td><td>4H),</td><td> 4,34</td><td>(q, 2H),</td><td>6.5 (t,</td><td>IH),</td><td> 7,18</td>

<td>(d,</td><td>1H), 7.9</td><td>(dd, 1H),</td><td> 8,28</td><td>(d,</td><td>2H), 8.51</td><td>(d, 1H)</td><td> , 9,7</td><td>(bs,</td>

IH).

EE 200000291 Α

Example 9

2- [2-Ethoxy-5-morpholine-4-sulfonyl) -phenyl-5,7-dimethyl-3-imidazo [5,1-f] -1,2,4-triazin-4-one

<img file="EE200000291A_D0077.tif" />

i

N

O

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,715 dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride, and 70 mg (0.784 mmol) of morpholine gives 28 mg (24.2% of theory) of 2- [2-ethoxy-5- (morpholine-4-sulfonyl) -phenyl] -5,7-dimethyl-3 H -imidazo [5,1- f] [1,2,4] Triazin-4-one.

200 MHz @ 1 H NMR (CDCl3₃) 1.53 (t, 3H), 2.69 (s, 3H), 2.72 (s, 3H), 3.06 (t, 4H), 3.77 (t, 4H), 4.39 ( q, 2H), 7.2 (d, 1H), 7.91 (dd, 1H), 8.51 (d, 1H), 9.78 (bs, 1H).

Example 10

2 -? 2-ethoxy-5- (1,4-dioxa-6-azaspiro [4,41] nonane-6-sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0078.tif" />

i

N

O

EE 200000291 Α

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride, and 100 mg (0.784 mmol) of 1,4-dioxa-6-azaspiro [4.4] nonane gives 45 mg (35.3% of theory) of 2- [2-ethoxy-5- (1,4-dioxa-6-azaspiro) [4.4] nonane-6-sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

<td>200 MHz</td><td>¹1 H-NMR (CDCl 3₃)</td><td> 1,58</td><td>(t,</td><td>3H),</td><td> 2,02</td><td>(t,</td><td>2H),</td><td>2.61 (s,</td>

<td colspan="3">3H), 2.65 (s, 3H), 3.32 (s,</td><td>2H),</td><td> 3,41</td><td>(t,</td><td>2H),</td><td> 3,88</td><td>(m, 4H),</td>

<td>10 4.34 (q,</td><td>2H), 7.17 (d,</td><td>IH),</td><td> 7,92</td><td>(dd,</td><td>IH),</td><td> 8,51</td><td>(d,</td><td>1H), 9.92</td>

(bs, 1H).

Example 11

Ν, Ν-bis (2-methoxyethyl) -4-ethoxy-3- (5,7-dimethyl-4-oxo-3,415 dihydroimidazo [5,1- f] [1,2,4] triazin-2-yl) benzenesulfonamide

<img file="EE200000291A_D0079.tif" />

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride, and 100 mg (0.784 mmol) of bis- (2-methoxyethyl) amine gives 37 mg (27.5% of theory) of N, N-bis (2-methoxyethyl) -4-ethoxy-3- (5,7-dimethyl-4-oxo) -3,430 dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonamide.

<td> 200</td><td>MHz</td><td>¹1 H-NMR (CDCl 3₃) 1,58</td><td>(t, 3H),</td><td> 2,61</td><td>(s, 3H), 2.64</td><td>(s,</td>

<td>3H),</td><td> 3,3</td><td>(s, 6H), 3.46 (t,</td><td>4H), 3.56</td><td>(t,</td><td>4H), 4.32 (q,</td><td>2H),</td>

<td> 7,12</td><td>(d,</td><td>1H), 7.95 (dd, 1H),</td><td>8.51 (d,</td><td>IH),</td><td>9.9 (bs, 1H).</td><td></td>

EE 200000291 Α

Example 12

N- (3-Isoxazolyl) -4-ethoxy-3- [5,7-dimethyl-4-oxo-3,4-dihydroimidazor 5,1-f [1,2,4] triazin-2-yl) benzenesulfonamide

<img file="EE200000291A_D0080.tif" />

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,715 dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride and mg (0.784 mmol) of 3-aminoisoxazole gives 20 mg (17.2% of theory) of N- (3isoxazolyl) -4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5 1-f] [1,2,4] triazin-2-yl) -benzenesulfonamide.

200 MHz ¹1 H-NMR (CDCl 3) 1.6 (t, 3H), 2.73 (s, 3H), 2.81 (s, 3H),

4.35 (q, 2H), 6.6 (d, 1H), 7.14 (d, 1H), 8.05 (dd, 1H), 8.27 (d, 1H), 8.63 (d) , 1H), 9.61 (bs, 1H).

Example 13

2- [2-Ethoxy-5- (2-tert-butoxycarbonylaminomethyl-morpholine-4sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] n, 2,4] triazin-4-one

<img file="EE200000291A_D0081.tif" />

O

EE 200000291 Α

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride, and 170 mg (0.784 mmol) of 2-tert-butoxycarbonylaminomethyl-morpholine give 64 mg (42.2% of theory) of 2- [2-ethoxy-5- (2-tert-butoxycarbonylaminomethyl-morpholine-4-sulfonyl) -phenyl] -5,7-dimethyl-31f. -imidazo [5,1-f] [1,2,4] triazin-4-one.

Mass Spectrum: 563 (M + H).

io Example 14

2- [2-Ethoxy-5- (4-phenyl-piperazine-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0082.tif" />

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride, and 130 mg (0.784 mmol) of 1-phenylpiperazine give 38 mg (28.3% of theory) of 2- [230 ethoxy-5- (4-phenylpiperazine-1-sulfonyl) phenyl] -5,7-dimethyl-3 H -imidazo [5,1-f] [1,2,4] triazin-4-one.

<td>2 00 MHZ ¹1 H-NMR (CDCl₃)</td><td> 1,62</td><td>(t, 3H),</td><td> 2,72</td><td>(s,</td><td>3H),</td><td> 2,77</td><td>(s,</td>

<td>3H), 3.25 (m, 8H), 4.38</td><td>(q,</td><td>2H), 6.92</td><td>(m,</td><td>2H),</td><td> 7,02</td><td>(d,</td><td>IH),</td>

<td>7.18-7.37 (m, 3H), 7.94</td><td>(dd,</td><td>1H), 8.55</td><td>(m,</td><td>IH),</td><td> 9,79</td><td>(bs,</td><td>IH).</td>

EE 200000291Α

Example 15

2- [2-Ethoxy-5- (3-hydroxy-3-methoxymethyl-pyrrolidine-1-sulfonyl) -phenyl] -5,7-dimethyl-3N-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0083.tif" />

l

N r ~ \

OH O-CH₃

By the same method, starting from 100 mg (0.261 mmol) of 4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride, and 100 mg (0.784 mmol) of 3-hydroxy-3-methoxymethylpyrrolidine give 30 mg (23.5% of theory) of 2- [2-ethoxy-5- (3-hydroxy-3-methoxymethyl-pyrrolidine-1-sulfonyl) -phenyl] -5 , 7-dimethyl-3 H -imidazo [5,1-f] [1,2,4] triazin-4-one.

Mass Spectrum: 478 (M + H).

Example 16

2- [2-Ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,4-triazin-4-one

<img file="EE200000291A_D0084.tif" />

EE 200000291 Α

1.23 g (3 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2- yl) Benzenesulfonyl chloride is dissolved in 40 ml of dichloromethane and cooled to 0 ° C. After the addition of DMAP at the spatula, 0.90 g (9.00 mmol) of N-methylpiperazine is added and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic layer is washed twice with water, dried over sodium sulfate and the solvent is removed under reduced pressure. Crystallization from ether gives 1.25 g (88%) of a colorless solid.

200 MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H), 1.59 (t, 3H), 1.88 (hex, 2H), 2.29 (s, 3H), 2.51 (m, 4H), 2.63 ( s, 3H), 3.00 (t, 2H), 3.08 (m, 4H), 4.33 (quart, 2H), 7.17 (d, 1H), 7.88 (dd, 1H), 8.44 (d, 1H), 9.75 (s, 1H).

Example 17

2- [2-Ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,4] triazin-4-one lactate

<img file="EE200000291A_D0085.tif" />

100 mg (0.211 mmol) of 2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4 The triazin-4-one is suspended in 5 ml of ether and mixed with 20 mg of 85% lactic acid in water. The mixture is stirred at room temperature for 10 minutes and evaporated to dryness. The residue is triturated with ether and suction filtered. 110 mg (92%) of 2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -5-methyl-7-propyl-3 H -imidazo [5,1-f] [1,2,4] are obtained. triazine-4-one lactate.

EE 200000291 Α

<td> 200</td><td>MHz ¹1 H-NMR (DMSO-d₆) 0,92</td><td>(t,</td><td>3H),</td><td>1.22 (d, 3H),</td><td>1.31 (t,</td>

<td>3H),</td><td>1.74 (m, 1H), 2.15 (s,</td><td>3H),</td><td> 2,38</td><td>(m, 4H), 2.81</td><td>(t, 2H),</td>

<td> 2,91</td><td>(m, 4H), 4.05 (quart,</td><td>IH),</td><td> 4,21</td><td>(quart, 2H),</td><td>7.40 (d,</td>

<td>IH),</td><td>7.85 (m, 2H), 11.71 (s,</td><td>wide,</td><td>IH).</td><td></td><td></td>

Example 18

2- [2-Ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one hydrochloride

<img file="EE200000291A_D0086.tif" />

100 mg (0.211 mmol) of 2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -5-methyl-7-propyl-37i-imidazo [5,1f] [1,2,4] triazin-4-one is suspended in 5 ml of diethyl ether, stirred

0.23 mL of 1M HCl in ether and stirred at room temperature for an additional 15 minutes. The solvent is removed under reduced pressure. 107 mg (97%) of 2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1f] [1,2,4] are obtained; ] triazine-4-one hydrochloride.

200 MHz ¹1 H-NMR (DMSO-d₆0.93 (t, 3H), 1.35 (t, 3H), 1.75 (sex, 2H), 2.72 (s, 3H), 2.86 (m, 4H), 3.15 ( m, 2H), 3.45 (m, 2H), 3.81 (m, 2H), 4.25 (quart, 2H), 7.45 (d, 1H), 7.95 (m,

2H), 11.39 (s, 1H), 11.90 (s, 1H).

EE 200000291 Α

Example 19

2- [2-Ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazole 5,1-f] [1,2,41-triazin-4-one

<img file="EE200000291A_D0087.tif" />

₁₅ h₃c

470 mg (1.14 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride are dissolved in In 20 ml of dicororethane and cooled to 0 ° C. 390 mg (3.42 mmol) of N-ethylpiperazine are added and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic layer is washed twice with water, dried over sodium sulfate and the solvent is removed under reduced pressure. Crystallization from diethyl ether gives

370 mg (66%) of a colorless solid.

400 MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H), 1.59 (t, 3H), 1.88 (hex, 2H), 2.42 (quart, 2H), 2.56 (m, 4H), 2.63 ( s, 3H), 3.00 (t, 2H), 3.10 (m, 4H), 4.33 (quart, 2H), 7.17 (d, 1H), 7.88 (dd, 1H), 8.44 (d, 1H), 9.75 (s, 1H).

EE 200000291 Α

Example 20

2- [2-Ethoxy-5- (4-ethyl-piperazin-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazor 5,1-f] -1,2,41-triazin-4-one hydrochloride

<img file="EE200000291A_D0088.tif" />

0.35 g (0.712 mmol) of 2- [2-Ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1 , 2,4] Triazin-4-one is suspended in 8 ml of ether and dichloromethane is added until a homogeneous solution is formed. 0.8 mL of 1M HCl in ether is added, the mixture is stirred at room temperature for 20 minutes and filtered under vacuum. 372 mg (99%) of 2- [2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] are obtained; ] triazin-4-one hydrochloride 25 di.

<td>200 MHz ¹H</td><td>-MR (DMSO-d₆)</td><td> 0,96</td><td>(t, 3H), 1.22 (t, 3H), 1.36</td><td>(t,</td>

<td>3H), 1.82</td><td>(sex, 2H), 2</td><td> ,61</td><td>(s, 3H), 2.88 (m, 2H), 3.08</td><td>(m,</td>

<td>6H), 3.50</td><td>(m, 2H), 3.70</td><td>(m,</td><td>2H), 4.25 (quart, 2H), 7.48</td><td>(d,</td>

<td>1H), 7.95</td><td>(m, 2H), 11.42</td><td>(s,</td><td>1H), 12.45 (s, 1H).</td><td></td>

Example 21 —F 2-Ethoxy-5- (4-methyl-1-aminopiperazine-1-sulfonyl) phenyl 5-methyl-7-propyl-3 H -imidazo [5,1-f] [1,2,4] triazine-4 -on h₃c-

<img file="EE200000291A_D0089.tif" />

N '.NH .N

By the same method, starting from 0.04 mg (0.097 mmol) of 4-ethoxy-3- (515 methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) benzenesulfonyl chloride and 0.03 mg (0.29 mmol) of 1-amino-4-methylpiperazine give 40 mg (83%) of 2- [2-ethoxy-5- (4-methyl-1-aminopiperazine-1-). sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.09 (dichloromethane / methanol 19: 1).

200 MHZ ¹1 H NMR (CDCl 3) 1.02 (t, 3H), 1.59 (t, 3H), 1.90 (sex,

2H), 2.22 (s, 3H), 2.40 (m, 4H), 2.62 (s, 3H), 2.71 (m, 4H), 3.00 (m, 2H), 4, 32 (quart, 2H), 7.14 (d, 1H), 8.05 (dd, 1H), 8.60 (d, 1H).

Example 22

2-R 2 -Ethoxy-5- (4-hydroxyethyl-1-aminopiperazine-1-sulfonyl) · phenyl 1-5-methyl-7-propyl-3β-imidazo [5,1-f] -1,2,41-triazine-4 · Oh

<img file="EE200000291A_D0090.tif" />

HO

By the same method, starting from 0.04 g (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 0.04 g (0.29 mmol) of 1-amino-4-hydroxyethylpiperazine give 46 mg (91%) of 25 [2-ethoxy-5- (4-hydroxyethyl-1-aminopiperazine-1-). sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one,

R_f = 0.08 (dichloromethane / methanol 19: 1).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.59 (t, 3H), 1.90 (sex,

2H), 2.49 (m, 6H), 2.62 (s, 3H), 2.71 (m, 4H), 3.00 (t, 2H), 3.55 (t, 2H), 4, 31 (quart, 2H), 7.14 (d, 1H), 8.05 (dd, 1H), 8.60 (d, 1H).

Example 23

N, N-Bishydroxyethylaminoethyl-4-ethoxy-3- (5-methyl- (4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,41-triazin-2-yl) -benzenesulfonamide

<img file="EE200000291A_D0091.tif" />

OH

OH

By the same method, starting from 0.04 g (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 0.043 g (0.29 mmol) of Ν, Ν-bishydroxyethylaminoethylamine give 46 mg (91%) of the title compound.

N, N-Bishydroxyethylaminoethyl-4-ethoxy-3- (5-methyl- (4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonate onamide.

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.53 (t, 3H), 1.70 (m,

2H), 1.86 (sex, 2H), 2.9 (m, 9H), 2.95 (t, 2H), 3.09 (t, 2H), 3.65 (t, 4H), 4, 28 (quart, 2H), 7.14 (d, 1H), 7.95 (dd, 1H),

8.35 (d, 1H).

Example 24

2- [2-Ethoxy-5- (4-dimethoxyphosphorylmethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0092.tif" />

By the same method, starting from 0.4 g (0.97 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] tri25 azin-2-yl) benzenesulfonyl chloride, 390 mg triethylamine and 0.86 g (2.99 mmol) of 4-dimethoxyphosphorylmethylpiperazine trifluoroacetate give 321 mg (53%) of 2- [2-ethoxy-5- (4-dimethoxyphosphorylmethylpiperazine-1-sulfonyl) ) phenyl] -5-methyl-7-propyl-3 H -imidazo [5,1- f] [1,2,4] triazin-4-one.

R_f = 0.4 (dichloromethane / methanol 20: 1).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.60 (t, 3H), 1.88 (sex, 2H), 2.62 (s, 3H), 2.75 (m, 4H), 3.02 ( t, 2H), 3.11 (m, 4H),

3.70 (s, 3H), 3.75 (s, 3H), 4.35 (quart, 2H), 5.30 (s, 2H),

7.18 (d, 1H), 7.88 (dd, 1H), 8.45 (d, 1H), 9.71 (s, 1H).

EE 200000291 Α

Example 25

2- {2-Ethoxy-5- (4-diethoxy-phosphorylmethyl-piperidine-1-sulfonyl) -phenyl-5-methyl-7-propyl-3'-imidazor-5,1-f [1,2,41-triazin-4-one

<img file="EE200000291A_D0093.tif" />

By the same method, starting from 0.4 g (0.97 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride and 0.86 g (3.7 mmol) of 4-diethoxyphosphorylmethylpiperidine to give 366 mg (49%) of 2- [2-ethoxy-5- (4-diethoxyphosphorylmethylpiperidine-1-sulfonyl) phenyl] -5- methyl 7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.4 (dichloromethane / methanol 20: 1).

200 MHZ ¹1 H-NMR (DMSO-d₆0.92 (t, 3H), 1.20 (t, 6H), 1.35 (t, 3H), 1.75 (m, 7H), 2.25 (m, 2H), 2.82 ( t, 2H), 3.61 (d, 2H),

3.95 (quin, 4H), 4.21 (quart, 2H), 7.38 (d, 1H), 7.87 (m, 2H), 11.70 (s, 1H).

EE 200000291Α

Example 26

2- {2-Ethoxy-5- (4-hydroxypiperidine-1-sulfonyl) -phenyl-5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0094.tif" />

By the same method, starting from 531 mg (1.29 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 393 mg (3.88 mmol) of 4-hydroxypiperidine give 400 mg (64%) of 2- [2-ethoxy-520 (4-hydroxypiperidine-1-sulfonyl) phenyl] -5-methyl-7 -propyl 3 H -imidazo [5,1-f] [1,2,4] triazin-4-one.

200 MHz ¹ 1 H-NMR (DMSO-d₆0.941 (t, 3H), 1.32 (t, 3H), 1.45 (m, 2H), 1.71 (m, 4H), 2.48 (s, 3H), 2.82 (m, 4H), 3.11 (m, 2H), 3.55 (m, 1H), 4.20 (quart, 2H), 4.72 (d, 1H), 7.39 (d, 1H),

7.87 (m, 2H), 11.70 (s, 1H).

Example 27

2- {2-Ethoxy-5- [4- (2-hydroxyethyl) piperazine-1-sulfonyl-phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,41] triazin-4-one

<img file="EE200000291A_D0095.tif" />

<img file="EE200000291A_D0096.tif" />

By the same method, starting from 411 mg (1 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-220-yl) benzenesulfonyl chloride and 391 mg (3 mmol) of 4-hydroxyethylpiperazine, 380 mg (75%) of 2- {2-ethoxy-5- [4- (2-hydroxyethyl) piperazine-1-sulfonyl] phenyl} -5-methyl-7- propyl 3 H -imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.198 (95: 5 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.61 (t, 3H), 1.87 (hex, 3H), 2.60 (m, 7H), 3.00 (t, 2H), 3.10 (m, 4H), 3.60 (t, 2H), 4.36 (quart, 2H), 7.18 (d, 1H), 7.89 (dd, 1H), 8.47 (d, 1H) , 9.71 (s, 1H).

EE 200000291 Α

Example 28

2- {2-Ethoxy-5- [4- (2-hydroxyethyl) piperazine-1-sulfonyl] phenyl] -5-methyl-4-propyl-5'-imidazor5,1'-1,2,4,4-triazin-4-one hydrochloride

<img file="EE200000291A_D0097.tif" />

200 mg (0.39 mmol) of 2- {2-ethoxy-5- [4- (2-hydroxyethyl) -piperidine-1-sulfonyl] phenyl} -5-methyl-7-propyl-3H-imidazo [5,1f] [1,2,4] Triazin-4-one is suspended in ether, mixed with 2 ml of 1M HCl in ether and stirred at room temperature for 20 minutes. The solvent is removed to give 209 mg (100%) of 2- {2-ethoxy-5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-25-propyl-3H-imidazo [5.1f] [ 1,2,4] Triazin-4-one hydrochloride.

200 MHz ¹1 H-NMR (DMSO-d₆) 0.96 (t, 3H), 1.35 (t, 3H), 1.70 (hex, 2H), 2.59 (s, 3H), 2.85 (t, 2H), 2.99 ( t, 2H), 3.18 (m, 4H), 3.59 (d, 2H), 3.75 (m, 4H), 4.25 (quart, 2H), 7.49 (d,

1H), 7.95 (m, 2H), 10.62 (s, 1H), 12.31 (s, 1H).

EE 200000291 Α

Example 29

2- {2-Ethoxy-5- [4- (3-hydroxypropyl) piperazine-1-sulfonyl ·} phenyl} -5-methyl-7-propyl -3 H -imidazo [5,1-f] -1,2,4} triazine -4oon

<img file="EE200000291A_D0098.tif" />

By the same method, starting from 150 mg (0.37 mmol) of 4-ethoxy-3- (520 methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) benzenesulfonyl chloride and 158 mg (1.09 mmol)

4- (3-Hydroxypropyl) piperazine gives 167 mg (83%) of 2- {2-ethoxy-5- [4- (3-hydroxypropyl) piperazine-1-sulfonyl] phenyl} -5-methyl-7-propyl-3H - imidazo [5,1-f] [1,2,4] triazine-425 one.

<td>Rf =</td><td>0.52 (dichloromethane / methanol 10:</td><td> 1) -</td><td></td><td></td><td></td>

<td> 200</td><td>MHz @ 1 H NMR (CDCl3₃) 1.02 (t, 3H),</td><td> 1,61</td><td>(t, 3H),</td><td> 1,70</td><td>(m,</td>

<td>5H),</td><td>2.62 (m, 8H), 3.00 (t, 2H), 3.10</td><td>(m,</td><td>4H), 3.72</td><td>(t,</td><td>2H),</td>

<td> 4,36</td><td>(quart, 2H), 7.18 (d, 1H), 7.89</td><td>(dd,</td><td>1H), 8.47</td><td>(d,</td><td>IH),</td>

<td> 9,71</td><td>(s, 1H).</td><td></td><td></td><td></td><td></td>

EE 200000291 Α β

Example 30

N-Allyl-4-ethoxy-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazor 5,1-f) -1,2,41-triazin-2-yl) benzenesulfonamide

<img file="EE200000291A_D0099.tif" />

By the same method, starting from 420 mg (1.02 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] ] triazin-2-yl) benzenesulfonyl chloride and 300 mg (3 mmol) of allylhydroxyethylamine give 400 mg (82%) of N-allyl-4-ethoxy-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7) -propyl-3,420 dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonamide.

<td>R_f =</td><td> 0,345</td><td>(dichloromethane / methanol 95: 5).</td><td></td><td></td><td></td>

<td> 200</td><td>MHZ ¹H</td><td>-TMR (CDCl₃) 1.02 (t, 3H), 1.61</td><td>(t, 3H),</td><td> 1,90</td><td>(m,</td>

<td>2H),</td><td> 2,22</td><td>(s, broad, 1H), 2.62 (s, 3H), 2.99</td><td>(t, 2H),</td><td> 3,31</td><td>(t,</td>

<td>2H),</td><td> 3,78</td><td colspan="2">(t, 2H), 3.92 (d, 2H), 4.37 (quart, 2H),</td><td> 5,23</td><td>(m,</td>

<td>2H),</td><td> 5,71</td><td>(m, 1H), 7.15 (d, 1H), 7.98 (dd,</td><td>1H), 8.56</td><td>(d,</td><td>IH),</td>

<td> 9,66</td><td>(S, 1]</td><td>H).</td><td></td><td></td><td></td>

Example 31

N-Ethyl-4-ethoxy-N- (2-hydroxyethyl) -3- [5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2- yl) benzenesulfonamide

<img file="EE200000291A_D0100.tif" />

By the same method, starting from 411 mg (1.0 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 267 mg (3 mmol) of ethyl hydroxyethylamine give 325 mg (70%) of N-ethyl-4-ethoxy-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl). 3,420 dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonamide.

R_f = 0.29 (95: 5 dichloromethane / methanol).

200 MHz ¹1 H NMR (CDCl 3 1.02 (t, 3H), 1.20 (t, 3H), 1.61 (t

3H), 1.88 (sex, 2H), 2.30 (s, broad, 1H), 2.62 (s, 3H), 2.99 (t, 2H), 3.32 (m, 4H), 3.78 (t, 2H), 3.80 (m, 2H), 4.37 (quart, 2H), 7.15 (d, 1H), 7.98 (dd, 1H), 8.56 (d) , 1H), 9.70 (s, 1H).

EE 200000291 Α

Example 32

N, N-Diethyl-4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,41-triazin-2-yl) benzenesulfonamide

<img file="EE200000291A_D0101.tif" />

ch₃ ch₃

By the same method, starting from 400 mg (0.97 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] ] triazin-2-yl) benzenesulfonyl chloride and 210 mg (2.92 mmol) of diethylamine, 398 mg (89%) of N, N-diethyl-4-ethoxy-3- (5-methyl-4-oxo-7-propyl) are obtained. 3,4-dihydroimidazo [5,1- f] [1,2,4] triazin-2-yl) benzenesulfonamide.

<td>20 Rs_f =</td><td>0.49 (dichloromethane / methanol</td><td> 20 :</td><td> 1) ·</td><td></td><td></td><td></td><td></td>

<td> 200</td><td>MHz 1 H-NMR (CDCl 3₃) 1.02 (t,</td><td>3H),</td><td> 1,20</td><td>(t,</td><td>6H),]</td><td>L, 49</td><td>(s),</td>

<td> 1,61</td><td>(t, 3H), 1.88 (sex, 2H),</td><td> 2,30</td><td>(s,</td><td>wide,</td><td>IH),</td><td> 2,62</td><td>(s,</td>

<td>3H),</td><td>2.99 (t, 2H), 3.32 (m, 4H),</td><td> 3,78</td><td>(t,</td><td>2H),</td><td> 3,80</td><td>(m,</td><td>2H),</td>

<td> 4,37</td><td>(quart, 2H), 7.15 (d, 1H),</td><td> 7,98</td><td>(dd,</td><td>IH),</td><td> 8,56</td><td>(d,</td><td>IH),</td>

<td> 25 9,70</td><td>(s, 1H).</td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 33

N- (2-Methoxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazor, 1 - [[1,2,4] triazin-2-yl) -4-ethoxybenzenesulfonamide

<img file="EE200000291A_D0102.tif" />

EE 200000291 Α

9/

By the same method, starting with 1.23 g (3 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazin-2-yl). Benzenesulfonyl chloride and 680 mg (9 mmol) of 2-methoxyethylamine give 900 mg (67%) of N- (2-methoxyethyl) -3- (55-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5.1f] ] [1,2,4] triazin-2-yl) -4-ethoxybenzenesulfonamide.

R_f = 0.25 (95: 5 dichloromethane / methanol).

400 MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H), 1.58 (t, 3H), 1.88 (sex, 2H), 2.62 (s, 3H), 3.01 (t, 2H), 3.18 ( quart, 2H), 3.30 (s,

3H), 3.45 (t, 2H), 4.32 (quart, 2H), 5.12 (t, 1H), 7.13 (d,

1H), 7.97 (dd, 1H), 8.53 (d, 1H), 9.82 (s, 1H).

Example 34

N- (2-N, N-dimethylethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-di¹⁵ hydroimidazo [5,1f] [1,2,41 triazin-2-yl) -4-ethoxybenzenesulfonamide

<img file="EE200000291A_D0103.tif" />

By the same method, starting from 210 mg (0.49 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 130 mg (9 mmol) of 230 N, N-dimethylethylamine give 150 mg (59%) of N- (2-N, N-dimethylethyl) -3- (5-methyl-4-oxo-7) -propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazin-2-yl) -4-ethoxybenzenesulfonamide.

200 MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H), 1.62 (m, 4H), 1.88 (sex,

2H), 2.11 (s, 6H), 2.39 (t, 2H), 2.63 (s, 3H), 3.01 (m, 3H),

4.38 (quart, 2H), 7.13 (d, 1H), 7.97 (dd, 1H), 8.53 (d, 1H), 9.82 (s, 1H).

EE 200000291Α

Example 35

N- [3- (1-Morpholino) propyl] -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] -1,2,4-triazin-2-yl) -4-ethoxybenzenesulfonamide

<img file="EE200000291A_D0104.tif" />

By the same method, starting from 1.23 g (3 mmol) of 4-ethoxy-3- (5-methyl-15 4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine -2-yl) benzenesulfonyl chloride and 1.3 g (9 mmol) of 3- (1-morpholino) propylamine give 1.38 g (88%) of N- [3- (1-morpholino) propyl] -3- (5-methyl) -4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-ethoxybenzenesulfonamide.

R_f = 0.23 (95: 5 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H), 1.58 (t, 3H), 1.72 (m,

2H), 1.88 (sex, 2H), 2.46 (m, 6H), 2.62 (s, 3H), 3.01 (t,

2H), 3.15 (t, 2H), 3.71 (t, 4H), 4.32 (quart, 2H), 7.13 (d,

1H), 7.97 (dd, 1H), 8.53 (d, 1H), 9.79 (s, 1H).

Example 36

N- {3- [1- (4-methyl) piperazino) propyl] -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] -1,2,4] triazine-2- yl) -4-ethoxybenzenesulfonamide

<img file="EE200000291A_D0105.tif" />

EE 200000291Α

By the same method, starting from 0.04 g (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 0.05 g (0.29 mmol)

3- [1- (4-methyl) piperazino] propylamine gives 0.04 g of 5 (77%) of N- {3- [1- (4-methyl) piperazino] propyl} -3- (5-methyl-4 -oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) 4-ethoxybenzenesulfonamide.

R_f = 0.11 (dichloromethane / methanol 95: 5).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H), 1.55 (t, 3H), 1.68 (m,

2H), 1.88 (sex, 2H), 2.27 (s, 3H), 2.45 (m, 8H), 2.62 (s,

3H), 2.98 (m, 3H), 3.10 (t, 2H), 3.46 (s, 1H), 4.30 (quart,

2H), 7.13 (d, 1H), 7.97 (dd, 1H), 8.53 (d, 1H).

Example 37 ¹⁵ 2-Ethoxy-5- {4- (2-methoxy-ethyl) -piperazine-1-sulfonyl-1-phenyl} -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0106.tif" />

By the same method, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2-one. yl) benzenesulfonyl chloride and 40 mg (0.29 mmol) 4-methoxyethylpiperazine give 50 mg (99%) of 2- {2-ethoxy35 5- [4- (2-methoxyethyl) piperazine-1-sulfonyl] phenyl} -5-methyl7 -propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.27 (95: 5 dichloromethane / methanol).

EE 200000291 Α

100

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.61 (t, 3H), 1.87 (hex,

3H), 2.60 (m, 9H), 2.97 (t, 2H), 3.10 (m, 4H), 3.60 (s, 3H),

3.46 (t, 2H), 4.36 (quart, 2H), 7.18 (d, 1H), 7.89 (dd, 1H),

8.47 (d, 1H), 9.71 (s, 1H).

Example 38

2- {2-Ethoxy-5- [4- (2-N, N-dimethylethyl) piperazine-1-sulfonyl] phenyl} -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,4] triazin-4-one

<img file="EE200000291A_D0107.tif" />

h₃c ch₃

By the same method, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] tri25 azine -2-yl) benzenesulfonyl chloride and 50 mg (0.29 mmol) of 4- (2-N, N-dimethyl) ethylpiperazine give 50 mg (99%) of 2- {2-ethoxy-5- [4- (2-N, N-dimethylethyl) piperazine-1-sulfonyl] phenyl} -5-methyl-7-propyl-3 H -imidazo [5,1- f] [1,2,4] triazin-4-one.

R_f = 0.11 (dichloromethane / methanol 95: 5).

<td colspan="3">200 MHZ ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.61 (t, 3H), 1.87 (hex,</td>

<td>3H),</td><td>2.20 (s,</td><td>6H), 2.42 (m, 4H), 2.58 (m, 4H), 2.63 (s, 3H),</td>

<td> 2,99</td><td>(m, 3H),</td><td>3.10 (m, 4H), 4.36 (quart, 2H), 7.18 (d, 1H),</td>

<td> 7,89</td><td>(dd, 1H),</td><td>8.47 (d, 1H), 9.71 (s, 1H).</td>

EE 200000291 Α

101

Example 39

2- [2-Ethoxy-5- [4- (3-N, N-dimethyl-propyl) -piperazine-1-sulfonyl] -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,41-triazine -4

<img file="EE200000291A_D0108.tif" />

CH₃

By the same method, starting from 100 mg (0.243 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2-one. yl) benzenesulfonyl chloride and 130 mg (0.73 mmol) 4- (3-N, N-dimethyl) propylpiperazine give 72 mg (54%) of 2- {2-ethoxy-5- [4- (3-N, N) -dimethylpropyl) piperazine-1-sulfonylphenyl] phenyl} -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.08 (95: 5 dichloromethane / methanol).

200 MHz @ 1 H NMR (CDCl3₃) 1.02 (t, 3H), 1.61 (t, 3H), 1.87 (sex, 3H), 2.20 (s, 6H), 2.25 (m, 2H), 2.38 ( t, 2H), 2.52 (m, 4H),

2.63 (s, 3H), 2.99 (m, 6H), 4.33 (quart, 2H), 7.18 (d, 1H), 7.89 (dd, 1H), 8.47 (d) , 1H), 9.71 (s, 1H).

102

Example 40

2- [2-Ethoxy-5- (4-dioxolanopiperidine-1-sulfonyl) -phenyl-5-methyl-7-prapyl-3H-imidazor 5,1-f] [1,2,4] triazin-4-one

<img file="EE200000291A_D0109.tif" />

By the same method, starting from 100 mg (0.243 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2-one. yl) benzenesulfonyl chloride and 100 mg (0.73 mmol) of 4-dioxolanopiperidine to give 111 mg (88%) of 2- [2-ethoxy20 5- (4-dioxolanopiperidine-1-sulfonyl) phenyl] -5-methyl-7-propyl -3β-imidazo [5,1-f] [1,2,4] triazin-4-one.

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.61 (t, 3H), 1.80 (m,

6H), 2.63 (s, 3H), 2.99 (t, 2H), 3.20 (m, 4H), 3.90 (s, 4H), 4.33 (quart, 2H), 7, 18 (d, 1H), 7.89 (dd, 1H), 8.47 (d, 1H),

9.71 (s, 1H).

103

Example 41

2- [2-Ethoxy-5- (4- (5-methyl-4-furoxanecarbonyl) piperazine-1sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazine-4-one

<img file="EE200000291A_D0110.tif" />

410 mg (1.0 mmol) 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) -benzenesulfonyl20 chloride is dissolved in 10 ml of dichloromethane and cooled to 0 ° C. 590 mg (2.00 mmol) of 1- (5-methyl-4-furoxanecarbonyl) piperazine trifluoroacetate and 400 mg of triethylamine are added and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic layer is washed with ammonium chloride solution, 1M hydrochloric acid and water, dried over sodium sulfate and the solvent is removed under reduced pressure. Crystallization from ether gives 448 mg (74%) of a colorless solid.

<td colspan="4">200 MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H), 1.59 (t, 3H), 1.88 (hex,</td>

<td>30 2H),</td><td>2.25 (s,</td><td>3H), 2.63 (s, 3H), 3.00 (t, 2H), 3.20</td><td>(m, 4H),</td>

<td> 3,90</td><td>(m, 2H),</td><td>4.02 (m, 2H), 4.33 (quart, 2H), 7.19</td><td>(d, 1H),</td>

<td> 7,89</td><td>(dd, 1H),</td><td>8.48 (d, 1H), 9.57 (s, 1H).</td><td></td>

104

Example 42

2- (2-Ethoxy-5- [4-acetyl-piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one

<img file="EE200000291A_D0111.tif" />

By the same method, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2-one. yl) benzenesulfonyl chloride and 40 mg (0.29 mmol) N 2 O-acetylpiperazine give 9 mg (18%) of 2- {2-ethoxy-5- [4-acetyl-piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.34 (95: 5 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.61 (t, 3H), 1.87 (sex,

3H), 2.05 (s, 3H), 2.63 (s, 3H), 3.00 (m, 6H), 3.59 (m, 2H), 3.72 (m, 2H), 4, 33 (quart, 2H), 7.18 (d, 1H), 7.89 (dd, 1H),

8.47 (d, 1H), 9.71 (s, 1H).

EE 200000291Α

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Example 43

2- {2-Ethoxy-5- [4-formyl-piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazor 5,1-f [1,2,41-triazin-4-one

<img file="EE200000291A_D0112.tif" />

By the same method, starting from 40 mg (0.097 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazine-2- yl) benzenesulfonyl chloride and 30 mg (0.29 mmol) of N 2 O-formylpiperazine give 35 mg (73%) of 2- {2-ethoxy-5- [4-formyl-piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,11f] [1,2,4] Triazin-4-one.

R_f = 0.29 (95: 5 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.61 (t, 3H), 1.87 (sex,

3H), 2.05 (s, 3H), 2.63 (s, 3H), 3.00 (m, 6H), 3.50 (m, 2H), 3.69 (m, 2H), 4, 33 (quart, 2H), 7.18 (d, 1H), 7.89 (dd, 1H), 8.00 (s, 1H), 8.47 (d, 1H), 9.71 (s, 1H) ).

EE 200000291 Α

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Example 44

2- [2-Ethoxy-5- (3-butylsulfonimine) -1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0113.tif" />

110 Dissolve 3 mg (0.6 mmol) of 3-butylsidonimine hydrochloride in 2.5 ml of pyridine and cool to 0 ° C. 210 mg (0.5 mmol) of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2 are added. -yl) benzenesulfonyl chloride, the reaction mixture is stirred at temperature

0 ° C for 2 hours and at room temperature overnight. The mixture is diluted with dichloromethane, the organic layer is washed with water, dried over sodium sulfate and the solvent is removed under reduced pressure. Chromatography (dichloromethane / methanol) yields 16 mg (6%) of 2- [2-ethoxy-5- (3-butylsidonimine) -1-sulfonyl) phenyl] 5-methyl-7-propyl-3H-imidazo [5 1-f] [1,2,4] triazin-4-one.

R_f = 0.41 (95: 5 dichloromethane / methanol).

200 MHZ ¹1 H-NMR (CDCl 3₃) 1.01 (2h, 6H), 1.47 (sex, 2H), 1.55 (t,

3H), 1.88 (m, 2H), 2.04 (quin, 2H), 2.62 (s, 3H), 2.98 (t,

2H), 4.29 (quart, 2H), 4.41 (t, 2H), 7.08 (d, 1H), 7.56 (s,

1H), 7.98 (dd, 1H), 8.58 (d, 1H), 9.79 (s, broad, 1H).

107

Example 45

5-Methyl-2- [5- (4-methyl-piperazine-1-sulfonyl) -2-propoxy-phenyl] -7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one

<img file="EE200000291A_D0114.tif" />

0.85 g (2 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) Dissolve the benzenesulfonyl chloride in 20 ml of dichloromethane and cool to 0 ° C. After the addition of DMAP at the spatula tip, 0.60 g (6.00 mmol) of N-methylpiperazine is added and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic layer is washed with ammonium chloride solution, dried over sodium sulfate and the solvent is removed under reduced pressure. Crystallization from ether gives 0.80 g (77%) of a colorless solid.

R_f = 0.233 (95: 5 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.00 (t, 3H), 1.15 (t, 3H), 1.87 (hex,

2H), 1.99 (hex, 2H), 2.30 (s, 3H), 2.52 (m, H4), 2.62 (s,

3H), 2.99 (t, 2H), 3.10 (m, 4H), 4.21 (t, 2H), 7.17 (d, 1H),

7.87 (dd, 1H), 8.48 (d, 1H), 9.70 (s, 1H).

108

Example 46

5-Methyl-2- [5- (4-methylpiperazine-1-sulfonyl) -2-propoxyphenyl] -7-propyl-3 H -imidazo [5,1-f] [1,2,4] triazin-4-one hydrochloride

<img file="EE200000291A_D0115.tif" />

mg (0.045 mmol) of 5-methyl-2- [5- (4-methylpiperazine-1-sulfonyl) -2-propoxyphenyl] -7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one is dissolved in 2 mL ether and 1 mL dichloromethane and mixed with 0.1 mL 1M HCl in ether. After 20 minutes, the precipitate is filtered off with suction and dried.

200 MHz ¹1 H-NMR (CDCl 3₃) 0.95 (t, 3H), 1.75 (m, 2H), 2.56 (s,

3H), 2.75 (m, 4H), 2.97 (t, 2H), 3.15 (m, 2H), 3.44 (m, 2H), 3.81 (m, 2H), 4, 15 (t, 2H), 7.47 (d, 1H), 7.95 (m, 2H), 11.12 (s, 1H), 12.22 (s, 1H).

Example 47

2- [5- (4-Hydroxypiperidine-1-sulfonyl) -2-propoxyphenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0116.tif" />

OH

EE 200000291Α

109

By the same method, starting from 850 mg (2 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 610 mg (6 mmol) of 4-hydroxypiperidine give 736 mg (75%) of 2- [5- (4-hydroxy-5-piperidin-1-sulfonyl) -2-propoxyphenyl] -5-methyl-7-propyl- 3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.07 (95: 5 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H), 1.16 (t, 3H), 1.80 (m, 9H), 2.65 (s, 3H), 3.00 (m, 4H), 3.32 ( m, 2H), 3.85 (m, 1H),

4.22 (t, 2H), 7.17 (d, 1H), 7.89 (dd, 1H), 8.50 (d, 1H), 11.70 (s, 1H).

Example 48

- [5- (4-Hydroxymethyl-1β-iperidine-1-sulfonyl) -2-propoxy¹⁵ phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,4-triazin-4-one

<img file="EE200000291A_D0117.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] ] triazin-2-yl) benzenesulfonyl chloride and 35 mg (0.3 mmol) of 4-hydroxymethylpiperidine, 41 mg (82%) of 2- [5- (4-hydroxymethylpiperidine-1-sulfonyl) -2-propoxyphenyl] -5-methyl propyl 3 H -imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.52 (9: 1 dichloromethane / methanol).

200 MHZ ¹ 1 H-NMR (CDCl 3₃) 1.001 (t, 3H), 1.16 (t, 3H), 1.60 (m, 4H), 1.82 (m, 5H), 2.31 (t, 2H), 2.62 (s, 3H), 2.98 (t, 2H),

EE 200000291 Α

110

3.48 (d, 2H), 3.85 (d, 2H), 4.21 (t, 2H), 7.17 (d, 1H), 7.88 (dd, 1H), 8.45 (d) , 1H), 9.71 (s, 1H).

Example 49

2- {5- [4- (2-Hydroxyethyl) piperazine-1-sulfonyl] -2-propoxyphenyl} · -5-methyl-7-propyl-3H-imidazor 5,1-fl [1,2,4 ] triazine-4oon

<img file="EE200000291A_D0118.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazine-2- yl) benzenesulfonyl chloride and 39 mg (0.3 mmol) of 4-hydroxymethylpiperazine give 50 mg (96%) of 2- {5- [4- (2-hydroxyethyl) piperazine-1-sulfonyl] -2-propoxyphenyl} -5-methyl-7 -propyl-3β-imidazo [5,1f] [1,2,4] triazin-4-one.

<td>^Rf =</td><td>0.43 (dichloromethane / meth:</td><td>anol</td><td> 9:1).</td><td></td><td></td><td></td>

<td> 200</td><td>MHz @ 1 H NMR (CDCl3₃) 1,01</td><td>(t,</td><td>3H), 1.15</td><td>(t,</td><td>3H),</td><td>1.88 (m,</td>

<td>2H),</td><td>2.00 (m, 2H), 2.62 (m,</td><td>9H),</td><td>3.00 (t,</td><td>2H),</td><td> 3,07</td><td>(m, 4H),</td>

<td> 3,58</td><td>(t, 2H), 4.23 (t, 2H),</td><td> 7,19</td><td>(d, 1H),</td><td> 7,88</td><td>(dd,</td><td>1H), 8.43</td>

<td>(d,</td><td>1H), 9.85 (s, 1H).</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

111

Example 50

N- (1,1-dioxotetrahydro-1α)⁶-thiophen-3-yl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] -1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide

<img file="EE200000291A_D0119.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 41 mg (0.3 mmol) of 220 aminosulfolane give 8 mg (14%) of N- (1,1-dioxotetrahydro-1⁶-thiophen-3-yl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) - 4-Propoxybenzenesulfonamide.

R_f = 0.49 (dichloromethane / methanol 9: 1).

<td> 25 200</td><td>MHz</td><td>¹1 H-NMR</td><td>(CDCl3) 1.01</td><td>(t,</td><td>3H),</td><td> 1,15</td><td>(t,</td><td>3H),</td><td> 1,85</td><td>(m</td>

<td>2H),</td><td colspan="2">1.99 (m,</td><td>2H), 2.30 (m,</td><td>IH),</td><td> 2,50</td><td>(m,</td><td>IH),</td><td> 2,62</td><td>(s,</td><td>3H)</td>

<td> 2,95</td><td>(m,</td><td>4H),</td><td>3.21 (m, 1H),</td><td> 4,20</td><td>(m,</td><td>3H),</td><td> 5,98</td><td>(s,</td><td>IH),</td><td>7, Γ</td>

<td>(d,</td><td>IH),</td><td> 7,98</td><td>(dd, 1H), 8.51</td><td>(d,</td><td>IH),</td><td> 9,71</td><td>(s,</td><td>IH).</td><td></td><td></td>

EE 200000291 Α

112

Example 51

N- (2-Dimethylaminoethyl) -N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] -1,2,4 L triazin-2-yl. ) -4-Propoxybenzenesulfonamide

<img file="EE200000291A_D0120.tif" />

I ch₃

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 31 mg (0.3 mmol) of 1,1,4-trimethyldiaminoethane give 39 mg (79%) of N- (2-dimethylaminoethyl) -N-methyl-3- (5-methyl-4- oxo-7-propyl-3,42o dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide.

R_f 0.28 (9: 1 dichloromethane / methanol).

<td> 200</td><td>MHz</td><td>¹1 H-NMR</td><td>(CDCl₃) 1,01</td><td>(t,</td><td>3H),</td><td> 1,15</td><td>(t,</td><td>3H),</td><td> 1,88</td><td>(m</td>

<td>2H),</td><td colspan="2">2.01 (m,</td><td>2H), 2.25 (s,</td><td>6H),</td><td> 2,50</td><td>(t,</td><td>2H),</td><td> 2,62</td><td>(s,</td><td>3H)</td>

<td> 25 2,82</td><td>(s,</td><td>3H),</td><td>3.01 (t, 2H),</td><td> 3,18</td><td>(t,</td><td>2H),</td><td> 4,21</td><td>(t,</td><td>2H),</td><td> 7,1'</td>

<td>(d,</td><td>IH),</td><td> 7,91</td><td>(dd, 1H), 8.50</td><td>(d,</td><td>IH),</td><td> 9,70</td><td>(s,</td><td>IH).</td><td></td><td></td>

Example 52

3- (5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] 1,2,4-l) ³⁰ Triazin-2-yl) -N- (3-morpholin-4-ylpropyl) -4-propoxybenzenesulfonamide

<img file="EE200000291A_D0121.tif" />

EE 200000291 Α, 13

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 43 mg (0.3 mmol) of 1- (3-aminopropyl) morpholine, 52 mg (97%) of 3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo) are obtained. [5,1-f] [1,2,4] triazin-2-yl) -N- (3-morpholin-4-ylpropyl) -4-propoxybenzenesulfonamide.

R_f = 0.33 (9: 1 dichloromethane / methanol).

<td> 200</td><td>MHz ¹1 H-NMR</td><td>(CD '</td><td>Cl₃) 1,01</td><td>(t,</td><td>3H),</td><td> 1,15</td><td>(t,</td><td>3H),</td><td>1.71 (m,</td>

<td>10 2H),</td><td>1.93 (m,</td><td>4H),</td><td>2.43 (m,</td><td>6H),</td><td> 2,62</td><td>(s,</td><td>3H),</td><td> 2,98</td><td>(t, 2H),</td>

<td> 3,12</td><td>(t, 2H),</td><td> 3,70</td><td>(m, 4H),</td><td> 4,21</td><td>(t,</td><td>2H),</td><td> 7,15</td><td>(d,</td><td>1H), 7.96</td>

<td>(dd,</td><td>1H), 8, 55</td><td>(d,</td><td>1H), 9.85</td><td>(s,</td><td>IH).</td><td></td><td></td><td></td><td></td>

Example 53 ¹⁵ N, N-Bis- (2-Hydroxyethyl) -3- (5-methyl-4-oxo-7- propyl-3,4-dihydroimidazo [5,1- f] -1,2,41-triazin-2-yl) -4-propoxybenzenesulfonamide

<img file="EE200000291A_D0122.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] tri30 azin-2-yl) benzenesulfonyl chloride and 32 mg (0.3 mmol) of bishydroxyethylamine give 34 mg (69%) of N, N-bis- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7) -propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide. R_f = 0.36 (9: 1 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H), 1.15 (t, 3H), 1.85 (m, 2H), 1.97 (m, 2H), 2.60 (s, 3H), 2.98 ( t, 2H), 3.33 (t, 4H),

EE 200000291 Α

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3.87 (t, 4H), 4.20 (t, 2H), 7.15 (d, 1H), 7.92 (dd, 1H), 8.49 (d, 1H), 9.85 (s , 1H).

Example 54

N- (3-Hydroxybenzyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] -1,2,41-triazin-2-yl) -4-propoxybenzenesulfonamide

<img file="EE200000291A_D0123.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -benzenesulfonyl chloride and 37 mg (0.3 mmol) of 3-hydroxybenzylamine give 4 mg (8%) of N- (3-hydroxybenzyl) -3- (5-methyl-4-oxo-7-propyl-3). , 4-Dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide.

R_f = 0.43 (9: 1 dichloromethane / methanol).

<td> 200</td><td>MHz ¹1 H-NMR</td><td>(CDCl3) 1.01</td><td>(t,</td><td>3H), 1.13</td><td>(t,</td><td>3H),</td><td>1.83 (m,</td>

<td>2H),</td><td>1.96 (m,</td><td>2H), 2.59 (s,</td><td>3H),</td><td>2.96 (t,</td><td>2H),</td><td> 4,16</td><td>(m, 4H),</td>

<td> 30 5,05</td><td>(t, 1H),</td><td>6.52 (s, 1H),</td><td> 6,70</td><td>(m, 2H),</td><td> 7,06</td><td>(m,</td><td>2H), 7.93</td>

<td>(dd,</td><td>1H), 8.41</td><td>(d, 1H), 9.77</td><td>(s,</td><td>IH).</td><td></td><td></td><td></td>

115

Example 55

N-Ethyl-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4 -propoxy-benzenesulfonamide

<img file="EE200000291A_D0124.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] Triazin-2-yl) -benzenesulfonyl chloride and 27 mg (0.3 mmol) of ethyl hydroxyethylamine give 18 mg (38%) of N-ethyl-N 2 O (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl). -3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide.

R_f = 0.48 (dichloromethane / methanol 9: 1).

<td> 200</td><td>MHz ¹i</td><td>1 H-NMR (CDCl 3) 1</td><td> ,01</td><td>(t, 3H), 1.15</td><td>(2h,</td><td>6H),</td><td>1.75 (s,</td>

<td>2H),</td><td> 1,85</td><td>(m, 2H), 1.98</td><td>(m,</td><td>2H), 2.40 (s,</td><td>IH),</td><td> 2,62</td><td>(s, 3H),</td>

<td> 2,99</td><td>(t,</td><td>2H), 3.32 (m,</td><td>4H),</td><td>3.90 (quart,</td><td>2H),</td><td> 4,21</td><td>(quart,</td>

<td>2H),</td><td> 7,15</td><td>(d, 1H), 7.95</td><td>(dd,</td><td>1H), 8.55 (d,</td><td>IH),</td><td> 9,73</td><td>(s, 1H).</td>

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Example 56

N- (3-Ethoxypropyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] -1,2,41-triazin-2-yl) -4-propoxybenzenesulfonamide

<img file="EE200000291A_D0125.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] ] triazin-2-yl) benzenesulfonyl chloride and 31 mg (0.3 mmol) of 3-ethoxypropylamine, 47 mg (96%) of N- (3-ethoxypropyl) -3- (5-methyl-4-oxo-7-propyl-3) are obtained. , 4-Dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide.

R_f = 0.60 (9: 1 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl₃) 1.01 (t, 3H), 1.15 (m, 6H), 1.89 (m, 7H), 2.62 (s, 3H), 3.00 (t, 2H), 3.12 ( quart, 2H), 3.46 (m, 4H), 4.20 (t, 2H), 5.52 (m, 1H), 7.15 (d, 1H), 7.98 (dd, 1H), 8.55 (d, 1H), 9.85 (s, 1H).

117

Example 57

- Γ 5- (4-Hydroxypiperidine-1-sulfonyl) -2-propoxyphenyl-5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0126.tif" />

By the same method, starting from 212 mg (0.5 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 152 mg (1.5 mmol) of 4-hydroxypiperidine give 125 mg (50%) of 2- [5- (4-hydroxypiperidine-1-sulfonyl) -2-propoxyphenyl] -5-methyl-7-propyl20 3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f 0.07 (19: 1 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃1.05 (t, 3H), 1.18 (t, 3H), 1.98 (m, 8H), 2.71 (s, 3H), 3.10 (m, 2H), 3.28 ( m, 4H), 3.88 (m, 1H), 4.28 (t, 2H), 7.21 (d, 1H), 7.97 (dd, 1H), 8.45 (d, 1H), 10.45 (s, 1H).

Example 58

3- (5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f) [1,2,4] triazin-2-yl) -4-propoxy-N-pyridin-4-yl-benzenesulf onamide

<img file="EE200000291A_D0127.tif" />

o

118

By the same method, starting from 85 mg (0.2 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride and 56 mg (0.6 mmol) of 4-aminopyridine, 24 mg (25%) of 3- (5-methyl-4-oxo-7-propyl-3) are obtained after heating at reflux for 1 hour in 1 ml of THF. 4-Dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxy-N-pyridin-4-yl-benzenesulfonamide.

R_f = 0.13 (9: 1 dichloromethane / methanol).

<td> 200</td><td>MHz ¹1 H-NMR</td><td colspan="2">(CDCl₃ +</td><td>cd₃od)</td><td> 1,</td><td>01 (t, 3H),</td><td> 1,09</td><td>(t,</td><td>3H), 1.90</td>

<td>io (m,</td><td>4H), 2.60</td><td>(s,</td><td>3H),</td><td> 2,99</td><td>(i.e.</td><td>, 2H), 4.16</td><td>(t,</td><td>2H),</td><td>7.05 (d,</td>

<td>2H)</td><td>, 7.15 (d,</td><td>IH),</td><td> 7,88</td><td colspan="2">(d, 2H),</td><td>, 8.05 (dd,</td><td>IH),</td><td> 8,41</td><td>(d, 1H).</td>

Example 59

N, N-Diethyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo¹⁵ [5,1-f] [1,2,4] Triazin-2-yl) -4-propoxybenzenesulfonamide

<img file="EE200000291A_D0128.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 22 mg (0.6 mmol) of diethylamine give 42 mg (92%) of N, N-diethyl-3- (5-methyl-430 oxo-7-propyl-3,4-dihydroimidazo [5 , 1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide.

R_f = 0.64 (9: 1 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl₃) 1.01 (t, 3H), 1.18 (2t, 9H), 1.92 (2hex, 4H), 2.62 (s, 3H), 3.00 (t, 2H), 3.29 (quart, 4H), 4.21 (t, 2H), 7.13 (d, 1H), 7.93 (dd, 1H), 8.51 (d, 1H), 9.85 (s, 1H) .

119

Example 60

1- [3- (5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo-5,1-f] -1,2,4-triazin-2-yl) -4-propoxy-benzenesulfonyl-piperidine-4-carboxylic acid

<img file="EE200000291A_D0129.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] tri20 azin-2-yl) benzenesulfonyl chloride and 14 mg (0.6 mmol) piperidine carboxylic acid in 1 ml THF / water (1: 1)

26.5 mg of sodium carbonate, 21 mg (41%) of 1- [3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine) are obtained. 2-yl) -4-propoxybenzenesulfonyl] piperidine-4-carboxylic acid.

R_f = 0.28 (9: 1 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 0.90 (t, 3H), 1.04 (t, 3H), 1.80 (m,

4H), 2.21 (m, 2H), 2.51 (s, 3H), 2.85 (m, 2H), 3.56 (m, 6H), 4.10 (t, 2H), 7, 12 (d, 1H), 7.71 (dd, 1H), 8.10 (d, 1H), 10.72 (s, broad, 1H).

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Example 61

5-Methyl-2- [5- (morpholine-4-sulfonyl) -2-propoxyphenyl] -7-propyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0130.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] ] triazin-2-yl) benzenesulfonyl chloride and 26 mg (0.3 mmol) of morpholine, 34 mg (71%) of 5-methyl-2- [5- (morpholine-4sulfonyl) -2-propoxyphenyl] -7- is obtained. propyl 3 H -imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.64 (9: 1 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H), 1.16 (t, 3H), 1.89 (hex,

2H), 2.00 (hex, 2H), 2.63 (s, 3H), 3.02 (m, 4H), 4.25 (t, 2H), 7.19 (d, 1H), 7, 89 (dd, 1H), 8.48 (d, 1H), 9.78 (s, 1H).

Example 62

N- (2-Hydroxyethyl) -N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1- f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide

<img file="EE200000291A_D0131.tif" />

OH

EE 200000291 Α

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By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 23 mg (0.63 mmol) of methyl hydroxyethylamine give 25 mg (54%) of N- (2-hydroxyethyl) -N-methyl-3- (5-methyl-4-oxo-7-propyl). -3,4-dihydroimidazo [5,1f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide.

<td>R_f =</td><td> 0,53</td><td colspan="2">(dichloromethane / methanol 9:</td><td> 1) -</td><td></td><td></td>

<td> 200</td><td>MHz ¹</td><td>1 H-NMR (CDCl 3₃) 1,01</td><td>(t, 3H),</td><td> 1,15</td><td>(t,</td><td>3H), 1.82 (m,</td>

<td>2H),</td><td> 1,99</td><td>(hex, 2H), 2.40</td><td>(s, wide,</td><td>IH),</td><td> 2,62</td><td>(s, 3H), 2.89</td>

<td>(S,</td><td>3H),</td><td>2.99 (t, 2H), 3.21</td><td>(t, 2H),</td><td> 3,80</td><td>(s,</td><td>broad, 2H), 4.21</td>

<td>(t,</td><td>2H),</td><td>7.16 (d, 1H), 7.92</td><td>(dd, 1H)</td><td> , 8,50</td><td>(d,</td><td>1H), 9.79 (s,</td>

IH).

Example 63

N- (2-Hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazor 5,1f] -1,2,4] triazin-2-yl) -4-propoxy-N -propylbenzenesulfonamide

<img file="EE200000291A_D0132.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazine -2-yl) benzenesulfonyl chloride and 31 mg (0.6 mmol) of propylhydroxyethylamine give 20 mg (40%) of N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4) -dihydroimidazo [5,1f] [1,2,4] triazin-2-yl) -4-propoxy-N-propylbenzenesulfonamide.

R_f = 0.52 (9: 1 dichloromethane / methanol).

EE 200000291 Α

<td colspan="8"> 122</td>

<td> 200</td><td>MHz ¹1 H-NMR (CDCl 3₃)</td><td>0.90 (t,</td><td>3H),</td><td> 1,01</td><td>(t,</td><td>3H), 1.15</td><td>(t,</td>

<td>3H),</td><td colspan="2">1.52 (m, 2H), 1.88 (m, 2H),</td><td> 2,00</td><td>(m,</td><td>2H),</td><td>2.40 (s,</td><td>IH),</td>

<td> 2,63</td><td>(s, 3H), 3.01 (t,</td><td colspan="2">2H), 3.22 (m,</td><td>4H),</td><td> 3,80</td><td>(quart,</td><td>2H),</td>

<td> 4,21</td><td>(t, 2H), 7.15 (d,</td><td>2H), 7.95</td><td>(dd,</td><td>IH),</td><td> 8,55</td><td>(d, 1H),</td><td> 9,75</td>

(s, 1H).

Example 64

N- [2- (3,4-Dimethoxyphenyl) ethyl] -N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] (1,2,41-triazine-2) -yl) -410 propoxybenzenesulfonamide

<img file="EE200000291A_D0133.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] tri25 azin-2-yl) benzenesulfonyl chloride and 59 mg (0.3 mmol) of N-methyl-3,4-dimethoxyphenylethylamine give 45 mg (78%) of N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl -3- (5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxy-benzenesulfonamide.

<td>R_f = 0,35</td><td colspan="3">(dichloromethane / methanol</td><td> 19 : 1) .</td><td></td><td></td><td></td><td></td>

<td>200 MHz ¹</td><td>1 H-NMR</td><td>(CDCl₃) 0,90</td><td colspan="2">(t, 3H), 1.07</td><td>(t,</td><td>3H),</td><td> 1,78</td><td>(m,</td>

<td>2H), 1.92</td><td>(m,</td><td>2H), 2.55 (s,</td><td>3H),</td><td>2.73 (s,</td><td>3H),</td><td> 2,78</td><td>(m,</td><td>2H),</td>

<td>2.89 (t,</td><td>2H),</td><td>3.23 (t, 2H),</td><td> 3,80</td><td>(s, 6H),</td><td> 4,15</td><td>(t,</td><td>2H),</td><td> 6,65</td>

<td>(m, 3H),</td><td> 7,05</td><td>(d, 1H), 7.75</td><td>(dd,</td><td>1H), 8.41</td><td>(d,</td><td>IH),</td><td> 9,67</td><td>(s,</td>

IH).

123

Example 65

N-Allyl-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] -1,2,41-triazin-2-yl) -4-propoxybenzenesulfonamide

<img file="EE200000291A_D0134.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride and 31 mg (0.3 mmol) allylhydroxyethylamine to give 34 mg (70%) of N-allyl-N 2 O (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl). -3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide.

R_f = 0.52 (9: 1 dichloromethane / methanol).

200 MHZ @ 1 H-NMR (CDCl3₃) 1,01

2H), 1.99 (m, 2H), 2.38 (s,

2H), 3.32 (t, 2H), 3.86 (t,

5.21 (m, 2H), 5.71 (m, 1H), (d, 1H), 9.77 (s, 1H).

<td>(t, 3H), 1.15 (t,</td><td>3H),</td><td> 1,85</td><td>(m,</td>

<td>wide, 1H), 2.63 (s,</td><td>3H),</td><td> 3,00</td><td>(t,</td>

<td>2H), 3.90 (d, 2H),</td><td> 4,25</td><td>(t,</td><td>2H),</td>

<td>7.15 (d, 1H), 7.95</td><td>(dd,</td><td>IH),</td><td> 8,55</td>

EE 200000291 Α

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Example 66

N-Allyl-N-cyclopentyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] -1,2,41-triazin-2-yl) -4-propoxybenzenesulfonamide

<img file="EE200000291A_D0135.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride and 38 mg (0.3 mmol) of allylcyclopentylamine give 33 mg (64%) of N-allyl-N 2 O-cyclopentyl-3- (5-methyl-4-oxo-7-propyl-3,4). -dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonamide.

<td>R_f -</td><td> 0,43</td><td colspan="2">(dichloromethane / methanol</td><td> 19 :</td><td> 1) -</td><td></td><td></td><td></td><td></td>

<td> 200</td><td>MHZ ¹</td><td>1 H-NMR (CDCl 3₃) 1,01</td><td>(t,:</td><td>3H),</td><td> 1,15</td><td>(t,</td><td>3H),</td><td> 1,53</td><td>(m,</td>

<td>9H),</td><td> 2,00</td><td>(m, 4H), 2.63 (s,</td><td>3H),</td><td> 3,00</td><td>¹ (t,</td><td>2H),</td><td> 3,80</td><td>(m,</td><td>2H),</td>

<td> 4,21</td><td>(t,</td><td>2H), 5.20 (m, 2H),</td><td> 5,88</td><td>(m,</td><td>IH),</td><td> 7,12</td><td>(d,</td><td>IH),</td><td> 7,95</td>

<td>(dd,</td><td>IH),</td><td>8.55 (d, 1H), 9.75</td><td>(S,</td><td>IH).</td><td></td><td></td><td></td><td></td><td></td>

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Example 67

N-Allyl-N-Ethyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,41-triazin-2-yl) -4-propoxybenzenesulfonamides

<img file="EE200000291A_D0136.tif" />

By the same method, starting from 42 mg (0.1 mmol) of 4-propoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 26 mg (0.3 mmol) of allyl ethylamine give 30 mg (64%) of N-allyl-N-ethyl-320 (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo) [5,11f] [1,2,4] Triazin-2-yl) -4-propoxybenzenesulfonamide.

R_f = 0.44 (dichloromethane / methanol 19: 1).

200 MHz ¹1 H-NMR (CDCl₃) 1.01 (t, 3H), 1.15 (t, 6H), 1.89 (m,

2H), 2.01 (m, 2H), 2.63 (s, 3H), 3.00 (t, 2H), 3.27 (quart,

2H), 3.87 (d, 2H), 4.23 (t, 2H), 5.20 (m, 2H), 5.72 (m, 1H),

7.15 (d, 1H), 7.95 (dd, 1H), 8.55 (d, 1H), 9.80 (s, 1H).

126

Example 68

2- [2-Ethoxy-4-methoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,41-triazin-4-one

<img file="EE200000291A_D0137.tif" />

mg (0.045 mmol) of 4-ethoxy-2-methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2 -yl) benzenesulfonyl chloride is dissolved in 0.5 mL of dichloromethane and dimethylaminopyridine and 14 mg (0.136 mmol) of N-methylpiperazine are added at the tip of the spatula. The reaction mixture is stirred at room temperature overnight. Purify on silica gel to give 12.8 mg (55%) of 2- [2-ethoxy-4-methoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5.1 -f] [1,2,4] 25 triazin-4-one.

<td>^Rf =</td><td> 0,22</td><td>(dichloromethane / methanol 20: 1).</td>

<td> 200</td><td>MHz ¹</td><td>1 H-NMR (CDCl 3₃) 0.94 (t, 3H), 1.55 (t, 3H), 1.80 (m,</td>

<td>2H),</td><td> 2,24</td><td>(s, 3H), 2.42 (t, 4H), 2.55 (s, 3H), 2.92 (t, 2H),</td>

<td> 3,19</td><td>(t,</td><td>4H), 3.91 (s, 3H), 4.25 (quart, 2H), 6.48 (s, 1H),</td>

<td> 8,57</td><td>(s,</td><td>1H), 9.54 (s, 1H).</td>

EE 200000291Α

127

Example 69

2- [2-Ethoxy-5- [4- (2-hydroxyethyl) piperazine-1-sulfonyl] -4-methoxyphenyl] -5-methyl-7-propyl-3H-imidazol-5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0138.tif" />

OH

By the same method, starting from 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2] , 4] Triazin-2-yl) benzenesulfonyl chloride and 18 mg (0.14 mmol) of 4-hydroxyethylpiperazine give 11 mg (46%) of 2- {2-ethoxy-5- [4- (2-hydroxyethyl) piperazine-1]. -sulfonyl] -4-methoxyphenyl} -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] tri25-azin-4-one.

<td>^Rf =</td><td colspan="2">0.34 (dichloromethane / methanol</td><td> 15 :</td><td> 1) ·</td><td></td><td></td><td></td><td></td>

<td> 200</td><td>MHz ¹1 H-NMR (CDCl 3₃) 0,94</td><td>(t,</td><td>3H),</td><td> 1,55</td><td>(t,</td><td>3H),</td><td> 1,80</td><td>(m,</td>

<td>3H),</td><td>2.52 (m, 9H), 2.92 (t,</td><td>2H),</td><td> 3,20</td><td>(t,</td><td>4H),</td><td> 3,44</td><td>(t,</td><td>2H),</td>

<td> 3,92</td><td>(s, 3H), 4.25 (quart,</td><td>2H),</td><td> 6,49</td><td>(s,</td><td>IH),</td><td> 8,56</td><td>(s,</td><td>IH),</td>

<td> 9,55</td><td>(s, 1H).</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

EE 200000291Α

128

Example 70

4-Ethoxy-N-ethyl-N- (2-hydroxyethyl) -2-methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] -1,2,4 L triazine -2-yl) benzenesulfonamide

<img file="EE200000291A_D0139.tif" />

By the same method, starting from 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [. 2,4] Triazin-2-yl) -benzenesulfonyl chloride and 12 mg (0.14 mmol) of ethyl hydroxyethylamine give 8 mg (34%) of 420 ethoxy-N-ethyl-N- (2-hydroxyethyl) -2-methoxy-5- (5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) -benzenesulfonamide.

<td>^Rf =</td><td> 0,45</td><td colspan="2">(dichloromethane / methanol</td><td> 15 :</td><td> 1) ·</td><td></td><td></td><td></td><td></td>

<td> 200</td><td>MHz ¹</td><td>1 H-NMR (CDCl 3₃) 1,02</td><td>(t,</td><td>3H),</td><td> 1,18</td><td>(t,</td><td>3H),</td><td> 1,61</td><td>(t,</td>

<td>2H),</td><td> 1,88</td><td>(m, 2H), 2.39 (s,</td><td>wide,</td><td>IH),</td><td> 2,65</td><td>(s,</td><td>3H),</td><td> 3,00</td><td>(t,</td>

<td>2H),</td><td> 3,38</td><td>(quart, 2H), 3.45</td><td>(t,</td><td>2H),</td><td> 3,78</td><td>(m,</td><td>2H),</td><td> 4,01</td><td>(S,</td>

<td>3H),</td><td> 4,20</td><td>(quart, 2H), 6.58</td><td>(s,</td><td>IH),</td><td> 8,67</td><td>(s,</td><td>IH),</td><td> 9,61</td><td>(s,</td>

IH).

EE 200000291 Α

129

Example 71

4-Ethoxy-N- (4-ethoxyphenyl) -2-methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] -1,4,4-triazin-2-yl). benzenesulfonamide

<img file="EE200000291A_D0140.tif" />

By the same method, starting from 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazin-2-yl) benzenesulfonyl chloride and 19 mg (0.14 mmol) of 4-ethoxyaniline gives 7 mg (34%) of 4-ethoxy20 N- (4-ethoxyphenyl) -2-methoxy-5- (5-methyl-4 -oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonamide

<td>di.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>^Rf =</td><td> 0,36</td><td>(dichloromethane / methanol</td><td> 20 : 1) .</td><td></td><td></td><td></td>

<td> 200</td><td>MHZ ¹</td><td>1 H-NMR (CDCl 3₃) 1.02 (t,</td><td>3H), 1.33</td><td>(t,</td><td>3H), 1.59</td><td>(t,</td>

<td>3H),</td><td> 1,86</td><td>(hex, 2H), 2.62 (s, 3H)</td><td>), 3.02 (t,</td><td>2H)</td><td colspan="2">, 3.92 (quart,</td>

<td>2H),</td><td> 4,11</td><td>(s, 3H), 4.31 (quart,</td><td>2H), 6.58</td><td>(s,</td><td>1H), 6.72</td><td>(d,</td>

<td>2H),</td><td> 6,88</td><td>(s, wide, 1H), 6.99 (d,</td><td>2H), 8.50</td><td>(s,</td><td>1H), 9.59</td><td>(s,</td>

<td>IH).</td><td></td><td></td><td></td><td></td><td></td><td></td>

130

Example 72

4-Ethoxy-N-ethyl-N- (2-hydroxyethyl) -3- [5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) benzenesulfonamide id

<img file="EE200000291A_D0141.tif" />

0.64 g (1.5 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) Benzenesulfonyl chloride is dissolved in 20 mL of dichloromethane and cooled to 0 ° C. After addition of a spatula dimethylaminopyridine, 0.40 g (4.50 mmol) of 2- (ethylamino) ethanol is added and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic layer is washed with water, dried over sodium sulfate and the solvent is removed under reduced pressure. Chromatography (95: 5 dichloromethane / methanol) gives 0.454 g (63%) of a colorless solid.

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.20 (t, 3H), 1.35 (t, 3H), 1.61 (t, 3H), 1.88 (sex, 2H), 2.25 ( s, broad, 1H), 3.01 (m, 4H), 3.32 (m, 4H), 3.70 (m, 2H), 3.80 (m, 2H), 4.37 (quart, 2H) ), 7.15 (d, 1H), 7.98 (dd, 1H), 8.56 (d, 1H), 9.70 (s, 1H).

EE 200000291Α

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Example 73

N- (2-Methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] 1,2,4-triazin-2-yl) -4-ethoxybenzenesulfonamide

<img file="EE200000291A_D0142.tif" />

By the same method, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] tri15-azine-2 -yl) benzenesulfonyl chloride and 21 mg (0.282 mmol) of 2-methoxyethylamine give 15 mg (34%) of N- (2-methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazole) [5,1-f] [1,2,4] triazin-2-yl) -4-ethoxybenzenesulfonamide.

R_f = 0.2 (ethyl acetate / cyclohexane 2: 1).

200 MHz ¹1 H-NMR (CDCl 3₃) 0.97 (t, 3H), 1.25 (t, 3H), 1.53 (t,

3H), 1.82 (sex, 2H), 2.97 (m, 4H), 3.11 (m, 2H), 3.22 (s,

3H), 3.39 (t, 2H), 4.37 (quart, 2H), 5.00 (t, 1H), 7.17 (d,

1H), 7.97 (dd, 1H), 8.53 (d, 1H), 9.82 (s, 1H).

Example 74

N, N-bis- (2-methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4- ethoxybenzenesulfonamide

<img file="EE200000291A_D0143.tif" />

o = s = oi

CH h₃c.

CH

132

By the same method, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazine-2- yl) benzenesulfonyl chloride and 38 mg (0.28 mmol) of bismethoxyethylamine give 17 mg (34%) of N, N-bis- (25-methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4) -dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -4-ethoxybenzenesulfonamide.

R_f = 0.34 (ethyl acetate / cyclohexane 2: 1).

<td>200 MHz ¹H</td><td>-TMR (CDCl₃)</td><td> 0,97</td><td>(t, 3H), 1.27</td><td>(t, 3H), 1.53</td><td>(t,</td>

<td>3H), 1.80</td><td>(sex, 2H),</td><td> 2,95</td><td>(m, 4H), 3.22</td><td>(s, 6H), 3.39</td><td>(m,</td>

<td>10 (4H), 3.49</td><td>(m, 4H), 4.27</td><td colspan="2">(quart, 2H), 7.17</td><td>(d, 1H), 7.97</td><td>(dd,</td>

<td>1H), 8.53</td><td>(d, 1H), 9.82</td><td>(s,</td><td>IH).</td><td></td><td></td>

Example 75

2- [5- (4-Hydroxypiperidine-1-sulfonyl) -2-ethoxyphenyl] -5¹⁵ Ethyl 7-propyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one

<img file="EE200000291A_D0144.tif" />

By the same method, starting from 640 mg (1.5 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 460 mg (4.5 mmol) of 430 hydroxypiperidine give 485 mg (66%) of 2- [5- (4-hydroxypiperidine-1-sulfonyl) -2-ethoxyphenyl] -5-ethyl-7- propyl 3 H -imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.37 (19: 1 dichloromethane / methanol).

200 MHz ¹1 H-NMR (CDCl 3₃) 1.02 (t, 3H), 1.32 (t, 3H), 1.60 (t,

3H), 1.80 (m, 7H), 2.97 (m, 6H), 3.30 (m, 2H), 3.82 (m, 1H),

4.34 (quart, 2H), 7.17 (d, 1H), 7.90 (dd, 1H), 8.45 (d, 1H),

9.75 (s, 1H).

EE 200000291 Α

133

Example 76

2- [5- (4-Hydroxymethyl-piperidine-1-sulfonyl) -2-ethoxy-phenyl] -15-ethyl-7-propyl-3H-imidazo [5,1-f] -1,2,4] triazin-4-one

<img file="EE200000291A_D0145.tif" />

By the same method, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2- yl) benzenesulfonyl chloride and 33 mg (0.28 mmol) 4-hydroxymethylpiperidine give 23 mg (48%) of 2- [5- (4-hydroxymethylpiperidine-1-sulfonyl) -2-ethoxyphenyl] -5-ethyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

<td>R_f =</td><td>0.38 (dichloromethane / methanol 10:</td><td> 1) ·</td><td></td><td></td><td></td><td></td>

<td> 200</td><td>MHz ¹1 H-NMR (CDCl 3₃) 1.01 (t, 3H),</td><td> 1,33</td><td>(t,</td><td>3H),</td><td> 1,60</td><td>(t,</td>

<td>3H),</td><td>1.80 (m, 8H), 2.41 (m, 2H), 3.00</td><td>(m,</td><td>4H),</td><td> 3,56</td><td>(m,</td><td>4H),</td>

<td> 4,35</td><td>(quart, 2H), 7.17 (d, 1H), 7.88</td><td>(dd,</td><td>IH),</td><td> 8,45</td><td>(d,</td><td>IH),</td>

<td> 9,71</td><td>(s, 1H).</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

134

Example 77

2- &lt;2-Ethoxy-5- [4- (2-hydroxyethyl) piperazine-1-sulfonylphenyl} -5-ethyl-7-propyl-3H-imidazo [5,1-f] [1,2,41 triazine-4-one

<img file="EE200000291A_D0146.tif" />

By the same method, starting from 40 mg (0.094 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine-2) -yl) benzenesulfonyl chloride and 37 mg (0.28 mmol) of 420 hydroxyethylpiperazine give 35 mg (71%) of 2- {2-ethoxy-5- [4- (2-hydroxyethyl) piperazine-1-sulfonyl] phenyl} -5-ethyl7 -propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one.

R_f = 0.65 (dichloromethane / methanol 10: 1).

Example 78

2- [2-Ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-ethyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one

<img file="EE200000291A_D0147.tif" />

EE 200000291 Α

135

By the same method, starting from 640 mg (1.50 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 450 mg (4.5 mmol) of 4-hydroxyethylpiperazine give 495 mg (66%) of 2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -5-ethyl-7-propyl 3 H -imidazo [5,11f] [1,2,4] triazin-4-one.

<td>Rf =</td><td> 0,30</td><td colspan="2">(dichloromethane / methanol</td><td> 19 : 1).</td><td></td><td></td><td></td>

<td> 200</td><td>MHz ¹:</td><td>1 H-NMR (CDCl 3) 1.01</td><td>(t,</td><td>3H), 1.35</td><td>(t, 3H),</td><td> 1,61</td><td>(t,</td>

<td>3H),</td><td> 1,89</td><td>(sex, 2H), 2.31</td><td>(s,</td><td>3H), 2.53</td><td>(m, 4H),</td><td> 3,05</td><td>(m,</td>

<td>ίο 8H),</td><td> 4,35</td><td>(quart, 2H), 7.17</td><td>(d,</td><td>1H), 7.89</td><td>(dd, 1H),</td><td> 8,48</td><td>(d,</td>

<td>IH),</td><td> 9,65</td><td>(s, 1H).</td><td></td><td></td><td></td><td></td><td></td>

Example 79

2- [2-Ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-ethyl-15H-propyl-3H-imidazo [5,1-f] -1,2,41-triazin-4-one hydrochloride

<img file="EE200000291A_D0148.tif" />

300 mg (0.61 mmol) 2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -5-ethyl-7-propyl-3 H -imidazo [5,1-f] [1,2, 4] Triazin-4-one is dissolved in a mixture of ether and dichloromethane and mixed with 2 ml of 1 M HCl in ether. After 20 minutes, the precipitated solid is filtered off with suction and dried. 200 MHz @ 1 H NMR (DMSO-d6)₆) 0.95 (t, 3H), 1.32 (2t, 6H), 1.80 (sex, 2H), 2.76 (m, 4H), 3.01 (m, 4H), 3.15 ( m, 2H), 3.44 (m, 2H), 3.81 (m, 2H), 4.25 (quart, 2H), 7.49 (d, 1H), 7.95 (m,

2H), 11.25 (s, 1H), 12.30 (s, 1H).

136

Example 80 - (5-Ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazin-2-yl) -N- (3-morpholin-4-ylpropyl) -4-Ethoxybenzenesulfonamide

<img file="EE200000291A_D0149.tif" />

By the same method, starting from 640 mg (1.5 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 650 mg (4.5 mmol) of 1- (3-aminopropyl) morpholine, 476 mg (59%) of 3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5 , 1-f] [1,2,4] tri20-azin-2-yl) -N- (3-morpholin-4-yl-propyl) -4-ethoxy-benzenesulfonamide.

R_f = 0.18 (dichloromethane / methanol 19: 1).

<td> 200</td><td>MHz ¹1 H-NMR (CDCl 3₃)</td><td> 1,01</td><td>(t, 3H), 1.32</td><td>(t, 3H),</td><td> 1,60</td><td>(t,</td>

<td>3H),</td><td>1.70 (m, 3H), 1.89</td><td>(sex</td><td>, 2H) 2.43 (m,</td><td>7H), 3.01</td><td>(m,</td><td>4H),</td>

<td> 25 3,15</td><td>(t, 2H), 3.70 (m,</td><td>4H),</td><td>4.35 (quart,</td><td>2H), 7.15</td><td>(d,</td><td>IH),</td>

<td> 7,95</td><td>(dd, 1H), 8.55 (d,</td><td>IH),</td><td>9.82 (s, 1H).</td><td></td><td></td><td></td>

137

Example 81

N- (2-Hydroxyethyl) -3- [5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1- f] -1,2,41-triazin-2-yl) -4-ethoxy-N-propylbenzenesulfonamide

<img file="EE200000291A_D0150.tif" />

By the same method, starting from 640 mg (1.5 mmol) of 4-ethoxy-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) benzenesulfonyl chloride and 464 mg (4.5 mmol) of propylhydroxyethylamine give 600 mg (81%) of N- (220-hydroxyethyl-3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo) [ 5,1-f] [1,2,4] triazin-2-yl) -4-ethoxy-N-propylbenzenesulfonamide.

<td>^Rf =</td><td> 0,73</td><td>(dichloromethane / meta</td><td>mole</td><td> 10 :</td><td> 1) ·</td><td></td><td></td><td></td>

<td> 200</td><td>MHz ¹</td><td>1 H-NMR (CDCl 3₃) 0,91</td><td>(t,</td><td>3H),</td><td> 1,01</td><td>(t,</td><td>3H),</td><td>1.32 (t,</td>

<td>3H),</td><td> 1,62</td><td>(m, 5H), 1.88 (m,</td><td>2H),</td><td> 2,32</td><td>(s,</td><td>IH),</td><td> 3,01</td><td>(m, 4H),</td>

<td> 3,22</td><td>(m,</td><td>4H), 3.80 (m, 2H),</td><td> 4,35</td><td>(t,</td><td>2H),</td><td> 7,15</td><td>(d,</td><td>2H), 7.95</td>

<td>(dd,</td><td>IH),</td><td>8.55 (d, 1H), 9.75</td><td>(s,</td><td>IH).</td><td></td><td></td><td></td><td></td>

The sulfonamides listed in Tables 1, 2, 3, 4 and 6 below were prepared by automated parallel synthesis of 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2 , 4] triazin-2-yl) benzenesulfonyl chloride and the appropriate amine using one of the three standard methods below.

The sulfonamides listed in Table 5 were prepared by automated parallel synthesis of 4-ethoxy-3- (5-ethyl-4EE 200000291A) by the same methods.

138 oxo-7-propyl-3,4-dihydroimidazo [5,1-5] [1,2,4] triazin-2-yl) benzenesulfonyl chloride and the appropriate amine.

The purity of the final products was determined by HPLC and characterized

LC-MS. The percentage of the desired compound according to HPLC-MS is given in the HPLC column in the tables. Standard method A was used for acidic amines, standard method B for neutral amines, standard method C for basic amines.

In some cases, the hydrogen formulas in the formulas in Tables 1, 2, 3, 4, 5 and 6 are not shown. Nitrogen atoms having a free valence bond are thus understood as -NH groups.

Reference method

Reaction with acidic amines

First, 0.05 mmol of amine, 0.042 mmol of sulfo20 nyl chloride and 0.10 mmol of Na are combined.₂CO₃ and add 0.5 ml THF / H by pipette₂O mixture. After 24 hours at room temperature, the mixture is stirred with 0.5 mL of 1 MH₂SO₄ solution and filter through a two-phase cartridge (500 mg Extrelut (supernatant) and 500 mg SiO₂, mobile phase ethyl acetate). The product is obtained after concentration of the filtrate under reduced pressure.

Reference method

Reaction with neutral amines

First, the synthesis of 0.125 mmol of amine and 0.03 mmol of pipetted sulfonyl chloride as a solution in 1,2-dichloroethane are combined. After 24 hours, the mixture is stirred with 0.5 mL of 1 MH₂SO₄ solution and filter through a two-phase cartridge (500 mg Extrelut (supernatant) and 500 mg SiO₂, mobile phase ethyl acetate). The filtrate is concentrated under reduced pressure.

EE 200000291Α

139

Reference method

Reaction with amine decra with basic properties

First, 0.05 mmol of the amine and 0.038 mmol of the sulfonyl chloride pipetted as a solution in 1,2-dichloroethane and 0.05 mmol of the triethylamine in 1,2-dichloroethane solution are combined. After 24 hours, the mixture is first stirred at 3 ml

NaHCO₃ saturated solution and the reaction mixture is filtered through a two phase cartridge. The product is obtained after concentration of the filtrate at reduced pressure.

All reactions are monitored by thin layer chromatography. If the reaction is not complete at room temperature after 24 hours, the reaction mixture is heated at 60 ° C for a further 12 hours and then the experiment is terminated.

140

Table:

<img file="EE200000291A_D0151.tif" />

<img file="EE200000291A_D0152.tif" />

141

<td>An example no</td><td colspan="2">Structure</td><td>M [g / mol</td><td>HPLC</td><td>M + H</td>

<td></td><td>CH 0</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>i jj u ^N '</td><td></td><td></td><td></td><td>J.</td>

<td> 85</td><td>X I</td><td>J</td><td> 477,58687</td><td> 76</td><td> 478</td>

<td></td><td>I N HO /</td><td></td><td></td><td></td><td></td>

<td></td><td>h₃c</td><td></td><td></td><td></td><td></td>

<td></td><td>CH 0 l A</td><td></td><td></td><td></td><td></td>

<td></td><td>Ό Ιίγ il</td><td> :{»</td><td></td><td></td><td></td>

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

<td> 86</td><td>o = s = o</td><td>CH,</td><td> 525,63147</td><td> 81</td><td> 526</td>

<td></td><td>H, C ii</td><td></td><td></td><td></td><td></td>

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

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

<td></td><td>CH, 0 Γ 1</td><td>CH,</td><td></td><td></td><td></td>

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

<td> 87</td><td>AJ o = s = o</td><td>\ CH,</td><td> 463,55978</td><td> 65</td><td> 464</td>

<td></td><td>X-VoH</td><td></td><td></td><td></td><td></td>

EE 200000291 Α

142

<td>An example no</td><td colspan="4">Structure</td><td>M fg / mol</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>CH, I</td><td>0 li</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>0 ΓΥ</td><td>No.</td><td>A</td><td></td><td></td><td></td>

<td> 88</td><td></td><td>O — StrzO</td><td></td><td></td><td> 531,67929</td><td> 83</td><td> 532</td>

<td></td><td>c</td><td>| U-</td><td>.OH</td><td></td><td></td><td></td><td></td>

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

<td></td><td></td><td>CH, r</td><td>0 II</td><td>«Λ</td><td></td><td></td><td></td>

<td></td><td></td><td>0 N (V</td><td>r v^N-</td><td> &lt;</td><td></td><td></td><td></td>

<td> 89</td><td></td><td>T O = S — 0</td><td></td><td>CH,</td><td> 463,55978</td><td> 40</td><td> 464</td>

<td></td><td>H, C HjC-</td><td>V</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>^kOH</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, I</td><td>0 II</td><td>θΗ,</td><td></td><td></td><td></td>

<td></td><td></td><td>s&gt; Λ</td><td>rA Ar</td><td> 4</td><td></td><td></td><td></td>

<td> 90</td><td></td><td>U</td><td></td><td></td><td> 463,55978</td><td> 44</td><td> 464</td>

<td></td><td></td><td>T o = s = I</td><td>o</td><td>θΗ,</td><td></td><td></td><td></td>

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

EE 200000291 Α

143

<td>An example no</td><td colspan="4">Structure</td><td>M (g / mol)</td><td>HPLC</td><td>M + H</td>

<td></td><td>CH, 1</td><td> 0 1</td><td colspan="2">CH,</td><td></td><td></td><td></td>

<td></td><td>Λ</td><td> »</td><td>hkA</td><td>N</td><td></td><td></td><td> -</td>

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

<td> 91</td><td colspan="2">O = Sr = ^ O</td><td></td><td>CH,</td><td> 581,6962</td><td> 76</td><td> 582</td>

<td></td><td>1 h, c γ γ</td><td>Γ)</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>J)</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CK</td><td>0 II</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>Ό fY</td><td></td><td>ί</td><td></td><td></td><td></td><td></td>

<td> 92</td><td></td><td></td><td></td><td></td><td> 475,5273</td><td> 61</td><td> 476</td>

<td></td><td>o = s = o</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> &lt;?</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH, I</td><td>0 II</td><td>ch₃</td><td></td><td></td><td></td><td></td>

<td></td><td>⁰ 1 Ar</td><td>A Α N</td><td> $</td><td></td><td></td><td></td><td></td>

<td> 93</td><td>V</td><td></td><td></td><td></td><td> 421,47851</td><td> 80</td><td> 422</td>

<td></td><td>o = s = o</td><td></td><td></td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>H, C_X N o</td><td></td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

144

<img file="EE200000291A_D0153.tif" />

EE 200000291 Α

145

<td>An example no</td><td colspan="3">Structure</td><td>M Ig / mol]</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>CH, 0 C 1</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>1 1 Γ (W '</td><td></td><td></td><td></td><td></td>

<td> 96</td><td></td><td>X</td><td>CH,</td><td> 567,7)274</td><td> 80</td><td> 568</td>

<td></td><td>o</td><td>N</td><td></td><td></td><td></td><td></td>

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

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

<td></td><td></td><td colspan="2">j? cii</td><td></td><td></td><td></td>

<td></td><td></td><td>/ LA /^NX [fj ^N</td><td></td><td></td><td></td><td></td>

<td> 97</td><td></td><td></td><td rowspan="2">CH,</td><td> 521,64045</td><td> 94</td><td> 522</td>

<td></td><td></td><td>o = s = o</td><td></td><td></td><td></td>

<td></td><td>θ '</td><td>X</td><td></td><td></td><td></td><td></td>

<td></td><td>HC</td><td>^:'- ° ck</td><td></td><td></td><td></td><td></td>

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

<td></td><td></td><td>0 Xv /</td><td></td><td></td><td></td><td></td>

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

<td> 98</td><td> 0</td><td>T = s = o</td><td>CH,</td><td> 477,58687</td><td> 70</td><td> 478</td>

<td></td><td></td><td>r^N</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>-Oh</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">HO θΗ,</td><td></td><td></td><td></td><td></td>

EE 200000291Α

146

<td>An example no</td><td colspan="3">Structure</td><td>M ig / mol</td><td>HPLC</td><td>Μ + H</td>

<td></td><td></td><td>CH, O 0 Λ</td><td></td><td></td><td></td><td></td>

<td> 99</td><td></td><td>XV</td><td></td><td> 535,62391</td><td> 88</td><td> 536</td>

<td></td><td>/ '' O</td><td>\ II ZM-- II o</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>CH, 0 l Λ</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>ό X ^ Xx xⁿ- LJ</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>0 = s = o</td><td>X</td><td></td><td></td><td></td>

<td> 100</td><td></td><td> 1</td><td></td><td> 553,68565</td><td> 88</td><td> 554</td>

<td></td><td></td><td> .0</td><td></td><td></td><td></td><td></td>

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

<td></td><td></td><td>CH, O 1 X</td><td>X</td><td></td><td></td><td></td>

<td> 101</td><td></td><td>XA xⁿφ</td><td>X</td><td> 529,61972</td><td> 85</td><td> 530</td>

<td></td><td>X?</td><td>oso</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>Xv / O,</td><td> 1</td><td></td><td></td><td></td><td></td>

EE 200000291 Α

147

<td>An example no</td><td>Structure</td><td>M Ig / mol]</td><td>HPLC</td><td>M + H</td>

<td> 102</td><td>9 / ° ΓΗ ; j / z / k ' ^CH3 | f / O = ZS ~ O</td><td> 539,65856</td><td> 91</td><td> 540</td>

<td> 103</td><td>CH, 0 p o = i = c&gt; ^CH* 1 .N ° yo h / ch,</td><td> 520,61209</td><td> 55</td><td> 521</td>

<td> 104</td><td>ζ AyC 1 CH, o = s ~ o 06V- »</td><td> 502,64038</td><td> 82</td><td> 503</td>

EE 200000291Α

148

<td>An example no</td><td colspan="4">Structure</td><td>M ig / mol</td><td>HPLC</td><td>Μ + H</td>

<td></td><td></td><td></td><td>0 II</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>% P</td><td>pA p ^ p</td><td>A M</td><td></td><td></td><td></td>

<td> 105</td><td></td><td></td><td></td><td rowspan="2">\ CH,</td><td> 564,71207</td><td> 86</td><td> 565</td>

<td></td><td></td><td colspan="2">o = s = o</td><td></td><td></td><td></td>

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

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

<td></td><td></td><td></td><td colspan="2">U CH,</td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">ι IP A / vp</td><td>N</td><td></td><td></td><td></td>

<td></td><td></td><td>Pp</td><td></td><td>A</td><td></td><td></td><td></td>

<td> 106</td><td></td><td>o = s = o</td><td></td><td>CH,</td><td> 524,64674</td><td> 85</td><td> 525</td>

<td></td><td></td><td>r^N</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>“S j.</td><td> /</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>c</td><td> )</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, Ü</td><td>0 II</td><td> «,</td><td></td><td></td><td></td>

<td></td><td></td><td>^ko rV</td><td>? Γ V '</td><td>t</td><td></td><td></td><td></td>

<td></td><td></td><td>U</td><td></td><td>Λ</td><td></td><td></td><td></td>

<td> 107</td><td></td><td>1 O — s = o I</td><td></td><td>CH,</td><td> 538,67383</td><td> 85</td><td> 539</td>

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

<td></td><td>α</td><td>'P</td><td></td><td></td><td></td><td></td><td></td>

149

<td>An example no</td><td colspan="4">Structure</td><td>M (g / mol)</td><td>HPLC</td><td>Μ + H</td>

<td></td><td></td><td>0% V</td><td>o 1</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> %</td><td>fT</td><td>k</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>^ fi</td><td></td><td></td><td></td>

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

<td> 108</td><td></td><td>T o = s = o 1</td><td></td><td>CH,</td><td> 546,69396</td><td> 84</td><td> 547</td>

<td></td><td></td><td>^ CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>ü</td><td>0 II</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>0 Ν '</td><td></td><td>X</td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">Λ / ν ^</td><td>com</td><td></td><td></td><td></td>

<td> 109</td><td></td><td></td><td></td><td rowspan="2">CH,</td><td> 504,61269</td><td> 90</td><td> 505</td>

<td></td><td></td><td>o = s = o</td><td></td><td></td><td></td><td></td>

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

<td></td><td> °0</td><td></td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

150

<td>Table 2:</td><td colspan="3"></td><td></td><td></td><td></td>

<td>An example no</td><td colspan="3">Structure</td><td>M ig / mol</td><td>HPLC</td><td>M + H</td>

<td></td><td>CA.</td><td>o II</td><td>CH,</td><td></td><td></td><td></td>

<td> 110</td><td>^kO dx</td><td></td><td> 1“</td><td> 507,6134</td><td> 74</td><td> 508</td>

<td></td><td colspan="2">o = s = o 1</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>^XCH,</td><td></td><td></td><td></td>

<td></td><td>CH, r</td><td>0 II</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td> . ^ko ίι 1</td><td>N -'-</td><td> 4</td><td></td><td></td><td></td>

<td> 111</td><td></td><td></td><td></td><td> 539,6586</td><td> 75</td><td> 540</td>

<td></td><td>o = s = |</td><td>: O</td><td>ch₃</td><td></td><td></td><td></td>

<td></td><td>CH,</td><td> 0</td><td></td><td></td><td></td><td></td>

EE 200000291 Α

151

<td>An example no</td><td colspan="4">Structure</td><td>M [g / mol]</td><td>HPLC</td><td>Μ + H</td>

<td></td><td></td><td>CH, 1</td><td>0 II</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>% A</td><td>γΆα *</td><td></td><td></td><td></td><td></td>

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

<td> 112</td><td>HO</td><td>CC = S = ^ - \ j \ —N</td><td>20th -yT</td><td>CH, CH, -0</td><td> 599,7115</td><td> 83</td><td> 600</td>

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

<td></td><td></td><td></td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, 1</td><td>0 II</td><td>CHa</td><td></td><td></td><td></td>

<td></td><td></td><td>^ko</td><td>/ Α / N. N</td><td> &lt;</td><td></td><td></td><td></td>

<td> 113</td><td>HO '</td><td></td><td>o</td><td>CH,</td><td> 535,6675</td><td> 60</td><td> 536</td>

<td></td><td></td><td>OH</td><td>^ CH,</td><td></td><td></td><td></td><td></td>

152

<td>An example no</td><td colspan="3">Structure</td><td>M [g / mol]</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>CH, 0 IX</td><td>CH3</td><td></td><td></td><td></td>

<td> 114</td><td></td><td>Ό</td><td> 4</td><td> 521,6405</td><td> 95</td><td> 522</td>

<td></td><td></td><td>T O = S — 0</td><td>^CH3</td><td></td><td></td><td></td>

<td></td><td>J * o &lt; o</td><td>/ N. OH</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ct-L O l X</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>Ό AAv</td><td> 4</td><td></td><td></td><td></td>

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

<td> 115</td><td>HO</td><td>Cc = S ~ O ZZ</td><td>CH,</td><td> 569,6851</td><td> 84</td><td> 570</td>

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

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

<td></td><td></td><td>Xh,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>ChL O f X</td><td>θΗβ</td><td></td><td></td><td></td>

<td></td><td></td><td>fz</td><td>b</td><td></td><td></td><td></td>

<td> 116</td><td>HO</td><td>O = S = O \! ^ = \</td><td>α</td><td> 608,5486</td><td> 85</td><td> 608</td>

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

153

<td>An example no</td><td colspan="3">Structure</td><td>M [g / mol</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td> ?^H3 O L 11</td><td>ch₃</td><td></td><td></td><td></td>

<td></td><td></td><td>Ό rA</td><td> 4</td><td></td><td></td><td></td>

<td> 117</td><td></td><td></td><td></td><td> 569,6851</td><td> 88</td><td> 570</td>

<td></td><td>HO</td><td>o = s = o</td><td>ChL^CH3 O</td><td></td><td></td><td></td>

<td></td><td></td><td>ChL O C λ</td><td> ,^CH3</td><td></td><td></td><td></td>

<td> 118</td><td></td><td>Ο fl</td><td> &lt;</td><td> 463,5598</td><td> 94</td><td> 464</td>

<td></td><td></td><td>o = s = o</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>J / N. .OH HC</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH O i 1</td><td>p</td><td></td><td></td><td></td>

<td> 119</td><td></td><td></td><td> 4</td><td> 535,6675</td><td> 93</td><td> 536</td>

<td></td><td></td><td>o = s = o 1</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>CH,</td><td></td><td></td><td></td>

EE 200000291Α

154

<td>An example no</td><td colspan="3">Structure</td><td>M [g / mol]</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>ch, o 11</td><td>ch₃</td><td></td><td></td><td></td>

<td> 120</td><td></td><td>φ + ν-</td><td></td><td> 517,6522</td><td> 71</td><td> 518</td>

<td></td><td> 0-</td><td>0 — sr = o Λ'ν ^ οη,</td><td>CH3</td><td></td><td></td><td></td>

<td></td><td></td><td>CH, 0 &lt;"Λ (V^v</td><td>J</td><td></td><td></td><td></td>

<td> 121</td><td>HC</td><td>o T \ _ o = s = o AJ CA.</td><td>Cb</td><td> 561,7058</td><td> 92</td><td> 562</td>

<td></td><td></td><td>CHe 0</td><td>P^H3</td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">Ό</td><td></td><td></td><td></td>

<td> 122</td><td>A</td><td>o = s = o</td><td>CH,</td><td> 539,6586</td><td> 85</td><td> 540</td>

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

EE 200000291Α

155

<td>An example no</td><td colspan="3">Structure</td><td>M ig / mol]</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>CH, O ! Λ</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>XyV</td><td> 4</td><td></td><td></td><td></td>

<td> 123</td><td>CH, i</td><td>o = s = o (</td><td></td><td> 518,6834</td><td> 87</td><td> 519</td>

<td></td><td>k</td><td>cip</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, 0 1 X</td><td>&lt;Α</td><td></td><td></td><td></td>

<td></td><td></td><td>0 N AjA-</td><td> 4</td><td></td><td></td><td></td>

<td> 124</td><td></td><td>O = s = o XXla</td><td></td><td> 588,1307</td><td> 30</td><td> 588</td>

<td></td><td></td><td>1 cip</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, O IX</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>1 i¹rA</td><td>c</td><td></td><td></td><td></td>

<td></td><td></td><td>T</td><td rowspan="2">CH,</td><td></td><td></td><td></td>

<td> 125</td><td></td><td>cc = s = o he</td><td> 550,685</td><td> 83</td><td> 551</td>

<td></td><td></td><td>A Sn</td><td></td><td></td><td></td><td></td>

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

156

<td>An example no</td><td colspan="3">Structure</td><td>M {g / mol</td><td>HPLC</td><td>Μ + H</td>

<td></td><td>CH, Γ</td><td> 0</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td colspan="3">ί fx</td><td></td><td></td><td></td>

<td></td><td>w</td><td></td><td rowspan="2">X CH,</td><td></td><td></td><td></td>

<td> 126</td><td>o = s = o 9th 0</td><td></td><td> 542,7057</td><td> 77</td><td> 543</td>

<td></td><td>CH, !</td><td> 0</td><td>CHa</td><td></td><td></td><td></td>

<td></td><td colspan="2">Ό il ίΓ ^N</td><td></td><td></td><td></td><td></td>

<td> 127</td><td>o = s = o</td><td></td><td>CH,</td><td> 502,6404</td><td> 91</td><td> 503</td>

<td></td><td>J X</td><td>1 CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>CH, 1</td><td>0 u</td><td></td><td></td><td></td><td></td>

<td></td><td>Ό ifV</td><td> 6</td><td></td><td></td><td></td><td></td>

<td> 128</td><td>Y</td><td></td><td rowspan="2">CH,</td><td> 490,6292</td><td> 45</td><td> 491</td>

<td></td><td>ChL 0 — SO ί I</td><td></td><td></td><td></td><td></td>

<td></td><td>/ N / -χ, Ν H / X ^ CH,</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

157

Example No.

Structure

M lg / mol]

HPLC

<img file="EE200000291A_D0154.tif" />

<img file="EE200000291A_D0155.tif" />

<img file="EE200000291A_D0156.tif" />

EE 200000291 Α

158

<td>An example no</td><td colspan="3">Structure</td><td>M · [g / mol]</td><td>HPLC</td><td>M + H</td>

<td></td><td>CA.</td><td>o o</td><td>ch₃</td><td></td><td></td><td></td>

<td></td><td>\&gt; ΙίΊ</td><td>Xⁿ</td><td>i</td><td></td><td></td><td></td>

<td> 132</td><td>lj</td><td></td><td></td><td> 576,7205</td><td> 87</td><td> 577</td>

<td></td><td>0 — s = c H&gt;^CX, N</td><td colspan="2">CH, OH (/ 0</td><td></td><td></td><td></td>

<td></td><td>ChL r</td><td>o She</td><td></td><td></td><td></td><td></td>

<td></td><td>% Ar</td><td>Αγ</td><td> $</td><td></td><td></td><td></td>

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

<td> 133</td><td>O = S2 = O j</td><td></td><td>CH,</td><td> 598,7296</td><td> 60</td><td> 599</td>

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

<td></td><td>q</td><td> )</td><td></td><td></td><td></td><td></td>

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

<td></td><td> \=/</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

159

<td>An example no</td><td colspan="3">Structure</td><td>M [g / mol]</td><td>HPLC</td><td>M + δ</td>

<td></td><td>CH, r</td><td></td><td>j? /⁰⁴³</td><td></td><td></td><td></td>

<td></td><td colspan="3">AA ^ A</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>✓J</td><td></td><td></td><td></td>

<td> 134</td><td colspan="2">o ~ s ~ 1 N</td><td>aL = 0 Ί</td><td> 516,6675</td><td> 95</td><td> 517</td>

<td></td><td>k f</td><td>sl</td><td></td><td></td><td></td><td></td>

<td></td><td>/ HaC</td><td></td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>CH 1</td><td></td><td>jj pi</td><td></td><td></td><td></td>

<td></td><td colspan="3">AA ^ A</td><td></td><td></td><td></td>

<td></td><td>A. _x</td><td></td><td></td><td></td><td></td><td></td>

<td> 135</td><td>o = s 1 N (</td><td></td><td>CH. = 0 *</td><td> 528,6786</td><td> 80</td><td> 529</td>

<td></td><td>k N</td><td> ) \</td><td></td><td></td><td></td><td></td>

ee 200000291 A

160

<td>An example no</td><td>Structure</td><td>M Ig / mol]</td><td>HPLC</td><td>M + H</td>

<td> 136</td><td>CH, 0 _rHjj jx XX T CH, O = S = O x = \ l &lt;6 / -NN-CH, 'XA CH,</td><td> 538,6738</td><td> 85</td><td> 539</td>

<td> 137</td><td>T CH, CH, O = S = O NA H, C ^ YH, CH,</td><td> 533,6981</td><td> 68</td><td> 534</td>

<td> 138</td><td>CH, O 1 CH, o = s = o / 1 N-CH,</td><td> 516,6675</td><td> 91</td><td> 517</td>

EE 200000291 Α

161

<td>An example no</td><td colspan="3">Structure</td><td>M {g / mol</td><td>HPLC</td><td>M + H</td>

<td></td><td>CH, O LX</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Ο A.Ä ^ -^N- il 1 ^</td><td></td><td></td><td></td><td></td><td></td>

<td> 139</td><td>AJ</td><td></td><td></td><td> 489,598</td><td> 85</td><td> 490</td>

<td></td><td>o = s = o / / —N OH A</td><td></td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>CH, O C i</td><td>fr</td><td></td><td></td><td></td><td></td>

<td></td><td>ό AA_v,</td><td> &lt;</td><td></td><td></td><td></td><td></td>

<td> 140</td><td>A</td><td></td><td></td><td> 475,5709</td><td> 83</td><td> 476</td>

<td></td><td>O = St = O 1 / Α</td><td></td><td>A</td><td></td><td></td><td></td>

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

<td></td><td>CH, 0 ι Λ</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Ό aaa</td><td> $</td><td></td><td></td><td></td><td></td>

<td> 141</td><td>AJ</td><td></td><td></td><td> 503,6251</td><td> 85</td><td> 504</td>

<td></td><td>o = s = o J</td><td colspan="2">CH,</td><td></td><td></td><td></td>

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

162

<td>An example no</td><td colspan="3">Structure</td><td>M [g / mol]</td><td>HPLC</td><td>M + H</td>

<td></td><td>CH, 0 L Jl</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>XX MK {l ™</td><td></td><td></td><td></td><td></td><td></td>

<td> 142</td><td>o = s = o ή</td><td colspan="2">CH,</td><td> 489,598</td><td> 91</td><td> 490</td>

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

<td></td><td>CH 0 I JL</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>Ό Ηγ X X - .Nil ^N</td><td> &lt;</td><td></td><td></td><td></td><td></td>

<td> 143</td><td>XX O = r S = O 1</td><td></td><td>CH,</td><td> 461,5438</td><td> 78</td><td> 462</td>

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

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

<td></td><td>ü 1</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>1 X ÄAz ·</td><td></td><td></td><td></td><td></td><td></td>

<td> 144</td><td>V o = s = o |</td><td></td><td>CH,</td><td> 539,6586</td><td> 88</td><td> 540</td>

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

EE 200000291 Α

163

<td>An example no</td><td colspan="3">Structure</td><td>M Ig / mol]</td><td>HPLC</td><td>Μ + H</td>

<td></td><td></td><td colspan="2">X j? ^CH3</td><td></td><td></td><td></td>

<td></td><td></td><td>1 O?</td><td>N</td><td></td><td></td><td></td>

<td> 145</td><td>Q.</td><td>V O = S = zO</td><td>X</td><td> 539,6586</td><td> 58</td><td> 538</td>

<td></td><td></td><td>/ - N CH, M OH</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, O i X</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ό IsT '</td><td> 4</td><td></td><td></td><td></td>

<td> 146</td><td></td><td>φ o = s = o 1</td><td>CH,</td><td> 511,6044</td><td> 80</td><td> 512</td>

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

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

<td></td><td></td><td>CH, 0</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>i X</td><td>t</td><td></td><td></td><td></td>

<td> 147</td><td>X</td><td>V o = s — o —K / OH CH,</td><td>CH,</td><td> 505,6411</td><td> 90</td><td> 506</td>

EE 200000291Α

164

<td>Table 3:</td><td colspan="5"></td><td colspan="2"> 1</td><td></td>

<td>An example no</td><td colspan="5">Structure</td><td>M fg / mol</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td></td><td>o II</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Λ</td><td>com</td><td></td><td></td><td></td><td></td><td></td>

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

<td> 148</td><td></td><td> 1</td><td></td><td></td><td>CH,</td><td> 565,70</td><td> 38</td><td> 566</td>

<td></td><td></td><td>rti</td><td>OH</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>1 AA</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>o II</td><td>y^CHj</td><td></td><td></td><td></td>

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

<td> 149</td><td colspan="2">* 3 ^ 0 L ^c 0 \</td><td>T = s = o V 6 of</td><td>o</td><td>CH, CH,</td><td> 643,77</td><td> 85</td><td> 644</td>

EE 200000291 Α

165

<td>An example no</td><td colspan="2">Structure</td><td>M fg / mol]</td><td>HPLC</td><td>Μ + H</td>

<td></td><td colspan="2"> ?^H3 2 CH,</td><td></td><td></td><td></td>

<td></td><td>Ό ιτγΑ (Γ ^N V</td><td>N</td><td></td><td></td><td></td>

<td> 150</td><td>O = S = rO H, C-N OH</td><td>CH,</td><td> 525,63</td><td> 80</td><td> 526</td>

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

<td></td><td>CH, 0 L Jt</td><td>A</td><td></td><td></td><td></td>

<td></td><td>Ο / L /^N(j</td><td>i</td><td></td><td></td><td></td>

<td> 151</td><td>O = s — O</td><td>CH,</td><td> 525,63</td><td> 78</td><td> 526</td>

<td></td><td>O ^ⁿ^°^h</td><td></td><td></td><td></td><td></td>

EE 200000291 Α

166

<td>An example no</td><td colspan="3">Structure</td><td>MG [g / ha</td><td>HPLC</td><td>M + H</td>

<td></td><td>CH 0 l JL</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Ό p</td><td> &gt;</td><td></td><td></td><td></td><td></td>

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

<td></td><td>o = s = o |</td><td></td><td>CH,</td><td></td><td></td><td></td>

<td> 152</td><td>0 Λ</td><td></td><td></td><td> 560,63</td><td> 51</td><td> 561</td>

<td></td><td>o-</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH, 0 1 X</td><td>Λ</td><td></td><td></td><td></td><td></td>

<td></td><td>Ό hrp; (Γ j</td><td></td><td></td><td></td><td></td><td></td>

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

<td> 153</td><td>o = s = o ή</td><td></td><td>CH,</td><td> 503,65</td><td> 78</td><td> 504</td>

<td></td><td>L H, C ^XCH,</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

167

<td>An example no</td><td>Structure</td><td>M [g / mol |</td><td>HPLC</td><td>Μ + H</td>

<td> 154</td><td>CH, 0n and others o = s = o ή o</td><td> 522,63</td><td> 82</td><td> 523</td>

<td> 155</td><td>l pr o = s = o 9th c /^J1 CH,</td><td> 502,60</td><td> 84</td><td> 503</td>

EE 200000291 Α

168

<td>An example no</td><td colspan="2">Structure</td><td>M fg / raol |</td><td>HPLC</td><td>M + H</td>

<td></td><td>CR O Ü X</td><td></td><td></td><td></td><td></td>

<td></td><td>ϊ A</td><td> $</td><td></td><td></td><td></td>

<td></td><td>fW '</td><td></td><td></td><td></td><td></td>

<td> 156</td><td>X</td><td>CH,</td><td> 488,57</td><td> 83</td><td> 489</td>

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

<td></td><td>y HO</td><td></td><td></td><td></td><td></td>

<td></td><td>CH 0 i</td><td></td><td></td><td></td><td></td>

<td></td><td>ϊ Π</td><td> 4</td><td></td><td></td><td></td>

<td></td><td>A. As</td><td rowspan="2"></td><td></td><td></td><td></td>

<td></td><td>(ιΥΆ</td><td></td><td></td><td></td>

<td></td><td>φ</td><td rowspan="2">CH,</td><td></td><td></td><td></td>

<td> 157</td><td>o = s = o 0</td><td> 536,66</td><td> 82</td><td> 537</td>

<td></td><td>sr Λ</td><td></td><td></td><td></td><td></td>

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

EE 200000291 Α

169

<td>An example no</td><td>Structure</td><td>Μ Ig / mol]</td><td>HPLC</td><td>M + H</td>

<td> 158</td><td>CH, 0 α xr XC T CH, O = S = O 1^NA^C!‘³1 CH,</td><td> 490,63</td><td> 90</td><td> 491</td>

<td> 159</td><td>CH, ⁰ CH^Ν'' ^ Ά o = s = o 0 ό</td><td> 537,65</td><td> 83</td><td> 538</td>

170

<td>An example no</td><td colspan="3">Structure</td><td>W Jg / moIJ</td><td>HPLC</td><td>M + H</td>

<td></td><td>CH, 1</td><td>O</td><td> /^CH3</td><td></td><td></td><td></td>

<td></td><td>Ό</td><td colspan="2">pk / p N \</td><td></td><td></td><td></td>

<td> 160</td><td></td><td></td><td></td><td> 504,66</td><td> 91</td><td> 505</td>

<td></td><td>O II —Ω— ' II</td><td>Ό</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td> 1</td><td>'' CH ...</td><td></td><td></td><td></td>

<td></td><td></td><td>k</td><td>XH,</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>Λ P</td><td></td><td></td><td></td>

<td></td><td></td><td>% Ar</td><td>pk Vc</td><td></td><td></td><td></td>

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

<td> 161</td><td colspan="2">o = s = o</td><td>CH,</td><td> 589,81</td><td> 65</td><td> 590</td>

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

<td></td><td></td><td></td><td>| ΡΌ + 1</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>XH,</td><td></td><td></td><td></td>

EE 200000291Α

171

<td>An example no</td><td>Structure</td><td>M [g / mol J</td><td>HPLC</td><td>M + H</td>

<td> 162</td><td>CH, O T CH. o = s = o ό \ —N \ CH,</td><td> 488,61</td><td> 88</td><td> 489</td>

<td> 163</td><td>9b ⁰ ΓΗ ! M ΑΑ · --ς T CH, O = Sr = O H, C</td><td> 566,73</td><td> 32</td><td> 567</td>

EE 200000291 Α

172

<td>An example no</td><td>Structure</td><td>M Ig / Lm</td><td>HPLC</td><td>M + H</td>

<td> 164</td><td>CH, O XN v T CH, o = s = o X i N^Z N vJ</td><td> 501,61</td><td> 75</td><td> 502</td>

<td> 165</td><td>3f yZ ° = XX i_y ° ZZ \ o \ o ) —Sf 3?</td><td> 491,61</td><td> 91</td><td> 492</td>

<td> 166</td><td>ζ, xc Ayy 1 CH, o = s = o</td><td> 477,59</td><td> 73</td><td> 478</td>

EE 200000291 Α

173

<td>Maide no</td><td>Structure</td><td>M fg / mol</td><td>HPLC</td><td>M + H</td>

<td> 167</td><td>CH, O Chiral o — s = o α^-*³</td><td> 525,63</td><td> 81</td><td> 526</td>

<td> 168</td><td> ?^H3 ⁰ rw ! ϊ^Λό A \ T CH, o = s = o 1 cr^No-⁷</td><td> 488,57</td><td> 70</td><td> 489</td>

174

<td>An example no</td><td colspan="4">Structure</td><td>M Ig / raol]</td><td>HPLC</td><td>Μ + H</td>

<td></td><td></td><td></td><td> 0</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">Ό Ν ^ γ = AY</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>YY '</td><td></td><td>s</td><td></td><td></td><td></td>

<td> 169</td><td></td><td>o = s = o I</td><td></td><td>CH,</td><td> 511,60</td><td> 76</td><td> 512</td>

<td></td><td></td><td>1 Q-^N</td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td></td><td>ü</td><td>0 li</td><td>X</td><td></td><td></td><td></td>

<td></td><td></td><td>ό</td><td></td><td>r $</td><td></td><td></td><td></td>

<td> 170</td><td></td><td>Y</td><td></td><td rowspan="2">CH,</td><td> 568,70</td><td> 50</td><td> 569</td>

<td></td><td>OH I</td><td>o = s =</td><td> 0</td><td></td><td></td><td></td>

<td></td><td>s</td><td>j</td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td></td><td>^cc</td><td>o il</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>% 9t</td><td>p</td><td>Y</td><td></td><td></td><td></td>

<td> 171</td><td>OH I</td><td>y o = s = o</td><td></td><td>\ CH,</td><td> 554,67</td><td> 63</td><td> 555</td>

<td></td><td>s</td><td>j XV^N</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Η /% Ύ</td><td>AJ</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

175

<td>An example no</td><td colspan="3">Structure</td><td>M Ig / molJ</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>Ü Λ</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ι ± A</td><td></td><td></td><td></td><td></td>

<td> 172</td><td>OH |</td><td>_L</td><td>CH,</td><td> 582,73</td><td> 50</td><td> 583</td>

<td></td><td></td><td>| i / r^N</td><td></td><td></td><td></td><td></td>

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

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

<td></td><td></td><td>i f&gt; AAc</td><td> ,ⁿ</td><td></td><td></td><td></td>

<td> 173</td><td>ü</td><td>Y</td><td rowspan="2">J CH,</td><td> 637,76</td><td> 30</td><td> 638</td>

<td></td><td>f</td><td>o = s = o ) AV^N</td><td></td><td></td><td></td>

<td></td><td></td><td>7j</td><td></td><td></td><td></td><td></td>

EE 200000291 Α

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<img file="EE200000291A_D0157.tif" />

EE 200000291 Α

177

<td>Table 4:</td><td></td><td></td><td> |</td><td></td>

<td>An example no</td><td>Structure</td><td>M Ig / raol)</td><td>HPLC</td><td>Μ + H</td>

<td> 176</td><td>7, \ Γ AA I CH- O = S = r0 hA ^ AA CH,</td><td> 477,59</td><td> 82</td><td> 478</td>

<td> 177</td><td>CH, ° ru AA AAA T CH, o = s — 0 ^ ° γΑ CH,</td><td> 491,61</td><td> 89</td><td> 492</td>

<td> 178</td><td>CH, ⁰ PH you. AA T CH, o = s = o 1 x ° A ch,</td><td> 505,64</td><td> 88</td><td> 506</td>

178

<td>An example no</td><td>Structure</td><td>M [g / raol]</td><td>HPLC</td><td>M + H</td>

<td> 179</td><td>° CH ό X T CH, AN O = S = O H, C</td><td> 513,62</td><td> 47</td><td> 514</td>

<td> 180</td><td>⁰ CH XX Xx 1 CH, CH = S = 0 i ³ | hX^NVX /ⁿXh,</td><td> 504,66</td><td> 83</td><td> 505</td>

<td> 181</td><td>CH, ⁰ CH 7 Xx Xx CLt "Γ</td><td> 552,70</td><td> 83</td><td> 553</td>

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<td>An example no</td><td colspan="4">Structure</td><td>M fg / mol}</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>CH, r</td><td>o II</td><td>y^CH&gt;</td><td></td><td></td><td></td>

<td></td><td></td><td>O t&gt; fV</td><td>Ά V</td><td> $</td><td></td><td></td><td></td>

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

<td> 182</td><td></td><td>T O = S2 = O</td><td></td><td>CH,</td><td> 492.60</td><td> 72</td><td> 493</td>

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

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

<td></td><td>r OH</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>ü</td><td>o</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>ύ</td><td>ί</td><td></td><td></td><td></td>

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

<td></td><td></td><td>1 0 — s = o</td><td></td><td>CH,</td><td></td><td></td><td></td>

<td> 183</td><td>c</td><td>.N</td><td></td><td></td><td> 593,75</td><td> 52</td><td> 594</td>

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

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<td>An example nr '</td><td colspan="2">Structure</td><td>M (g / mol</td><td>HPLC</td><td>M + H</td>

<td></td><td>CH, 1</td><td>Et al</td><td></td><td></td><td></td>

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

<td></td><td></td><td>I 1, N</td><td></td><td></td><td></td>

<td></td><td>Λ</td><td>Px .Np ' PP</td><td></td><td></td><td></td>

<td> 184</td><td></td><td>CH,</td><td> 504,66</td><td> 82</td><td> 505</td>

<td></td><td>o = s =</td><td> 0 *</td><td></td><td></td><td></td>

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

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

<td></td><td>Η, Ο-'Ν ^CH3</td><td></td><td></td><td></td><td></td>

<td></td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>CH. P</td><td>ip³</td><td></td><td></td><td></td>

<td></td><td>Ό</td><td>pA</td><td></td><td></td><td></td>

<td></td><td>ίΤΎ</td><td>Pp</td><td></td><td></td><td></td>

<td></td><td>1 PP</td><td rowspan="2">s CH,</td><td></td><td></td><td></td>

<td></td><td>0 = s = o</td><td></td><td></td><td></td>

<td> 185</td><td> 1</td><td></td><td> 582,75</td><td> 59</td><td> 583</td>

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

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

EE 200000291 Α

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<td>An example no</td><td colspan="5">Structure</td><td>M {g / mol]</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>CH,</td><td>0 II</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ό (fS</td><td>H</td><td> &lt;</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>LJ</td><td></td><td>A,</td><td></td><td></td><td></td><td></td>

<td> 186</td><td></td><td>dictionary- 1</td><td>: O</td><td></td><td>CH,</td><td> 566,68</td><td> 60</td><td> 567</td>

<td></td><td>f</td><td>V^N</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>j</td><td>J Ό</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, 1</td><td>0 II</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>% Λ</td><td>L Αχ. / fk</td><td>j</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>o = s =</td><td>Ό</td><td></td><td>CH,</td><td></td><td></td><td></td>

<td> 187</td><td>ζ</td><td> 1</td><td></td><td></td><td></td><td> 579,73</td><td> 30</td><td> 580</td>

<td></td><td></td><td>o.</td><td>CH,</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

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<td>An example no</td><td colspan="3">Structure</td><td>M [g / min</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>ChL 0 1 X</td><td>γ</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>6th XL</td><td></td><td></td><td></td>

<td> 188</td><td></td><td>φ 0 — s = o |</td><td>s CH,</td><td> 548,63</td><td> 73</td><td> 549</td>

<td></td><td>I</td><td>^ γΝ</td><td></td><td></td><td></td><td></td>

<td></td><td>X i /</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">CL 0</td><td></td><td></td><td></td><td></td>

<td></td><td>ii</td><td>'Ο Ι ^ Ύ</td><td> $</td><td></td><td></td><td></td>

<td></td><td>(I</td><td>χχΧ</td><td></td><td></td><td></td><td></td>

<td> 189</td><td>o =</td><td>= S — Ο</td><td>CH,</td><td> 548,63</td><td> 72</td><td> 549</td>

<td></td><td>f / r</td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td>L L</td><td>-Ν &gt;</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>/ 'Ν</td><td></td><td></td><td></td><td></td>

EE 200000291Α

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<td>An example no</td><td colspan="4">Structure</td><td>M (g / mol)</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>CH, 1</td><td>o II</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>or ΓΎ</td><td>^r'r</td><td>c</td><td></td><td></td><td></td>

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

<td> 190</td><td></td><td>o = s = o</td><td></td><td>CH,</td><td> 559,67</td><td> 54</td><td> 560</td>

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

<td></td><td>A</td><td>J</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>H, C</td><td> %</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, 1</td><td>0 Η</td><td>CH3</td><td></td><td></td><td></td>

<td></td><td></td><td>^ko / Α /</td><td>• M</td><td></td><td></td><td></td><td></td>

<td> 191</td><td></td><td> 44</td><td></td><td rowspan="2"> 4</td><td> 511,60</td><td> 70</td><td> 512</td>

<td></td><td>OH j</td><td colspan="2">o = s = o</td><td></td><td></td><td></td>

<td></td><td> 4</td><td>V^N</td><td></td><td></td><td></td><td></td><td></td>

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

EE 200000291 Α

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<td>An example no</td><td>Structure</td><td>Μ [g / mol]</td><td>HPLC</td><td>M + H</td>

<td> 192</td><td>CH, θ ΓΗ '-, 1 1 ι /,^ΝΛΗ Π £ \ Τ CH, \ / O = S = O ³ —^Ν- \ / α_ν ___ Ό</td><td> 580,76</td><td> 68</td><td> 581</td>

<td> 193</td><td>ζ, Λα Αχ Τ CH, O = S =: O 1 H, C. .Ν \³ Ν CH, 1 CH,</td><td> 476,60</td><td> 89</td><td> 477</td>

<td> 194</td><td>CH, ° ru Ά άΑ I CH, o = s = o</td><td> 583,71</td><td> 80</td><td> 584</td>

185

<td>An example no</td><td colspan="2">Structure</td><td>M [g / mol]</td><td>HPLC</td><td>m + h</td>

<td></td><td>CA.</td><td>Λ P</td><td></td><td></td><td></td>

<td> 195</td><td>Ό N ' (Y</td><td>x&gt; N</td><td> 505,64</td><td> 84</td><td> 506</td>

<td></td><td>o = s = o 1</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>CH, 0 II</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td colspan="2">AY</td><td></td><td></td><td></td>

<td> 196</td><td>AX</td><td rowspan="2">CH. CH,</td><td> 518,68</td><td> 40</td><td> 519</td>

<td></td><td>o — s = o j</td><td></td><td></td><td></td>

<td></td><td>CH,</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>ü et al</td><td>com</td><td></td><td></td><td></td>

<td></td><td>Y</td><td> 1</td><td></td><td></td><td></td>

<td></td><td>V</td><td>X</td><td></td><td></td><td></td>

<td> 197</td><td>1 o = s = o 9th ϋ</td><td>CH,</td><td> 528,68</td><td> 82 ?</td><td> 529</td>

EE 200000291 Α

186

<td>An example no</td><td colspan="4">Structure</td><td>M [g / mol</td><td>HPLC</td><td>Μ + H</td>

<td></td><td></td><td> 0</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">Ό AA &lt;</td><td> 4</td><td></td><td></td><td></td><td></td>

<td></td><td>AA</td><td></td><td></td><td rowspan="2">Cb</td><td></td><td></td><td></td>

<td></td><td>o = s = o I</td><td></td><td></td><td></td><td></td><td></td>

<td> 198</td><td>0 Al</td><td></td><td></td><td></td><td> 566,68</td><td> 63</td><td> 567</td>

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

<td></td><td>o o—</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH, I</td><td></td><td>o II</td><td>γ</td><td></td><td></td><td></td>

<td></td><td>^ko Λ</td><td>f</td><td>A /^N' N</td><td>i</td><td></td><td></td><td></td>

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

<td> 199</td><td>V o = s = I</td><td> =0</td><td></td><td>CH,</td><td> 553,69</td><td> 87</td><td> 554</td>

<td></td><td>1 lf</td><td>k</td><td></td><td></td><td></td><td></td><td></td>

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

EE 200000291Α

187

<img file="EE200000291A_D0158.tif" />

EE 200000291Α

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<td colspan="9">Tahel5 | jj</td>

<td>An example no</td><td colspan="4">Structure</td><td>M</td><td>HPLC</td><td colspan="2">M + H</td>

<td></td><td></td><td>c</td><td>o ll</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ό llY</td><td>Λ sx</td><td></td><td></td><td></td><td></td><td></td>

<td> 201</td><td></td><td>I o = s = o</td><td></td><td>Ci</td><td> 516,67</td><td> 87</td><td> 517</td><td></td>

<td></td><td></td><td>N r^J 0</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>^CH3 I</td><td> 0</td><td>r-Ci</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">/ LX // Ni Y^N</td><td> &gt;</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>XX</td><td></td><td rowspan="2">Ci</td><td></td><td></td><td></td><td></td>

<td> 202</td><td></td><td>o = s = o I</td><td></td><td> 502,64</td><td> 84</td><td> 503</td><td></td>

<td></td><td></td><td>I N J</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>I uh</td><td></td><td></td><td></td><td></td><td></td><td></td>

EE 200000291Α

189

<td>Shark no</td><td colspan="3">Structure</td><td>M</td><td>HPLC</td><td>M +</td><td colspan="2">H</td>

<td></td><td></td><td>o</td><td>CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td colspan="3">AA- &lt;A</td><td></td><td></td><td></td><td></td><td></td>

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

<td> 203</td><td>o = s = o</td><td></td><td>CH,</td><td> 516,67</td><td> 87</td><td> 517</td><td></td><td></td>

<td></td><td>N</td><td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>ü</td><td>ί r</td><td>-CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Ό ί rV</td><td>y</td><td></td><td></td><td></td><td></td><td></td><td></td>

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

<td> 204</td><td>I o = s = o I</td><td></td><td>CH,</td><td> 538,67</td><td> 91</td><td> 539</td><td></td><td></td>

<td></td><td>f N k</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>I</td><td>Π</td><td></td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td>—O</td><td>0 II</td><td>r-CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Ό Λ</td><td>A fV</td><td> &gt;</td><td></td><td></td><td></td><td></td><td></td>

<td> 205</td><td>Ύ O = S—</td><td>-O</td><td>CH,</td><td> 533,7</td><td> 85</td><td> 534</td><td></td><td></td>

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

<td></td><td>H, C</td><td>^ CH,</td><td></td><td></td><td></td><td></td><td></td><td></td>

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<td>An example no</td><td colspan="2">Structure</td><td>M</td><td>HPLC</td><td>M +</td><td colspan="2">H</td>

<td></td><td>CH, O I 11</td><td>y-CH,</td><td></td><td></td><td></td><td></td><td></td>

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

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

<td> 206</td><td>o = s = o I</td><td>CH,</td><td> 518,68</td><td> 77</td><td> 519</td><td></td><td></td>

<td></td><td>I N</td><td></td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td>I CH,</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH, O l il</td><td>r-CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>o Jp AA/^N</td><td></td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td>Oh — S ~ o</td><td>CH,</td><td></td><td></td><td></td><td></td><td></td>

<td> 207</td><td>I N</td><td></td><td> 566,73</td><td> 92</td><td> 567</td><td></td><td></td>

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

<td></td><td>r?</td><td></td><td></td><td></td><td></td><td></td><td></td>

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

EE 200000291Α

191

<img file="EE200000291A_D0159.tif" />

192

<td>An example no</td><td colspan="3">Structure</td><td>M</td><td>HPLC</td><td>M +</td><td colspan="2">H</td>

<td></td><td colspan="2"></td><td>0 r-^CH3</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> (|</td><td colspan="2"> 1 16</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> [1</td><td colspan="2">P ^Ly</td><td></td><td></td><td></td><td></td><td></td>

<td> 210</td><td>o =</td><td>s = |</td><td>^c’</td><td> 560,72</td><td> 62</td><td> 561</td><td></td><td></td>

<td></td><td></td><td>1 N</td><td></td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td>CH, 1</td><td></td><td>ϊ y</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>% Ä</td><td> %</td><td>yy</td><td></td><td></td><td></td><td></td><td></td>

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

<td> 211</td><td>1 O = S— I</td><td> -0</td><td>CH,</td><td> 568,7</td><td> 88</td><td> 569</td><td></td><td></td>

<td></td><td>1 N ή</td><td></td><td>P</td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td>CH, i</td><td></td><td>IF</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>y rS</td><td>r</td><td>yy</td><td></td><td></td><td></td><td></td><td></td>

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

<td> 212</td><td colspan="2">o = s = o 1</td><td>CH,</td><td> 582,73</td><td> 89</td><td> 583</td><td></td><td></td>

<td></td><td>N I</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Λ</td><td></td><td>/ CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>u</td><td></td><td>/ V- OH</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291Α

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<img file="EE200000291A_D0160.tif" />

EE 200000291Α

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<td>An example no</td><td colspan="4">Structure</td><td>M</td><td>HPLC</td><td>M +</td><td>H</td>

<td></td><td></td><td>O II</td><td>r</td><td>-CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>Ό t / (ΙΊ</td><td>r , Ζ '</td><td> &lt;</td><td></td><td></td><td></td><td></td><td></td>

<td> 216</td><td>ΟΣ = s = o</td><td></td><td></td><td>CH,</td><td> 548,71</td><td> 78</td><td> 549</td><td></td>

<td></td><td>1 HO</td><td> 1</td><td>CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>hA</td><td>J</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH,</td><td>O</td><td></td><td>r-CH,</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="3">% / N (ΑτΆμ</td><td>N</td><td></td><td></td><td></td><td></td>

<td> 217</td><td>\ J</td><td></td><td></td><td></td><td> 490,63</td><td> 87</td><td> 491</td><td></td>

<td></td><td>o = s = o j</td><td></td><td></td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>³ N CH, I ⁵</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH,</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH, | *</td><td>0 II</td><td> /</td><td>-CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>Ό N</td><td>4 S&gt; .NN</td><td> 4 4</td><td>N</td><td></td><td></td><td></td><td></td>

<td> 218</td><td>\ J CH, O = S-0</td><td></td><td></td><td>CH,</td><td> 532,71</td><td> 93</td><td> 533</td><td></td>

<td></td><td colspan="2">L _N. .CH, ^ CH,</td><td></td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

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<img file="EE200000291A_D0161.tif" />

196

<td>taiete no</td><td colspan="3">Structure</td><td>M</td><td>HPLC</td><td>M +</td><td>H</td>

<td></td><td colspan="2">CH, 0 __ 1 II Λ</td><td>X</td><td></td><td></td><td></td><td></td>

<td></td><td>ii</td><td colspan="2">Xv^Nf</td><td></td><td></td><td></td><td></td>

<td> 221</td><td>(I</td><td>sJ</td><td></td><td> 516,67</td><td> 92</td><td> 517</td><td></td>

<td></td><td>o—</td><td>: S = O 1</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2"></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Xh,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH, 0 1 night</td><td>/ —- CH,</td><td></td><td></td><td></td><td></td>

<td> 222</td><td></td><td>j jj XT^N</td><td></td><td> 504,66</td><td> 83</td><td> 505</td><td></td>

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

<td></td><td>CX</td><td>I O = SrrO |</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>/ N</td><td>/ X A / CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH. 0 Yeah</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ό J AJ</td><td>A nX</td><td></td><td></td><td></td><td></td>

<td> 223</td><td></td><td>U</td><td></td><td> 558,75</td><td> 90</td><td> 559</td><td></td>

<td></td><td>r ~ \</td><td>T o = s = o</td><td>^CX</td><td></td><td></td><td></td><td></td>

<td></td><td>xx</td><td>CH,</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

197

<td>An example no</td><td colspan="3">Structure</td><td>M</td><td>HPLC</td><td>M +</td><td>H</td>

<td></td><td>CH, 0 I li</td><td>r</td><td>ch₃</td><td></td><td></td><td></td><td></td>

<td></td><td>ΛΑ-</td><td>A</td><td></td><td></td><td></td><td></td><td></td>

<td> 224</td><td></td><td></td><td></td><td> 532,71</td><td> 86</td><td> 533</td><td></td>

<td></td><td>0 — S = o |</td><td>cn,</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>T^cY^NvZA CH,</td><td>^Ach₃</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH,</td><td>i /</td><td>—CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>O Λ</td><td>A;</td><td>N</td><td></td><td></td><td></td><td></td>

<td> 225</td><td></td><td></td><td></td><td> 572,78</td><td> 68</td><td> 573</td><td></td>

<td></td><td>T CH, O = S-0 I ³ ·</td><td></td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>-'A</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>ü</td><td>S r</td><td>'CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>Ό hT LL</td><td>^Är&gt; nA</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>u</td><td>V.</td><td>Λ</td><td></td><td></td><td></td><td></td>

<td> 226</td><td colspan="2">O = S = O HO Α⁰³</td><td>CH,</td><td> 582,73</td><td> 87</td><td> 583</td><td></td>

<td></td><td>J N— J</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Q.</td><td></td><td></td><td></td><td></td><td></td><td></td>

EE 200000291Α

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<td>An example no</td><td colspan="4">Structure</td><td>M</td><td>HPLC</td><td>M +</td><td>H</td>

<td></td><td colspan="4">&lt;A o _ch,</td><td></td><td></td><td></td><td></td>

<td></td><td>f</td><td colspan="2">AAvⁿaⁿ</td><td></td><td></td><td></td><td></td><td></td>

<td> 227</td><td>[I 0 = h₃c-</td><td>= s = o N °^H</td><td>Y N -CH,</td><td>CH,</td><td> 548,71</td><td> 85</td><td> 549</td><td></td>

<td></td><td></td><td>Ü</td><td>0 II</td><td>γΗ,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>/ b ·</td><td>Αλ</td><td></td><td></td><td></td><td></td><td></td>

<td> 228</td><td>h, c— \ N- L</td><td>\ ν o = s = Ά&gt; \ —N</td><td>b</td><td>CH,</td><td> 594,78</td><td> 97</td><td> 595</td><td></td>

<td></td><td></td><td>CH, ί</td><td>o u /</td><td>—CH,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CO (V</td><td>LJ,</td><td>N</td><td></td><td></td><td></td><td></td>

<td> 229</td><td></td><td>V o = s = o</td><td></td><td>CH,</td><td> 590,75</td><td> 90</td><td> 591</td><td></td>

<td></td><td></td><td colspan="3">Ά N, °</td><td></td><td></td><td></td><td></td>

EE 200000291 Α

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<img file="EE200000291A_D0162.tif" />

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<td>An example ,. Μ. .</td><td colspan="2">Structure</td><td>M</td><td>HPLC</td><td>M +</td><td>H</td>

<td></td><td>CH, Ο l Ö /</td><td>—CH,</td><td></td><td></td><td></td><td></td>

<td> 233</td><td>ΧΑ Χρ φ ^Ν</td><td>Ν</td><td> 534,68</td><td> 65</td><td> 535</td><td></td>

<td></td><td>O = S = O CH,</td><td>ch,</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">/ χ / Ρ / Ρ HCT Ρη,</td><td></td><td></td><td></td><td></td>

<td></td><td>CH, 0 ϊ II Γ</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>Ό ^Ν|^_νΛΑχ</td><td></td><td></td><td></td><td></td><td></td>

<td> 234</td><td>o = s = o Μ ΟΗ CH, \ - Ν X</td><td></td><td> 520,66</td><td> 83</td><td> 521</td><td></td>

<td></td><td>ϋ 5</td><td>pCH,</td><td></td><td></td><td></td><td></td>

<td> 235</td><td>Ό Xp Α</td><td> &lt;</td><td> 530,69</td><td> 89</td><td> 531</td><td></td>

<td></td><td>τ o = s = o &lt;ΧΧ-^Ν~ ^CH3</td><td>CH,</td><td></td><td></td><td></td><td></td>

EE 200000291Α

201

<td>Wharf no</td><td colspan="3">Structure</td><td>M</td><td>HPLC</td><td>M +</td><td>H</td>

<td></td><td>L</td><td> 0 ||</td><td>r-CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>Ό</td><td>X</td><td> 5</td><td></td><td></td><td></td><td></td>

<td></td><td rowspan="2">X o = s = o ή</td><td>ΑΧ</td><td rowspan="2">Y CL</td><td></td><td></td><td></td><td></td>

<td> 236</td><td></td><td> 542,71</td><td> 70</td><td> 543</td><td></td>

<td></td><td>T 0</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CL ί</td><td> 0 ||</td><td>^ CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>X</td><td>Χγ</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Α, N.</td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td>I AA</td><td></td><td rowspan="2">X</td><td></td><td></td><td></td><td></td>

<td></td><td>o = s = o J</td><td></td><td></td><td></td><td></td><td></td>

<td> 237</td><td>0 Λ</td><td></td><td></td><td> 580,71</td><td> 81</td><td> 581</td><td></td>

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

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

202

<td>An example no</td><td colspan="4">Structure</td><td>M</td><td>HPLC</td><td>M +</td><td>H</td>

<td></td><td colspan="2">CH, O t 1!</td><td></td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>if</td><td>Ό Ν ‘^ Χ; A / N- YN</td><td>γ</td><td></td><td></td><td></td><td></td><td></td>

<td> 238</td><td> (1</td><td></td><td></td><td></td><td> 504,66</td><td> 81</td><td> 505</td><td></td>

<td></td><td>o =</td><td>: S = O |</td><td></td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>Η / χ /</td><td>, Ν ^^ ΟΗ,</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>1 CH,</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH,</td><td>S r</td><td>-CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>X X</td><td>xx = A Ap</td><td></td><td></td><td></td><td></td><td></td><td></td>

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

<td> 239</td><td>T o = s = [</td><td> 0</td><td>θΑ</td><td></td><td> 551,67</td><td> 86</td><td> 552</td><td></td>

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

<td></td><td>u 1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

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

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

<td></td><td>ü</td><td>5 r</td><td>-CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Ό X</td><td>iXpX Ap</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 240</td><td>V o = s = 1</td><td> -0</td><td>CH,</td><td></td><td> 518,68</td><td> 85</td><td> 519</td><td></td>

<td></td><td>1 XX</td><td>ΆΧγ 1</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>ΤΗ,</td><td></td><td></td><td></td><td></td><td></td><td></td>

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<img file="EE200000291A_D0163.tif" />

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<td colspan="3">Table 6</td><td></td><td colspan="2"></td>

<td>An example no</td><td colspan="2">Structure</td><td>M</td><td>HPLC</td><td>M + H</td>

<td></td><td>ChL O l et al</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>/ A Aa / N-</td><td>X</td><td></td><td></td><td></td>

<td> 243</td><td>1 j ^N</td><td></td><td> 477,5869</td><td> 86</td><td> 478</td>

<td></td><td>o = s = o f</td><td>Cb</td><td></td><td></td><td></td>

<td></td><td>N</td><td>Cb</td><td></td><td></td><td></td>

<td></td><td>ü 1</td><td></td><td></td><td></td><td></td>

<td></td><td>'ό _fZ AAr</td><td> 4</td><td></td><td></td><td></td>

<td> 244</td><td></td><td>Χγ</td><td> 495,605</td><td> 62</td><td> 496</td>

<td></td><td>o = s = o</td><td>Cb</td><td></td><td></td><td></td>

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

<td></td><td>k</td><td>J</td><td></td><td></td><td></td>

<td></td><td>ü i</td><td>Cb</td><td></td><td></td><td></td>

<td></td><td>ί X "^rÄA ^.</td><td></td><td></td><td></td><td></td>

<td> 245</td><td>V</td><td></td><td> 511,6044</td><td> 50</td><td> 512</td>

<td></td><td>T o = s = o</td><td>Cb</td><td></td><td></td><td></td>

<td></td><td> | ^NUh</td><td></td><td></td><td></td><td></td>

<td></td><td>XX-</td><td>_Ab</td><td></td><td></td><td></td>

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205

<td>An example no</td><td colspan="4">Structure</td><td>M</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>o II</td><td></td><td>X</td><td></td><td></td><td></td>

<td></td><td>ίίΊ</td><td>Ά</td><td>r rc</td><td>X</td><td></td><td></td><td></td>

<td></td><td>X4</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 246</td><td>o = s = o 1</td><td>α</td><td></td><td>CH,</td><td> 564,495</td><td> 40</td><td> 565</td>

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

<td></td><td>cY</td><td></td><td>lj</td><td></td><td></td><td></td><td></td>

<td></td><td>CH. ü</td><td>o</td><td></td><td>X</td><td></td><td></td><td></td>

<td></td><td>X (ΓΎ</td><td colspan="2">fr</td><td> /</td><td></td><td></td><td></td>

<td></td><td>XJ</td><td></td><td></td><td rowspan="2">A cx</td><td></td><td></td><td></td>

<td> 247</td><td>o = s = o 1</td><td></td><td></td><td> 555,658</td><td> 61</td><td> 556</td>

<td></td><td> 1 ^N\</td><td></td><td> ¥</td><td>o / 5</td><td></td><td></td><td></td>

<td></td><td></td><td> 4/</td><td>II</td><td>^ CH,</td><td></td><td></td><td></td>

<td></td><td>ü</td><td>o II</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Ό (V</td><td>A V</td><td>r rc</td><td>X</td><td></td><td></td><td></td>

<td> 248</td><td>τ o = s = o |</td><td></td><td></td><td>CX</td><td> 497,5773</td><td> 60</td><td> 498</td>

<td></td><td>Y</td><td>X</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>A</td><td>o I</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td colspan="2">CH,</td><td></td><td></td><td></td>

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<td>An example no</td><td colspan="2">Structure</td><td>M</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>CH, Ο _rHY Ai XX</td><td></td><td></td><td></td>

<td> 249</td><td>YY ° Y</td><td>YX 0 = 1 = 0 Xz^N</td><td> 581,6963</td><td> 77</td><td> 582</td>

<td></td><td>? CH,</td><td>J</td><td></td><td></td><td></td>

<td></td><td>CH, 1</td><td>j? /</td><td></td><td></td><td></td>

<td></td><td>Y XY</td><td>YA Ä XX Ν ξ</td><td></td><td></td><td></td>

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

<td> 250</td><td>o = s = J</td><td>CH, Ό</td><td> 557,6303</td><td> 76</td><td> 558</td>

<td></td><td>Ί</td><td>Pj</td><td></td><td></td><td></td>

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

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

<td></td><td>Ci X</td><td>7</td><td></td><td></td><td></td>

<td></td><td>Y Λ</td><td>1 I /^N/ vX</td><td></td><td></td><td></td>

<td></td><td>u</td><td>s</td><td></td><td></td><td></td>

<td> 251</td><td>Y O = s = I</td><td> 0</td><td> 539,615</td><td> 74</td><td> 540</td>

<td></td><td>N,</td><td>χχ</td><td></td><td></td><td></td>

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

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

<td></td><td></td><td>1 ci</td><td></td><td></td><td></td>

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<img file="EE200000291A_D0164.tif" />

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<td>An example no</td><td colspan="2">Structure</td><td>M</td><td>HPLC</td><td>1M + H</td>

<td></td><td>CH, O 1 li</td><td>ch,</td><td></td><td></td><td></td>

<td></td><td colspan="2">ΛΛ V [/ »0</td><td></td><td></td><td></td>

<td> 255</td><td>A / o = s = o 1 N</td><td>CH,</td><td> 551,5486</td><td> 78</td><td> 552</td>

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

<td></td><td> \</td><td>r</td><td></td><td></td><td></td>

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

<td></td><td>CH, O 11</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td colspan="2">Ό ÄtA /</td><td></td><td></td><td></td>

<td> 256</td><td>AA o = s = o A_j</td><td>CH, : A NHj</td><td> 574,6824</td><td> 59</td><td> 575</td>

<td></td><td>CH, 0 1 II</td><td>ch,</td><td></td><td></td><td></td>

<td></td><td colspan="2">Ό h / = A I 1 1 //^NAh</td><td></td><td></td><td></td>

<td> 257</td><td>o = s = o |</td><td>CH,</td><td> 497,5773</td><td> 40</td><td> 498</td>

<td></td><td>Ά</td><td>OH</td><td></td><td></td><td></td>

209

<td>An example no</td><td colspan="3">Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td></td><td>CH O L 11</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>AA /ⁿ- (X</td><td> &gt;</td><td></td><td></td><td></td><td></td>

<td> 258</td><td>o = s = o |</td><td></td><td>CH,</td><td> 459,5715</td><td> 90</td><td> 460</td>

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

<td></td><td>ü 1</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>? X AA-</td><td> &gt;</td><td></td><td></td><td></td><td></td>

<td> 259</td><td>k O = S — o A</td><td></td><td>X</td><td> 473,5986</td><td> 80</td><td> 474</td>

<td></td><td>Y CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH, 0 l X</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>? X</td><td>ΐ</td><td></td><td></td><td></td><td></td>

<td> 260</td><td>V o = s = o</td><td></td><td>X</td><td> 461,5439</td><td> 83</td><td> 462</td>

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

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

EE 200000291 Α

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<td>An example no</td><td colspan="2">Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td></td><td>CH, r</td><td>H ^CH,</td><td></td><td></td><td></td>

<td></td><td colspan="2">Ϊ ΪΧ Λ As · zM fixr ^N \</td><td></td><td></td><td></td>

<td> 261</td><td>xp O = r S = O 1</td><td>CH,</td><td> 503,6687</td><td> 71</td><td> 504</td>

<td></td><td>AA CH, H, C</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>CH, L</td><td>XA</td><td></td><td></td><td></td>

<td></td><td>Ό A</td><td>AA 1&gt; /^NGet</td><td></td><td></td><td></td>

<td> 262</td><td>V o = s = o 1</td><td> \</td><td> 517,6086</td><td> 71</td><td> 518</td>

<td></td><td>Λ - 0</td><td></td><td></td><td></td><td></td>

<td></td><td>CH, 0 Yeah</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>Ό br '' AA</td><td> 4</td><td></td><td></td><td></td>

<td> 263</td><td>° χ ° x</td><td>CH, ||</td><td> 511,6044</td><td> 76</td><td> 512</td>

<td></td><td>^NAx</td><td>a</td><td></td><td></td><td></td>

<td></td><td colspan="2">o— / o</td><td></td><td></td><td></td>

EE 200000291Α

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<td></td><td></td><td> 2 ^CK&gt;</td><td></td><td></td><td></td>

<td></td><td colspan="2">ϊ ΪΑ In v</td><td></td><td></td><td></td>

<td> 264</td><td>o = s ~ I</td><td></td><td> 518,5989</td><td> 74</td><td> 519</td>

<td></td><td>! N</td><td></td><td></td><td></td><td></td>

<td></td><td>A</td><td>ii</td><td></td><td></td><td></td>

<td></td><td>A ^ a</td><td>Π</td><td></td><td></td><td></td>

<td></td><td>CH, 1</td><td>1 N</td><td></td><td></td><td></td>

<td></td><td>A ίίΊΓ</td><td>The $ N ξ</td><td></td><td></td><td></td>

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

<td> 265</td><td>A o = s =</td><td> 0</td><td> 552,6573</td><td> 91</td><td> 553</td>

<td></td><td>s</td><td>Π</td><td></td><td></td><td></td>

<td></td><td>t</td><td>'kz_;A</td><td></td><td></td><td></td>

<td></td><td>CH, 1</td><td>Λ P</td><td></td><td></td><td></td>

<td></td><td>A k</td><td>nAA AA</td><td></td><td></td><td></td>

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

<td> 266</td><td>T o = s = |</td><td>CHa = O</td><td> 566,6844</td><td> 71</td><td> 567</td>

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

<td></td><td>CH, A</td><td></td><td></td><td></td><td></td>

<td></td><td>Ä</td><td> 1</td><td></td><td></td><td></td>

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

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<td></td><td>CH, I</td><td>o Jl</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>X</td><td>X</td><td> $</td><td></td><td></td><td></td><td></td>

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

<td></td><td>ίίΊ</td><td>N</td><td></td><td></td><td></td><td></td><td></td>

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

<td> 267</td><td>o = s = o I</td><td>O</td><td></td><td>CH,</td><td> 567,6692</td><td> 48</td><td> 568</td>

<td></td><td colspan="2">X ^</td><td colspan="2">X</td><td></td><td></td><td></td>

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

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

<td></td><td>CH, I</td><td>O H</td><td>CL</td><td></td><td></td><td></td><td></td>

<td></td><td>X</td><td>nXa</td><td>L</td><td></td><td></td><td></td><td></td>

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

<td></td><td>tiY</td><td>N</td><td></td><td></td><td></td><td></td><td></td>

<td> 268</td><td>LA</td><td></td><td></td><td>CH,</td><td> 477,6084</td><td> 90</td><td> 478</td>

<td></td><td>o = s = o I</td><td></td><td></td><td></td><td></td><td></td><td></td>

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

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

<td></td><td></td><td>0 χ</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>X I</td><td>Yr</td><td> &lt;</td><td></td><td></td><td></td><td></td>

<td></td><td>X</td><td></td><td>χ</td><td></td><td></td><td></td><td></td>

<td> 269</td><td>Y</td><td></td><td>X</td><td rowspan="2">CL</td><td> 569,6851</td><td> 73</td><td> 570</td>

<td></td><td>O— S = O |</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>t</td><td></td><td>o.</td><td></td><td></td><td></td><td></td>

<td></td><td>L^c</td><td>Y</td><td colspan="2">r ch,</td><td></td><td></td><td></td>

<td></td><td></td><td>Y</td><td colspan="2">YCH,</td><td></td><td></td><td></td>

213

<td>An example no</td><td colspan="3">Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td></td><td colspan="2">CH O 1 II</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>0 N '' '^ XXy</td><td>4 p</td><td></td><td></td><td></td>

<td></td><td>k.</td><td>p</td><td>^ p</td><td></td><td></td><td></td>

<td> 270</td><td>o =</td><td>s = o</td><td>CH,</td><td> 651,766</td><td> 65</td><td> 652</td>

<td></td><td>Π /</td><td>\ Γ</td><td> (1</td><td></td><td></td><td></td>

<td></td><td>T</td><td></td><td>JJ</td><td></td><td></td><td></td>

<td></td><td>o = š = o</td><td></td><td></td><td></td><td></td><td></td>

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

<td></td><td>^CH3 1</td><td>0 II</td><td>p</td><td></td><td></td><td></td>

<td></td><td>y</td><td>hip / P y p N</td><td> &lt;</td><td></td><td></td><td></td>

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

<td> 271</td><td>o = s = 1 p</td><td> =0</td><td>CH,</td><td> 541,6309</td><td> 71</td><td> 542</td>

<td></td><td>ΓΥ</td><td>ΌΗ</td><td></td><td></td><td></td><td></td>

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

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

<td></td><td></td><td>ü</td><td>X 4</td><td></td><td></td><td></td>

<td></td><td></td><td>Ό N rV</td><td>γ</td><td></td><td></td><td></td>

<td> 272</td><td></td><td>T O— s = o I</td><td> \</td><td> 607,6133</td><td> 39</td><td> 608</td>

<td></td><td>ΥϊΎ</td><td> 1 ^\/^N</td><td></td><td></td><td></td><td></td>

<td></td><td>Ρθ / ky F</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

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<td>An example no</td><td colspan="4">Structure</td><td>M</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>0 II</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>F</td><td>1 'aSa</td><td> 5</td><td></td><td></td><td></td><td></td>

<td> 273</td><td>o = s =</td><td> =0</td><td></td><td>CH,</td><td> 511,6044</td><td> 92</td><td> 512</td>

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

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

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

<td></td><td>CH, I</td><td>0 II</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>^ko flV</td><td>bfp: L ΑΝ</td><td> &lt;</td><td></td><td></td><td></td><td></td>

<td> 274</td><td>u</td><td></td><td></td><td></td><td> 589,7164</td><td> &gt;95</td><td> 590</td>

<td></td><td>0 II F 0</td><td>X</td><td> )</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>X 0</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CH I</td><td>0 II</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td>X com ίΑ</td><td>N ^ p? Vⁿ'</td><td>s</td><td></td><td></td><td></td><td></td>

<td> 275</td><td>Ιψ</td><td></td><td></td><td></td><td> 477,5869</td><td> &gt;95</td><td> 478</td>

<td></td><td>o = s = o I</td><td></td><td></td><td>ch₃</td><td></td><td></td><td></td>

<td></td><td>I ζΆ Ζ H, C</td><td>^ OH</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

215

<td>An example. • no</td><td colspan="5">Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td></td><td>CH, I</td><td></td><td>o</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="4">(l ^N \</td><td></td><td></td><td></td><td></td>

<td> - 276</td><td>[I</td><td></td><td></td><td></td><td></td><td> 463,5598</td><td> 64</td><td> 464</td>

<td></td><td>O =:</td><td>; = o</td><td></td><td></td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>"OH</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">CH, I</td><td>O II</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>ό Λγ</td><td>fr -Tr</td><td></td><td></td><td></td><td></td><td></td>

<td> 277</td><td></td><td>u</td><td></td><td></td><td></td><td> 449,5327</td><td> &gt;95</td><td> 450</td>

<td></td><td>O:</td><td>t = s = o</td><td></td><td></td><td>CH,</td><td></td><td></td><td></td>

<td></td><td></td><td>1 N</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>0 II</td><td>CH,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>^ko Λ</td><td>fr Ar-</td><td>j.</td><td></td><td></td><td></td><td></td>

<td> 278</td><td></td><td>LJ</td><td></td><td></td><td></td><td> 507,6134</td><td> &gt;95</td><td> 508</td>

<td></td><td></td><td>1 o = s = /</td><td> 0</td><td></td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>J¹o / o )</td><td> /</td><td> ^^CH&gt;</td><td></td><td></td><td></td><td></td><td></td>

EE 200000291 Α

216

<td>An example no</td><td>Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td> 279</td><td>CH, O ' I CH, o = s = o 0 Α / Νγ⁰° Ί CH,</td><td> 532,6232</td><td> &gt;95</td><td> 533</td>

<td> 280</td><td>CH, O _r, i 9 Ap όΑ T CH, o = s = o X &lt;/^Νγ ° Op / CH, ^ Ih,</td><td> 560,6775</td><td> 89</td><td> 561</td>

EE 200000291 Α

217

<td>An example no</td><td colspan="3">Structure</td><td>M</td><td>HPLC</td><td>M + H</td>

<td></td><td>η</td><td>? f</td><td rowspan="2">: χ</td><td></td><td></td><td></td>

<td></td><td>(f</td><td>A</td><td></td><td></td><td></td>

<td> 281</td><td>o =;</td><td> ? 3=0</td><td></td><td> 636,8199</td><td> 88</td><td> 637</td>

<td></td><td>° o</td><td></td><td>X)</td><td></td><td></td><td></td>

<td></td><td>ca</td><td>0 II</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>Ό Ar</td><td>Ν ''^ΗχA</td><td>A</td><td></td><td></td><td></td>

<td> 282</td><td colspan="2">AA o = s = o /</td><td>A CH,</td><td> 476,5585</td><td> 50</td><td> 477</td>

<td></td><td>&lt;n ok</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>o</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td colspan="2">Ό hT ^ // V</td><td> &lt;</td><td></td><td></td><td></td>

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

<td> 283</td><td>o = s — o 1</td><td></td><td>CH,</td><td> 489,5981</td><td> 93</td><td> 490</td>

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

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

218

<td>An example no</td><td colspan="3">Structure</td><td>M '</td><td>HPLC</td><td>M + H</td>

<td></td><td></td><td>CH, 0 C 1</td><td>CX</td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">Ϊ 1 X AA</td><td></td><td></td><td></td>

<td> 284</td><td></td><td>XX o = s = o \</td><td>CX Π</td><td> 622,7928</td><td> 68</td><td> 623</td>

<td></td><td>cr</td><td>XA_N/ \ y</td><td>JJ</td><td></td><td></td><td></td>

<td></td><td></td><td>CH, 0 1 11</td><td>CX</td><td></td><td></td><td></td>

<td></td><td></td><td>XX</td><td>4 nX</td><td></td><td></td><td></td>

<td> 285</td><td></td><td>V o = s = o</td><td>CH,</td><td> 608,7657</td><td> &gt;95</td><td> 609</td>

<td></td><td>Cf</td><td colspan="2"></td><td></td><td></td><td></td>

<td></td><td colspan="2">CH, O II</td><td> 7</td><td></td><td></td><td></td>

<td></td><td>rf</td><td>1 X</td><td> $</td><td></td><td></td><td></td>

<td></td><td>A</td><td>J</td><td></td><td></td><td></td><td></td>

<td> 286</td><td> 0=</td><td>T : S = O 1</td><td>CX</td><td> 583,6873</td><td> 85</td><td> 584</td>

<td></td><td></td><td>li</td><td>XX</td><td></td><td></td><td></td>

<td></td><td></td><td>UJ</td><td>X</td><td></td><td></td><td></td>

<td></td><td></td><td>1 OH</td><td></td><td></td><td></td><td></td>

EE 200000291Α

219

<td>An example no</td><td>Structure</td><td>M</td><td>HPLC</td><td>M + H</td>

<td> 287</td><td>al T CH, O = S — o jr '</td><td> 511,6044</td><td> &gt;95</td><td> 512</td>

<td> 288</td><td>ζ Xx YY I CH, o = s = o rj^JOH</td><td> 541,6309</td><td> &gt;95</td><td> 542</td>

<td> 289</td><td>L Αγ III .ν X I CH, o = s — o I N H, ^_OXP OH</td><td> 541,6309</td><td> &gt;95</td><td> 542</td>

EE 200000291 Α

220

<td>An example no</td><td>Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td> 290</td><td>k yz ι ι ι / N Ά T CH, μ ° = r ΗΟ ^ γ ^ / 0 bc</td><td> 571,6574</td><td> 73</td><td> 572</td>

<td> 291</td><td>CH, O r « C, AX AA T CH, O = S = O 1 N Ä b</td><td> 569,6851</td><td> 83</td><td> 570</td>

<td> 292</td><td>k AA AA 1 CH, o = s = o 1 N^vkA ° i H, C ^OCH,</td><td> 597,7393</td><td> 89</td><td> 598</td>

221

<img file="EE200000291A_D0165.tif" />

222

<td>An example no</td><td>Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td> 295</td><td>CH. O pu 6Y 1 CH, O = S — o 1 N cX CH,</td><td> 609,7504</td><td> 77</td><td> 610</td>

<td> 296</td><td>CH, Ο _Γμü ΛΑ At T CH, · O = S = O \ N jY CH,</td><td> 583,7122</td><td> 82</td><td> 584</td>

<td> 297</td><td>CH, O γ Υχ T CH, o = s = o \ N oX Οχ CH,</td><td> 611,7227</td><td> 88</td><td> 612</td>

EE 200000291Α

223

<td>An example no</td><td>Structure</td><td>M</td><td>HPLC</td><td>M + H</td>

<td> 298</td><td>CH O X ΛΧ (Xt I CH, o = s = o A cx CH,</td><td> 571,6574</td><td> 89</td><td> 572</td>

<td> 299</td><td>CH, 0p, X AA | I 1 .N XX T CH, O = S = O N^ί:Υ-φ Ύ CH,</td><td> 567,6692</td><td> 81</td><td> 568</td>

<td> 300</td><td>V -V 1 CH, O— s = o 1 N ΑύΑΨ ° C ° ° C,</td><td> 627,7221</td><td> 82</td><td> 628</td>

224

<td>An example no</td><td>Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td> 301</td><td>k Y ι ι ι,^N1 CH, o = s ~ o k-A</td><td> 661,7396</td><td> 64</td><td> 662</td>

<td> 302</td><td>CH. O CU k AX O — s = o 1Y H, C 0-1 ° X</td><td> 599,668</td><td> 77</td><td> 600</td>

<td> 303</td><td>k ay 1 1 'λ^νΥΎ 1 CH, o = s = o \ N • male⁰ j CH, ° 'CH,</td><td> 555,658</td><td> 83</td><td> 556</td>

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<td></td><td></td><td colspan="2">ch / o _ruii ι,ⁿ</td><td></td><td></td><td></td>

<td></td><td></td><td>'va 0 — s = o |</td><td>CH,</td><td></td><td></td><td></td>

<td> 304</td><td> 0</td><td>1 N 4 Ά</td><td></td><td> 654,7916</td><td> 60</td><td> 655</td>

<td></td><td>H, C</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">CH 1</td><td>i T</td><td></td><td></td><td></td>

<td></td><td>ii</td><td>Ό N^xi. Jks //^x</td><td></td><td></td><td></td><td></td>

<td> 305</td><td>H o =</td><td>7th : S = O \</td><td>s CH,</td><td> 626,7374</td><td> 86</td><td> 627</td>

<td></td><td>^ce /, / 6</td><td>N Φ c / CH,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 9₀Ä</td><td> 1 * /^N//-¾</td><td></td><td></td><td></td>

<td> 306</td><td></td><td>V o = ^ ~ N</td><td> 0</td><td> 627,7221</td><td> 82</td><td> 628</td>

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

<td></td><td></td><td>-Ltd</td><td></td><td></td><td></td><td></td>

<td></td><td> 0</td><td colspan="2">Ah,</td><td></td><td></td><td></td>

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<td></td><td></td><td>CH O ι 1</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ό ri p A..A.— xⁿίι I ^N</td><td>Λ z &lt;</td><td></td><td></td><td></td><td></td>

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

<td> 307</td><td></td><td>o = s = o /</td><td></td><td>CH,</td><td> 583,7122</td><td> 81</td><td> 584</td>

<td></td><td></td><td>1 N A</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CH,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ü A</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>1 ΪA ιΛΑ</td><td> $</td><td></td><td></td><td></td><td></td>

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

<td></td><td></td><td>T o = s = o</td><td></td><td>CH,</td><td></td><td></td><td></td>

<td> 308</td><td></td><td>i N</td><td></td><td></td><td> 631,7568</td><td> 29</td><td> 632</td>

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

<td></td><td></td><td>XA / * ·</td><td></td><td></td><td></td><td></td><td></td>

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

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

<td></td><td></td><td>Ü A</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>i A ÄA</td><td>p ^ y</td><td></td><td></td><td></td><td></td>

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

<td> 309</td><td></td><td>1 O = s = o 1</td><td></td><td>CH,</td><td> 569,6851</td><td> 60</td><td> 570</td>

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

<td></td><td>CH,</td><td>V</td><td></td><td></td><td></td><td></td><td></td>

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<td></td><td></td><td>ü X</td><td>X</td><td></td><td></td><td></td>

<td></td><td></td><td>yy τ XX</td><td>p</td><td></td><td></td><td></td>

<td> 310</td><td></td><td>T o = s = o 1</td><td>CH,</td><td> 597,7393</td><td> 62</td><td> 598</td>

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

<td></td><td>Η, Χ'γΧ ''</td><td>V</td><td></td><td></td><td></td><td></td>

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

<td></td><td></td><td>ü 1</td><td>X</td><td></td><td></td><td></td>

<td></td><td></td><td>1 ± A xxxxX-</td><td>t</td><td></td><td></td><td></td>

<td></td><td></td><td>V</td><td>X</td><td></td><td></td><td></td>

<td> 311</td><td></td><td>I 0 = 1 = 0</td><td>CH,</td><td> 581,6963</td><td> 87</td><td> 582</td>

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

<td></td><td></td><td>ί z -o</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>C JA</td><td></td><td></td><td></td><td></td>

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

<td></td><td></td><td>X</td><td rowspan="2">X CH,</td><td></td><td></td><td></td>

<td> 312</td><td></td><td>0 = S = 0 1</td><td> 609,7504</td><td> 71</td><td> 610</td>

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

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

<td></td><td>u</td><td>X CH,</td><td></td><td></td><td></td><td></td>

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<td> 313</td><td>II * z^NYY T CH 0x ^ 0 ηρΎ . '. AJ &lt;</td><td> 633,7291</td><td> 47</td><td> 634</td>

<td> 314</td><td>CH, θ rn XYX O = S = O ^&lt;*^H&gt;X Y</td><td> 570,629</td><td> 59</td><td> 571</td>

<td> 315</td><td>b γ- Φ -χ O = | = O '• Xl ·' /</td><td> 633,7291</td><td> 35</td><td> 634</td>

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<td></td><td></td><td></td><td>use AA</td><td></td><td></td><td></td><td></td>

<td> 316</td><td></td><td>Yeah %</td><td>v ^v0 = ^ = 0 A</td><td>CH,</td><td> 583,7122</td><td> 51</td><td> 584</td>

<td></td><td></td><td>&lt;2 J</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>L,</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>AA</td><td> 3</td><td></td><td></td><td></td>

<td> 317</td><td></td><td></td><td>V o = 7; = o</td><td>Λ CH,</td><td> 611,7227</td><td> 51</td><td> 612</td>

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

<td></td><td></td><td></td><td>V &lt;K CH,</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>ζ xc</td><td></td><td></td><td></td><td></td>

<td> 318</td><td></td><td></td><td>T o = s = o</td><td>λ CH,</td><td> 571,6574</td><td> 75</td><td> 572</td>

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

<td></td><td></td><td></td><td>A CH,</td><td></td><td></td><td></td><td></td>

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<td> 319</td><td>xy T CH, o = s = o xi ό "</td><td> 603,7026</td><td> 64</td><td> 604</td>

<td> 320</td><td>txx Lx | ch, o = s = o Y O_xCH,</td><td> 567,6692</td><td> 74</td><td> 568</td>

<td> 321</td><td>ix 1 CH, o = s = o χΤ xX °^ch=</td><td> 597,652</td><td> 88</td><td> 598</td>

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<td> ; 322</td><td>X UA l CH, o — s — o^ch&gt; °</td><td> 627,7221</td><td> 80</td><td> 628</td>

<td> 323</td><td>CK 0 Υλ T CH,_rrA U \</td><td> 647,7562</td><td> 47</td><td> 648</td>

<td> 324</td><td>X ΧγΛ I CH, o = s = o .._VA CH, ° ^ CH,</td><td> 555,658</td><td> 43</td><td> 556</td>

232

<td>An example no</td><td>Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td> 325</td><td>'7 Xf II 1 .n ψ Ά O = S3 = O ....... X ' j X ch, J</td><td> 654,7916</td><td> 54</td><td> 655</td>

<td> 326</td><td>Yeah T CH, Oz = S = 0</td><td> 624,7214</td><td> 71</td><td> 625</td>

<td> 327</td><td>7 J Yeah o = s = o Yeah m.p. H.Jfl H</td><td> 689,8375</td><td> 42</td><td> 690</td>

233

<td>An example no</td><td>Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td> 328</td><td>CH. 0_rucy · 1 CH, o = s = o hc yy yy i</td><td> 583,7122</td><td> 40</td><td> 584</td>

<td> 329</td><td>CH, 0 rw T CH, O = S = O , .. y &lt;X CH,</td><td> 555,658</td><td> 49</td><td> 556</td>

<td> 330</td><td>CH, 0 _PM Chiral y; T CH. o = s = o oX-</td><td> 525,6315</td><td> 83</td><td> 526</td>

234

<td>An example no</td><td colspan="2">Structure</td><td>M</td><td>HPLC</td><td>Μ + H</td>

<td></td><td colspan="2">CH, O _ru Chirat 1 II /</td><td></td><td></td><td></td>

<td></td><td>ο YY</td><td>N</td><td></td><td></td><td></td>

<td> 331</td><td>o = s = o 1</td><td>CH,</td><td> 525,6315</td><td> 71</td><td> 526</td>

<td></td><td> 1 ^NC Xax</td><td></td><td></td><td></td><td></td>

<td></td><td>CH, O C x</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>O XAzⁿAf</td><td></td><td></td><td></td><td></td>

<td> 332</td><td>o = s = o</td><td>CH,</td><td> 555,658</td><td> 91</td><td> 556</td>

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

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

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

<td></td><td>CH, O 1 X</td><td></td><td></td><td></td><td></td>

<td></td><td>ÄÄ γ- ΓΎ</td><td> $</td><td></td><td></td><td></td>

<td> 333</td><td>o = s = o I</td><td>CH,</td><td> 477,5869</td><td> 76</td><td> 478</td>

<td></td><td>1 N ho J</td><td></td><td></td><td></td><td></td>

<td></td><td>H₃C</td><td></td><td></td><td></td><td></td>

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<td></td><td></td><td> 0</td><td>CH,</td><td></td><td></td><td></td>

<td></td><td colspan="2">ό AA Αχ /ⁿ- ίι ^N</td><td>i</td><td></td><td></td><td></td>

<td> 334</td><td>V</td><td></td><td></td><td> 478,5745</td><td> 62</td><td> 479</td>

<td></td><td>o = s = o</td><td></td><td>CH,</td><td></td><td></td><td></td>

<td></td><td>h₂n</td><td>^XOH</td><td></td><td></td><td></td><td></td>

<td></td><td>ü</td><td> 0 1</td><td>A</td><td></td><td></td><td></td>

<td></td><td>X (A</td><td>A 'x</td><td></td><td></td><td></td><td></td>

<td> 335</td><td>A o = s = o I</td><td></td><td>A CH,</td><td> 490,6292</td><td> 42</td><td> 491</td>

<td></td><td>1 N</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>XA o— '</td><td></td><td></td><td></td><td></td><td></td>

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Example 336

2- [2-Ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one hydrochloride trihydrate

<img file="EE200000291A_D0166.tif" />

Crystallization of the free base from Example 19 in a mixture of an organic solvent and dilute aqueous hydrochloric acid affords the hydrochloride trihydrate.

M.p .: 218 ° C.

Water content: 9.4% (K. Fischer).

Chloride content: 6.1%.

Example 337

2- [2-Ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl-5-methyl-7-propyl-3H-imidazo [5,1-f] -1,2,41-triazine-4-one hydrochloride

<img file="EE200000291A_D0167.tif" />

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0.35 g (0.712 mmol) of 2- [2-Ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1 , 2,4] Triazin-4-one is suspended in 8 ml of ether and dichloromethane is added until a homogeneous solution is formed. Adding

24th ml of 1M HCl solution in ether, the mixture is stirred at room temperature for 20 minutes and filtered under vacuum. 372 mg (99%) of 2- [2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] are obtained. triazine-4-one hydrochloride.

<td> 10 200</td><td>MHz</td><td>¹H-</td><td>-TMR</td><td>(DMSO-d₆)</td><td> 0,96</td><td>(t,</td><td>3H),</td><td>1.22 (t,</td><td>3H),</td><td> 1,36</td><td>(t,</td>

<td>3H),</td><td> 1,</td><td> 82</td><td colspan="2">(sex, 2H), 2</td><td> ,61</td><td>(s,</td><td>3H), 2</td><td>, 88 (m,</td><td>2H),</td><td> 3,08</td><td>(m,</td>

<td>6H),</td><td> 3,</td><td> 50</td><td>(m,</td><td>2H), 3.70</td><td>(m,</td><td>2H)</td><td> , 4,25</td><td>(quart,</td><td>2H),</td><td> 7,48</td><td>(d,</td>

1H), 7.95 (m, 2H), 11.42 (s, 1H), 12.45 (s, 1H).