CA2395558C

Intermediates for 2-phenyl substituted imidazotriazinones asphosphodiesterase inhibitors

Abstract

Compounds of the general formula (II) or (IV) are intermediates in the preparation of 2-phenyl-substituted imidazotriazinones, which have pharmaceutical activity. <IMG> wherein R1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms; R2 represents straight- chain alkyl having up to 4 carbon atoms; L represents straight-chain or branched alkyl having up to 4 carbon atoms; and R5 and R6 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms. Also provided are processes for preparing the compounds (II) and (IV).

CA2395558C, drawing sheet 1 — Sheet 1 of 198

Term

Term ended

Expired 31 October 2018, 7.9 years ago.

17 claims: 3 independent, 14 dependent

1
CLAIMS:1. A compound of the general formula (II) (II) wherein: R1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms;R2 represents straight-chain alkyl having up to 4 carbon atoms ;and L represents straight-chain or branched alkyl having up to 4 carbon atoms .
6
the reaction of step (a) in the presence of a the reaction of step
9
-266- (IV) wherein:R1 and R2 are as defined in claim 1;and R5 and R6 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms.

Independent claims3

2,118 paragraphs in 276 sections, as filed

(57) Abrégé/Abstract:

Compounds of the general formula (II) or (IV) are intermediates in the preparation of 2-phenyl-substituted imidazotriazinones, which have pharmaceutical activity, (see formula II) (see formula IV) wherein R1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms; R2 represents straight-chain alkyl having up to 4 carbon atoms; L represents straight-chain or branched alkyl having up to 4 carbon atoms; and R5 and R6 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms. Also provided are processes for preparing the compounds (II) and (IV).

Canada http://opic.gc.ca · Ottawa-Hull KIA 0C9 · http://cipo.gc.ca

OPIC-CIPO 191

CA 2395558 C 2007/07/17 (72) lnventeurs(suite)/lnventors(continued): PERZBORN, ELISABETH, DE; DEMBOWSKY, KLAUS, US;

SERNO, PETER, DE; NOWAKOWSKI, MARC, DE (11)(21) 2 395 558 (13) C

-2CA 02395558 2002-09-03

23189-8549D

Abstract

Compounds of the general formula (II) or (IV) are intermediates in the preparation of 2-phenyl-substituted imidazotriazinones, which have pharmaceutical activity.

(II)

(IV) wherein R1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms; R2 represents straightchain alkyl having up to 4 carbon atoms; L represents straight-chain or branched alkyl having up to 4 carbon atoms; and R5 and R6 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms. Also provided are processes for preparing the compounds (II) and (IV).

CA 02395558 2002-09-03

DEMANDES OU BREVETS VOLUMINEUX

LA PRÉSENTE PARTIE DE CETTE DEMANDE OU CE BREVETS COMPREND PLUS D’UN TOME.

CECI EST LE TOME__/ DE cl

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.

JUMBO APPLICATIONS / PATENTS

THIS SECTION OF THE APPLICATION ! PATENT CONTAINS MORE THAN ONE VOLUME.

THIS IS VOLUME__/ OF <SNOTE: For additional volumes please contact the Canadian Patent Office.

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23189-8549(D)

-1This application is a divisional application of copending application 2,309,332, filed October 31, 1998.

2-phenyl-subsituted imidazotriazinones as phosphodiesterase inhibitors

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

The published specification DE 28 11 780 describes imidazotriazines as bronchodilators having spasmolytic activity and inhibitory activity against phosphodiesterases which metabolize cyclic adenosin monophosphate (cAMP-PDEs, nomenclature according to Beavo: PDE-ΙΠ and PDE-IV). An inhibitory action against phosphodiesterases which metabolize cyclic guanosin monophosphate (cGMP-PDEs, nomenclature according to Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990) PDE-I, PDE-Q and PDE-V) has not been described. Compounds bavins a sulphonamide group in the aryl radical in the 2-position are not claimed. Furthermore, FR 22 13 058, CH 59 46 71, DE 22 55 172, DE 23 64 076 and EP 000 9384 describe imidazotriazinones which do not have a substituted aryl radical in the

2-position and are likewise said to be bronchodilators having cAMP-PDE inhibitory action.

WO 94/28902 describes pyrazolopyrimidinones which are suitable for treating impotence.

The compounds according to the invention are potent inhibitors either of one or of more of the phosphodiesterases which metabolize cyclic guanosin 3'.5'-monophosphate (cGMP-PDEs). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990) these are the phosphodiesterase isoenzymes PDE-I, PDE-Π and PDE-V.

An increase of -the cGMP concentration can lead to beneficial antiaggregatory, antithrombotic, antiprolific, antivasospastic. vasodilative, natriuretic and diuretic effects. It can influence the short- or long-term modulation of vascular and cardiac

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Le A 32 733-Foreign countries -2inotropy, of the pulse and of cardiac conduction (J.C. Stoclet, T. Keravis, N. Komas and C. Kugnier, Exp. Opin. Invest. Drugs (1995), 4(11), 1081-1100).

The present invention, accordingly, provides 2-phenyl-substituted imidazotriazinones of the general formula (I)

in which

R1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R2 represents straight-chain alkyl having up to 4 carbon atoms,

R3 and R4 are identical or different and each represents hydrogen or represents straight-chain or branched alkenyl or alkoxy having in each case up to 8 carbon atoms, or represents a straight-chain or branched alkyl chain having up to 10 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of trifluoromethyl, trifluoromethoxy, hydroxyl, halogen, carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms and/or by radicals of the formulae -SO3H, -(A)a-NR7R8, -O-CONR7'R8’, -S(O)b-R9, -P(O)(OR,0)(OR’'),

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R31 represents hydrogen or has the meaning of R9 given above and is identical to or different from it,

R32 and R33 have the meanings of R10 and Rl 1 given above and are identical to or different from them,

R34 and R35 are identical or different and each represents hydrogen or straightchain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms, or

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R34 and R35 together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may contain a further heteroatom from the group consisting of S and O, or a radical of the formula -NR36, in which

R36 represents hydrogen, hydroxyl, straight-chain or branched alkoxycarbonyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by hydroxyl, or

R3 and R4 together with the nitrogen atom form a 5- to 7-membered unsaturated or saturated or partially unsaturated, optionally benzofused heterocycle which may optionally contain up to 3 heteroatoms from the group consisting of S, N and O, or a radical of the formula -NR37, in which

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- 11 -(D)f.NR38R39, -C0-(CH2)g-O-C0-R4°, -CO-(CH2)h-OR4’ or -P(O)(OR42)(OR43), in which g and h are identical or different and each represents a number 1, 2, 3 or 4, and f represents a number 0 or 1,

D represents a group of the formula -CO or -SO2,

R38 and R39 are identical or different and each has the meaning of R7 and R8 given above,

R40 represents straight-chain or branched alkyl having up to 6 carbon atoms,

R41 represents straight-chain or branched alkyl having up to 6 carbon atoms,

R42 and R43 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or

R37 represents a radical of the formula -(CO)j-E, in which

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- 12i represents a number 0 or 1,

E represents cycloalkyl having 3 to 7 carbon atoms or benzyl, represents aryl having 6 to 10 carbon atoms or a 5- to 6-membered aromatic heterocycle having up to 4 heteroatoms from the group consisting of S, N and O, where the abovementioned ring systems are optionally mono- or polysubstituted by identical or different constituents selected from the group consisting of nitro, halogen, -SO3H, straightchain or branched alkoxy having up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy, or by a radical of the formula -SO2-NR44R45, in which

R44 and R45 have the meanings of R18 and R19 given above and are identical to or different from them,

E represents radicals of the formulae '

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- 13□ A and the heterocycle listed under R and R , which is formed together with the nitrogen atom, is optionally mono- or polysubstituted, if appropriate also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro and groups of the formulae -PkOXOR^XOR47),

—(ΟΟ)^4^50 in which

R46 and R47 have the meanings of R10 and R11 given above and are identical to or different from them,

R48 represents hydroxyl or straight-chain or branched alkoxy having up to carbon atoms, j represents a number 0 or 1, and

R49 and R50 are identical or different and have the meanings of R14 and R15 given above, and/or the heterocycle listed under R3 and R4, which is formed together with the nitrogen atom, is optionally substituted by straightchain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different

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- 18(Cg-Cio)-Arvl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, cycloalkyl having 3 to 8 or 3 to 7 carbon atoms represents, for example, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Preference is given to: cyclopropyl, cyclopentyl and cyclohexyl.

In the context of the invention, cycloalkyloxy having 3 to 8 carbon atoms represents cyclopropyloxy, cyclopentyloxy, cyclobutyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy. Preference is given to: cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.

In the context of the invention, halogen generally represents fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine and bromine. Particular preference is given to fluorine and chlorine.

In the context of the invention and depending on the abovementioned substituents, a 5to 6-membered or 7-membered saturated heterocycle, which may contain a further heteroatom from the group consisting of S, N and O represents, for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or tetrahydrofuranyl. Preference is given to morpholinyl, tetrahydropyranyl, piperidinyl and piperazinyl.

In the context of the invention, a 5- to 6-membered aromatic heterocycle having up to 3 or 4 heteroatoms from the group consisting of S, O and N represents, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Preference is given to pyridyl, pyrimidyl, pyridazinyl, furyl and thiazolyl.

In the context of the invention, a 5- to 6-membered unsaturated, partially unsaturated and saturated heterocycle which may contain up to 3 or 4 heteroatoms from the group consisting of S, O and N represents, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl or __ — . CA 02395558 2002-09-03

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- 19morpholinyl. Preference is given to pyridyl, pyrimidyl, piperazinyl, pyridazinyl, morpholinyl, furyl and thiazolyl.

The compounds according to the invention, in particular the salts, may also be present as hydrates. In the context of the invention, hydrates are those compounds which contain water in the crystal. Such compounds may contain one or more, typically 1 to 5, equivalents of water. Hydrates can be prepared, for example, by crystallizing the compound in question from water or from a water-containing solvent.

Preference is given to compounds of the general formula (I) according to the invention in which

R1 represents straight-chain or branched alkyl having up to 3 carbon atoms,

R2 represents straight-chain alkyl having up to 3 carbon atoms,

R3 and R4 are identical or different and each represents hydrogen or represents straight-chain or branched alkenyl or alkoxy having in each case up to 6 carbon atoms, or represents a straight-chain or branched alkyl chain having up to 8 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different constituents selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, and/or by radicals of the formulae -SO3H, -(A)a-NR7R8, -OCO-NR7 R8', -S(O)b-R9, -P(O)(OR,0)(OR'1),

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and/or

in which a and b are identical or different and each represents a number 0 or 1,

A represents a radical CO or SO?,

R7, R7, R8 and R8 are identical or different and each represents hydrogen, or cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl and pyridyl, where the abovementioned ring systems are optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, fluorine, chlorine, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by a group of the formula -(SO?)C-NR12R13, in which represents a number 0 or 1, » . — · CA 02395558 2002-09-03

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-21 R12 and R13 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or

R7, R7, R8 and R8 each represent straight-chain or branched alkoxy having up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 7 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, phenyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by a group of the formula -(CO)d-NRl4R15, in which

R14 and R15 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, and d represents a number 0 or 1, · or

R7 and R8 and/or R7 and R8 together with the nitrogen atom form a pyrrolidinyl, morpholinyl, piperidinyl or triazolyl ring or radicals of the formulae

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ch3

in which

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

R9 represents straight-chain or branched alkyl having up to 3 carbon atoms,

R10 and R11 are identical or different and each represents hydrogen or straightchain or branched alkyl having up to 3 carbon atoms, and/or the alkyl chain listed under R3/R4 is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, quinolyl, pyrrolidinyl, pyrimidyl, morpholinyl, furyl, piperidinyl, tetrahydrofuranyl or by radicals of the formulae

in which

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-23R17 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl or alkoxy having in each case up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 4 carbon atoms, and where phenyl and the heterocycles are optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, -SO3H, straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, hydroxyl, and/or by a radical of the formula -SO2-NR18R19, in which

-26and/or where alkyl is optionally substituted by radicals of the formulae -CO-NR28R29 or -CO-R30, in which

R28 and R29 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or

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

R30 represents phenyl or adamantyl,

R24 and R25 have the meanings of R18 and R19 given above and are identical to or different from them,

R26 and R27 have the meanings of R10 and R11 given above and are identical to or different from them and/or cycloaikyl, phenyl and/or the heterocycles are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl or by groups of the formula -SO2-R31, -P(O)(OR32)(OR33) or -NR34R35, in which

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-27R31 has the meaning of R9 given above and is identical to or different from it,

R32 and R33 have the meanings of R10 and R11 given above and are identical to or different from them,

R34 and R35 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms, or

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

or in which

R36 represents hydrogen, hydroxyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl,

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

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in which

R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 5 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl, trifluoromethyl, carboxyl, straightchain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by groups of the formula -(D)f.NR38R39, -CO-(CH2)g-O-CO-R40, -CO-(CH2)h-OR41 or -P(O)(OR42)(OR43), in which g and h are identical or different and each represents a number

1,2 or 3, and f represents a number 0 or 1,

D represents a group of the formula -CO or -SO2,

R38 and R39 are identical or different and have the meanings of

R and R given above.

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-29R40 represents straight-chain or branched alkyl having up to carbon atoms,

R41 represents straight-chain or branched alkyl having up to 4 carbon atoms,

R42 and R43 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or

R37 represents a radical of the formula -(CO)i-E, in which i represents a number 0 or 1,

E represents cyclopentyl, cyclohexyl, cycioheptyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, where the abovementioned ring systems are optionally rhono- or disubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, -SO3H, straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy or by a radical of the formula -SCL-NR^R45, in which

R44 and R45 have the meanings of R18 and R19 given above and are identical to or different from them,

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-30E represents radicals of the formulae

and the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro and groups of the formulae -P(O)(OR46)(OR47),

— (00)^4¾50 in which

R46 and R47 have the meanings of R10 and R11 given above and are identical to or different from them,

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-31R48 represents hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms, j represents a number 0 or 1, and

R49 and R50 are identical or different and have the meanings of R14 and R15 given above, and/or the heterocycles listed under R^ and R4, which are formed together with the nitrogen atom, are optionally substituted by straightchain or branched alkyl having up to 5 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by a radical of the formula -SO3H, -NR51R52 or -P(O)ORS3OR54, in which

R51 and R5 are identical or different and each represents hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,

R53 and R54 are identical or different and have the meanings of R10 and R1' given above, and/or the alkyl is optionally substituted by phenyl which for its part may be mono- to trisubstituted by identical or different substituents

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-32selected from the group consisting of fluorine, chlorine, hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms, or by a group of the formula -NR51 R52, in which

R51 and R52 have the meanings of R51 and R52 given above and are identical to or different from them, and/or the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally substituted by phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl, optionally also attached via a nitrogen function, where the ring systems for their part may be substituted by hydroxyl or by straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or

R3 and R4 together with the nitrogen atom form radicals of the formulae

O--N

CH3 or

N

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-33R5 and R6 are identical or different and each represents hydrogen, hydroxyl or represents straight-chain or branched alkoxy having up to 4 carbon atoms, and their salts, N-oxides, hydrates and isomeric forms.

Particular preference is given to compounds of the general formula (I) according to the invention in which

R1 represents straight-chain or branched alkyl having up to 3 carbon atoms,

R2 represents straight-chain alkyl having up to 3 carbon atoms,

R3 and R4 are identical or different and each represents hydrogen or represents straight-chain or branched alkenyl or alkoxy having in each case up to 4 carbon atoms, or represents a straight-chain or branched alkyl chain having up to 6 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, and/or by radicals of the formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7R8, -S(O)b-R9, -P(O)(ORl0)(OR),

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in which a and b are identical or different and each represents a number 0 or 1,

A represents a radical CO or SO2,

R7, R7 , R8 and R8 are identical or different and each represents hydrogen, or represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl and pyridyl, where the abovementioned ring systems are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, nitro, carboxyl, fluorine, chlorine, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by a group of the formula -(SO2)C-NR12R13, in which represents a number 0 or 1,

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-35R12 and R13 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or

R7, R7, R8 and R8 each represent methoxy, or represent straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, phenyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by a group of the formula -(CO)d-NRl4R15, in which

R14 and R15 are identical or different and each represents hydrogen, methyl or ethyl, and d represents a number 0 or I, or

R7 and R8 and/or R7 and R8 together with the nitrogen atom form a morpholinyl, piperidinyl or triazolyl ring or radicals of the formulae

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in which

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

R9 represents methyl,

R10 and R11 are identical or different and each represents hydrogen, methyl or ethyl, and/or the alkyl chain listed under R3/R4 is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, furyl, tetrahydrofuranyl, or by radicals of the formulae

in which

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-37R17 represents hydrogen, hydroxyl, formyl, acetyl or alkoxy having up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 3 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 3 carbon atoms, and where phenyl and the heterocycles are optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, -SO3H, straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms, hydroxyl, and/or by a radical of the formula -SO2.NRI8R19, in which

R18 and R19 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, and/or

R3 or R4 represents a group of the formula -NR20R2‘, in which

R20 and R21 have the meanings of R18 and R19 given above and are identical to or different from them, and/or

CA 02395558 2002-09-03 • 23189-8549(S)

-38R3 or R4 represents adamantyl, or represents radicals of the formulae

or represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl, or represents radicals of the formulae

—R22 or

in which

R22 has the meaning of R16 given above and is identical to or different from it, or represents formyl or acetyl.

and where cycloalkyl, phenyl and/or the heterocycles are optionally mono- or disubstituted by identical or different substituents selected

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-39from the group consisting of fluorine, chlorine, triazolyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, and/or by groups of the formulae -SO3H, -OR23, (SO2)eNR24R25, -P(0)(OR26)(OR27), in which e represents a number 0 or 1,

R23 represents a radical of the formula , or represents cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl, represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by cyclopropyl, cyclohexyl, benzyloxy, tetrahydropyranyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, benzyloxycarbonyl or phenyl which for its part may be mono- or disubstituted by identical or different substituents selected from the group consisting of methoxy, hydroxyl, fluorine or chlorine, and/or where alkyl is optionally substituted by radicals of the formulae -CO-NR28R29 or -CO-R30, in which

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-40R28 and R29 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or

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

R30 represents phenyl or adamantyl,

R24 and R25 have the meanings of R18 and R19 given above and are identical to or different from them,

R26 and R27 have the meanings of R10 and R11 given above and are identical to or different from them and/or cycloalkyl, phenyl and/or the heterocycles are optionally substituted by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl or by groups of the formula -SO2-R31, P(0)(OR32)(OR33) or -NR34R35, in which

R31 represents methyl,

R32 and R33 have the meanings of R10 and R11 given above and are identical to or different from them.

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-41R34 and R35 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl or methoxy, or

R34 and R35 together with the nitrogen atom form a morpholinyl, triazolyl or thiomorpholinyl ring, or a radical of the formula /—\ —N N-R in which

R36 represents hydrogen, hydroxyl, straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms or straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl, or

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

in which

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-42R37 represents hydrogen, hydroxyl, formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by groups of the formula -(D)f.NR38R39, -CO-(CH2)g-O-CO-R40, -CO-(CH2)h-OR41 or -P(O)(OR42)(OR43), in which g and h are identical or different and each represents a number or 2, and f represents a number 0 or 1,

D represents a group of the formula -CO or -SO2,

R1 represents methyl or ethyl.

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-47R2 represents ethyl or propyl,

R3 and R4 are identical or different and each represents a straight-chain or branched alkyl chain having up to 5 carbon atoms which is optionally substituted up to two times by identical or different substituents selected from the group consisting of hydroxyl and methoxy, or

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

in which

R37 represents hydrogen, formyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 3 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by groups of the formulae -(D)f.NR38R39 or -P(O)(OR42)(OR43), in which represents a number 0 or 1,

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-48D represents a group of the formula -CO,

R38 and R39 are identical or different and each represents hydrogen or methyl,

R42 and R43 are identical or different and each represents hydrogen, methyl or ethyl, or

R37 represents cyclopentyl, and the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally mono- or disubstituted, optionally also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 3 carbon atoms, or groups of the formulae -P(O)(OR46)(OR47) or -(CO)iNR49R50, in which

R46 and R47 are identical or different and each represents hydrogen, methyl or ethyl, j represents a number 0 or 1, and

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-49R49 and R50 are identical or different and each represents hydrogen or methyl and/or the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally substituted by straightchain or branched alkyl having up to 3 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, carboxyl, or by a radical of the formula P(O)OR53OR54, in which

R53 and RS4 are identical or different and each represents hydrogen, methyl or ethyl, and/or the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally substituted by pyrrolidinyl or piperidinyl attached via nitrogen,

R5 represents hydrogen, and

R6 represents ethoxy or propoxy, and their salts, hydrates, N-oxides and isomeric forms.

Likewise, very particular preference is given to those compounds of the general formula (I) according to the invention in which R5 represents hydrogen and the radicals R6 and -SOiNR^R4 are in a position para to one another at the phenyl ring.

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-50Particularly preferred compounds are listed in Table A.

Table A:

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23189-8549(S)

The invention furthermore provides a process for preparing the compounds of the general formula (I) . The process comprises reacting a compound of the general formula (V)

in which R1, R2, R5 and R6 are as defined above, with an amine of general formula (VI)

HNR3R4 (VI) in which R3 and R4 are as defined above, in inert solvent.

The compound of formula (I) can then be converted to a salt, especially a pharmaceutically acceptable salt, or a hydrate, if required.

The compound of formula (V) can be prepared by reacting a compound of the general formula (II)

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73189-8549(S)

O R1 O

O in which

R1 and R2 are each as defined above and

L represents straight-chain or branched alkyl having up to 4 5 carbon atoms, with a compound of the general formula (III)

x HCI (Hl) in which

R5 and R6 are each as defined above, in a two-step reaction in the systems ethanol and phosphorus oxytrichloride/ dichloroethane into a compound of the general formula (IV)

in which

R1, R2, Rs and R6 are each as defined above.

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This is reacted in a further step with chlorosulphonic acid to give the compound of the general formula (V)

in which

R1, R2, Rs and Rs are each as defined above.

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

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HCI

T 1. ethanol

V 2. phosphorus oxytrichloride / dichlorethane

Solvents which are suitable for the individual steps are the customary 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

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-58halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the abovementioned solvents. Particular preference is given to ethanol for the first step and dichloroethane for the second step.

The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out in a range of from -20°C to 200°C, preferably of from 0°C to 70°C.

The process steps according to the invention are generally carried out under atmospheric pressure. However, it is also possible to operate under superatmospheric pressure or under reduced pressure (for example, in a range of from 0.5 to 5 bar).

The reaction to give the compounds of the general formula (V) is carried out in a temperature range of from 0°C to room temperature, and at atmospheric pressure.

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

The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out at temperatures in a range of from -20°C to 200°C, preferably of from 0°C to room temperature.

The reaction is generally carried out at atmospheric pressure. However, it is also possible to operate under superatmospheric pressure or under reduced pressure (for example in a range of from 0.5 to 5 bar).

Some of the compounds of the general formula (Π) are known, or they are novel, and they can then be prepared by

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-59converting compounds of the general formula (VII)

R2-CO-T (VU) in which

R2 is as defined above and

Moreover, the compounds according to the invention enhance the activity of substances such as, for example EDRF (endothelium derived relaxing factor), ANP (atrial natriuretic peptide), of nitrovasodilators and all other substances which increase the cGMP concentration in a manner different from that of phosphodiesterase inhibitors.

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-66The compounds according to the invention are also suitable for use in veterinary medicine. For use in veterinary medicine, the compounds or their non-toxic salts can be administered in a suitable formulation in accordance with general veterinary practice. 5 Depending on the kind of animal to be treated, the veterinary surgeon can determine the nature of use and the dosage.

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Starting materials

Example 1A

2-Butyrylaminopropionic acid

22.27 g (250 mmol) of D,L-alanine 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 for 1 hour at room temperature and for 1 hour at 40°C. After cooling to -10°C, 26.64 g (250 mmol) of butyryl chloride are added dropwise, and the resulting mixture is stirred for 2 hours at - 10°C and for one hour at room temperature.

With ice-cooling, 125 ml of water are added dropwise and the reaction mixture is stirred at room temperature for 15 minutes. The aqueous phase is evaporated to dryness, the residue is titrated with acetone and the mother liquor is filtered off with suction. The solvent is removed and the residue is chromatographed. The resulting product is dissolved in 3N aqueous sodium hydroxide solution and the resulting solution is evaporated to dryness. The residue is taken up in cone. HC1 and once more evaporated to dryness. The residue is stirred with acetone, precipitated solid is filtered off with suction and the solvent is removed under reduced pressure. This gives 28.2 g (71%) of a viscous oil which crystallizes after some time.

200 MHz 'H-NMR (DMSO-d6): 0.84, t, 3H; 1.22, d, 3H; 1.50, hex, 2H; 2.07, t, 2H; 4.20, quin., IH; 8.09, d, IH.

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Example 2A

2-Butyrylamino butyric acid

CH3

25.78 g of 2-aminobutyric 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 for 1 hour at room temperature and for 1 hour at 40°C. After cooling to -10°C, 26.64g (250 mmol) of butyryl chloride are added dropwise, and the resulting mixture is stirred for 2 hours at -10°C and for one hour at room temperature.

With ice-cooling, 125 ml of water are added dropwise, and the reaction mixture is stirred at room temperature for 15 minutes. The organic phase is admixed with aqueous sodium hydroxide solution and the organic solvent is removed under reduced pressure. After acidification, the precipitated solid is stirred once with water and twice with petroleum ether and dried at 45°C under reduced pressure. This gives 29.1 g (67%) of a colourless solid.

200 MHz ‘H-NMR (DMSO-d6):0.88, 2t, 6H; 1.51, quart., 2H, 1.65, m, 2H, 2.09, t, 2H, 4.10, m, IH; 8.01, d, IH; 12.25, s, m IH.

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-69Exampie 3A

2-Ethoxybenzonitrile

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

200 MHz ’H-NMR (DMSO-d6): 1.48, t, 3H; 4.15, quart., 2H; 6.99, dt, 2H; 7.51, dt,

2H.

Example 4A

2-Ethoxybenzamidine hydrochloride

CIH »

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 trimethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until the evolution of gas has ceased. After addition of 29.44 g (200 mmol) of 2ethoxybenzonitrile, the reaction mixture is stirred at 80°C (bath) overnight.

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-70With ice-cooling, the cooled reaction 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 for 30 minutes. The mixture is filtered off with suction, and the filter residue is washed with the same amount of methanol. The mother liquor is concentrated, the resulting residue is stirred with a mixture of dichloromethane and methanol (9:1), the solid is filtered off with suction and the mother liquor is concentrated. This gives

30.4 g (76%) of a colourless solid.

200 MHz ’H-NMR (DMSO-d6): 1.36, t, 3H; 4.12, quart., 2H; 7.10, t, IH; 7.21, d, IH; 7.52, m, 2H; 9.30, s, broad, 4H.

Example 5A

2-Propoxybenzonitrile

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

b.p.: 89°C (0.7 mbar)

Yield: 95.1 g (93.7%)

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-75ethanol, and the resulting suspension is stirred at room temperature for another 10 minutes. The ethanolic solution described above is added to this reaction mixture, and the mixture is stirred at a bath temperature of 70°C for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure.

This residue is dissolved in 60 ml of 1,2-dichloroethane and, after addition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Chromatography using ethyl acetate and crystallization afford 4.00 g (28%) of a colourless solid, Rf = 0.42 (dichloromethane/methanol = 95:5)

200 MHz 'H-NMR (CDC13): 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, IH; 8.17, dd, IH; 10.00, s, IH.

Example 11A

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

7.16 g (45 mmol) of 2-butyrylaminopropionic acid and 10.67 g of pyridine are dissolved in 45 ml of tetrahydrofuran and, after addition of a spatula tip of dimethylaminopyridine, 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

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-76mixture is poured into ice-water and extracted three times with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 15 ml of ethanol and refluxed with 2.15 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.

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

This residue is dissolved in 60 ml of 1,2-dichloroethane and, after addition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Crystallization from ethyl acetate gives 2.85 g (19.1%) of a yellow solid, chromatographic purification of the mother liquor gives a further 1.25 g (8.4%) of the product. Rf = 0.45 (dichloromethane/methanol = 95:5)

200 MHz ‘H-NMR (CDCh): 1.03, 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, IH; 8.17, dd, IH; 10.02, s, IH.

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-77Example 12A

2-(2-Ethoxy-4-methoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-/)( 1,2,4]triazin4-one

CH3

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 a spatula tip of dimethylaminopyridine, heated to reflux. 9.43 g (69 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, and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 11 ml of methanol and refluxed with 1.65 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.

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

This residue is dissolved in 46 ml of 1,2-dichloroethane and, after addition of 5.74 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed

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-78under reduced pressure. Chromatography (dichloromethane:methanol = 50:1) gives

0.31 g (2.5%) of a solid.

Rf = 0.46 (dichloromethane:methanol = 20:1 )

200 MHz ‘H-NMR (CDC13): 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, IH, 6.67, dd, IH; 8.14, d, IH; 9.54, s, IH.

Example 13A

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

29.06 g (167.8 mmol) of 2-butyrylaminobutyric acid and 39.76 g of pyridine are dissolved in 170 ml of tetrahydrofuran and, after addition of a spatula tip of dimethylaminopyridine, 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, and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 15 ml of methanol, and half of the solution is refluxed with 7.96 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.

With ice-cooling, 4.20 g (83.9 mmol) of hydrazine hydrate are added dropwise to a solution of 16.83 g (83.9 mmol) of 2-ethoxybenzamidine hydrochloride in 85 ml of ethanol, and the resulting suspension is stirred at room temperature for another 10 minutes. The methanolic solution described above is added to this reaction mixture,

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-79and the mixture is stirred at a bath temperature of 70°C for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure.

This residue is dissolved in 112 ml of 1,2-dichloroethane and, after addition of 14 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Chromatography (dichloromethane:methanol = 50:1) gives 3.69 g (12.4%) of a colourless solid, Rf = 0.46 (dichloromethanermethanol = 20:1)

200 MHz 'H-NMR (CDCIj): 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, IH; 7.12, t, IH; 7.50, dt, IH, 8.16, dd, IH; 9.91, s, IH.

Example 14A

4-Ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][ 1,2,4]triazin-2-yl)-

7.25 g (25.5 mmol) of 2-(2-ethoxyphenyl)-5,7-dimethyl-3//-imidazo[5,l-f][1,2,4]triazin-4-one are initially charged, and 26.74 g (0.23 mol) of chlorosulphonic acid are added with ice-cooling. The mixture is stirred at room temperature overnight and poured into ice-water, and the crystals are filtered off with suction and dried in a vacuum desiccator.

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- 80 Yield: 9.5 g (97% of theory)

200 MHz ‘H-NMR (d*-DMSO): 1.32, t, 3H; 2.63, s, 3H; 2.73, s, 3H; 4.13, q, 2H;

7.15, d, IH; 7.77, m, 2H; 12.5, s, IH;

Example 15A

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

At 0°C, 2.00 g (6.4 mmol) of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3/7imidazo[5,l-f][l,2,4]triazin-4-one are slowly added to 3.83 ml of chlorosulphonic acid. At room temperature, the reaction mixture is stirred overnight, and then poured into ice-water and extracted with dichloromethane. This gives 2.40 g (91%) of a 15 colourless foam.

200 MHz 'H-NMR (CDCI3): 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, IH; 8.20, dd, IH; 8.67, d, IH; 10.18, s, IH.

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-81 Example 16A

4-Propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -fj[ 1,2,4]triazin-

2-yl)-benzenesulphonyl chloride

At 0°C, 2.80 g (8.6 mmol) of 2-(2-propoxy-phenyl)-5-methyl-7-propyl-3Himidazo[5,l-f][l,2,4]triazin-4-one are added slowly to 5.13 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 3.50 g (96%) of a 10 colourless foam.

Rf = 0.49 (dichloromethane/methanol = 95:5)

200 MHz ‘H-NMR (CDC13): 1.03, 2t, 6H; 1.95, m, 4H; 2.81, s, 3H; 3.22, t, 2H; 4.11, t., 2H; 7.09, m, IH; 8.06, dd, IH; 8.21 m, IH; 12.0, s, IH.

Example 17A

4-Ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4dihydroimidazo[5,1 -f][ 1,2,4]triazin-2-yl)-benzenesulphonyl chloride

O=S=O I Cl

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-82At 0°C, 0.31 g (0.9 mmol) of 2-(2-ethoxy-4-methoxyphenyl)-5-methyl-7-propyl-3Zfimidazo[5,l-/)-(1,2,4]triazin-4-one are added slowly to 0.54 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 0.355 g (89%) of a colourless foam.

Rf = 0.50 (dichloromethane/methanol = 20:1)

200 MHz 'H-NMR (CDCh): 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, IH, 8.72, s, IH; 9.75, s, IH.

Example 18A

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

At 0°C, 1.70 g (5.21 mmol) of 2-(2-ethoxy-phenyl)-5-ethyl-7-propyl-3Wimidazo[5,l-f][l,2,4]triazin-4-one are added slowly to 3.12 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 2.10 g (94%) of a colourless foam.

400 MHz ‘H-NMR (CDCh): 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, IH; 8.19, dd, IH; 8.70, d, IH; 10.08, s, broad, IH.

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- 83 Example 19 A

Diethyl (4-piperidinylmethyl)-phosphonate

2.11 g (528 mmol) of 60% strength sodium hydride are initially charged in 50 ml of absolute tetrahydrofuran, and 15.7 g (52.8 mmol) of diethyl methanediphosphonate are added dropwise. The mixture is stirred at room temperature for another 30 minutes, and 10.1 g (52.8 mmol) of l-benzyl-4-piperidone are then added. The mixture is stirred for one hour at room temperature and for one hour under reflux, 10 concentrated, admixed with water and extracted three times with dichloromethane, and the organic phases are dried over sodium sulphate and concentrated. The residue is hydrogenated in 50 ml of ethanol over 1.7 g of 10% palladium-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 MHz, ‘H-NMR (CDC13): 1.13, m, 2H; 1.32, (, 6H; 1.69, dd, 2H; 1.74 - 1.95, m,

4H; 2.62, dt, 2H; 3.05, m, 2H; 4.1, m, 4H.

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-84Example 20A

g (571 mmol) of crotonaldehyde are dissolved in 80 ml of acetic acid and, at 0°C, admixed dropwise with a solution of 137 g (1.99 mol) of sodium nitrite in 300 ml of water. The mixture is stirred at room temperature for 2 hours, diluted with 800 ml of water and extracted 3 times with dichloromethane. The organic phase is dried, and chromatography (cyclohexane/ethyl acetate) gives 13.8 g (18.9%) of 5-methyl-

4- furoxanecarbaldehyde.

200 MHz ‘H-NMR (CDC13):2.39, s, 3H; 10.10, s, 1H.

Example 21A

5- Methyl-4-furoxanecarbonyl chloride

13.5 g (105 mmol) of 5-methyl-4-furoxanecarbaldehyde are dissolved in 200 ml of acetone and, at 0°C, admixed dropwise with a solution of 16.86 g (168 mmol) of chromium trioxide in 120 ml of a 2.2M sulphuric acid. The mixture is stirred at ΙΟΙ 5°C for 2 hours and then at room temperature overnight. With cooling, 100 ml of isopropanol are added dropwise and, after 30 minutes, the solvent is removed under reduced pressure. The aqueous phase is extracted 3 times with ether, the organic phase is dried over magnesium sulphate and the solvent is removed under reduced pressure. The residue is dissolved in IM sodium hydroxide solution and the solution

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-85is extracted 3 times with ether. The aqueous phase is acidified and extracted 3 times with ether. The organic phase is dried and the solvent is removed under reduced pressure. The residue is stirred with petroleum ether and filtered off with suction.

6.92 g of the residue are refluxed with 10 ml of thionyl chloride in 20 ml of dichloromethane for 6 hours. The mixture is diluted with toluene, filtered and concentrated using a rotary evaporator. The residue is once more taken up in dichloromethane, admixed with 10 ml of thionyl chloride and refluxed for 48 hours. The solvent is removed under reduced pressure and the residue is distilled under reduced pressure. This gives 2.00 g (25%) of colourless crystals.

200 MHz 'H-NMR (CDCb): 2.41, s.

Example 22A l-(5-Methyl-4-furoxanecarbonyl)-4-tert-butyl-oxycarbonyl-piperazine

H

2.75 g (14.7 mmol) of Boc-piperazine and 1.49 g of triethylamine are dissolved in 20 ml of dichloromethane and, at 0°C, admixed a little at a time with 2.00 g (12.3 mmol) of 5-methyI-4-furoxanecarbonyI chloride. The mixture is stirred for 30 minutes at 0°C and for 2 hours at room temperature, diluted with dichloromethane and washed with water. The solvent is removed under reduced pressure and the residue is purified by chromatography (cyclohexanè/ethyl acetate). This gives 3.33 g (87%) of 1 -(5-methyl-4-furoxanecarbonyI)-4-tert-butyl-oxycarbonyl-piperazine.

200 MHz ‘H-NMR (CDCI3): 1.50, s, 9H, 2.30, s, 3H; 3.55, m, 4H; 3.78, m, 2H; 3.87, m, 2H.

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-86Example 23A

-(5-Methyl-4-furoxanecarbonyl)-piperazine trifluoroacetate

3.12 g (10 mmol) of 1-(5-methy l-4-furoxanecarbonyl)-4-tert-buty 1-oxycarbonylpiperazine are dissolved in 20 ml of dichloromethane and, at 0°C, admixed 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. This gives 2.47 g (83%) of l-(5-methyl-4-furoxanecarbonyl)10 piperazine trifluoroacetate.

200 MHz ‘H-NMR (DMSO-de): 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.

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- 87 Preparation examples

Example 1

2-[2-Ethoxy-5-(4-methyl-piperazine-1 -sulphonyl)-phenyl]-5,7-dimethyl-3/fimidazo[5,1 -f]-[ 1,2,4]triazin-4-one

I

CH3

0.1 g (0.26 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 10 ml of dichloromethane and cooled to 0°C. After addition of a spatula tip of DMAP, 80 mg (0.784 mmol) of N-methylpiperazine are added and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution and dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is chromatographed over silica gel (dichloromethane/methanol 9:1).

Yield: 40 mg (34.5% of theory)

Mass spectrum: 447 (M+H); 284; 256; 224.

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-91 Example 5

2-[2-Ethoxy-5-(3-hydroxypyrrolidine-l-sulphonyl)-phenyl]-5,7-dimethyl-3Himidazo[5,1 -f]-[ 1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-

3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,l-f][l,2,4]triazin-2-yl)benzenesulphonyl chloride and 70 mg (0.784 mmol) of 3-hydroxypyrrolidine, 13 mg (11.1% of theory) of 2-[2-ethoxy-5-(3-hydroxy-pyrrolidine-l-sulphonyl)-phenyl]10 5,7-dimethyl-3W-imidazo-[5,l-f][l,2,4]triazin-4-one are obtained.

Mass spectrum: 434 (M+H)

Example 6

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

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-92By the same method, starting with 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)benzenesulphonyl chloride and 70 mg (0.784 mmol) of 2-(ethylamino)-ethanol, 23 mg (20.1% of theory) of 4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-3-(5,7-dimethyl-

4- oxo-3,4-dihydroimidazo-[5, l-f][ 1,2,4]triazin-2-yl)-benzene-suiphonamide are obtained.

200 MHz 'H-NMR (CDC13): 1.2, t, 3H; 1.6, t, 3H; 2.17, bs, IH; 2.69, s, 3H; 2.75, s, 3H; 3.33, m, 4H; 3.8, t, 2H; 4.36, q, 2H; 7.18, d, IH; 7.99, dd, IH; 8.6, d, IH; 9.84, bs,lH.

Example 7

N,N-Diethyl-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,lf][ 1,2,4]triazin-2-yl)-benzenesulphonamide

By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 60 mg (0.784 mmol) of diethylamine, 21 mg (18.6% of theory) of N,N-diethyl-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5, l-f][ 1,2,4]triazin-2-yl)-benzenesulphonamide are obtained.

200 MHz 'H-NMR (CDC13): 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, IH;7.95.dd, lH;8.58,d, IH; 9.8, bs, IH.

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-96Example 11

N,N-Bis-(2-methoxyethyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1 -f]-[ 1,2,4]triazin-2-yI)-benzenesulphonamide

By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5, l-f][ 1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 100 mg (0,784 mmol) of bis-(2-methoxyethyl)-amine, 37 mg (27.5% of theory) of N,N-bis-(2-methoxy-ethyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo10 3,4-dihydroimidazo[5, l-f][ 1,2,4]triazin-2-yl)-benzenesulphonamide are obtained.

200 MHz ’H-NMR (CDC13):1.58, t, 3H; 2.61, s, 3H; 2.64, s, 3H; 3.3, s, 6H; 3.46, t,

4H; 3.56, t, 4H; 4.32, q, 2H; 7.12, d, IH; 7.95, dd, IH; 8.51, d, IH; 9.9, bs, IH

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-97Example 12

N-(3-Isoxazolyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonamide

By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1 -f][ 1,2,4]triazin-2-yl)benzenesulphonyl chloride and 70 mg (0.784 mmol) of 3-aminoisoxazol, 20 mg (17.2% of theory) N-(3-isoxazolyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo10 3,4-dihydroimidazo[5,1 -f][ 1,2,4]triazin-2-yl)-benzenesulphonamide are obtained.

200 MHz ‘H-NMR (CDCh): 1,6, t, 3H; 2.73, s, 3H; 2.81, s, 3H; 4.35, q, 2H; 6.6, d, IH; 7.14, d, IH; 8.05, dd, IH; 8.27, d, IH; 8.63, d, IH; 9.61, bs, IH.

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-98Example 13

2-[2-Ethoxy-5-(2-t-butoxycarbonylaminomethylmorpholine-4-sulphonyl)-phenyl]5,7-dimethyl-3W-imidazo[5, l-f][ 1,2,4]triazin-4-one

H

O = S = O

I

By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,l-f][ 1,2,4]triazin-2-yl)benzenesulphonyl chloride and 170 mg (0.784 mmol) of 2-t-butoxycarbonylaminomethylmorpholine, 64 mg (42.2 % of theory) of 2-[2-ethoxy-5-(2-tbutoxycarbonylaminomethylmorpholine-4-sulphonyl)-phenyl]-5,7-dimethyl-3Himidazo[5,l-f][l,2,4]triazin-4-one are obtained.

Mass spectrum: 563 (M+H)

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-99Example 14

2- [2-Ethoxy-5-(4-phenylpiperazine-1 -sulphonyI)-phenyl]-5,7-dimethyl-3 Himidazo[5, l-f]-[ l,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1 -f][ 1,2,4]triazin-2-yl)benzenesulphonyl chloride and 130 mg (0.784 mmol) of 1-phenylpiperazine, 38 mg (28,3 % of theory) of 2-[2-ethoxy-5-(4-phenylpiperazine-l-sulphonyl)-phenylJ10 5,7-dimethyl-3W-imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

200 MHz 'H-NMR (CDC13):1.62, t, 3H; 2.72, s, 3H; 2.77, s, 3H; 3.25, m, 8H; 4.38, q, 2H; 6.92, m, 2H; 7.02, d, IH; 7.18-7.37, m, 3H; 7.94, dd, IH; 8.55, m, IH; 9.79, bs, IH.

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-100Example 15

2-(2-Ethoxy-5-(3-hydroxy-3-methoxymethylpyrrolidine-l-sulphonyl)-phenyl]5,7-dimethyl-3 W-imidazo(5,1 -f] [ 1,2,4]triazin-4-one

OH O-CH3

By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,l-f][l,2,4]triazin-2-yl)benzenesulphonyl chloride and 100 mg (0.784 mmol) of 3-hydroxy3-methoxymethylpyrrolidine, 30 mg (23.5% of theory) of 2-[2-ethoxy-5-(3-hydroxy3-methoxymethylpyrrolidine-l-sulphonyl)-phenyl]-5,7-dimethyl-3ttimidazo[5,l-f][l,2,4]triazin-4-one are obtained.

Mass spectrum: 478 (M+H)

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- 101 Example 16

2-[2-Ethoxy-5-(4-methyl-piperazine-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3Himidazo[5,1 -f] [ 1,2,4]triazin-4-one

l. 23 g (3 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,lf][l,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 40 ml of dichloromethane and cooled to 0°C. After addition of a spatula tip of DMAP, 0.90 g (9.00 mmol) of N-methylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed twice with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 1.25 g (88%) of a colourless solid.

200 MHz 'H-NMR (CDCh): 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, IH; 8.44, d, IH; 9.75, s, IH.

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- 102Example 17

2-[2-Ethoxy-5-(4-methyl-piperazine-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3Himidazo[5,1 -f][ 1,2,4]triazin-4-one lactate

100 mg (0.211 mmol) of 2-[2-ethoxy-5-(4-methyl-piperazine-l-sulphonyl)-phenylJ-

5-methyl-7-propyl-3Z/-imidazo[5,l-f][l,2,4]triazin-4-one are suspended in 5 ml of ether and admixed with 20 mg of an 85% strength solution of lactic acid in water. The mixture is stirred at room temperature for 10 minutes and evaporated to dryness.

The residue is titrated with ether and filtered off with suction. This gives 110 mg (92%) of 2-[2-ethoxy-5-(4-methyl-piperazine- l-sulphonyl)-phenyl]-5-methyl7-propyl-3H-imidazo[5, l-f][l,2,4]triazin-4-one lactate.

200 MHz ‘H-NMR (DMSO-dô): 0.92, t, 3H; 1.22, d, 3H; 1.31, t, 3H; 1.74, m, 1H;

2.15, s, 3H; 2.38, m, 4H; 2.81, t, 2H; 2.91, m, 4H; 4.05, quart., 1H; 4.21, quart., 2H;

7.40, d, 1H; 7.85, m, 2H; 11.71, s, broad, 1H.

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-103Exampie 18

2-[2-Ethoxy-5-(4-methyI-piperazine-l-sulphonyI)-phenyl]-5-methyl-7-propyl-3Wimidazo[5, l-f][ 1,2,4]triazin-4-one hydrochloride

100 mg (0.211 mmol) of 2-[2-ethoxy-5-(4-methyl-piperazine-l-sulphonyl)-phenyl]5-methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one are suspended in 5 ml of diethyl ether, admixed with 0.23 ml of a IM solution of HCl in ether and stirred at room temperature for 15 minutes. The solvent is removed under reduced pressure.

This gives 107 mg (97%) of 2-[2-ethoxy-5-(4-methyl-piperazine-I-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one hydrochloride.

200 MHz 'H-NMR (DMSO-d6): 0.93, 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, IH;

7.95, m, 2H; 11.39, s, IH; 11.90, s, IH.

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- 104Example 19

2-[2-Ethoxy-5-(4-ethyl-piperazine-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3Wimidazo[5,1 -f][ 1,2,4]triazin-4-one

470 mg (1.14 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,l-f](l,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 20 ml of dichloromethane 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 10 is diluted with dichloromethane, the organic phase is washed twice with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 370 mg (66%) of a colourless solid.

400 MHz lH-NMR (CDC13): 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, IH; 8.44, d, IH; 9.75, s, IH.

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- 105Example 20

2-[2-Ethoxy-5-(4-ethyl-piperazine-l-suiphonyl)-phenyl]-5-methyl-7-propyl-3Himidazo[5, l-f][ 1,2,4]triazin-4-one hydrochloride

0.35 g (0.712 mmol) of 2-[2-ethoxy-5-(4-ethyl-piperazine-l-sulphonyl)-phenyl]-5methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one are suspended in 8 ml of ether and dichloromethane is added until a homogeneous solution is formed. 0.8 ml of a IM solution of HC1 in ether is added, and the mixture is stirred at room temperature for 20 minutes and filtered off with suction. This gives 372 mg (99%) of

2-[2-ethoxy-5-(4-ethyl-piperazine-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3//imidazo[5,1 -f][ 1,2,4]triazin-4-one hydrochloride.

200 MHz *H-NMR (DMSO-d6): 0.96, t, 3H; 1.22,' t, 3H; 1.36, t, 3H; 1.82, sex., 2H;

2.61, s, 3H; 2.88, m, 2H; 3.08, m, 6H; 3.50, m, 2H; 3.70, m, 2H; 4.25, quart., 2H;

7.48, d, IH; 7.95, m, 2H; 11.42, s, IH; 12.45, s, IH.

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- 106Example 21

2-[2-Ethoxy-5-(4-methyl-1 -amino-piperazine-1 -sulphonyl)-phenyl]-5-methyl-7propyl-3W-imidazo[5,1 -f][ l,2,4]triazin-4-one

By the same method, starting with 0.04 g (0.097 mmol) of 4-ethoxy-3-(5-methyl-

4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 0.03 g (0.29 mmol) of 1 -amino-4-methylpiperazine, 40 mg (83%) of 2-[2-ethoxy-5-(4-methyl-l-amino-piperazine-l-sulphonyl)-phenyl]-5-methyl-7- propyl-3//-imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

Rf = 0.09 (dichloromethane/methanol = 19:1)

200 MHz ‘H-NMR (CDCb): 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, IH;

8.05, dd, IH; 8.60, d, IH.

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- 107Example 22

2-[2-Ethoxy-5-(4-hydroxyethyl-l-amino-piperazine-l-sulphonyl)-phenyl]-5-methyl7-propyl-3Zf-imidazo[5,1 -f] [ 1,2,4]triazin-4-one

By the same method, starting with 0.04 g (0.097 mmol) of 4-ethoxy-3-(5-methyl-

4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f|[l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 0.04 g (0.29 mmol) of l-amino-4-hydroxyethylpiperazine, 46 mg (91%) of 2-[2-ethoxy-5-(4-hydroxyethyl-1 -amino-piperazine-1 -sulphonyl)-phenyl]-5- methyl-7-propyl-3//-imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

Rf = 0.08 (dichloromethane/methanol = 19:1)

200 MHz ‘H-NMR (CDCls): 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, IH; 8.05, dd, IH; 8.60, d, IH.

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- 108Example 23

N,N-bishydroxyethylamindethyl-4-ethoxy-3-(5-methyl(-4-bxo-7-propyl3,4-dihydro-imidazo /5,î-£77ï, 2, AJtriazin-2-y 1) benzenesulphonamide

By the sane method, starting with 0.04 g (0.097 nmol) of 4-ethoxy-3(5-methyl4-oxo-7-propyl-3,4-dihydro-inddazo/5, l-f//l, 2,4/triazin-2-yl) benzensulphcnyl charade and 0.043 g (0.29 nmol) of N,N-bishydroxyetiiylarrdno-ethylamino, 46 mg (91%) of N,l^ishydroxyethylanndnoethyl-4-ettioxy-3-(5-methyl-4-oxo-7-prcpyl-3,4- : dihydro-inddazo. l-f7/l,2,$triazin-2-yl)benzenesalphcnandde are obtained.

200 MHz ’H-NMR (CDCI3): 1.02, t, 3H; 1.53, ς 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, IH; 7.95, dd, IH; 8.35, d, IH.

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- 109 Example 24

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

By the same method, starting with 0.4 g (0.97 mmol) of 4-ethoxy-3-(5-methyl-4-oxo7-propyl-3,4-dihydro-imidazo[5, l-f][ 1,2,4]triazin-2-yl)-benzenesulphonyl chloride, 390 mg of triethylamine and 0.86 g (2.99 mmol) of 4-dimethoxyphosphorylmethylpiperazine trifluoroacetate, 321 mg (53%) of 2-[2-ethoxy-5-(4-dimethoxyphosphoryl10 methyl-piperazine-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3W-imidazo[5,lf][l,2,4]triazin-4-one are obtained.

Rf = 0.4 (dichloromethane/methanol = 20:1)

200 MHz 'H-NMR (CDClj): 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, IH; 7.88, dd, IH; 8.45, d, IH; 9.71, s, IH.

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- 110Example 25

2-[2-Ethoxy-5-(4-diethoxyphosphorylmethyl-piperidine-l-sulphonyl)-phenyl]-5methyl-7-propyl-3#-imidazo(5,1 -f][ 1,2,4]triazin-4-one

By the same method, starting with 0.4 g (0.97 mmol) of 4-ethoxy-3-(5-methyl-4-oxo7-propyl-3,4-dihydro-imidazo[5, l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 0.86 g (3.7 mmol) of 4-diethoxyphosphorylmethyl-piperidine, 366 mg (49%) of 2-[2-ethoxy-5-(4-diethoxyphosphorylmethyI-piperidine-l-sulphonyl)-phenyl]10 5-methyl-7-propyl-3H-imidazo[5,1 -f][ 1,2,4]triazin-4-one are obtained.

Rf = 0.4 (dichloromethane/methanol = 20:1)

200 MHz ‘H-NMR (DMSO-d«): 0.92, 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, IH;

7.87, m,2H; 11.70, s, IH.

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- Ill Example 26

2-[2-Ethoxy-5-(4-hydroxy-piperidine-l-sulphonyl)-phenyl]-5-methyl-7-propyl-377- imidazo[5,1 -f] [ 1,2,4] triazin-4-one

By the same method, starting with 531 mg (1.29 mmol) of 4-ethoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f] [ 1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 393 mg (3.88 mmol) of 4-hydroxypiperidine, 400 mg (64%) of 2-(2ethoxy-5-(4-hydroxy-piperidine-1 -sulphonyl)-phenyl]-5-methyl-7-propyl-3/710 imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

200 MHz 'H-NMR (DMSO-d6): 0.941, t, 3H; 1.32, t, 3H; 1.45, m, 2H; 1.71, m, 4H;

2.48, s, 3H; 2.82, m, 4H; 3.1 l,m, 2H; 3.55, m, IH; 4.20, quart., 2H; 4.72, d, IH, 7.39, d,lH; 7.87, m, 2H; 11.70, s, IH.

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-112Example 27

2-{2-Ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-l-sulphonyl]-phenyl}-5-methyl7-propyl-3W-imidazo[5, l-f][ 1,2,4]triazin-4-one

By the same method, starting with 411 mg (1 mmol) of 4-ethoxy-3-(5-methyl-4-oxo7-propyl-3,4-dihydro-imidazo[5,1 -f][ l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 391 mg (3 mmol) of 4-hydroxyethylpiperazine, 380 mg (75%) of 2-{2-ethoxy-

5-[4-(2-hydroxy-ethyl)-piperazine-1 -sulphonyl]-phenyl }-5-methyl-7-propyl-3H- imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

Rf = 0.198 (dichloromethane/methanol = 95:5)

200 MHz ‘H-NMR (CDCl3):1.02, t, 3H; 1.61, t, 3H; 1.87, hex., 3H; 2.60, m, 7H;

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- 116 Example 31

N-Ethyl-4-ethoxy-N-(2-hydroxy-ethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1 -f][ 1,2,4]triazin-2-yl)benzenesulphonamide

By the same method, starting with 411 mg (1.0 mmol) of 4-ethoxy-3-(5-methyl-

4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f] [ 1,2,4]triazin-2-y l)-benzenesulphonyl chloride and 267 mg (3 mmol) of ethylhydroxyethylamine, 325 mg (70%) of N-ethyl4-ethoxy-N-(2-hydroxy-ethyl)-3-(5-methyl~4-oxo-7-propyl-3,4-dihydro- imidazo[5,1 -f][ 1,2,4]triazin-2-yl)benzenesulphonamide are obtained.

Rf = 0.29 (dichloromethane/methanol = 95:5)

200 MHz ‘H-NMR (CDC13):1.O2, t, 3H; 1.20, t, 3H; 1.61, t, 3H; 1.88, sex., 2H; 2.30, s, broad, IH; 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, IH; 7.98, dd, IH; 8.56, d, IH; 9.70, s, IH.

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-117Exampie 32

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

ch3 ch3

By the same method, starting with 400 mg (0.97 mmol) of 4-ethoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f] [ 1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 210 mg (2.92 mmol) of diethylamine, 398 mg (89%) of N,N-diethyl-4ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin10 2-yl)benzenesulphonamide are obtained.

Rf = 0.49 (dichloromethane/methanol = 20:1)

200 MHz ‘H-NMR (CDC13):1.O2, t, 3H; 1.20, t, 6H; 1.49, t, 1.61, t, 3H; 1.88, sex.,

2H; 2.30, s, broad, IH; 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, IH; 7.98, dd, IH; 8.56, d, IH; 9.70, s, IH.

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- 118Example 33

N-(2-Methoxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5, l-f][l ,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamide

By the same method, starting with 1.23 g (3 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yI)-benzenesulphonyl chloride and 680 mg (9 mmol) of 2-methoxyethylamine, 900 mg (67%) of N-(2-methoxyethyl)-

3-(5-methy l-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f] [ 1,2,4]triazin-2-yl)-4-ethoxy10 benzenesulphonamide are obtained.

Rf = 0.25 (dichloromethane/methanol = 95:5)

400 MHz 'H-NMR (CDC13): 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, IH;

7.13, d, IH, 7.97, dd, IH, 8.53, d, 1H; 9.82, s, IH.

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- 119Example 34

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

CH3

By the same method, starting with 210 mg (0.49 mmol) of 4-ethoxy-3-(5-methyl-

4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 130 mg (9 mmol) of 2-N,N-dimethylethylamine, 150 mg (59%) of N-(2N,N-dimethylethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-

f][ 1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamide are obtained.

200 MHz ‘H-NMR (CDC13): 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.

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- 120Example 35

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

By the same method, starting with 1.23 g (3 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7propyl-3,4-dihydro-imidazo[5,1 -f][ 1,2,4]triazin-2-yl)-benzenesulphonyl chloride and

1.3 g (9 mmol) of 3-(l-morpholino)-propylamine, 1.38 g (88%) of N-[3-(l-morpholino)propyl]-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro10 imidazo[5,l-f][l,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamide are obtained.

Rf = 0.23 (dichloromethane/methanol = 95:5)

200 MHz ‘H-NMR (CDC13): 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.

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- 121 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]triazin-2-yl)-4-ethoxy-benzenesulphonamide

By the same method, starting with 0.04 g (0.097 mmol) of 4-ethoxy-3-(5-methyl4-oxo-7-propyi-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 0.05 g (0.29 mmol) of 3-[l-(4-methyl-)piperazino]-propylamine, 0.04 g (77%) of N-{3-[ l-(4-methyl)piperazino]-propyl }-3-(5-methyl-4-oxo-7-propyl10 3,4-dihydro-imidazo[5,1 -f] [ 1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamide is obtained.

Rf = 0.11 (dichloromethane/methanol = 95:5)

200 MHz ‘H-NMR (CDC13): 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, IH; 4.30, quart., 2H; 7.13, d, IH, 7.97, dd, IH, 8.53, d, IH.

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- 122Example 37

2- {2-Ethoxy-5-[4-(2-methoxy-ethyl)-piperazine-1 -sulphonyl]-phenyl} -5-methyl-

7-propyl-3H-imidazo[5, l-f][ 1,2,4]triazin-4-one

By the same method, starting with 40 mg (0.097 mmol) of 4-ethoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 40 mg (0.29 mmol) of 4-methoxyethylpiperazine, 50 mg (99%) of 2-{2ethoxy-5-[4-(2-methoxy-ethyl)-piperazine-1 -sulphonyl]-phenyl} -5-methy 1-7-propyl10 3H-imidazo[5,1 -f][ 1,2,4]triazin-4-one are obtained.

Rf = 0.27 (dichloromethane/methanol = 95:5)

200 MHz ‘H-NMR (CDCl3):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, IH, 7.89, dd, IH, 8.47, d, IH, 9.71, s, IH.

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- 123 Example 38

2- {2-Ethoxy-5-[4-(2-N,N-dimethyl-ethyl)-piperazine-1 -sulphonylj-phenyl} -5methyl-7-propyl-3//-imidazo[5, l-f][ l,2,4]triazin-4-one

By the same method, starting with 40 mg (0.097 mmol) of 4-ethoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 50 mg (0.29 mmol) of 4-(2-N,N-dimethyl)-ethylpiperazine, 50 mg (99%) of 2-{2-ethoxy-5-[4-(2-N,N-dimethyl-ethyI)-piperazine-l-sulphonyl]-phenyl}10 5-methyl-7-propyl-3//-imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

Rf = 0.11 (dichloromethane/methanol = 95:5)

200 MHz 'H-NMR (CDCl3):1.02, t, 3H; 1.61, t, 3H; 1.87, hex., 3H; 2.20, s, 6H; 2.42, m, 4H; 2.58, m, 4H; 2.63, s, 3H; 2.99, m, 3H; 3.10, m, 4H; 4.36, quart., 2H; 7.18, d,

IH, 7.89, dd, IH, 8.47, d, IH, 9.71, s, IH.

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- 124Example 39

2-{2-Ethoxy-5-[4-(3-N,N-dimethyl-propyl)-piperazin-l-sulphonyl]-phenyl}-5methyl-7-propyl-3W-imidazo[5,1 -f][ 1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.243 mmol) of 4-ethoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f] [ 1,2,4] triazin-2-y l)-benzenesulphony 1 chloride and 130 mg (0.73 mmol) of 4-(3-N,N-dimethyl)-propylpiperazine, 72 mg (54%) of 2- {2-ethoxy-5-[4-(3-N,N-dimethyl-propyl)-piperazine-1 -sulphonyl]10 phenyl)-5-methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

Rf = 0.08 (dichloromethane/methanol = 95:5)

200 MHz 'H-NMR (CDCl3):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,

IH, 7.89, dd, IH, 8.47, d, IH, 9.71, s, IH.

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- 125Example 40

2-[2-Ethoxy-5-(4-dioxolano-piperidine-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3Himidazo[5,1 -f] [ 1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.243 mmol) of 4-ethoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f] [ 1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 100 mg (0.73 mmol) of 4-dioxolanopiperidine, 111 mg (88%) of 2-[2-ethoxy-5-(4-dioxolano-piperidine-l-sulphonyl)-phenyl]-5-methyl-7-propyl-37710 imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

200 MHz ‘H-NMR (CDCl3):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, IH, 7.89, dd, IH, 8.47, d, IH,

9.71, s, IH.

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- 126Example 41

2-[2-Ethoxy-5-(4-(5-methyl-4-furoxanecarbonyl)-piperazine-l-sulphonyl)-phenyl]5-methyl-7-propyl-377-imidazo[5,1 -f][ 1,2,4]triazin-4-one

410 mg (l.Ommol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 10 ml of dichloromethane and cooled to 0°C. 590 mg (2.00 mmol) of l-(5-methyl4-furoxanecarbonyl)-piperazine trifluoroacetate and 400 mg of triethylamine are 10 added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution, IM hydrochloric acid and water and dried over sodium sulphate and the solvent is removed under reduced pressuré. Crystallization from ether gives 448 mg (74%) of a colourless solid.

200 MHz ‘H-NMR (CDCIj): 1.01, t, 3H; 1.59, t, 3H; 1.88, hex, 2H; 2.25, s, 3H; 2.63, s, 3H; 3.00, t, 2H; 3.20, m, 4H; 3.90, m, 2H; 4.02, m, 2H; 4.33, quart., 2H, 7.19, d, 1H; 7.89, dd, 1H; 8.48, d, 1H; 9.57, s, 1H.

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- 127Example 42

2- {2-Ethoxy-5-[4-acetyl-piperazine-1 -sulphonylj-phenyl} -5-methyl-7-propyl-3Himidazo[5,1 -f][ 1,2,4]triazin-4-one

By the same method, starting with 40 mg (0.097 mmol) of 4-ethoxy-3-(5-methyl-

4- oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 40 mg (0.29 mmol) of N-acetylpiperazine, 9 mg (18%) of 2-{2-ethoxy-

5- [4-acetyl-piperazine-l-sulphonylj-phenyl }-5-methyl-7-propyl-3/f-imidazo[5, Ι-

ΙΟ f] [ 1,2,4] triazin-4-one are obtained.

Rf = 0.34 (dichloromethane/methanol = 95:5)

200 MHz 'H-NMR (CDCI3):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, IH, 7.89, dd,

IH, 8.47, d, IH, 9.71, s, IH.

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- 128 Example 43

2- {2-Ethoxy-5-[4-formyl-piperazine-1 -sulphonylj-phenyl} -5-methyl-7-propyl-3ffimidazo[5,1 -f][ 1,2,4]triazin-4-one

By the same method, starting with 40 mg (0.097 mmol) of 4-ethoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yI)-benzenesulphonyl chloride and 30 mg (0.29 mmol) of N-formylpiperazine, 35 mg (73%) of 2-{2ethoxy-5-[4-formyl-piperazine-l-sulphonylj-phenyl }-5-methyl-7-propyl-3H10 imidazo[5, 1 -fj [ 1,2,4] triazin-4-one are obtained.

Rf = 0.29 (dichloromethane/methanol = 95:5)

200 MHz ‘H-NMR (CDC13): 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, IH, 7.89, dd,

1H, 8.00, s, IH; 8.47, d, IH, 9.71, s, IH.

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- 129Example 44

2-[2-Ethoxy-5-(3-butylsydnoneimine)-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3Himidazo[5,1 -f][ 1,2,4]triazin-4-one

110 mg (0.6 mmol) of 3-butylsydnoneimine hydrochoride are dissolved in 2.5 ml of pyridine and cooled to 0°C. 210 mg (0.5 mmol) of 4-ethoxy-3-(5-methyl-4-oxo7-propyl-3,4-dihydro-imidazo[5,1 -f] [ 1,2,4]triazin-2-yl)-benzenesulphonyl chloride are added, and the reaction mixture is stirred for 2 hours at 0°C and overnight at room temperature. The mixture is diluted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Chromatography (dichloromethane/methanol) gives 16 mg (6%) of 2-[2-ethoxy-5-(3-butylsydnoneimine)-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3Himidazo[5,1 -f] [ 1,2,4]triazin-4-one.

Rf = 0.41 (dichloromethane/methanol = 95:5)

200 MHz 'H-NMR (CDCb): LOI, 2t, 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, IH;

7.56, s, IH; 7.98, dd, IH; 8.58, d, IH; 9.79, s, broad, IH.

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- 130Example 45

5-Methyi-2-[5-(4-methyl-piperazine-l-sulphonyl)-2-propoxy-phenyl]-7-propyl-3Z/- imidazo[5,1 -f][ 1,2,4]triazin-4-one

0.85 g (2 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,l-f][l,2,4]-triazin-2-yl)-benzenesulphonyl chloride are dissolved in 20 ml of dichloromethane and cooled to 0°C. After addition of a spatula tip of DMAP, 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 phase is washed with ammonium chloride solution and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 0.80 g (77%) of a colourless solid.

Rf = 0.233 (dichloromethane/methanol = 95:5)

200 MHz 'H-NMR (CDC13): LOO, t, 3H; 1.15, t, 3H; 1.87, hex, 2H; 1.99, hex., 2H;

2.30, s, 3H; 2.52, m, 4H; 2.62, s, 3H; 2.99, t, 2H; 3.10, m, 4H; 4.21, t, 2H; 7.17, d, IH; 7.87, dd, Ih, 8.48, d, IH, 9.70, s, IH.

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- 131 Example 46

5-Methyl-2-[5-(4-methyl-piperazine-l-sulphonyl)-2-propoxy-phenyl]-7-propyl-3Himidazo[5,1 -f][ 1,2,4]triazin-4-one hydrochloride

mg (0.045 mmol) of 5-methyl-2-[5-(4-methyl-piperazine-l-sulphonyl)-2-propoxyphenyl]-7-propyl-3//-imidazo[5,l-f][l,2,4]triaziiM-one are dissolved in 2 ml of ether and 1 ml of dichloromethane and admixed with 0.1 ml of a IM solution of HC1 in ether. After 20 minutes, the precipitate is filtered off with suction and dried.

200 MHz 'H-NMR (CDClj): 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, IH; 7.95, m, 2H; 11.12, s, IH; 12.22, s, IH.

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- 132 Example 47

2-[5-(4-Hydroxy piperidine-1-sulphony 1)-2-propoxy-phenyl]-5-me thy 1-7-propyl-3Himidazo[5,1 -f] [ 1,2,4]triazin-4-one

By the same method, starting with 850 mg (2 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 610 mg (6 mmol) of 4-hydroxypiperidine, 736 mg (75%) of 2-[5-(4-hydroxypiperidine-l-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-37f10 imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

Rf = 0.07 (dichloromethane/methanol = 95:5)

200 MHz 'H-NMR (CDC13): 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, IH; 4.22, t., 2H; 7.17, d,lH; 7.89, dd, IH; 8.50, d, IH;

11.70, s, IH.

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- 133 Example 48

2-[5-(4-Hydroxymethylpiperidine-l-sulphonyl)-2-propoxy-phenyl]-5-methyl-7propyl-3/f-imidazo[5,1 -f] [ 1,2,4]triazin-4-one

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 35 mg (0.3 mmol) of 4-hydroxymethylpiperidine, 41 mg (82%) of 2-[5-(4-hydroxymethylpiperidine-l-sulphonyl)-2-propoxy-phenyl]-5-methyl-710 propyl-3/f-imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

Rf = 0.52 (dichloromethane/methanol = 9:1)

200 MHz ‘H-NMR (CDC13): 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, ; 3.48, d, 2H;'3.85, d, 2H; 4.21, t, 2H; 7.,17, d,

IH; 7.88, dd, IH, 8.45, d, IH; 9. 71, s, IH.

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- 134Example 49

2- {5-[4-(2-hydroxyethyl)-piperazine-1 -sulphonyl]-2-propoxy-phenyl} -5-methyl7-propy 1-3/7-imidazo [5,1 -f] [ 1,2,4]triazin-4-one

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -fj [ 1,2,4]triazin-2-yl)-benzenesulphony 1 chloride and 39 mg (0.3 mmol) of 4-hydroxymethylpiperazine, 50 mg (96%) of 2- {5-[4-(2-hydroxyethyl)-piperazine-1 -sulphonyl]-2-propoxy-phenyl} -5-methyl10 7-propyl-3W-imidazo[5,l-f][l,2,4]triazin-4-one are obtained.

Rf = 0.43 (dichloromethane/methanol = 9:1)

200 MHz ‘H-NMR (CDC13): 1.01, t, 3H; 1.15, t, 3H, 1.88, m, 2H, 2.00, m, 2H, 2.62, m, 9H, 3.00, t, 2H, 3.07, m, 4H, 3.58, t, 2H, 4.23, t, 2H; 7.19, d, 1H; 7.88, dd, 1H, 8.43, d, 1H, 9.85, s, 1H.

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- 135 Example 50

N-( 1,1-Dioxotetrahydro-1 X6-thiophene-3-yl)-3-(5-methyl-4-oxo-7-propy 13,4-dihydro-imidazo- [5,1 -f][ 1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f] [ 1,2,4]triazin-2-yl)-benzenesulphony 1 chloride and 41 mg (0.3 mmol) of 2-aminosulphoIane, 8 mg (14%) of N-(l,ldioxotetrahydro-lX6-thiophene-3-yl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro10 imidazo-[5,l-f][ 1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide are obtained.

Rf = 0.49 (dichloromethane/methanol = 9:1)

200 MHz 'H-NMR (CDC13): 1.01, t, 3H, 1.15, t, 3H, 1.85, m, 2H; 1.99, m, 2H; 2.30, m, IH; 2.50, m, IH; 2.62, s, 3H; 2.95, m, 4H; 3.21, m, IH; 4.20, m, 3H; 5.98, s, IH;

7.18, d, IH, 7.98, dd, lH;8.51,d, IH, 9.71, s, IH.

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- 136Exampie 51

N-(2-Dimethylaminoethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyI-3,4-dihydroimidazo[5,1 -f] [ 1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

CH

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f][l ,2,4]triazin-2-yl)-benzenesulphonyl chloride and 31 mg (0.3 mmol) of 1,1,4-trimethyldiaminoethane, 39 mg (79%) of N-(2-dimethylaminoethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro10 imidazo[5,l-f][l,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide are obtained.

Rf = 0.28 (dichloromethane/methanol = 9:1)

200 MHz 'H-NMR (CDCh): 1.01, t, 3H, 1.15, t, 3H, 1.88, m, 2H; 2.01, m, 2H; 2.25, s, 6H; 2.50, t, 2H; 2.62, s, 3H; 2.82, s, 3H; 3.01, t, 2H; 3.18, t, 2H; 4.21, t, 2H; 7.16, d, IH, 7.91, dd, IH, 8.50, d, IH; 9.70, s, IH.

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- 137 Example 52

3-(5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5, l-f][l ,2,4]triazin-2-yl)-N- (3-morpholin-4-yl-propyl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-

4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f][ 1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 43 mg (0.3 mmol) of l-(3-aminopropyl)-morpholine, 52 mg (97%) of 3(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-N-(3- morpholin-4-yl-propyl)-4-propoxy-benzenesulphonamide are obtained.

Rf = 0.33 (dichloromethane/methanol = 9:1)

200 MHz 'H-NMR (CDC13): 1.01, t, 3H, 1.15, t, 3H, 1.71, m, 2H; 1.93, m, 4H; 2.43, m, 6H; 2.62, s, 3H; 2.98, t, 2H; 3.12, t, 2H; 3.70, m, 4H; 4.21, t, 2H; 7.15, d, 1H;

7.96, dd, 1H; 8.55, d, 1H; 9.85, s, 1H.

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- 138 Example 53

N,N-Bis-(2-hydroxyethy l)-3-(5-methy l-4-oxo-7 -propy 1-3,4-dihydroimidazo[5,1 -f| [ 1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f] [ 1,2,4Jtriazin-2-yl)-benzenesulphonyl chloride and 32 mg (0.3 mmol) of bishydroxyethylamine, 34 mg (69%) of N,N-bis(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro10 imidazo[5, l-f][ 1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide are obtained.

Rf = 0.36 (dichloromethane/methanol = 9:1)

200 MHz ‘H-NMR (CDC13): 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; 3.87, t, 4H; 4.20, t, 2H; 7.15, d, IH; 7.92, dd, IH;

8.49, d, IH; 9.85, s, IH.

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-139Example 54

N-(3-HydroxybenzyI)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1 -f] ( 1,2,4]triazin-2-y!)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl -3,4-dihydro-imidazo[5,1 -f] [ 1,2,4]triazin-2-y l)-benzenesulphony 1 chloride and 37 mg (0.3 mmol) of 3-hydroxybenzylamine, 4 mg (8%) of N-(3hydroxybenzyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5, ΙΙΟ f] [ 1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide are obtained.

Rf = 0.43 (dichloromethane/methanol =9:1)

200 MHz 'H-NMR (CDCl3):1.01, t, 3H, 1.13, t, 3H; 1.83, m, 2H; 1.96, m, 2H; 2.59, s, 3H, 2.96, t, 2H, 4.16, m, 4H, 5.05, t, IH; 6.52,'s, IH; 6.70, m, 2H; 7.06, m, 2H;

7.93, dd, IH, 8.41, d, IH, 9.77, s, IH.

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- 140Example 55

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

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f][ 1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 27 mg (0.3 mmol) of ethylhydroxyethylamine, 18 mg (38%) of N-ethylN-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,l10 f][ 1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide are obtained.

Rf = 0.48 (dichloromethane/methanol = 9:1)

200 MHz 'H-NMR (CDC13) :1.01, t, 3H; 1.15, 2t, 6H; 1.75, s, 2H; 1.85, m, 2H; 1.98, m, 2H; 2.40, s, 1H; 2.62, s, 3H; 2.99, t, 2H; 3.32, m, 4H; 3.90, quart., 2H, 4.21, 15 quart., 2H; 7.15, d, 1H; 7.95, dd, 1H; 8.55, d, 1H, 9-73, s, 1H.

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- 141 Example 56

N-(3-Ethoxypropyl)-3-(5-methyl-4-oxo-7-propyI-3,4-dihydroimidazo[5,l-f][l,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyI chloride and 31 mg (0.3 mmol) of 3-ethoxypropylamine, 47 mg (96%) of N-(3ethoxypropyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1 -f][ 1,2,4]triazin10 2-yl)-4-propoxy-benzenesulphonamide are obtained.

Rf = 0.60 (dichloromethane/methanol = 9:1)

200 MHz ’H-NMR (CDCI3): 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, 15 1H; 8.55, d, 1H, 9.85, s, 1H.

Le A 32 733-Foreign countries

- 148Example 63

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

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo(5,1-f] [ 1,2,4]triazin-2-yl)-benzenesulphony 1 chloride and 31 mg (0.6 mmol) of propylhydroxyethylamine, 20 mg (40%) of N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4J10 triazin-2-yl)-4-propoxy-N-propyl-benzenesulphonamide are obtained.

Rf = 0.52 (dichloromethane/methanol = 9:1)

200 MHz ‘H-NMR (CDC13): 0.90, t, ,3H; 1.01, t, 3H; 1.15, t, 3H; 1.52, m, 2H, 1.88, m, 2H, 2.00, m, 2H; 2.40, s, IH; 2.63, s, 3H, 3.01, t, 2H, 3.22, m, 4H; 3.80, quart.,

2H; 4.21, t, 2H, 7.15, d, 2H, 7.95, dd, IH, 8.55, d, IH; 9.75, s, IH.

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- 152Example 67

N-Ally l-N-ethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1 -f] [ l ,2,4]triazin-2-yl)-4-propoxy benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 26 mg (0.3 mmol) of allylethylamine, 30 mg (64%) of N-allyl-N-ethyl3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,l-f][1.2,4]triazin-2-yl)-4-propoxy10 benzenesulphonamide are obtained.

Rf = 0.44 (dichloromethane/methanol = 19:1)

200 MHz ‘H-NMR (CDC13): 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, IH;

7.15, d, IH, 7.95, dd, 1H, 8.55, d, IH; 9.80, s, IH. .

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- 153Example 68

2-[2-Ethoxy-4-methoxy-5-(4-methylpiperazine-l-sulphonyl)-phenyl]-5-methyl7-propyl-3H-imidazo[5,1 -f][ 1,2,4]triazin-4-one

mg (0.045mmol) of 4-ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4dihydroimidazo-[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 0.5 ml of dichloromethane and admixed with a spatula tip of dimethylaminopyridine and 14 mg (0.136 mmol) of N-methylpiperazine, and the reaction mixture is stirred at room temperature overnight. Purification over silica gel gives 12.8 mg (55%) of 2-[2-ethoxy-4-methoxy-5-(4-methylpiperazine-lsulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1 -f][ 1,2,4]triazin-4-one.

Rf = 0.22 (dichloromethane/methanol = 20:1).

200 MHz 'H-NMR (CDClj): 0.94, t, 3H; 1.55, t, 3H; 1.80, m, 2H; 2.24, s, 3H; 2.42, t, 4H; 2.55, s, ,3H; 2.92, t, 2H; 3.19, t, 4H, 3.91, s, 3H; 4.25, quart., 2H; 6.48, s, IH; 8.57, s, IH; 9.54, s, IH.

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- 154Example 69

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

OH

By the same method, starting with 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,l-f][l,2,4]triazin-2-yl)benzenesulphonyl chloride and 18 mg (0.14 mmol) of 4-hydroxyethylpiperazine, mg (46%) of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)-piperazine-l-sulphonyl]-

4-methoxyphenyl} -5-methyl-7-propyl-3H-imidazo[5,1 -f][ 1,2,4]triazin-4-one are obtained.

Rf = 0.34 (dichloromethane/methanol = 15:1)

200 MHz ‘H-NMR (CDC13): 0.94, t, 3H; 1.55, t, 3H; 1.80, m, 3H; 2.52, m, 9H; 2.92, t, 2H; 3.20, t, 4H; 3.44, t, 2H; 3.92, s, 3H; 4.25, quart., 2H; 6.49, s, IH; 8.56, s, IH;

9.55, s, IH.

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- 155Exampie 70

4-Ethoxy-N-ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl3,4-dihydro-imidazo[5,1 -f}[ l,2,4]triazin-2-yl)-benzenesulphonamide

By the same method, starting from 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)benzenesulphonyl chloride and 12 mg (0.14 mmol) of ethylhydroxyethylamine, 8 mg (34%) of 4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(5-methyl-4-oxo10 7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2.-yl)-benzenesulphonamide are obtained.

Rf = 0.45 (dichloromethane/methanol = 15:1)

200 MHz ‘H-NMR (CDCb); 1.02, t, 3H; 1.18, t, 3H; 1.61, t, 2H; 1.88, m, 2H; 2.39, s, broad, IH; 2.65, s, 3H; 3.00, t, 2H; 3.38, quart., 2H; 3.45, t, 2H; 3.78, m, 2H; 4.01, s, 3H; 4.20, quart., 2H; 6.58, s, IH; 8.67, s, IH; 9.61, s, IH.

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- 156 Example 71

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

By the same method, starting with 20 mg (0.045 mmol) of 4-ethoxy-2-methoxy5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and 19 mg (0.14 mmol) of 4-ethoxyaniline, 7 mg (34%) of 4-ethoxy-N-(4-ethoxyphenyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro10 imidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonamide are obtained.

Rf = 0.36 (dichloromethane/methanol = 20:1)

200 MHz 'H-NMR (CDClj): 1-02, t, 3H; 1.33, t, 3H, 1.59, t, 3H, 1.86, hex., 2H,

2.62, s, 3H; 3.02, t, 2H; 3.92, quart., 2H; 4.11, s, 3H; 4.31, quart., 2H; 6.58, s, IH,

6.72, d, 2H; 6.88, s, broad, IH; 6.99, d, 2H, 8.50, s* IH; 9.59, s, IH.

The sulphonamides listed in Tables 1,2, 3,4 and 6 below were prepared by means of automated parallelsynthesis from 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,l-f][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and the appropriate amine using one of the three standard procedures below.

The sulphonamides listed in Table 5 were prepared by the same methods by means of automated parallelsynthesis from 4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroCA 02395558 2002-09-03

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- 167 imidazo[5,l-6][l,2,4]triazin-2-yl)-benzenesulphonyl chloride and the appropriate amine.

The purity of the final products was determined by means of HPLC, and they were characterized by LC-MS. The content of the desired compound according to HPLCMS is given in per cent in the tables in the column HPLC. Standard procedure A was used with amines having acidic functionalities, standard procedure B was used with amines having neutral functionalities, standard procedure C was used with amines having additional basic functionalities.

In the structural formulae of Tables 1, 2, 3, 4, 5 and 6 below, hydrogen atoms are in some cases not shown. Nitrogen atoms having a free valency are therefore to be understood as -NH- radical.

Standard procedure A: Reaction of amines having acidic functionalities

0.05 mmol of amine, 0.042 mmol of sulphonyl chloride and 0.10 mmol of NajCCb are initially charged, and 0.5 ml of a mixture of THF/HjO is pipetted in by hand. After 24 h at RT, the mixture is admixed with 0.5 ml of IM H2SO4 solution and filtered through a two-phase cartridge (500 mg of Extrelut (upper phase) and 500 mg of SiOo, mobile phase ethyl acetate). The product is obtained after concentrating the filtrate under reduced pressure.

Standard procedure B: Reaction of amines having neutral functionalities

0.125 mmol of amine are initially charged and 0.03 mmol of sulphonyl chloride as a solution in 1,2-dichloroethane is pipetted in by the synthesizer. After 24 h, the mixture is admixed with 0.5 ml of IM H2SO4 and filtered through a two-phase cartridge (500 mg of Extrelut (upper phase) and 500 mg of SiO2, mobile phase: ethyl acetate). The filtrate is concentrated under reduced pressure.

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-168 Standard procedure C: Reaction of amines having basic functionalities

0.05 mmol of amine are initially charged and 0.038 mmol of sulphonyl chloride as a solution in 1,2-dichloroethane and 0.05 mmol of triethylamine as a solution in 1,2-dichloroethane is pipetted in by the synthesizer. After 24 h, the solution is initially admixed with 3 ml of saturated NaHCO3 solution and the reaction mixture is filtered through a two-phase cartridge. The product is obtained after concentrating the filtrate under reduced pressure.

All reactions are monitored by thin-layer chromatography. If the reaction is not complete after 24 h at RT, the mixture is heated to 60°C for a further 12 h and the experiment is subsequently terminated.

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- 169-

Le A 32 733-Foreign Countries

Le A 32 733-Foreign Countries

-202-

<td> Ex. No.</td><td> Structure</td><td> MW [g/mol]</td><td> HPLC</td><td> MZ + H</td>

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<td> Ex. No.</td><td> Structure</td><td> MW [g/mol]</td><td> HPLC</td><td> MZ + H</td>

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-204-

<td> Table 4:</td><td></td><td></td><td></td><td></td>

<td> Ex. No.</td><td> Structure</td><td> MW [g/mol]</td><td> HPLC</td><td> MZ+H</td>

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-205-

<td> Ex. No.</td><td> Structure</td><td> MW (g/mol|</td><td> HPLC</td><td> MZ+H</td>

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-206-

<td> Ex. No.</td><td> Structure</td><td> MW Ig/mol)</td><td> HPLC</td><td> MZ+H</td>

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-214-

<td> Table 5</td><td></td><td></td><td></td><td></td>

<td> Ex. No.</td><td> Structure</td><td> MW</td><td> HPLC</td><td> MZ+H</td>

<td> 201</td><td> ζ nAZCH1 Am I CH, o=s=o 3 1 N 0</td><td> 516.67</td><td> 87</td><td> 517</td>

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-215-

<td> Ex. No.</td><td colspan="3"> Structure</td><td> MW</td><td> HPLC</td><td> MZ+H</td>

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-216-

Le A 32 733-Foreign Countries

-221 -

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-222-

<td> Ex. No.</td><td> Structure</td><td> MW</td><td> HPLC</td><td> MZ+H</td>

<td> 222</td><td> ζ, naach· My 1 CH, CH, 0=S=0 1 3 1 XX XX h3cx sch3</td><td> 504.66</td><td> 83</td><td> 505</td>

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- 229 -

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-248-

<td> Ex. No.</td><td> Structure</td><td> MW</td><td> HPLC</td><td> MZ+H</td>

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DEMANDES OU BREVETS VOLUMINEUX

LA PRÉSENTE PARTIE DE CETTE DEMANDE OU CE BREVETS COMPREND PLUS D’UN TOME.

CECI EST LE TOME_I DE d

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.

JUMBO APPLICATIONS I PATENTS

THIS SECTION OF THE APPLICATION t PATENT CONTAINS MORE THAN ONE VOLUME.

THIS IS VOLUME__/ OF âNOTE: For additional volumes please contact the Canadian Patent Office.

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23189-8549D

-264-

Contents276

125 members in 49 offices

This recordMember, by publication datePriority claim39 more offices are in the list below

Priority claims19

Priority claims
Document	Office	Kind	Date
197500854	Germany	–	1997-11-12
19750085	Germany	A	1997-11-12
19750085	Germany	A	1997-11-12
198124627	Germany	–	1998-03-23
19812462	Germany	A	1998-03-23
19812462	Germany	A	1998-03-23
198402899	Germany	–	1998-09-04
19840289	Germany	A	1998-09-04
19840289	Germany	A	1998-09-04
2309332	Canada	A	1998-10-31
2309332	Canada	A	1998-10-31
002309332	–	–	–
197500854	–	–	–
198124627	–	–	–
198402899	–	–	–
CA19982309332	–	–	–
DE1997150085	–	–	–
DE1998112462	–	–	–
DE1998140289	–	–	–

Members125

Family members, oldest first
Document	Office	Kind
HN1998000175A	Honduras	A	1999-01-08
SV1998000135A	El Salvador	A	1999-03-09
CA2309332A1	Canada	A1	1999-05-20
CA2395558A1	Canada	A1	1999-05-20
DE19750085A1	Germany	A1	1999-05-20
WO9924433A1	World Intellectual Property Organization (WIPO)	A1	1999-05-20
ZA9810297B	South Africa	B	1999-05-20
AU1558799A	Australia	A	1999-05-31
DE19812462A1	Germany	A1	1999-09-30
PE131799A1	Peru	A1	1999-12-30
DE19840289A1	Germany	A1	2000-03-09
UY25671A1	Uruguay	A1	2000-03-31
GT199800183A	Guatemala	A	2000-05-04
DK200000766A	Denmark	A	2000-05-09
FI20001086A	Finland	A	2000-05-09
NO20002444D0	Norway	D0	2000-05-11
NO20002444L	Norway	L	2000-05-11
NO20021714L	Norway	L	2000-05-11
SE0001745D0	Sweden	D0	2000-05-11
SE0001745L	Sweden	L	2000-05-11
GB0010974D0	United Kingdom	D0	2000-06-28
TR200001338T2	Türkiye	T2	2000-08-21
GB2346877A	United Kingdom	A	2000-08-23
DE19881732D2	Germany	D2	2000-08-24
BR9812785A	Brazil	A	2000-10-10
CZ20001759A3	Czechia	A3	2000-10-11
EP1049695A1	European Patent Office (EPO)	A1	2000-11-08
ID25871A	Indonesia	A	2000-11-09
CO4980861A1	Colombia	A1	2000-11-27
LU90561B1	Luxembourg	B1	2000-12-01
CN1278822A	China	A	2001-01-03
AR013759A1	Argentina	A1	2001-01-10
PL340400A1	Poland	A1	2001-01-29
SK7092000A3	Slovakia	A3	2001-03-12
KR20010031944A	Republic of Korea	A	2001-04-16
HRP20000292A2	Croatia	A2	2001-04-30
IL135462D0	Israel	D0	2001-05-20
EE200000291A	Estonia	A	2001-06-15
HK1031730A1	Hong Kong, China	A1	2001-06-22
UY25246A1	Uruguay	A1	2001-08-27
BG104406A	Bulgaria	A	2001-08-31
NZ504436A	New Zealand	A	2001-08-31
AU738675B2	Australia	B2	2001-09-20
HU0100394A2	Hungary	A2	2001-09-28
HUP0100394A2	Hungary	A2	2001-09-28
JP2001522851A	Japan	A	2001-11-20
GB2346877B	United Kingdom	B	2001-12-05
EP1174431A2	European Patent Office (EPO)	A2	2002-01-23
EP1174431A3	European Patent Office (EPO)	A3	2002-01-30
DE19881732C1	Germany	C1	2002-01-31
EP1049695B1	European Patent Office (EPO)	B1	2002-02-13
AT213246T	Austria	T	2002-02-15
ATE213246T1	Austria	T1	2002-02-15
DE59803108D1	Germany	D1	2002-03-21
US6362178B1	United States of America	B1	2002-03-26
NO20021714D0	Norway	D0	2002-04-11
DK1049695T3	Denmark	T3	2002-05-13
UA46166C2	Ukraine	C2	2002-05-15
HU0100394A3	Hungary	A3	2002-05-28
HUP0100394A3	Hungary	A3	2002-05-28
ECSP024267A	Ecuador	A	2002-06-26
SI1049695T1	Slovenia	T1	2002-06-30
PT1049695E	Portugal	E	2002-07-31
IN188419B	India	B	2002-09-21
ES2172945T3	Spain	T3	2002-10-01
CA2309332C	Canada	C	2002-12-03
JP2002348290A	Japan	A	2002-12-04
TW513431B	Taiwan Province of China	B	2002-12-11
JP3356428B2	Japan	B2	2002-12-16
US6566360B1	United States of America	B1	2003-05-20
NO314940B1	Norway	B1	2003-06-16
CN1123573C	China	C	2003-10-08
ES2194567A1	Spain	A1	2003-11-16
KR20040014591A	Republic of Korea	A	2004-02-14
SE522809C2	Sweden	C2	2004-03-09
US2004067945A1	United States of America	A1	2004-04-08
KR100430355B1	Republic of Korea	B1	2004-05-04
CH693954A5	Switzerland	A5	2004-05-14
FI113772B	Finland	B	2004-06-15
CN1508137A	China	A	2004-06-30
AR035972A2	Argentina	A2	2004-07-28
ES2194567B1	Spain	B1	2005-03-01
TWI229081B	Taiwan Province of China	B	2005-03-11
US2005070541A1	United States of America	A1	2005-03-31
HK1067124A1	Hong Kong, China	A1	2005-04-01
US6890922B2	United States of America	B2	2005-05-10
CU23063A3	Cuba	A3	2005-07-19
RU2260593C2	Russian Federation	C2	2005-09-20
HRP20020585A2	Croatia	A2	2005-10-31
KR100548120B1	Republic of Korea	B1	2006-02-02
IL135462A	Israel	A	2006-04-10
US2006189615A1	United States of America	A1	2006-08-24
US7122540B2	United States of America	B2	2006-10-17
EE04781B1	Estonia	B1	2007-02-15
CA2395558CThis record	Canada	C	2007-07-17
PL194801B1	Poland	B1	2007-07-31
BG65257B1	Bulgaria	B1	2007-10-31
US7314871B2	United States of America	B2	2008-01-01
US2008113972A1	United States of America	A1	2008-05-15
HRP20000292B1	Croatia	B1	2008-09-30

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Events

Legal events, newest first
	Event	Code
2010-11-01	LapsedLapsedMKLA	MKLA
2003-07-17	Examination requestEEER	EEER