Purin-6-one derivatives

• US 5,861,396 A
• Filed: 10/30/1996
• Issued: 01/19/1999
• Est. Priority Date: 11/06/1995
• Status: Expired due to Fees

• Current Assignee: Bayer AG
• Original Assignee: Bayer AG
• Inventors: Perzborn, Elisabeth, Bischoff, Erwin, Niewohner, Ulrich, Hutter, Joachim, Schutz, Helmuth
• Primary Examiner(s): Berch, Mark L.
• Application Number:
  US08/739,742
• Time in Patent Office: 811 Days
• Field of Search: 544/265, 544/118, 514/234.2, 514/262
• US Class Current: 514/234.2
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems

Abstract

Purin-6-one derivatives are prepared by acylating appropriately substituted imidazole carboxamides and then cyclizing to give the purines. The purin-6-one derivatives are suitable as active compounds in medicaments, in particular for the treatment of cardiovascular disorders, disorders of the vascular system and of the urogenital system.

Claims

1. Purin-6-one derivative of the formula (I) ##STR152## in which R¹ represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,

R² represents straight-chain or branched alkanoyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl, azido or by a group of the formula --NR³ R⁴ or --OSO₂ R⁵,

in which

R³ and R⁴ are identical and different and denote cycloalkyl having 3 to 6 carbon atoms, hydrogen, formyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula --(CO)_a --NR⁶ R⁷,

in which

a denotes a number 0 or 1,

R⁶ and R⁷ are identical or different and denote hydrogen, formyl, hydroxyl, phenyl or straight-chain 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 5 carbon atoms,

or

R³ and/or R⁴ denote straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or carboxyl,

or

R³ and/or R⁴ denote a radical of the formula --(CO)_b --T--NR⁸ R⁹, --CO--R¹⁰, --SO₂ R¹¹ or --SO₂ NR¹² R¹³, in which

b denotes the number 1,

T denotes straight-chain or branched alkyl having up to 5 carbon atoms,

or T can also denote a bond,

R⁸ and R⁹ have the meaning of R⁶ and R⁷ indicated above and are identical to or different from this,

R¹⁰ denotes a saturated, partially unsaturated or unsaturated 5- to 7-membered heterocycle having up to 3 heteroatoms selected from the group consisting of S, N and O, which can optionally be substituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, carboxyl, benzyloxycarbonyl or hydroxyl,

R¹¹ denotes straight-chain or branched alkyl having up to 5 carbon atoms, benzyl or phenyl,

R¹² and R¹³ are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

or

R³ and R⁴, together with the nitrogen atom, form a 5- or 6-membered saturated, partially unsaturated or unsaturated heterocycle which can contain up to 3 heteroatoms selected from the group consisting of N, S and O or a radical --NR¹⁴, and which is optionally substituted by carboxyl, by straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or by straight-chain or branched alkyl having up to 5 carbon atoms, which can be substituted by hydroxyl, carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,

in which

R¹⁴ denotes hydrogen, or straight-chain or branched alkyl or alkoxycarbonyl each having up to 5 carbon atoms,

and

R⁵ denotes phenyl or straight-chain or branched alkyl having up to 5 carbon atoms

A represents a straight-chain or branched alkylene or alkenylene chain each having up to 6 carbon atoms,

D and L are identical or different and represent aryl having 6 to 10 carbon atoms or a 5- to 7-membered aromatic, optionally benzo-fused heterocycle having up to 3 heteroatoms selected from the group consisting of S, N and O, each of said aryl or heterocycle being optionally substituted up to 3 times identically or differently by halogen, hydroxyl, nitro, trifluoromethyl, carboxyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula --(V_c)--NR¹⁵ R¹⁶ and/or --OR¹⁷,

in which

c denotes a number 0 or 1,

V denotes a radical of the formula --CO or --SO₂,

R¹⁵ and R¹⁶ are identical or different and have the meaning of R³ and R⁴ indicated above,

R¹⁷ denotes hydrogen, straight-chain or branched alkenyl having up to 8 carbon atoms or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted up to 3 times identically or differently by hydroxyl, carboxyl or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms,

and/or said aryl or heterocycle D or L is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered aromatic, optionally benzo-fused heterocycle having up to 3 heteroatoms selected from the group consisting of S, N and O, each of which aryl or heterocycle substituent on D or L is optionally substituted up to 2 times identically or differently by halogen, hydroxyl, nitro, carboxyl, trifluoromethyl or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms or by a group of the formula(V'"'"'_d)--NR¹⁸ R¹⁹,

in which

d has the meaning of a indicated above and is identical to or different from this,

R¹⁸ and R¹⁹ have the meaning of R³ and R⁴ indicated above and are identical to or different from this,

V'"'"' has the meaning of V indicated above and is identical to or different from this,

or

D represents a radical of the formula ##STR153## and E represents a radical of the formula --CH₂ --Y--Z--,

in which

Y denotes a bond or an oxygen or sulphur atom or the --NH group,

Z denotes a straight-chain or branched alkylene chain having up to 5 carbon atoms,

or a tautomer or a salt thereof.

2. Purin-6-one derivative of the formula (I) according to claim 1, in which

R¹ represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

R² represents straight-chain or branched alkanoyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, azido or by a group of the formula --NR³ R⁴ or O--SO₂ --R⁵,

in which

R³ and R⁴ are identical and different and denote cyclopentyl, cyclohexyl, hydrogen, formyl or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by hydroxyl, carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 5 carbon atoms or by a group of the formula --(CO)_a --NR⁶ R⁷,

in which

a denotes the number 0 or 1,

R⁶ and R⁷ are identical or different and denote hydrogen, formyl, hydroxyl, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms,

or

R³ and/or R⁴ denote straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, or carboxyl,

or

R³ and/or R⁴ denote a radical of the formula --(CO)_b --T--NR⁸ R⁹, --CO--R¹⁰, --SO₂ R¹¹ or --SO₂ NR¹² R¹³, in which

b denotes the number 1,

T denotes straight-chain or branched alkyl having up to 4 carbon atoms,

or T can also denote a bond,

R⁸ and R⁹ have the meaning of R⁶ and R⁷ indicated above and are identical to or different from this,

R¹⁰ denotes morpholino, imidazolyl, pyridyl, piperazinyl, piperidinyl or pyrrolidinyl, each of which can optionally be substituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, carboxyl, benzyloxycarbonyl or hydroxyl,

R¹¹ denotes straight-chain or branched alkyl having up to 4 carbon atoms, benzyl or phenyl,

R¹² and R¹³ are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,

or

R³ and R⁴, together with the nitrogen atom, form a pyrrolidinyl, morpholinyl, imidazolyl, piperidinyl or piperazinyl ring, each of which optionally can be substituted by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, carboxyl, or by straight-chain or branched alkyl having up to 4 carbon atoms, which can be substituted by carboxyl, hydroxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms,

and

R⁵ denotes phenyl or straight-chain or branched alkyl having up to 4 carbon atoms

A represents a straight-chain or branched alkylene or alkenylene chain each having up to 5 carbon atoms,

D and L are identical or different and represent phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, indolyl or furyl, each of which is optionally substituted up to 3 times identically or differently by fluorine, chlorine, bromine, trifluoromethyl, nitro, carboxyl, straight-chain or branched alkyl or alkoxycarbonyl each having up to 5 carbon atoms or by a group of the formula --(V_c)--NR¹⁵ R¹⁶ and/or --OR¹⁷,

in which

c denotes a number 0 or 1,

V denotes a radical of the formula --CO or --SO₂,

R¹⁵ and R¹⁶ are identical or different and have the meaning of R³ and R⁴ indicated above,

R¹⁷ denotes hydrogen, straight-chain or branched alkenyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted up to 2 times identically or differently by hydroxyl, carboxyl or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms,

and/or said aryl or heterocycle D or L is optionally substituted by naphthyl, phenyl, pyridyl, indolyl, thienyl, furyl, pyridazinyl, pyridyl, pyrryl or pyrimidyl, each of which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, nitro, carboxyl, trifluoromethyl or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms or by a group of the formula(V'"'"'_d)--NR¹⁸ R¹⁹,

in which

d has the meaning of a indicated above and is identical to or different from this,

V'"'"' has the meaning of V indicated above and is identical to or different from this,

R¹⁸ and R¹⁹ have the meaning of R³ and R⁴ indicated above,

or

D represents a radical of the formula ##STR154## and

E represents a radical of the formula --CH₂ --Y--Z--,

in which

Y denotes a bond or an oxygen or sulphur atom or the --NH group,

Z denotes a straight-chain or branched alkylene chain having up to 4 carbon atoms,

or a tautomer or a salt thereof.

3. Purin-6-one derivative of the formula (I) according to claim 1, in which

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

R² represents straight-chain or branched alkanoyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by hydroxyl, azido or by a group of the formula --NR³ R⁴ or O--SO₂ R⁵,

in which

R³ and R⁴ are identical and different and denote cyclopentyl, hydrogen, formyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms or by a group of the formula --(CO)_a --NR⁶ R⁷,

in which

a denotes a number 0 or 1,

R⁶ and R⁷ are identical or different and denote hydrogen, formyl, hydroxyl, or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxyl or by straight-chain or branched alkoxy having up to 3 carbon atoms,

or

R³ and/or R⁴ denote straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or carboxyl,

or

R³ and/or R⁴ denote a radical of the formula --(CO)_b --T--NR⁸ R⁹, --CO--R¹⁰, --SO₂ R¹¹ or --SO₂ NR¹² R¹³, in which

b denotes the number 1,

T denotes straight-chain or branched alkyl having up to 3 carbon atoms,

or T can also denote a bond,

R⁸ and R⁹ have the meaning of R⁶ and R⁷ indicated above and are identical to or different from this,

R¹⁰ denotes morpholino, piperidinyl, piperazinyl or pyrrolidinyl, each of which can optionally be substituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, benzyloxycarbonyl, carboxyl or hydroxyl,

R¹¹ denotes straight-chain or branched alkyl having up to 3 carbon atoms, benzyl or phenyl,

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

or

R³ and R⁴, together with the nitrogen atom, form a pyrrolidinyl, morpholinyl, imidazolyl, piperidinyl or piperazinyl ring, each of which optionally can be substituted by straight-chain or branched alkoxycarbonyl each having up to 3 carbon atoms or carboxyl or by straight-chain or branched alkyl having up to 3 carbon atoms, which can be substituted by carboxyl, hydroxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,

and

R⁵ denotes phenyl or straight-chain or branched alkyl having up to 3 carbon atoms

A represents an ethenylene (-vinylene) or an alkylene chain having up to 4 carbon atoms,

in which

D and L are identical or different and represent phenyl, naphthyl, furyl, thienyl, indolyl or pyridyl, each of which is optionally substituted up to 2 times identically or differently by fluorine, chlorine, bromine, nitro, carboxyl, trifluoromethyl, straight-chain or branched alkyl or alkoxycarbonyl each having up to 4 carbon atoms or by a group of the formula --(V_c)--NR¹⁵ R¹⁶ and/or --OR¹⁷,

in which

c denotes a number 0 or 1,

V denotes a radical of the formula --CO or --SO₂,

R¹⁵ and R¹⁶ are identical or different and having the meaning of R³ and R⁴ indicated above,

R¹⁷ denotes hydrogen, straight-chain or branched alkenyl having up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted up to 2 times identically or differently by hydroxyl, carboxyl or by straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, and/or said aryl or heterocycle D or L is optionally substituted by phenyl, pyrimidyl, pyridazinyl, pyridyl, thienyl or furyl, each of which is optionally substituted up to 2 times identically or differently by fluorine, chlorine, bromine, hydroxyl, nitro, carboxyl, trifluoromethyl or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms or by a group of the formula(V'"'"'_d)--NR¹⁸ R¹⁹,

in which

d has the meaning of a indicated above and is identical to or different from this,

V'"'"' has the meaning of V indicated above and is identical to or different from this,

R¹⁸ and R¹⁹ have the meaning of R³ and R⁴ indicated above,

or

D represents a radical of the formula ##STR155## and

E represents a radical of the formula --CH₂ --Y--Z--,

in which

Y denotes a bond or an oxygen or sulphur atom or the --NH group,

Z denotes a straight-chain or branched alkylene chain having up to 4 carbon atoms,

or a tautomer or a salt thereof.

4. A method of treating hypertrophy in a patient in need thereof which comprises administering to said patient an amount effective therefor of the compound or a tautomer or salt thereof according to claim 1.

5. A method of treating impotence in a patient in need thereof which comprises administering to said patient an amount effective therefor of the compound or a tautomer or salt thereof according to claim 1.

6. A method of treating incontinence in a patient in need thereof which comprises administering to said patient an amount effective therefor of the compound or a tautomer or salt thereof according to claim 1.