Substituted pyrazole derivatives condensed with six-membered heterocyclic rings

• US 6,743,798 B1
• Filed: 04/11/2001
• Issued: 06/01/2004
• Est. Priority Date: 07/29/1998
• Status: Expired due to Term

• Current Assignee: Adverio Pharma GmbH (Bayer AG)
• Original Assignee: Bayer AG
• Inventors: Perzborn, Elisabeth, Stasch, Johannes-Peter, Dembowsky, Klaus, Feurer, Achim, Straub, Alexander, Hütter, Joachim, Alonso-Alija, Cristina, Stahl, Elke
• Primary Examiner(s): Ford, John M.
• Application Number:
  US09/744,830
• Time in Patent Office: 1,147 Days
• Field of Search: 544/319, 544/122, 544/327, 544/298, 544/328, 544/333, 544/60, 544/362, 544/335, 544/243, 544/262, 544/58.2, 544/310, 544/316, 544/324, 544/331, 544/6, 544/57, 544/58.6, 544/123, 544/118, 544/157, 544/244, 544/264, 514/117, 514/269, 514/235.8, 514/252.18, 514/227.8, 514/256, 514/266, 514/263.2, 514/81, 514/85, 514/212.02, 514/217.06, 514/218, 514/226.8, 514/228.5, 514/252.14, 514/252.15, 514/252.16, 514/272, 514/274, 514/275, 540/601, 540/544, 540/575, 540/553
• US Class Current: 514/256
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to novel substituted pyrazole derivatives of the general formula (I)

in which R¹, R², R³ and A are each as defined, and to processes for their preparation and to their use as medicaments, in particular as medicaments for the treatment of cardiovascular disorders.

Claims

1. A compound of the formula (I)

in which

R¹ represents pyrimidinyl group,

which is optionally substituted up to 2 times by identical or different radicals from the group (i) consisting of

hydrogen, amino, azido, formyl, mercaptyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms which for its part may be substituted by hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula —

OR⁴

 

in which

R⁴ represents straight-chain or branched acyl having up to 5 carbon atoms

and/or is substituted by a radical of the formula  

—

S(O)_c—

NR⁶R⁷

 

in which

a, b and b′

are identical or different and each represents a number 0, 1, 2 or 3,

R⁵ is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

c is a number 1 or 2 and

R⁶ and R⁷ are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms which for its part may be substituted by halogen,

or

represents aryl having 6 to 10 carbon atoms which is optionally substituted by halogen,

 

or

represents cycloalkyl having 3 to 7 carbon atoms,

 

or

R⁶ and R⁷ together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further oxygen atom or a radical —

NR⁸

 

in which

R⁸ represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

 

or benzyl or phenyl where the ring systems are optionally substituted by halogen,

and which is substituted by at least one radical selected from the group (ii) consisting of

imidazolyl, imidazolinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl, pyrrolyl, thiomorpholinyl, S-oxothiomorpholinyl, S,S-dioxothiomorpholinyl, thiazolyl, and thiadiazolyl, and which is optionally mono- or polysubstituted by a 5- or 6-membered ring which contains two oxygen atoms as ring members and forms a bicyclic unit or a spiro unit with the ring to which it is attached, and/or by hydroxyl, cyano, straight-chain or branched alkyl, acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, where alkyl, acyl and alkoxycarbonyl may be substituted by hydroxyl, amino, halogen, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms, and

an aryl ring having 6 to 10 carbon atoms which is substituted by straight-chain or branched alkyl having up to 4 carbon atoms,

and

(C₂-C₁₀)alkenyl, (C₂-C₁₀)alkinyl, (C₇-C₂₀)alkyl, which is optionally substituted by aryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamine, hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula —

OR⁴

 

in which

R⁴ represents straight-chain or branched acyl having up to 5 carbon atoms

and

(C₁-C₆)alkyl which is substituted 1- to 3 times by aryl, halogen(s), cyano, dialkylamino, alkylamino or cycloalkyl

and

acyl, which is substituted by halogen, acyloxy, or arylthio,

and

—

NO or radicals of the formulae —

SO₃H and —

S(O)_dR⁹,

 

in which

d represents a number 1 or 2,

R⁹ represents straight-chain or branched alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or thienyl, where the ring systems may optionally be substituted by halogen or by straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,

and

a radical of the formula PO(OR¹⁰)(OR¹¹)

 

in which

R¹⁰ and R¹¹ are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or benzyl,

and

oxycycloalkyl having 3 to 8 ring members or radicals of the formulae —

CON═

C(NH₂)₂, —

C═

NH(NH₂), —

NH—

C(═

NH)NH₂ or (CO)_eNR¹²R¹³

 

in which

e represents a number 0 or 1,

R¹² and R¹³ are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms, or aryl having 6 to 10 carbon atoms, where the abovementioned radicals may optionally be substituted by aryl having 6 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, hydroxyl, amino or straight-chain or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 6 carbon atoms,

and, in the case that e=1,

R¹² and R¹³, together with the nitrogen atom to which they are attached, may also form a morpholinyl, pyrrolidinyl, or piperidinyl group, which may optionally be substituted up to 3 times by hydroxyl, alkoxy or alkyl having in each case up to 8 carbon atoms,

and, in the case that e=0,

R¹² and R¹³ may also represent straight-chain, branched or cyclic acyl having up to 14 carbon atoms, hydroxyalkyl, straight-chain or branched alkoxycarbonyl or acyloxyalkyl having in each case up to 6 carbon atoms, or a radical of the formula —

SO₂R¹⁴

 

in which

R¹⁴ represents straight-chain or branched alkyl having up to 4 carbon atoms,

and/or

R¹² and R¹³ also represent radicals of the formulae

 

in which

R¹⁵-R¹⁶ and R¹⁸-R³¹ are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

g represents a number 0, 1 or 2,

and

R¹⁷ represents phenyl, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

with the proviso that, if e=0, R¹² and R¹³ do not simultaneously represent hydrogen,

or

R¹ represents a purine radical which may optionally be substituted up to three times by halogen, azido, cyano, hydroxyl, amino, monoalkylamino having up to 5 carbon atoms, dialkylamino having in each case up to 5 carbon atoms, alkyl having up to 5 carbon atoms and/or alkoxy having up to 5 carbon atoms,

R² and R³, together with the double bond, form a fused pyridyl ring, which is optionally substituted up to three times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms which for its part may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,

and/or which is optionally substituted by a group of the formula —

NR³²R³³

 

in which

R³² and R³³ are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

or

R³² represents hydrogen and

R³³ represents acyl,

and/or which is optionally substituted by phenyl which for its part may be substituted up to 2 times by identical or different substituents from the group consisting of halogen and straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,

and/or which is optionally substituted by a group of the formula —

N═

CH—

NR³⁴R³⁵

 

in which

R³⁴ and R³⁵ are identical or different and each represents hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

A represents thienyl tetrahydropyranyl, tetrahydrofuranyl, phenyl, morpholinyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl which are optionally substituted up to 3 times by identical or different substituents from the group consisting of amino, mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms which for its part may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,

and/or is substituted by a group of the formula —

(CO)_h—

NR³⁶R³⁷

 

in which

h represents a number 0 or 1,

R³⁶ and R³⁷ are identical or different and each represents hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms,

or a stereoisomeric form or salt thereof.

2. The compound of formula (I) according to claim 1

in which

R¹ represents a pyrimidinyl group,

which is optionally substituted up to 2 times by identical or different radicals from the group (i) consisting of

hydrogen, amino, azido, formyl, mercaptyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms which for its part may be substituted by hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula — OR⁴

 

in which

R⁴ represents straight-chain or branched acyl having up to 5 carbon atoms

and/or is substituted by a radical of the formula

 

in which

a, b and b′

are identical or different and each represents a number 0, 1, 2 or 3,

R⁵ is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

and which is substituted by at least one radical selected from the group (ii) consisting of

imidazolyl, imidazolinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl, pyrrolyl, thiomorpholinyl, S-oxothiomorpholinyl, S,S-dioxothiomorpholinyl, thiazolyl, and thiadiazolyl and which is optionally mono- or polysubstituted by a 5- or 6-membered ring which contains two oxygen atoms as ring members and forms a bicyclic unit or a spiro unit with the ring to which it is attached, and/or by hydroxyl, cyano, straight-chain or branched alkyl, acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, where alkyl, acyl and alkoxycarbonyl may be substituted by hydroxyl, amino, halogen, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms,

and

an aryl ring having 6 to 10 carbon atoms which is substituted by straight-chain or branched alkyl having up to 4 carbon atoms,

and

(C₂-C10)alkenyl, (C₂-C₁₀)alkynyl, (C₇-C₂₀)alkyl, which is optionally substituted by aryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamine, hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula —

OR⁴

 

in which

R⁴ represents straight-chain or branched acyl having up to 5 carbon atoms

and

(C₁-C₆)alkyl which is substituted 1- to 3 times by aryl, halogen(s), cyano, dialkylamino, alkylamino or cycloalkyl

and

acyl, which is substituted by halogen, or by acyloxy, or arylthio,

and

—

NO or radicals of the formulae —

SO₃H and —

S(O)_dR⁹,

 

in which

d represents a number 1 or 2,

R⁹ represents straight-chain or branched alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or thienyl, where the ring systems may optionally be substituted by halogen or by straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,

and

a radical of the formula PO(OR¹⁰)(OR¹¹)

 

in which

R¹⁰ and R¹¹ are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or benzyl,

and

oxycycloalkyl having 3 to 8 ring members or radicals of the formulae —

CON═

C(NH₂)₂, —

C═

NH(NH₂), —

NH—

C(═

NH)NH₂ or (CO)_eNR¹²R¹³

 

in which

e represents a number 0 or 1,

R¹² and R¹³ are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms, or aryl having 6 to 10 carbon atoms, where the abovementioned radicals may optionally be substituted by aryl having 6 to carbon atoms, cycloalkyl having 3 to 7 carbon atoms, hydroxyl, amino or straight-chain or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 6 carbon atoms,

and, in the case that e=1,

R¹² and R¹³, together with the nitrogen atom to which they are attached, may also form a piperidinyl, morpholinyl, or pyrrolidinyl group, which may optionally substituted up to 3 times by hydroxyl, alkoxy or alkyl having in each case up to 8 carbon atoms,

and, in the case that e=0,

R¹² and R¹³ may also represent straight-chain, branched or cyclic acyl having up to 14 carbon atoms, hydroxyalkyl, straight-chain or branched alkoxycarbonyl or acyloxyalkyl having in each case up to 6 carbon atoms, or a radical of the formula —

SO₂R¹⁴

 

in which

R¹⁴ represents straight-chain or branched alkyl having up to 4 carbon atoms,

and/or

R¹² and R¹³ also represent radicals of the formulae

 

in which

R¹⁵-R¹⁶ and R¹⁸-R³¹ are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

g represents a number 0, 1 or 2,

and

R¹⁷ represents phenyl, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

with the proviso that, if e=0, R¹² and R¹³ do not simultaneously represent hydrogen,

or

R¹ represents a purine radical which may optionally be substituted up to three times by halogen, azido, cyano, hydroxyl, amino, monoalkylamino having up to 5 carbon atoms, dialkylamino having in each case up to 5 carbon atoms, alkyl having up to 5 carbon atoms and/or alkoxy having up to 5 carbon atoms,

R² and R³, together with the double bond, form a fused pyridyl ring,

which is optionally substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl, alkylthio or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms which for its part may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,

and/or

the abovementioned fused pyridyl ring is optionally substituted by a group of the formula —

NR³²R³³

 

in which

R³² and R³³ are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms

or

R³² represents hydrogen

and

R³³ represents formyl

and/or the abovementioned fused pyridyl ring is optionally substituted by phenyl which for its part may be substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,

A represents thienyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, morpholinyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl which are optionally substituted up to 2 times by identical or different substituents from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine and bromine,

or a stereoisomeric form or salt thereof.

3. The compound of formula (I) according to claim 1

in which

R¹ represents a pyrimidinyl group

which is optionally substituted up to 2 times by identical or different radicals from the group (i) consisting of

hydrogen, amino, hydroxyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, cyano or halogen,

and which is substituted by at least one radical selected from the group (ii) consisting of

imidazolyl, imidazolinyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl, pyrrolyl and thiomorpholinyl and which is optionally mono- or polysubstituted by a 5-membered ring which contains two oxygen atoms as ring members and which forms, with the ring to which it is attached, a bicyclic unit or a spiro unit, and/or by hydroxyl, cyano, straight-chain or branched alkyl, acyl or alkoxycarbonyl having in each case up to 3 carbon atoms, where alkyl, acyl and alkoxycarbonyl may be substituted by hydroxyl, amino, halogen, carboxyl, straight-chain or branched acyl or alkoxy having in each case up to 3 carbon atoms,

and

a tolyl radical,

and

C₇-alkyl which is optionally substituted by cyano,

and

(C₁-C₅)alkyl, which is 1- to 3-times substituted by halogen(s), cyano, or aryl,

and

—

NO or radicals of the formula —

S(O)_dR⁹,

 

in which

d represents a number 1 or 2,

R⁹ represents straight-chain or branched alkyl having 1 to 4 carbon atoms, aryl having 6 carbon atoms or thienyl,

and

a radical of the formula PO(OR¹⁰)(OR¹¹),

 

in which

R¹⁰ and R¹¹ are identical or different and each represents straight-chain or branched alkyl having up to 3 carbon atoms,

and

radicals of the formulae —

NH—

C(═

NH)NH₂ and or (CO)_eNR¹²R¹³

 

in which

e represents a number 0 or 1,

R¹² and R¹³ are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 carbon atoms, where the abovementioned radicals may optionally be substituted by aryl having 6 carbon atoms, furyl, cycloalkyl having 3 carbon atoms, hydroxyl, straight-chain alkoxy having up to 2 carbon atoms,

and, in the case that e=1,

R¹² and R ¹³, together with the nitrogen atom to which they are attached, may also form a piperidinyl, morpholinyl, or pyrrolidinyl group which may optionally be substituted up to 2 times by hydroxyl or methyl,

and, in the case that e=0,

R¹² and R¹³ may also represent straight-chain acyl having up to 14 carbon atoms,

and/or

R¹² and R¹³ also represent a radical of the formula

 

with the proviso that in the case that e=0, R¹² and R¹³ do not simultaneously represent hydrogen,

or

R¹ represents a purine radical which may optionally be substituted up to two times by halogen, azido, amino, monoalkylamino having up to 4 carbon atoms and/or methyl,

R² and R³ together with the double bond form a fused pyridyl ring,

A represents phenyl or pyrimidyl, which are optionally substituted by fluorine, chlorine or bromine,

or a stereoisomeric form or salt thereof.

4. The compound according to claim 1,

where

R¹ represents a radical of the formula

 

in which

R′

represents NH₂,

R″

represents optionally substituted morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl or thiomorpholinyl

and

R′

″

represents hydrogen or NH₂.

5. Compounds according to claim 4 in which R″

represents morpholinyl.

6. A process for preparing compounds of formula (I) of claim 1,

characterized in that

in the case that R¹ represents an optionally substituted pyrimidine radical, amidines of the formula (IX)

 

in which

A, R² and R³ are each as defined above in claim 1,

are reacted with compounds of the formula (X), (Xa), (Xb) or (Xc)

in which

R^1′

represents the optionally substituted cycloalkyl radical listed above under R¹;

Alk represents straight-chain or branched alkyl having up to 8 carbon atoms,

and

Z represents an NH₂ group, a monoalkylamino group having up to 7 carbon atoms, a dialkylamino group having up to 7 carbon atoms, a piperidinyl or morpholinyl radical which is attached via the nitrogen, hydroxyl, alkoxy having up to 7 carbon atoms, acyloxy having up to 7 carbon atoms or aroyloxy having 6 to 10 carbon atoms,

and, in the case of the groups —

S(O)_cNR⁶R⁷ and —

S(O)_c′

NR^6′

R^7′

, starting from the unsubstituted compounds of the formula (1), reacted initially with thionyl chloride and, in a second step, with the appropriate amines

and the substituents listed under X, Y, R¹, R², R³ and/or R⁴ are modified or introduced by acylation of free amino groups or hydroxyl groups, chlorination, catalytic, hydrogenation, reduction, oxidation, removal of protective groups and/or nucleophilic substitution.

7. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.

8. A method of treating the cardiovascular disease hypertension comprising administering to a mammal an effective amount of a compound according to claim 1.