CA2489452A1 - Phenylaminopyrimidines and their use as rho-kinase inhibitors - Google Patents

Phenylaminopyrimidines and their use as rho-kinase inhibitors Download PDF

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Publication number
CA2489452A1
CA2489452A1 CA002489452A CA2489452A CA2489452A1 CA 2489452 A1 CA2489452 A1 CA 2489452A1 CA 002489452 A CA002489452 A CA 002489452A CA 2489452 A CA2489452 A CA 2489452A CA 2489452 A1 CA2489452 A1 CA 2489452A1
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alkyl
substituted
radical
nitrogen atom
chlorine
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CA002489452A
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French (fr)
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CA2489452C (en
Inventor
Achim Feurer
Samir Bennabi
Heike Heckroth
Jens Ergueden
Thomas Schenke
Markus Bauser
Raimund Kast
Johannes-Peter Stasch
Elke Stahl
Klaus Muenter
Dieter Lang
Heimo Ehmke
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Abstract

The invention relates to phenylaminopyrimidines and processes for their preparation, and to their use for preparing pharmaceuticals for the treatment and/or prophylaxis of diseases, in particular cardiovascular diseases. In a specific embodiment, the invention relates to a compound of the formula (see formula I), in which R1 represents amino or hydroxyl, R2 represents hydrogen, (C1-C6)-alkyl or (C3-C8)-cycloalkyl, R3 and R4 independently of one another represent cyano, hydrogen, fluorine or chlorine, A represents a radical (see formula II), (see formula III) or (see formula IV) in which R5 and R6 independently of one another represent hydrogen, fluorine or chlorine, D (1) represents a radical selected from the group consisting of phenyl, etc; quinoline, etc; pyridylmethyl, etc; pyridyl, etc; etc or a salt, hydrate, hydrate of the salt or solvate thereof.

Claims (8)

1. Compounds of the formula in which R1 represents amino or hydroxyl, R2 represents hydrogen, (C1-C6)-alkyl or (C3-C8)-cycloalkyl, R3 and R4 independently of one another represent cyano, hydrogen, fluorine or chlorine, A represents a radical in which R5 and R6 independently of one another represent hydrogen, fluorine or chlorine, D (1) represents a radical selected from the group consisting of phenyl, which for its part is substituted by (C1-C4)-alkyl-carbonylamino, hydroxymethyl, cyano, (C1-C4)-alkoxymethyl or 1,2-dioxymethylene, quinoline, isoquinoline, indole or 6-membered heteroaryl having 2 or 3 nitrogen atoms, where the rings are in each case attached via a carbon atom, pyridylmethyl, 2-oxo-2H-pyridin-1-yl, 4-oxo-4H-pyridin-1-yl, which for their part may be substituted by fluorine, chlorine or (C1-C4)-alkyl, and pyridyl, which for its part is substituted by fluorine, chlorine or (C1-C4)-alkyl, or (2) represents a radical *-OR7, in which R7 represents phenyl which may be substituted by trifluoromethyl, trifluoromethoxy, nitro, cyano, *-NR8R9, fluorine, chlorine or 1,2-dioxymethylene or by (C1-C4)-alkyl or (C1-C4)-alkoxy, which for their part may be substituted by hydroxyl and/or *-NR8R9, 3- to 7-membered heterocyclyl having a nitrogen atom which may be substituted by hydrogen, (C1-C6)-alkyl or (C3-C8)-cycloalkyl, 5- or 6-membered heteroaryl having up to three nitrogen atoms, (C1-C6)-alkyl or (C3-C7)-cycloalkyl which for their part may be substituted by hydroxyl or *-NR8R9, thienyl, furyl, pyridylmethyl, naphthyl or benzyl, in which R8 and R9 independently of one another represent hydrogen or (C1-C4)-alkyl which for its part may be substituted by hydroxyl or amino, or R8 and R9 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle which may have an additional oxygen atom or a group N-H or N-(C1-C4)-alkyl in the ring, or (3) represents a radical *-NR10R11, in which R10 represents hydrogen or (C1-C4)-alkyl and R11 represents amino-substituted (C3-C8)-cycloalkyl or a radical *-(CH2)x-phenyl, where phenyl may be substituted up to four times independently of one another by fluorine, chlorine or (C1-C4)-alkyl, or represents *-(CH2)y-E, in which x represents 1, 2 or 3, y represents 0, 1, 2 or 3 and E represents pyrrolidine or piperidine, which for their part may be substituted by (C1-C4)-alkyl, or represents pyridyl which may be substituted up to four times independently of one another by fluorine, chlorine or (C1-C4)-alkyl, or R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which is substituted by *-NR12R13, 1,1-dioxyethylene, (C1-C4)-alkoxy, hydroxyl-or (C1-C4)-alkoxy-substituted (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl or 5- or 6-membered heterocyclyl having one or two heteroatoms N
and/or O, which for its part may be substituted by (C1-C4)-alkyl, in which R12 and R13 independently of one another represent hydrogen, (C1-C6)-alkyl, (C1-C4)-alkoxy-carbonyl, (C3-C8)-cycloalkyl or (C1-C4)-alkanoyl or R12 and R13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, or R10 and R11 together with the nitrogen atom to which they are attached form a 7- to 12-membered bicyclic heterocycle which is fused or spirocyclic and may have one or two further heteroatoms from the group consisting of N and O in the ring and which may be substituted by (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkanoyl or benzyl, or R10 and R11 together with the nitrogen atom to which they are attached form a radical in which R14 represents (C2-C6)-alkenyl, (C1-C4)-alkoxycarbonyl or *(CH2)z-G
in which z represents 0 or 1 and G represents (C3-C8)-cycloalkyl, pyridyl, optionally (C1-C4)-alkyl- or (C1-C4)-alkoxy-substituted phenyl, tetrahydrofuran or 1,3-dioxolane, and R15 represents hydrogen or (C1-C4)-alkyl, and their salts, hydrates, hydrates of the salts and solvates.
2. Compounds of the formula (I) according to Claim 1, in which R1 represents amino, R2 represents hydrogen, R3 and R4 independently of one another represent hydrogen, fluorine or chlorine, A represents a radical in which R5 and R6 represent hydrogen, D (1) represents a radical selected from the group consisting of phenyl which is substituted by (C1-C4)-alkylcarbonylamino, hydroxymethyl, (C1-C4)-alkoxymethyl or 1,2-dioxymethylene, quinoline, indole or 6-membered heteroaryl having 2 or 3 nitrogen atoms, where the rings are in each case attached via a carbon atom, pyridylmethyl, which may be substituted by (C1-C4)-alkyl, and pyridyl, which is substituted by (C1-C4)-alkyl, or (2) represents a radical *-OR7, in which R7 represents phenyl, which may be substituted by fluorine, chlorine, (C1-C4)-alkyl, (C1-C4)-alkoxy or 1,2-dioxymethylene, (C1-C6)-alkyl or (C3-C8)-cycloalkyl, which for their part may be substituted by hydroxyl or *-NR8R9, naphthyl or benzyl, in which R8 and R9 independently of one another represent hydrogen or (C1-C4)-alkyl or R8 and R9 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle which may have an additional oxygen atom or a group N-H or N-(C1-C4)-alkyl in the ring, or (3) represents a radical *-NR10R11, in which R10 represents hydrogen or (C1-C4)-alkyl and R11 represents amino-substituted (C3-C8)-cycloalkyl or a radical *-(CH2)x-phenyl, where phenyl may be substituted up to four times independently of one another by fluorine, chlorine or (C1-C4)-alkyl, or represents *-(CH2)y-E, in which x represents 1 or 2, y represents 0, 1 or 2 and E represents pyrrolidine or piperidine, which for their part may be substituted by (C1-C4)-alkyl, or represents pyridyl which may be substituted up to four times independently of one another by fluorine, chlorine or (C1-C4)-alkyl, or R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which is substituted by *-NR12R13, 1,1-dioxymethylene, (C1-C4)-alkoxymethyl or by 5- or 6-membered heterocyclyl having one or two heteroatoms N and/or O, which for its part may be substituted by (C1-C4)-alkyl, in which R12 and R13 independently of one another represent hydrogen, (C1-C6)alkyl, (C3-C8)-cycloalkyl or (C1-C4)-alkanoyl or R12 and R13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, or R10 and R11 together with the nitrogen atom to which they are attached form an 8- to 10-membered bicyclic heterocycle which is fused or spirocyclic and may have one or two further heteroatoms from the group consisting of N and O in the ring and which may be substituted by (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkanoyl or benzyl, or R10 and R11 together with the nitrogen atom to which they are attached form a radical in which R14 represents (C3-C8)-cycloalkyl, (C2-C6)-alkenyl, (C1-C4)-alkoxycarbonyl or tetrahydrofuran-2-ylmethyl, and R15 represents hydrogen or (C1-C4)-alkyl, and their salts, hydrates, hydrates of the salts and solvates.
3. Compounds of the formula (I) according to Claim 1, in which R1 represents amino, R2 represents hydrogen, R3 and R4 independently of one another represent hydrogen, fluorine or chlorine, A represents a radical in which R5 and R6 represent hydrogen, D (1) represents a radical which is selected from the group consisting of quinoline, indole, pyrazine, pyridazine and triazine, where the rings are in each case attached via a carbon atom, or (2) represents a radical *-OR7 in which R7 represents phenyl which may be substituted by fluorine, chlorine, (C1-C4)-alkyl, (C1-C4)-alkoxy or 1,2-dioxymethylene, (C1-C6)-alkyl or (C3-C8)-cycloalkyl which for their part may be substituted by hydroxyl or *-NR8R9, in which R8 and R9 independently of one another represent hydrogen or (C1-C4)-alkyl or R8 and R9 together with the nitrogen atom to which they are attached form a morpholine or piperazine ring, where the second nitrogen atom of the piperazine ring may be substituted by(C1-C4)-alkyl, or (3) represents a radical *-NR10R11, in which R10 represents hydrogen or (C1-C4)-alkyl and R11 represents amino-substituted (C3-C8)-cycloalkyl or a radical *-(CH2)y-E, in which y represents 0 or 1 and E represents pyrrolidine or pyridyl, which for their part may be substituted by (C1-C4)-alkyl, or R10 and R11 together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring which may be substituted by *-NR12R13, 1,1-dioxymethylene, (C1-C4)-alkoxymethyl or 5- or 6-membered hetero-cyclyl having one or two heteroatoms N and/or O, which for its part may be substituted by (C1-C4)-alkyl, in which R12 and R13 independently of one another represent hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or (C1-C4)-alkanoyl or R12 and R13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, or R10 and R11 together with the nitrogen atom to which they are attached form an 8- to 10-membered bicyclic heterocycle which is fused or spirocyclic and may have one or two further heteroatoms from the group consisting of N and O and which may be substituted by (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkanoyl or benzyl, and their salts, hydrates, hydrates of the salts and solvates.
4. Process for preparing compounds of the formula (I) according to Claim 1, characterized in that either [A] compounds of the formula (II) in which A, R1, R2, R3 and R4 are as defined in Claim 1, are reacted with compounds of the formula (III) D-X1 (III) in which D is as defined in Claim 1 and X1 represents hydrogen or *-B(OH)2 or [B] compounds of the formula (IV) in which D is as defined in Claim 1 are reacted with compounds of the formula (V) in which A, R2, R3 and R4 are as defined in Claim 1.
5. Compounds of the formula (I) as defined in Claim 1 for the treatment and/or prophylaxis of disorders.
6. Pharmaceutical, comprising at least one compound of the formula (I) as defined in Claim 1 and at least one auxiliary.
7. Pharmaceutical, comprising at least one compound of the formula (I) as defined in Claim 1 and at least one further active compound.
8. Use of compounds of the formula (I) as defined in Claim 1 for preparing pharmaceuticals for the treatment and/or prophylaxis of cardiovascular disorders.
CA2489452A 2002-06-17 2003-06-04 Phenylaminopyrimidines and their use as rho-kinase inhibitors Expired - Fee Related CA2489452C (en)

Applications Claiming Priority (3)

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DE10226943A DE10226943A1 (en) 2002-06-17 2002-06-17 Phenylaminopyrimidines and their use
DE10226943.2 2002-06-17
PCT/EP2003/005827 WO2003106450A1 (en) 2002-06-17 2003-06-04 Phenylaminopyrimidines and their use as rho-kinase inhibitors

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CA2489452A1 true CA2489452A1 (en) 2003-12-24
CA2489452C CA2489452C (en) 2011-08-23

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EP (1) EP1515965B1 (en)
JP (1) JP4559851B2 (en)
AU (1) AU2003232848A1 (en)
CA (1) CA2489452C (en)
DE (2) DE10226943A1 (en)
ES (1) ES2353279T3 (en)
WO (1) WO2003106450A1 (en)

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US8329716B2 (en) 2004-04-08 2012-12-11 Bayer Intellectual Property Gmbh Hetaryloxy-substituted phenylamino pyrimidines as Rho kinase inhibitors
CN110903285A (en) * 2019-12-13 2020-03-24 南京恒道医药科技有限公司 Method for producing moxifloxacin side chain by using secondary rectification

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Publication number Priority date Publication date Assignee Title
US8329716B2 (en) 2004-04-08 2012-12-11 Bayer Intellectual Property Gmbh Hetaryloxy-substituted phenylamino pyrimidines as Rho kinase inhibitors
CN110903285A (en) * 2019-12-13 2020-03-24 南京恒道医药科技有限公司 Method for producing moxifloxacin side chain by using secondary rectification

Also Published As

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EP1515965A1 (en) 2005-03-23
JP4559851B2 (en) 2010-10-13
JP2005538962A (en) 2005-12-22
ES2353279T3 (en) 2011-02-28
WO2003106450A1 (en) 2003-12-24
AU2003232848A8 (en) 2003-12-31
CA2489452C (en) 2011-08-23
AU2003232848A1 (en) 2003-12-31
EP1515965B1 (en) 2010-10-06
DE10226943A1 (en) 2004-01-08
DE50313157D1 (en) 2010-11-18
WO2003106450A8 (en) 2005-02-03

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