EP1812405A1 - Nouveaux antagonistes de la bradykinine b1, procedes de production et d'utilisation en tant que medicaments associes, - Google Patents

Nouveaux antagonistes de la bradykinine b1, procedes de production et d'utilisation en tant que medicaments associes,

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Publication number
EP1812405A1
EP1812405A1 EP05800514A EP05800514A EP1812405A1 EP 1812405 A1 EP1812405 A1 EP 1812405A1 EP 05800514 A EP05800514 A EP 05800514A EP 05800514 A EP05800514 A EP 05800514A EP 1812405 A1 EP1812405 A1 EP 1812405A1
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EP
European Patent Office
Prior art keywords
phenyl
ethyl
dihydro
imidazol
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP05800514A
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German (de)
English (en)
Inventor
Iris Kauffmann-Hefner
Norbert Hauel
Henri Doods
Angelo Ceci
Stefan Peters
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Priority claimed from DE102004054053A external-priority patent/DE102004054053A1/de
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Publication of EP1812405A1 publication Critical patent/EP1812405A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Novel bradykinin B1 antagonists processes for their preparation and their use as pharmaceuticals
  • the present invention relates to bradykinin B1 antagonists of the general formula
  • A, Ar, G, Q, R 1 and R 4 are as defined in claim 1, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases, which have valuable properties , their preparation, the medicaments containing the pharmacologically active compounds, their preparation and their use.
  • R 1 is a phenyl, naphthyl or heteroaryl group, a phenyl-C- ⁇ . 3- alkyl or C 3-7 -cycloalkyl group,
  • R 4 is a hydrogen atom or a Ci- 6 alkyl group
  • G is the group - (CH 2 ) m -, in which m is the number 2 or 3 and in which one to three hydrogen atoms can be replaced independently of one another by C 1-3 -alkyl groups,
  • Ar is a phenylene or heteroarylene group
  • Q is the group - (CH 2 ) P -, in which p is the number 2 or 3 and in which one to three hydrogen atoms are independently of one another by Ci. 3- alkyl groups can be replaced,
  • A is a radical of the general formula (IIa) to (Mi) linked via a nitrogen atom to the sulfonyl group in formula (I)
  • R 2 is a hydrogen atom, a Ci -6 alkyl, C 2 - methyl-5 -alkenyl, C. 2 5- alkynyl-methyl, C 3-7 -cycloalkyl or a phenyl group and
  • R 3 is a hydrogen atom, a phenyl, Ci- 6 alkyl, C 2 - 5 alkenyl-methyl, C 2-5 alkynyl or C 3-7 cycloalkyl-methyl or a group -CH 2 -CF 3 , -CH 2 -CHF 2 or -CH 2 -CH 2 F,
  • heteroaryl group a monocyclic 5- or 6-membered or a bicyclic 9- or 10-membered heterocyclic, aromatic ring system which in addition to at least one carbon atom one or more heteroatoms selected from N, O and / or S includes, for example
  • Ci- 3 alkyl optionally substituted by a Ci- 3 alkyl, phenyl, amino-C 2 - 3 alkyl, ds-alkylamino-Ca-s-alkyl- or di- (Ci-C3 alkyl.) -amino-C2- 3 alkyl group, by a 4- to 7-membered cycloalkyleneimino-C 1 . 3 alkyl or phenyl-Ci -3 alkyl substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or one containing optionally substituted by a Ci- 3 alkyl or phenyl-Ci -3 alkyl substituted imino group and two or three nitrogen atoms, or
  • a bicyclic 9-membered heteroaryl group consisting of one of the above-mentioned 5-membered heteroaryl groups condensed with one of the above-mentioned 6-membered heteroaryl groups through two adjacent carbon atoms or a carbon atom and an adjacent nitrogen atom to form a bicyclic nucleus;
  • the heteroaryl group may also be replaced by a cyclopentadienyl group or the 6-membered heteroaryl group by a phenyl ring, or
  • bicyclic 10-membered heteroaryl group consisting of a phenyl ring and one of the above-mentioned 6-membered heteroaryl groups or two of the above-mentioned 6-membered heteroaryl groups each condensed through two adjacent carbon atoms to a bicyclic group,
  • Heteroaryl groups additionally in the carbon skeleton by fluorine, chlorine; Bromo- or iodine atoms or mono-, di- or trisubstituted by Ci-3-alkyl groups and the substituents may be the same or different, and
  • heteroarylene group refers to the abovementioned mono- or bicyclic heteroaryl groups, but which are linked to the adjacent groups via two carbon atoms or one carbon atom and one nitrogen atom,
  • alkyl and alkoxy groups having more than two carbon atoms contained in the above-mentioned definitions may be straight-chain or branched, and wherein the hydrogen atoms of the methyl or ethyl groups contained in the above-mentioned definitions may be wholly or partly replaced by fluorine atoms,
  • Examples of monocyclic heteroaryl groups are the pyridyl, ⁇ / -oxypyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1, 2,3] triazinyl, [1, 3,5] triazinyl, [ 1, 2,4] triazinyl, pyrrolyl, imidazolyl, [1, 2,4] triazolyl, [1, 2,3] triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, [1, 2,3] oxadiazolyl, [1, 2,4] oxadiazolyl, [1, 2,5] oxadiazolyl, [1, 3,4] oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl or [1, 2 , 4] thiadiazolyl group.
  • bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo [c] furanyl, benzo [b] thiophenyl, benzo [c] thiophenyl, benzothiazolyl, benzo [c] isothiazolyl, benzo [d] isothiazolyl, Benzooxazolyl, benzo [c] isoxazolyl, benzo [d] isoxazolyl, benzo [1, 2,5] oxadiazolyl, benzo [1, 2,5] thiadiazolyl, benzo [1,2,3] thia- diazolyl, benzo [d] [1, 2,3] triazinyl, benzo [1,2,4] triazinyl, benzotriazolyl, cinnolinyl, quinolinyl, N-oxy quinolinyl, indazolyl, purinyl, Naphthyridinyl, pteridinyl,
  • Ci -6- alkyl groups are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, ferf-butyl, 1-pentyl , 2-pentyl, 3-pentyl, ⁇ eo-pentyl, 1-hexyl, 2-hexyl or 3-hexyl.
  • a second embodiment of the present invention consists in the compounds of the above general formula (I) in which
  • R 1 is a phenyl, naphthyl, or heteroaryl group, a phenyl-Ci -3 alkyl or C 3-6 cycloalkyl group
  • R 4 is a hydrogen atom or a Ci -4 alkyl group
  • G is the group - (CH 2) m - in which m is the number 2 or 3 and in which one to three hydrogen atoms independently replaced by Ci -3 alkyl groups, for example methyl groups may be replaced,
  • Ar is a phenylene group
  • Q is the group - (CH 2) P -, where p is the number 2 or 3 and in which one to three hydrogen atoms independently replaced by Ci -3 alkyl groups, for example methyl groups may be replaced,
  • A is a radical linked via a nitrogen atom to the sulfonyl group in formula (I), of the general formula (IIa), (IIb), (Hc), (Hd), (He), (Hf), (Hg), (Mh) or (Hi) 1
  • n is the number 2 or 3
  • R 2 is a hydrogen atom, a Ci -4 alkyl, C 2 - 5 alkenyl-methyl, C 3 - 6 cycloalkyl or a phenyl group and
  • R 3 is a hydrogen atom, a C- ⁇ - 4 alkyl, C 2 - 5 alkenyl-methyl, or C 3-6 cycloalkyl group or a Ci. 3- alkyl group in which each methyl group may be substituted by up to three and each methylene group may be substituted by up to two fluorine atoms,
  • naphthyl groups contained in the above-mentioned definitions by fluorine, chlorine or bromine atoms, by Ci. 3- alkyl, amino or di (C 1-3 alkyl) - amino groups may be mono- or disubstituted and the substituents may be the same or different,
  • heteroaryl group is to be understood as meaning a monocyclic 5- or 6-membered or a bicyclic 9- or 10-membered heterocyclic, aromatic ring system, for example
  • an imino group optionally substituted by a C 1-3 -alkyl, phenyl or phenyl-C 1-3 -alkyl group, an oxygen or sulfur atom or
  • Ci. 3 -alkyl or phenyl group an optionally by a Ci. 3 -alkyl or phenyl group, by a 5- to 7-membered cycloalkyleneimino-Ci-s-alkyl or a phenyl-Ci- 3 -alkyl group-substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or optionally substituted by a Ci- 3 alkyl or phenyl-Ci. 3 -alkyl group substituted imino group and additionally contains two nitrogen atoms, or
  • a bicyclic 9-membered heteroaryl group consisting of one of the aforementioned 5-membered heteroaryl groups fused to one of the aforementioned 6-membered heteroaryl groups via two adjacent carbon atoms or a carbon and an adjacent nitrogen atom to form a bicyclic compound; also be replaced by a cyclopentadienyl or the 6-membered heteroaryl group by a phenyl ring, or heteroaryl group may also be replaced by a phenyl ring
  • bicyclic 10-membered heteroaryl group consisting of a phenyl ring and one of the above-mentioned 6-membered heteroaryl groups or two of the above-mentioned 6-membered heteroaryl groups each condensed through two adjacent carbon atoms to a bicyclic group,
  • heteroarylene group refers to the abovementioned mono- or bicyclic heteroaryl groups, but which are linked to the adjacent groups via two carbon atoms or one carbon atom and one nitrogen atom,
  • alkyl and alkoxy groups having more than two carbon atoms contained in the above-mentioned definitions, unless otherwise mentioned, may be straight-chain or branched, and
  • a third embodiment of the present invention consists in the compounds of the above general formula (I) in which
  • R 1 is optionally substituted by fluorine, chlorine or bromine atoms, nitro, cyano, Ci- 3 -AlkyIsulfonyl-, Ci- 5 alkyl, trifluoromethyl, hydroxy, Ci -5 alkyloxy, trifluoromethoxy, phenyloxy , Morpholin-4-ylsulfonyl, phenyl,
  • a C 3 - 6 cycloalkyl for example the cyclopropyl
  • R 4 is a hydrogen atom or a methyl group
  • G is the group - (CH2) m -, in which m is the number 2 or 3 or the group - (CH 2 ) m -, in which m is the number 2 or 3 and in which one, two or three hydrogen atoms are independently replaced by methyl or ethyl groups,
  • Ar is a phenylene group
  • Q is the group - (CH 2 ) P -, where p is the number 2, or
  • A is a radical of the general formula (IIa), (IIb), (IIc), (Hd), (Me), (Hf), (IIg) linked via the position marked * with the sulfonyl group in formula (I), (Hh) or (Hi),
  • n is the number 2 or 3
  • R 2 is a hydrogen atom, a C 1-3 alkyl, cyclopropyl or a phenyl group and
  • R 3 is a hydrogen atom, a cyclopropyl group, a linear or branched Ci -3 alkyl group, F 3 C-CH 2 -, F 2 CH-CH 2 - or H 2 FC-CH 2 group,
  • a fourth embodiment of the present invention consists in the compounds of the above general formula (I) in which R 1 is an isopropyl, cyclopropyl, phenyl, phenylmethyl, 2,4-dichlorophenylmethyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl -, 3-fluorophenyl, 4-fluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5 - dichlorophenyl, 2,4,5-trichlorophenyl, 3,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-cyanophenyl, 5-fluoro-2-methylphenyl, 2-ch
  • R 4 is a hydrogen atom or a methyl group
  • G is the group - (CH 2 ) m-, where m is 2 or 3 or the group - (CH 2 ) m -, in which m is the number 2 or 3 and in which one or two hydrogen atoms are independently replaced by methyl groups,
  • Ar is an -3 alkyl, trifluoromethyl, Ci -3 alkyloxy or trifluoromethoxy groups independently of one another mono- or disubstituted optionally substituted by fluorine, chlorine or bromine atoms, cyano, Ci, however, preferably unsubstituted phenylene,
  • Q is the group - (CH 2 ) P -, where p is the number 2, or
  • A is a radical of the general formula (IIa), (IIb), (Mc) 1 (Hd), (Me), (Hf), (Mg) 1 linked via the position marked * with the sulfonyl group in formula (I) (Hh) or (Hi), but preferably a radical of the formula (IIa), (IIb), (Hc), (Ile), (Hf), (Hg), (Hh) or (Hi),
  • n is the number 2 or 3
  • R 2 is a hydrogen atom, a methyl, ethyl, n-propyl, i-propyl, cyclopropyl or phenyl group and
  • R 3 represents a hydrogen atom, a methyl, ethyl, n-propyl, i-propyl, 2-monofluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or cyclopropyl group,
  • phenyl groups or the phenyl groups contained in the abovementioned radicals are independently of one another fluorine, chlorine or bromine atoms, Cyano, Ci -3 alkyl, trifluoromethyl, mono- 3 d- alkyloxy or trifluoromethoxy, or may be di-substituted, but preferably unsubstituted,
  • R 1 is a phenyl or heteroaryl group
  • R 4 is a hydrogen atom or a C 1-6 -alkyl group
  • n 2 or 3
  • Ar is a phenylene or heteroarylene group
  • A is a radical of the general formula
  • n is the number 2 or 3
  • o the number 1, 2 or 3
  • R 2 is a hydrogen atom, a d- ⁇ -alkyl, C 2 - 3 alkenyl, C 2 - 3 alkynyl, C 3 .7-cyclo- alkyl or a phenyl group and
  • R 3 is a hydrogen atom, a Ci. 6 alkyl, C 2 . 3 alkenyl, C 2-3 alkynyl or C 3-7 cycloalkyl group,
  • heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group, where
  • the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
  • C- ⁇ -3 alkyl phenyl, amino C 2 . 3- alkyl, C 1-3 -alkyl-amino-C 2 . 3 alkyl-, di- (Ci. 3 alkyl) amino-C 2-3 alkyl-, a 4- to 7-membered alkyleneimino cyclo-Ci-3-alkyl or phenyl-C- ⁇ - 3 alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or
  • alkyl and alkoxy groups having more than two carbon atoms contained in the above-mentioned definitions, unless otherwise mentioned, may be straight-chain or branched,
  • the hydrogen atoms of the methyl or ethyl groups contained in the above-mentioned definitions may be wholly or partly replaced by fluorine atoms
  • the phenyl groups contained in the abovementioned definitions can be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, C 1-3 -alkyl, trifluoromethyl, C 1-3 -alkyloxy or trifluoromethyloxy groups
  • a second, particularly to be mentioned embodiment of the present invention consists in the compounds of general formula (I 1 ), in which
  • R 1 is an optionally mono-, di- or trisubstituted phenyl group by chlorine atoms or methyl groups, where the substituents may be identical or different,
  • R 4 is a hydrogen atom
  • Ar is a phenylene group
  • A is a radical of the general formula
  • n is the number 2 or 3
  • R 2 is a hydrogen atom, a Ci -3 alkyl, cyclopropyl or phenyl group and
  • R 3 is a hydrogen atom or a methyl group
  • the compounds of general formula (I) are prepared by methods known in principle. The following processes have proven particularly suitable for the preparation of the compounds of general formula (I) according to the invention: (a) For the preparation of compounds of the general formula (I) in which R 1 , R 4 , G, A, Q and Ar are defined as mentioned in the introduction:
  • the reaction is preferably carried out at a temperature of 40 0 C to 150 ° C in a solvent such as tetrahydrofuran, dioxane, n-hexane, cyclohexane, benzene, toluene or xylene.
  • a solvent such as tetrahydrofuran, dioxane, n-hexane, cyclohexane, benzene, toluene or xylene.
  • the reaction is carried out with the addition of P 2 S 5 or sulfur.
  • R 1 , G, A, Q and Ar are defined as mentioned above and PG is an amine protecting group, for example the tert-butyloxycarbonyl protective group, the benzyloxycarbonyl, methoxycarbonyl or ethoxycarbonyl group, according to literature methods (see, for example: Protective Groups in Organic Chemistry, 2nd Edition, Ed .: TWGreene, PMGWuts, John Wiley &
  • the intermediates (III) and (V) can be prepared by forming a carboxylic acid amide linkage from carboxylic acid and amino moieties selected from the group consisting of (wherein in the following formulas (VIa) to (VId ) the ethylene group linked with Ar is only an example of the meanings of the group Q in formula (I))
  • Ar, R 1 , R 2 , R 3 , m, n and o are defined as mentioned above and PG is an amine protecting group, for example the fert-butyloxycarbonyl protecting group, the benzyloxycarbonyl, methoxycarbonyl or ethoxycarbonyl group.
  • the coupling is preferably carried out using methods known from peptide chemistry (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2), for example carbodiimides, such as, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylaminopropyl) carbodiimide, O- (1 / - / - benzotriazol-1-yl) - ⁇ /, ⁇ / - / V, / V-tetramethyluronium hexafluorophosphate (HBTU ) or tetrafluoroborate (TBTU) or 1 H-benzotriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP).
  • DEC dicyclohexylcarbodiimide
  • DIC diisopropylcarbod
  • the reaction rate can be increased.
  • the couplings are usually between equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), ⁇ / -methylpyrrolidone (NMP) or mixtures of these and at temperatures between -3O 0 C and +30 0 C, preferably -20 0 C and + 25 ° C performed.
  • solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), ⁇ / -methylpyrrolidone (NMP) or mixtures of these and at temperatures between -3O 0 C and +30 0 C, preferably -20 0 C and + 25 ° C performed.
  • DIEA ⁇ / -Ethyldiisopropylamin
  • N - Ar - Q - X t (V
  • Ar and Q are defined as mentioned above and X represents a nucleofugic group, for example the chlorine, bromine or iodine atom, the methanesulfonyl or toluenesulfonyl group.
  • the reaction takes place under the action of a base such as, for example, potassium tert-butoxide or sodium hydride, preferably in a solvent such as dimethylformamide or dimethyl sulfoxide.
  • a base such as, for example, potassium tert-butoxide or sodium hydride
  • a solvent such as dimethylformamide or dimethyl sulfoxide.
  • R 1 , Q and Ar are defined as mentioned above and A corresponds to a radical of the abovementioned general formula (Md):
  • R 1 and R 2 are defined as mentioned above and X has the meaning of a nucleofugic group, such as the chlorine, bromine or iodine atom, the methanesulfonyl or toluenesulfonyl group.
  • the reaction takes place under the action of a base such as butyllithium or lithium diisopropylamide, preferably in a solvent such as tetrahydrofuran or in a solvent mixture of tetrahydrofuran with hexane or toluene.
  • a base such as butyllithium or lithium diisopropylamide
  • a solvent such as tetrahydrofuran or in a solvent mixture of tetrahydrofuran with hexane or toluene.
  • the compounds of the general formula (I) obtained may, provided they contain suitable basic functions, be converted, in particular for pharmaceutical applications, into their physiologically acceptable salts with inorganic or organic acids.
  • suitable acids are hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, acetic, fumaric, succinic, lactic, mandelic, malic, citric, tartaric and maleic acids.
  • novel compounds of the formula (I), if they contain carboxylic acid function, can if desired be converted into their addition salts with inorganic or organic bases, in particular for the pharmaceutical application, into their physiologically tolerable addition salts.
  • Suitable bases for this example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine into consideration.
  • the present invention relates to racemates, provided that the compounds of the general formula (I) have only one chiral element.
  • the application also includes the individual pairs of diastereomeric antipodes or mixtures thereof which are present when more than one chiral element is present in the compounds of general formula (I) and the individual optically active enantiomers constituting the racemates mentioned.
  • Also included in the subject matter of this invention are the compounds according to the invention, including their salts, in which one or more hydrogen atoms are replaced by deuterium.
  • novel compounds of the general formula (I) and their physiologically tolerated salts have valuable pharmacological properties. they provide Bradykinin B1 antagonists.
  • CHO cells expressing the hBK1 receptor are cultured in "Dulbecco's modified medium.” From confluent cultures, the medium is removed, the cells are washed with PBS buffer, scraped and isolated by centrifugation, then the cells are homogenized in suspension , the homogenate is centrifuged and resuspended. After determining the protein content of the membrane preparation thus obtained is stored frozen at -8O 0 C.
  • the bound radioactivity is defined in the presence of 1.0 // M kallidine (DesArg10, Leu9), [3,4-prolyl-3,43H (N)].
  • concentration-binding curve is carried out by means of a computer-aided non-linear curve fitting. From the data thus obtained, the corresponding Ki value is determined for the test substance.
  • novel compounds and their physiologically acceptable salts are useful in the treatment of diseases and disease symptoms caused, at least in part, by the stimulation of bradykinin B1 receptors.
  • the compounds of the invention can be used in methods which serve to alleviate or treat pain, wherein a patient is administered a therapeutically effective amount of the compound of the invention.
  • neuropathic pain or post-operative pain are suitable for the treatment of patients with chronic pain, neuropathic pain or post-operative pain, inflammatory pain, perioperative pain, migraine, arthralgia, neuropathies, nerve injuries, diabetic neuropathy, neurodegeneration, neurotic skin diseases, stroke, hypersensitivity of the bladder, irritable bowel Respiratory diseases such as asthma or chronic obstructive pulmonary disease, irritation of the skin, eyes or mucous membranes, duodenal and gastric ulcers, gastritis or others Inflammatory diseases, pain caused by osteoarthritis, back pain, as well as pain associated with another etiology.
  • Respiratory diseases such as asthma or chronic obstructive pulmonary disease, irritation of the skin, eyes or mucous membranes, duodenal and gastric ulcers, gastritis or others
  • Inflammatory diseases pain caused by osteoarthritis, back pain, as well as pain associated with another etiology.
  • the dose required to produce an analgesic effect is advantageously 0.01 to 3 mg / kg body weight, preferably 0.1 to 1 mg / kg when given intravenously, and 0.1 to 8 mg / kg body weight, preferably 0.5 to 3 mg / kg, respectively, when given orally 1 to 3 times a day.
  • the compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, in particular aerosol formulations being suitable for inhalation.
  • they may be combined with one or more inert conventional carriers and / or diluents, e.g.
  • lactose cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures be incorporated into common pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, metered aerosols or suppositories.
  • IR, 1 H-NMR and / or mass spectra are generally present.
  • the ratios stated for the flow agents refer to Volume units of the respective solvents.
  • the indicated volume units at NH 3 refer to a concentrated solution of NH 3 in water.
  • the acid, base and salt solutions used in the workup of the reaction solutions are aqueous systems of the indicated concentrations.
  • silica gel from Millipore 35-70 ⁇ m
  • Alox E. Merck, Darmstadt, aluminum oxide 90 standardized, 63-200 ⁇ m, article no: 1.01097.9050
  • V-methyl-acetamide hydrochloride was prepared analogously to 1 i) from 0.5 g (0.97 mmol) of 2- [4- (2- ⁇ [2- (benzenesulfonylmethylamino) -acetyl] -methylamino ⁇ -ethyl) -phenyl] -4 Tert-butyl 5-dihydroimidazole-1-carboxylate and 5 ml trifluoroacetic acid in 15 ml
  • 2-yl) -phenyl] - / V-methylpropionamide was analogous to 13b) from 0.7 g (1.49 mmol) of 3- (4-cyanophenyl) - ⁇ / - ⁇ 3 - [(2,3-dichlorobenzenesulfonyl) -methylamino] - propyl ⁇ - ⁇ / -methylpropionamide, 0.1 g (3.12 mmol) of sulfur and 3 ml of ethylenediamine.
  • the crude product thus obtained was purified by column chromatography on silica gel (eluent: dichloromethane / methanol / NH 3 13: 1: 0.1 to 8: 1: 0.1). The product was then transferred to the hydrochloride with ethereal hydrochloric acid and lyophilized.
  • Example 55 3 - [(2-chloro-4-trifluoromethylbenzenesulfonyl) methylamino] - ⁇ / - ⁇ 2- [4- (4,5-dihydro-1H-imidazol-2-yl) -phenyl] -ethyl ⁇ - ⁇ / -methylpropionamide trifluoroacetate

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Abstract

L'invention concerne des antagonistes de la bradykinine B1 de formule (I), dans laquelle A, Ar, G, Q, R<SUP>1</SUP> et R<SUP>4</SUP> sont spécifiés dans la revendication 1, leurs énantiomères, leurs diastéréomères, leurs mélanges et leurs sels, en particulier leurs sels phyiologiquement acceptables comprenant des acides ou des bases organiques ou inorganiques, lesquels présentent des propriétés précieuses. L'invention concerne également leur production, des médicaments contenant les composés pharmaceutiquement actifs, leurs production et leur utilisation.
EP05800514A 2004-11-05 2005-10-29 Nouveaux antagonistes de la bradykinine b1, procedes de production et d'utilisation en tant que medicaments associes, Withdrawn EP1812405A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102004054053A DE102004054053A1 (de) 2004-11-05 2004-11-05 Neue Bradykinin-B1-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
DE102005013967A DE102005013967A1 (de) 2004-11-05 2005-03-26 Neue Bradykinin-B1-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
PCT/EP2005/011602 WO2006048209A1 (fr) 2004-11-05 2005-10-29 Nouveaux antagonistes de la bradykinine b1, procedes de production et d'utilisation en tant que medicaments associes,

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EP1812405A1 true EP1812405A1 (fr) 2007-08-01

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WO (1) WO2006048209A1 (fr)

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DE102005013967A1 (de) 2006-10-05
US7291642B2 (en) 2007-11-06

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