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EP1360170A1 - Amides d'acide carboxylique, leur preparation et leur utilisation comme produit pharmaceutique - Google Patents

Amides d'acide carboxylique, leur preparation et leur utilisation comme produit pharmaceutique

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Publication number
EP1360170A1
EP1360170A1 EP02710038A EP02710038A EP1360170A1 EP 1360170 A1 EP1360170 A1 EP 1360170A1 EP 02710038 A EP02710038 A EP 02710038A EP 02710038 A EP02710038 A EP 02710038A EP 1360170 A1 EP1360170 A1 EP 1360170A1
Authority
EP
European Patent Office
Prior art keywords
group
phenyl
alkyl
carbonyl
pyrrolidin
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.)
Withdrawn
Application number
EP02710038A
Other languages
German (de)
English (en)
Inventor
Uwe-Jörg RIES
Henning Priepke
Herbert Nar
Jean-Marie Stassen
Wolfgang Wienen
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 Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE10104598A external-priority patent/DE10104598A1/de
Priority claimed from DE2001136434 external-priority patent/DE10136434A1/de
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1360170A1 publication Critical patent/EP1360170A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms

Definitions

  • the present invention relates to carboxamides of the general formula
  • compositions containing the pharmacologically active compounds their preparation, the pharmaceutical compositions containing the pharmacologically active compounds, their preparation and use.
  • the hydrogen atom of the -NH group can be replaced by a C 3 alkyl, C 3 alkyl carbonyl, phenylcarbonyl or phenylsulfonyl group,
  • a terminal in the alkyl part optionally by an amino, C ⁇ . 3 -alkylamino- or di- (C 1 - 3 -alkyl) -amino group substituted C ⁇ - 6 -alkylcarbonyl group, a group of the formula R f R g N- (CH 2 ) m- (R h ) N-CO-, in which
  • R f , R g and R independently of one another each represent a hydrogen atom or a C 3 alkyl group and m is one of the numbers 2, 3, 4, 5 or 6,
  • the phenyl substituent may be substituted by an amidino group which is optionally substituted by one or two C 3 alkyl groups, by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C 3 alkyl 3 or C 3 alkoxy group can
  • a C 3 - 7 cycloalkylamino group which is substituted on the nitrogen atom by a C 3 alkyl alkyl C 3 alkyl or di (C 3 alkyl) amino C 3 alkyl group,
  • R 2 is a trifluoromethyl group and / or R 5 is an amino-C ⁇ - 3 alkyl-,
  • R 6 is a carboxy-C 3 alkoxy or C - [- 4 alkoxy-carbonyl-C 3 alkoxy group or / and at least one of the radicals Rs or Rg has a different meaning than that of the hydrogen atom assumes an unsubstituted 4- to 7-membered cycloalkyleneimino-carbonyl or cycloalkyleneimino-sulfonyl group, a C 3 . 7- Cycloalkylamino- or
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C 1-4 alkyl group, in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a hydroxy or C 3 alkoxy group,
  • R 3 is a hydrogen atom or a C ⁇ . 3 -alkyl group
  • R is a hydrogen atom or a C 3 alkyl group which may be substituted by a carboxy group or a group which can be converted into a carboxy group in vivo,
  • Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R ⁇ and R 7 , where
  • R 5 is a cyano group, an amidino group which is optionally substituted by one or two C 3 alkyl groups, an amino C 3 alkyl 3 , C 3 alkylamino
  • R ⁇ is a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C 1 - 3 - alkyl, hydroxy, hydroxy-C ⁇ - 3 -alkyl-, C- ⁇ - 3 -alkoxy-, cis-alkoxy- Ci-s-alkyl, carboxy, carboxy -CC. 3 -alkyl-, carboxy-C ⁇ - 3 -alkoxy-, C- ⁇ _ 4 -alkoxy-carbonyl-
  • R represents a hydrogen, fluorine, chlorine or bromine atom or a C 3 alkyl group
  • R 8 and R 9 which may be the same or different, each represent a hydrogen atom, one optionally substituted by a phenyl or heteroaryl group C ⁇ - 3 alkyl group or one optionally by one or two C-. 3 -alkyl- or C ⁇ - 3 -alkyl-carbonyl-substituted amino group,
  • an imino group optionally substituted by a C-u-alkyl or C ⁇ - alkyl carbonyl group, an oxygen or sulfur atom,
  • an imino group which is optionally substituted by a C 4 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom,
  • a phenyl ring can be fused to the 5- or 6-membered heteroaryl groups mentioned above via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed can be bonded via the heteroaromatic or carbocyclic part,
  • amino and imino groups mentioned in the definition of the abovementioned radicals can be substituted by a radical which can be split off in vivo.
  • a radical which can be split off in vivo.
  • Such groups are described, for example, in WO 98/46576 and by N.M. Nielsen et al. in International Journal of Pharmaceutics 39, 75-85 (1987).
  • a group which can be converted into a carboxy group in vivo is, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C-
  • 3 -alkyl groups can be substituted, a Cs-s-cycloalkanol in which a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an optionally by a C 3 alkyl, phenyl 3 C 3 alkyl, phenyl-C ⁇ - 3 -alkoxycarbonyl or C 2 - 6 alkanoyl group substituted imino group is replaced and the cycloalkanol moiety 3 alkyl groups may additionally be substituted by one or two C ⁇ -, C. -Cycloalkenol, a C 3 - 5 -alkenol, a phenyl-C 3 - 5 -alkenol, a C 3 . 5 -alkinol or
  • R a is a ds-alkyl, Cs-r-cycloalkyl, phenyl or phenyl-C ⁇ - 3 alkyl group,
  • R b is a hydrogen atom, a -C 3 alkyl, C 5 - 7 cycloalkyl or phenyl group and R c represents a hydrogen atom or a C 3 alkyl group,
  • an imino or amino group in vivo for example a hydroxyl group, an acyl group such as one optionally by fluorine, chlorine, bromine or iodine atoms, by C 1-4 alkyl or C 3 alkoxy groups disubstituted phenylcarbonyl group, where the substituents can be the same or different, a pyridinoyl group or a C ⁇ . ⁇ 6 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl group or allyloxycarbonyl group, a C ⁇ .
  • an imino or amino group in vivo for example a hydroxyl group, an acyl group such as one optionally by fluorine, chlorine, bromine or iodine atoms, by C 1-4 alkyl or C 3 alkoxy groups disubstitute
  • 6- alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl group in which the amino group is substituted by C 1 -C 6 -alkyl or C 3 .
  • Cycloalkyl groups mono- or disubstituted and the substituents may be identical or different, represent a C ⁇ - 3 alkylsulfonyl-C 2-4 alkoxycarbonyl, C ⁇ - 3 alkoxy C 2 - 4 alkoxy-C 2 - alkoxycarbonyl, R a -CO-O- (R b CR c ) -O-CO-, de-alkyl-CO-NH- (R d CR e ) -O-CO- or d ⁇ alkyl-CO-0- (F ⁇ CReM ⁇ CRe) -0-CO group, in which R a to R c are defined as mentioned above,
  • R d and R e which may be the same or different, represent hydrogen atoms or C 3 alkyl groups
  • saturated alkyl and alkoxy parts which contain more than 2 carbon atoms also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc.
  • Ri a C 5 . 7- Cycloalkyl-carbonyl group in which the methylene group in the 3- or 4-position is replaced by an -NH group in which
  • a terminally substituted in the alkyl part optionally by a C 3 alkylamino or di (C 3 alkyl) amino group, d 3 alkyl carbonyl group,
  • Rf, R g and R h independently of one another each represent a hydrogen atom or a d- 3 -alkyl group and m is one of the numbers 2, 3 or 4,
  • heteroaryl portion is a 6-membered heteroaryl group containing one or two nitrogen atoms and attached to it via two adjacent carbon atoms Phenyl ring can be fused, wherein the bicyclic heteroaryl groups thus formed can be bound via the heteroaromatic or carbocyclic part, for example a 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, Isoquinolinyl, quinoxalinyl or quinazolinyl group,
  • the phenyl substituent can be substituted by an amidino group which may be substituted by one or two C 3 alkyl groups, by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C 3 alkyl or C 3 alkoxy group,
  • R 2 is a trifluoromethyl group and / or R 5 is an amino-C 3 alkyl or C 3 -alkylamino-C 3 -alkyl group or / and R 6 is a carboxy C 3 -alkoxy or C 1 - -Alkoxy-carbonyl-C ⁇ - 3 -alkoxy group or / and at least one of the radicals Rs or Rg has a different meaning than that of the hydrogen atom, an unsubstituted 4- to 7-membered cycloalkyleneiminocarbonyl group, a C 5 . 7- cycloalkyl-amino or N- (d- 3 -alkyl) -C 5 _ 7 -cycloalkylamino group,
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom, ad- 3 -alkyl, trifluoromethyl or d- 3 -alkoxy group,
  • R3 is a hydrogen atom or ad 3 -alkyl group
  • R is a hydrogen atom or a d-3-alkyl group
  • Ar is a phenyl group substituted by the radicals R 5 and R 6 , where
  • R 5 is a cyano group, an amidino group optionally substituted by one or two d- 3 -alkyl groups, an amino-C ⁇ - 3- alkyl or d- 3 -alkylamino-Ci- 3 -alkyl group and
  • R & a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C 1 - 3 -
  • Alkyl hydroxy, C 3 alkoxy, carboxy C 1. 3 -alkoxy- or C ⁇ - alkoxy-carbonyl-d- 3 -alkoxy group, and
  • Rg which may be the same or different, each have a hydrogen atom, an optionally substituted by a phenyl or pyridinyl group C ⁇ - 3 alkyl group or an optionally by one or two C ⁇ - 3 alkyl or C ⁇ - 3 alkyl - carbonyl-substituted amino group,
  • Ar represents a phenyl group substituted by the radicals R 5 and R 6 , where
  • R 5 is bonded in the 3-position if RQ represents a hydrogen atom, or is bonded in the 5-position if R ⁇ takes on a meaning other than that of the hydrogen atom, and an amidino group which is optionally substituted by one or two d- 3 -alkyl groups , an amino-C 3 alkyl or C 3 alkyl-amino 3 alkyl group and
  • R ⁇ is a hydrogen atom or a trifluoromethyl-, C1-3-, alkyl-, hydroxy-, C ⁇ - 3 -alkoxy-, carboxy-C ⁇ - 3 -alkoxy- or C ⁇ - 4 -alkoxy-carbonyl- C ⁇ - 3 bonded in the 2-position -alkoxy group means
  • R- ⁇ is bound in the 4-position of the phenyl radical of formula I and
  • a phenylcarbonyl or pyridylcarbonyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C 3 -C 3 -alkyl group,
  • the phenyl substituent may be monosubstituted by a C 3 alkyl or an amidino group or may be disubstituted by a C 3 alkyl and an amidino group,
  • R 2 is a trifluoromethyl group and / or R 5 is an amino C 3 alkyl group or / and R 6 is a carboxy C 3 alkoxy or C 4 alkoxy-carbonyl C 3 alkoxy - Group or / and at least one of the radicals Rs or Rg has a different meaning than that of the hydrogen atom, represents an unsubstituted 5- to 7-membered cycloalkyleneimino-carbonyl or cycloalkyleneimino-sulfonyl group and R 2 is a hydrogen atom or a substituent bonded in the 3-position of the phenyl radical, selected from fluorine, chlorine, bromine, C 3 alkyl, C 3 alkoxy and trifluoromethyl,
  • R 3 and R 4 each represent a hydrogen atom
  • Ar is a phenyl group substituted by the radicals R 5 and R 6 , where
  • R 5 is bonded in the 3-position when RQ represents a hydrogen atom, or is bonded in the 5-position when R $ has a meaning other than that of the hydrogen atom, and an amidino or amino-C ⁇ - 3 alkyl group and
  • R ⁇ represents a hydrogen atom or a bonded in the 2-position hydroxy, d- 3 alkoxy, carboxy-C 3 alkoxy or C 4 -alkoxy-carbonyl-C 3 alkoxy group, and
  • Rs and Rg which may be the same or different, each have a hydrogen atom, an optionally substituted by a phenyl, 4- (C ⁇ - 3 alkoxycarbonyl) phenyl or pyridinyl group C ⁇ - 3 alkyl group or an optionally by one or two C ⁇ _ 3 alkyl or d- 3 alkyl carbonyl groups substituted amino group,
  • amidino group can additionally be substituted by a C 6 alkoxycarbonyl or phenylcarbonyl group, and their salts.
  • the compounds of general formula I are obtained by processes known per se, for example by the following processes:
  • R 8 and R 9 are defined as mentioned at the outset and Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R 6 and R 7 , where R 5 is a cyano group and R 6 and R 7 are as defined at the outset, means, or with their reactive derivatives and subsequent conversion of the cyano compound thus obtained into an amidino compound.
  • the acylation is advantageously carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • the acylation can also be carried out with the free acid or an ester, if appropriate in the presence of an acid-activating agent or a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride , Phosphorus pentoxide, triethylamine, N, N'-dicyclohexylcarbodiimide, N.N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, O- (benzotriazol-1-yl) -N, N, N ', N , -tetramethyluronium tetrafluoroborate / N-methylmorpholine, propanephosphonic acid cyclo-anhydride / N-methylmorpho
  • R ⁇ and R 7 are defined as mentioned at the outset and R 5 represents an amidino group optionally substituted by one or two C 3 alkyl groups: Reaction of a compound of the general formula optionally formed in the reaction mixture
  • Ar ' is a phenyl or naphthyl group substituted by the radicals R 6 and R 7 , where R ⁇ and R 7 are as defined at the outset, and
  • Z 1 is an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as that
  • R 10 and R 11 which may be the same or different, each have a hydrogen atom, a C ⁇ - 3 alkyl or optionally by one or two C ⁇ - 3 alkyl or d.
  • 3- Alkyl-carbonyl groups substituted amino group, or with it
  • the reaction is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 80 ° C., with an amine of the general formula V or with a corresponding acid addition salt such as ammonium carbonate or ammonium acetate.
  • a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane
  • an amine of the general formula V or with a corresponding acid addition salt such as ammonium carbonate or ammonium acetate.
  • a compound of general formula IV is obtained, for example, by reacting an appropriate cyano compound with an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting an appropriate amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, but preferably at 20 ° C, or a corresponding nitrile with hydrogen sulfide, advantageously in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the thioamide formed with a corresponding alkyl or aralkyl halide.
  • an appropriate cyano compound with an appropriate alcohol such as methanol, ethanol, n-propanol
  • Ar represents a phenyl or naphthyl group substituted by the radicals R 5 , R 6 and R 7 , R 1 to R 4 and R 6 to Rg are defined as mentioned at the outset and R 5 represents a cyano group, and optionally subsequent alkylation with a compound of the formula
  • R 12 represents a C 3 alkyl group and Z 2 represents a leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine, bromine or iodine atom or a trifluoromethylsulfonyloxy group.
  • the catalytic hydrogenation is carried out with hydrogen in the presence of a catalyst such as palladium / carbon, platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C. , but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, or, for example, with Raney nickel, preferably in methanolic ammonia solution.
  • a catalyst such as palladium / carbon, platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid
  • the optionally subsequent alkylation is advantageously carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane, dimethyl sulfoxide or sulfolane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane, dimethyl sulfoxide or sulfolane
  • an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g.
  • methyl iodide ethyl bromide, dimethyl sulfate or benzyl chloride
  • a tertiary organic base advantageously at temperatures between 0 and 150 ° C., preferably at temperatures between
  • the subsequent acylation is advantageously carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • an acid activating agent or a dehydrating agent e.
  • 1-Hydroxy-benzotriazole N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C., but preferably at temperatures between -10 and 160 ° C.
  • the subsequent hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol , water / ethanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane, followed by decarboxylation in the presence of an acid beschrie above ⁇ ben at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the Boiling temperature of the reaction mixture carried out.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof
  • a base such as lithium hydroxide,
  • the subsequent esterification is conveniently carried out with an appropriate alcohol in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene or tetrahydrofuran Dioxane, but preferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N.
  • a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene or tetrahydrofuran Diox
  • any reactive groups present such as hydroxyl, carboxy, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
  • protective residues for a carboxyl group the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and as a protective radical for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group in addition the phthalyl group into consideration.
  • the subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by means of ether cleavage, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
  • an aqueous solvent e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
  • an alkali base such as lithium hydroxide
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is cleaved off, for example, by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar.
  • a catalyst such as palladium / carbon
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to
  • a methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • an oxidizing agent such as cerium (IV) ammonium nitrate
  • a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • a methoxy group is advantageously removed in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25 ° C.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or Ethe 's .
  • a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
  • An allyloxycarbonyl radical is split off by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C, preferably at room temperature and under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (l) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo [ 2.2.2] octane at temperatures between 20 and 70 ° C.
  • a catalytic amount of tetrakis (triphenylphosphine) palladium (0) preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Aliinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)
  • Separate compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physicochemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, subsequently as mentioned above can be separated into the enantiomers.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
  • Suitable optically active alcohols are, for example, (+) - or (-) - menthol, and optically active acyl radicals in amides are, for example, the (+) - or (-) - menthyloxycarbonyl radicals.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • acids for this are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid,
  • Citric acid tartaric acid or maleic acid.
  • the new compounds of formula I thus obtained contain a carboxy group, they can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • Bases which can be used here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of the general formula I and the compounds 2- (5-carbamimidoyl-2-hydroxyphenyI) -N- [3-chloro-4- (pyrrolidin-1-yl-carbonyl) phenyl ] acetamide, 2- (5-carbamimidoyl-2-hydroxyphenyl) - N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenyl] acetamide, 2- (5-carbamimidoyl-2 - hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyI) -phenyI] -acetamide and_2- (5-carbamidoyl-2-hydroxy-phenyl) -N- [3-methoxy- 4- (pyrrolidin-1-yl-carbonyl) -phenyl] acetamide and its salts have valuable properties.
  • Methodology Enzyme kinetic measurement with a chromogenic substrate.
  • the amount of p-nitroaniline (pNA) released from the colorless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used.
  • the inhibition of the enzyme activity by the test substance is determined at different test substance concentrations and the IC 50 is calculated from this as the concentration which inhibits the factor Xa used by 50%.
  • Tris (hydroxymethyl) aminomethane buffer 100 mmol
  • sodium chloride 150 mmol
  • Chromozym X substrate (Röche), final concentration: 200 ⁇ mol / l per reaction mixture
  • Test substance final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 ⁇ mol / l
  • the compounds produced according to the invention are well tolerated since no toxic side effects could be observed at therapeutic doses.
  • the new compounds are suitable, with the exception of those compounds in which Ar is one by the radicals R 5 , R 6 and R 7 substituted phenyl or naphthyl group and R 5 is a cyano group, and their physiologically tolerable salts for the prevention and treatment of venous and arterial thrombotic diseases, such as the treatment of deep vein thrombosis, the prevention of Reocclu - Sections after bypass surgery or angioplasty (PT (C) A), as well as occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts.
  • venous and arterial thrombotic diseases such as the treatment of deep vein thrombosis, the prevention of Reocclu - Sections after bypass surgery or angioplasty (PT (C) A)
  • PT (C) A) angioplasty
  • peripheral arterial diseases such as
  • the compounds according to the invention are for antithrombotic support in thrombolytic treatment, such as, for example, with Alteplase, Reteplase, Tenecteplase, Staphylokinase or Streptokinase, for the prevention of long-term restenosis according to PT (C) A, for the prophylaxis and treatment of ischemic incidents in patients with unstable angina or non-transmural heart attack, to prevent metastasis and growth of coagulation-dependent tumors and fibrin-dependent inflammatory processes, e.g.
  • the new compounds and their physiologically tolerable salts can be used therapeutically in combination with inhibitors of platelet aggregation such as fibrinogen.
  • Receptor antagonists eg abciximab, eptifibatide, tirofiban
  • inhibitors of ADP-induced aggregation eg clopidogrel, ticlopidine
  • P 2 T receptor antagonists eg Cangrelor
  • combined thromboxane receptor antagonists / synthetase inhibitors eg become.
  • the dosage required to achieve a corresponding effect is expediently 3 to 30 mg / kg, preferably 1 to 10 mg / kg for intravenous administration, and 5 to 50 mg / kg, preferably 3 to 30 mg / kg, 1 to each for oral administration 4 times a day.
  • the compounds of the formula I prepared according to the invention optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Water water/ Incorporate ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.
  • inert customary carriers and / or diluents for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Water water/ Incorporate
  • tert-Butoxycarbonylamino- (3-cyanophenyl) -acetic acid benzyl ester 11.4 g (27 mmol) (3-bromophenyl) -tert.butoxycarbonylamino-acetic acid benzyl ester are dissolved in 100 ml dimethylformamide and after adding 4.8 g (53.6 mmol) copper (I) -cyanide and 0.7 g (0.6 mmol) of tetrakis-triphenylphosphine-palladium- (O) stirred at 145 ° C for 8 hours. The warm suspension is suctioned off and the mother liquor is distributed in sodium chloride solution / ethyl acetate.
  • N- [3-Methyl-4- (pyrrolidin-1 -yl-sulfonyl) -phenyl1-acetamide 7.0 g (28.4 mmol) of 4-acetylamino-2-methyl-benzenesulfonic acid chloride are dissolved in 70 ml of water and 60 ml of 0.5 molar sodium hydroxide solution suspended and mixed at 0 ° C with a solution of 2.5 ml (29.8 mmol) of pyrrolidine in 60 ml of acetone. After 12 hours at room temperature, the resulting solution is acidified with 2 molar hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are dried and evaporated.
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.
  • Preparation (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 12 mm.
  • (1) is triturated with (3). This rubbing becomes more intense with the mixture of (2) and (4). Mixture added.
  • This powder mix is filled into size 3 hard gelatin capsules on a capsule filling machine.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
  • This powder mixture is filled into size 0 hard gelatin capsules on a capsule filling machine.
  • Suppositories with 100 mg of active ingredient 1 suppository contains:
  • Polyethylene glycol (M.G. 1500) 600.0 mg
  • the polyethylene glycol is melted together with polyethylene sorbitan monostearate.
  • the milled active substance is homogeneously dispersed in the melt at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

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Abstract

La présente invention concerne des composés anti-thrombotiques de formule générale (I) dans laquelle R1 à R4, R8, R9 et Ar correspondent aux éléments indiqués dans la revendication 1, tels que 2-(5-carbamimidoyl-2-hydroxy-phényl)-N-[3-chlor-4-(pyrrolidine-1-yl-carbonyl)-phényl]-acétamide, ses tautomères, stéréoisomères, mélanges, promédicaments et sels. Les composés ayant la formule générale (I) indiquée ci-dessus, dans lesquels Ar représente un groupe phényle ou naphthyle substitué par les radicaux R5, R6 et R7, et R5 représente un groupe cyano, correspondent à des produits intermédiaires intéressants pour la production des composés correspondants de formule générale (I) dans lesquels R5 représente un groupe aminido éventuellement substitué par un ou deux groupes alkyle en C1-3. Les composés de formule (I) indiquée ci-dessus, à l'exception de ceux dans lesquels Ar est un groupe phényle ou naphthyle substitué par les radicaux R5, R6 et R7, et R5 est un groupe cyano, ont des propriétés pharmacologiques intéressantes, notamment une action anti-thrombotique et une action d'inhibition du facteur Xa.
EP02710038A 2001-02-02 2002-01-26 Amides d'acide carboxylique, leur preparation et leur utilisation comme produit pharmaceutique Withdrawn EP1360170A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10104598A DE10104598A1 (de) 2001-02-02 2001-02-02 Carbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel
DE10104598 2001-02-02
DE2001136434 DE10136434A1 (de) 2001-07-26 2001-07-26 Carbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel
DE10136434 2001-07-26
PCT/EP2002/000827 WO2002062748A1 (fr) 2001-02-02 2002-01-26 Amides d'acide carboxylique, leur preparation et leur utilisation comme produit pharmaceutique

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AU6834000A (en) 1999-08-07 2001-03-05 Boehringer Ingelheim Pharma Kg Carboxylic acid amides, their production and their use as drugs
PL374971A1 (en) 2002-08-09 2005-11-14 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
CN1832920A (zh) 2003-08-08 2006-09-13 特兰斯泰克制药公司 芳基和杂芳基化合物,组合物及其使用方法
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
WO2005014532A1 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions et procedes associes

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US5039805A (en) * 1988-12-08 1991-08-13 Hoffmann-La Roche Inc. Novel benzoic and phenylacetic acid derivatives
IL110172A (en) * 1993-07-22 2001-10-31 Lilly Co Eli Bicyclic compounds and pharmaceutical compositions containing them
AU6834000A (en) * 1999-08-07 2001-03-05 Boehringer Ingelheim Pharma Kg Carboxylic acid amides, their production and their use as drugs

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