WO2005121103A1 - Benzimidazole, verfahren zu deren herstellung und deren verwendung als arzneimittel - Google Patents
Benzimidazole, verfahren zu deren herstellung und deren verwendung als arzneimittel Download PDFInfo
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- WO2005121103A1 WO2005121103A1 PCT/EP2005/005963 EP2005005963W WO2005121103A1 WO 2005121103 A1 WO2005121103 A1 WO 2005121103A1 EP 2005005963 W EP2005005963 W EP 2005005963W WO 2005121103 A1 WO2005121103 A1 WO 2005121103A1
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- 0 CC(CC*)(CC1CC1)CN(C)C Chemical compound CC(CC*)(CC1CC1)CN(C)C 0.000 description 7
- RBGPAZSQQSBZOS-UHFFFAOYSA-N CC(C)(CN1C)COC1=O Chemical compound CC(C)(CN1C)COC1=O RBGPAZSQQSBZOS-UHFFFAOYSA-N 0.000 description 1
- WDKDTBGSUALSGU-UHFFFAOYSA-N CC(CN1)(CN(C)S1(=O)=O)N Chemical compound CC(CN1)(CN(C)S1(=O)=O)N WDKDTBGSUALSGU-UHFFFAOYSA-N 0.000 description 1
- GGYVTHJIUNGKFZ-UHFFFAOYSA-N CN(CCCC1)C1=O Chemical compound CN(CCCC1)C1=O GGYVTHJIUNGKFZ-UHFFFAOYSA-N 0.000 description 1
- ANVUCPZCQYCSTF-UHFFFAOYSA-N CN(CCCC1)S1(=O)=O Chemical compound CN(CCCC1)S1(=O)=O ANVUCPZCQYCSTF-UHFFFAOYSA-N 0.000 description 1
- JVPFSCJXEJOFQS-UHFFFAOYSA-N CN(CCCCO1)C1=O Chemical compound CN(CCCCO1)C1=O JVPFSCJXEJOFQS-UHFFFAOYSA-N 0.000 description 1
- LZYVAWDWKPVARG-UHFFFAOYSA-N CN(CCCOC1)C1=O Chemical compound CN(CCCOC1)C1=O LZYVAWDWKPVARG-UHFFFAOYSA-N 0.000 description 1
- FGQBGDBLZZPFCM-UHFFFAOYSA-N CN(CCOC1)C1=O Chemical compound CN(CCOC1)C1=O FGQBGDBLZZPFCM-UHFFFAOYSA-N 0.000 description 1
- BQWLOYVMLJNTCR-UHFFFAOYSA-N CN(CCOCC1)C1=O Chemical compound CN(CCOCC1)C1=O BQWLOYVMLJNTCR-UHFFFAOYSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N CN1CCOCC1 Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- IFFQMALEAGTIQV-UHFFFAOYSA-N Cc1cc(NC(C2(CCN(C)CC2)c2nc(ccc(Cl)c3)c3[nH]2)=O)ccc1C(N1CCCC1)=O Chemical compound Cc1cc(NC(C2(CCN(C)CC2)c2nc(ccc(Cl)c3)c3[nH]2)=O)ccc1C(N1CCCC1)=O IFFQMALEAGTIQV-UHFFFAOYSA-N 0.000 description 1
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- 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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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
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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
- C07D401/14—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
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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
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- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
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- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to new substituted benzimidazoles of the general formula
- the compounds of the above general formula I and their tautomers, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, and their stereoisomers have valuable pharmacological properties, in particular an antithrombotic effect and a factor Xa inhibitory effect.
- the present application thus relates to the new compounds of the general formula I above, their preparation, the pharmaceutical compositions containing the pharmacologically active compounds, their preparation and use.
- the cycloalkyleneimino part in the carbon skeleton by one or two fluorine atoms, one or two C ⁇ -3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl,
- Cycloalkylenimino group can be replaced by a sulfur atom, a sulfinyl or sulfonyl group, or
- Sulfur atom, a carbonyl, sulfinyl or sulfonyl group or by a -NH group which is optionally substituted by a C 3 alkyl, formyl or C 3 alkyl carbonyl group may, in addition to which a methylene group adjacent to the nitrogen atom to which the cycloalkyleneimino group is bonded, be replaced by a carbonyl, sulfinyl or sulfonyl group, with the proviso that when substituting the above-mentioned 6- to 7-membered cycloalkyleneimino radicals, at where a methylene group is replaced by an oxygen or sulfur atom, a sulfinyl or sulfonyl group, two heteroatoms are separated from one another by at least two carbon atoms,
- C 3 alkyl amino C 3 alkyl, Ci-s alkylamino cis alkyl, di (C 3 alkyl) amino C 3 alkyl -, A 4- to 7-membered cycloalkyleneimino -C 3 -3 alkyl, phenyl, phenyl -C 3 -3 alkyl, heteroaryl, heteroaryl -C 3 alkyl, aminocarbonyl,
- Double bond is not bound to the imino nitrogen atom
- n 1 or 2
- R 7a are each independently a hydrogen or
- R 7b are each independently a hydrogen atom or a q i is -5 alkyl group
- R 7c each independently represents a hydrogen atom, a C 5 alkyl, C- ⁇ - 5 alkylcarbonyl or C ⁇ means -5 alkoxycarbonyl, X 1 represents a carbonyl, thiocarbonyl or sulfonyl group,
- X 2 represents an oxygen atom or an -NR 7b group
- X 3 is an oxygen or sulfur atom or an -NR 7c group, a radical of the general formula
- R 7a , R 7b and R 7c are as defined above,
- Y 1 represents an oxygen atom or a -CH 2 -, -CHR 7b - or -NR 7c group
- Y 2 represents an oxygen or sulfur atom, a - NR 7c group
- Y 3 represents a carbonyl or sulfonyl group
- R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C 1 -C 3 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a C 2-3 alkenyl, C 2-3 - Alkynyl, C 3 -3 alkoxy, a mono-, di- or trifluoromethoxy group means
- R 3 represents a hydrogen or halogen atom or ad 3 -alkyl group
- R 4 is a hydrogen atom, an amino, d- 5 alkylcarbonylamino, d- 5 alkoxycarbonylamino, a C 2-3 alkenyl or C 2-3 alkynyl group, a straight-chain or branched C -5 alkyl group , which may be replaced by a fluorine atom, a mono-, di- or trifluoromethyl, a nitrile, hydroxyl, a C ⁇ -5 -alkoxy group, in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a mercapto, C ⁇ - 3 -Alkylsulfanyl-, d- 3 -Alkylsulfinyl-, d- 3 -Alkylsulfonyl-, Amino-, C 1-3 -Alkylamino-, Di- (C ⁇ -3 -alkyl) -amino-, a 4- to 7-member
- R 5 represents a hydrogen atom or ad -3 alkyl group
- R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group, one of the methylene groups of the C 3-6 cycloalkyl group thus formed being represented by an oxygen or sulfur atom, an imino, C ⁇ - 3 alkylimino or acylimino group can be replaced,
- R 6 is a hydrogen, fluorine, chlorine or bromine atom, ad 3 -alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a C 2-3 alkenyl or C 2-3 alkynyl group represents a hydroxy, d- 3 -alkoxy, trifluoromethoxy, amino, nitro or cyano group,
- heteroaryl group one in the carbon skeleton, if appropriate, by a fluorine, chlorine, bromine or iodine atom, ad -3 alkyl, amino, C 3 -3 -Alkylamino-, di- (C 1-3 -alkyl) -amino-, d- 3 -alkoxy-, carboxy-, d- 3 -alkoxycarbonyl- or C 1-3 -alkoxycarbonylamino group substituted monocyclic 5- or 6-membered heteroaryl group is to be understood, wherein the 6-membered heteroaryl group has one, two or three nitrogen atoms and the 5-membered heteroaryl group is an imino group which is optionally substituted by a d- 3- alkyl or phenyl-d- 3- alkyl group, an oxygen or sulfur atom or one optionally by ad -3 -alkyl-, amino
- alkyl and alkoxy groups contained in the definitions mentioned above which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the aforementioned dialkylated radicals, for example the dialkylamino groups, are the same or different could be,
- Examples of monocyclic heteroaryl groups are the pyridyl, ⁇ / -oxy-pyridyl, 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, furazanyl, thiophenyl, thiazolyl, isothiazolyl, [1, 2.3] thiadiazolyl, [1, 2.4] thiadiazolyl or [1 , 2,5] thiadiazolyl group.
- bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo [c] furanyl, benzothiophenyl, benzo [c] thiophenyl, benzothiazolyl, benzo [c] isothiazolyl, benzo [cQisothiazolyl, benzooxazolyl], benzooxazolyl isoxazolyl, benzo [] isoxazolyl, benzo [1, 2.5] oxadiazolyl, benzo [1, 2.5] thiadiazolyl, benzo [1, 2.3] thiadiazolyl, benzo [cl [1, 2, 3] triazinyl, benzo [1, 2,4] triazinyl, benzotriazolyl, cinnolinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, indolyl, isoindolyl or 1-o
- 5 -alkyl groups are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, ferf-butyl, 1-pentyl, 2-pentyl or 3-pentyl group.
- Examples of the above-mentioned in the definitions C ⁇ -5 alkoxy groups are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, 1-pentyloxy , 2-pentyloxy or 3-pentyloxy group.
- R 1 is a 4- to 7-membered cycloalkyleneiminocarbonyl group, the cycloalkyleneimino part in the carbon skeleton being replaced by one or two fluorine atoms, one or two d- 3 -alkyl-, hydroxy-C ⁇ -3 -alkyl-, heteroaryl-d- 3 -alkyl-, Amino -CC -3 -alkyl-, -C ⁇ -5 -alkylamino- d- 3 -alkyl-, di- (C ⁇ -5 -alkyl) -amino-C ⁇ -3 -alkyl-, a 4- to 7-membered cycloalkylenimino- C 1-3 -alkyl-, carboxy-C ⁇ -3 -alkyl-, C ⁇ .
- R 7a each independently of one another is a hydrogen or fluorine atom or a C 1-5 alkyl, amino-Ci.s-alkyl, ds-alkylamino-ds-alkyl, di- (C ⁇ -5 -alkyl) -amino-C ⁇ -5 -alkyl-, hydroxy-, hydroxy-C ⁇ -5 -alkyl-, C ⁇ -5 -alkoxy-, amino-, C ⁇ - 5 -alkylamino- or di- (C ⁇ - 5- Alkyl) -amino group, where in the above-mentioned substituted 5- to 7-membered radicals R 1, the heteroatoms F, O or N optionally introduced with R 7a as substituents are not replaced by exactly one carbon atom from a heteroatom from the group N , O, S are separated,
- R 7b each independently represents a hydrogen atom or a C 5 alkyl group
- R 7c each independently represents a hydrogen atom, ad -5 alkyl or C -5 alkylcarbonyl group
- X 1 represents a carbonyl or sulfonyl group
- X 2 represents an oxygen atom or an -NR 7b group
- X 3 is an oxygen or sulfur atom or a - 10 NR 7c group, a radical of the general formula
- R 5 7'a a , D R7'b D and i 0 R7'c c are as defined above,
- Y 1 represents an oxygen atom or a -CH 2 -, -CHR 7b - or -NR 7c group
- Y 2 represents an oxygen or sulfur atom, an - NR 7c group, and Y 3 represents a carbonyl or sulfonyl group,
- R 2 is a hydrogen, fluorine, chlorine or bromine atom, ad 3 -alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a C 2-3 alkenyl, C 2-3 alkynyl , d- 3 -alkoxy, a mono-, di- or trifluoromethoxy group,
- R 3 represents a hydrogen or fluorine, chlorine or bromine atom or ad 3 -alkyl group
- R 4 is a hydrogen atom, an amino, d- 5 -alkylcarbonylamino, d- 5 -alkoxycarbonylamino, a C 2-3 -alkenyl or C 2-3 -alkynyl group, a straight-chain or branched d -5 -alkyl group, which may be replaced by a fluorine atom, a mono-, di- or trifluoromethyl, a hydroxyl, ad- alkoxy group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, d -3 -alkylsulfanyl-, d- 3 - Alkylsulfinyl-, d -3 -alkylsulfonyl-, amino-, d- 3 -alkylamino-, di- (-C ⁇ -3- alkyl) -amino-, a 4- to 7-membered cycloalkylenimino-, carb
- R 5 represents a hydrogen atom or ad -3 alkyl group, or R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group, wherein one of the methylene groups of a C thus formed -6 cycloalkyl group through an oxygen or sulfur atom, an imino, d- 3 -Alkylimino- or acylimino group can be replaced means, and
- R 6 represents a fluorine, chlorine or bromine atom, a methyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, an ethenyl or ethinyl, a methoxy or cyano group,
- heteroaryl group one in the carbon skeleton, optionally by a fluorine, chlorine, bromine or iodine atom, a C 1-3 alkyl, amino, C 1 - 3 -Alkylamino-, di- (C ⁇ -3 -alkyl) -amino-, d -3 -alkoxy-, carboxy-, d- 3 -alkoxycarbonyl- or d- 3 -alkoxycarbonylamino group substituted pyridyl, pyrazolyl, pyridazinyl, Pyrimidinyl, pyrazinyl, [1, 3.5] triazinyl, pyrrolyl, imidazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl group is to be
- alkyl and alkoxy groups contained in the definitions mentioned above which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the aforementioned dialkylated radicals, for example the dialkylamino groups, are the same or different could be,
- R 1 is a 5- or 6-membered cycloalkyleneimino carbonyl group, where the cycloalkyleneimino part in the carbon skeleton can be substituted by one or two d- 3 -alkyl groups, and / or a methylene group in the 3-position of a 5-membered cycloalkyleneimino group can be replaced by a sulfur atom, or a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group can be replaced by an oxygen or sulfur atom or by an -NH group which is optionally substituted by a d -3 -alkyl, formyl or d- 3- alkylcarbonyl group , a 5- or 6-membered cycloalkenyleneimino carbonyl group optionally substituted by one or two d- 3 -alkyl groups, the double bond not being bound to the imino nitrogen atom, a radical of the general formula
- R 7a each independently represents a hydrogen or a Ci.s-alkyl group
- R 2 represents a hydrogen, chlorine or bromine atom, a methyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a methoxy, a mono-, di- or trifluoromethoxy group,
- R represents a hydrogen atom
- R 4 is a hydrogen atom, an amino, d -5 alkylcarbonylamino, d- alkoxycarbonylamino, a C 2-3 alkenyl or C 2-3 alkynyl group, a straight-chain or branched C- alkyl group which optionally by a mono-, di- or trifluoromethyl, a hydroxyl or a methoxy group, in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, -C -2 alkyl sulfanyl, C -2 alkyl sulfinyl, d -2 - Alkylsulfonyl, amino, C -2 alkylamino, di (C 2 alkyl) amino, a 4- to 6-membered cycloalkylenimino, carboxy or methoxycarbonyl group is substituted, a phenyl, pyridyl or Thiophenyl group means
- R 5 represents a hydrogen atom or a C 2 alkyl group, or R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group, preferably a C 4-6 cycloalkyl group, wherein one of the methylene groups of a C 3-6 cycloalkyl group or C thus formed 4- 6 -cycloalkyl group can be replaced by an oxygen or sulfur atom, an imino, d- 3- alkylimino or acylimino group, and
- R 6 represents a chlorine or bromine atom or an ethynyl group
- alkyl and alkoxy groups contained in the definitions mentioned above which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the aforementioned dialkylated radicals, for example the dialkylamino groups, are the same or different could be,
- the compounds of the general formula I are obtained by processes known per se, for example by the following processes:
- R 1 to R 6 are defined as mentioned at the beginning:
- R 4 to R 6 are defined as mentioned at the outset and X represents a hydroxyl, d-4-alkoxy group or a halogen atom or the group C (O) X represents an activated form of a carboxylic acid, such as, for example, a carboxylic anhydride, with a compound the general formula
- R 1 to R 3 are defined as mentioned at the beginning.
- acylation is conveniently carried out with the free acid or an ester, optionally in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane,
- Triphenylphosphine / carbon tetrachloride in a solvent or solvent mixture such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide or sulfolane and optionally with the addition of an auxiliary base such as for example ⁇ / -methylmorpholine, triethylamine, diisopropylethylamine, potassium carbonate or sodium bicarbonate at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 100 ° C, or also thermally optionally with additional microwave radiation in a solvent or solvent mixture such as dimethylformamide, Sulfolane, dimethyl sulfoxide, ⁇ / -methylpyrrolidinone, toluene or xylyol at temperatures between 100 and 250 ° C but preferably between 130 and 200 ° C.
- the acylation can also be carried out using 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, performed.
- 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, performed.
- R 4 , R 5 and R are defined as mentioned at the outset and Y 'denotes a hydrogen atom or a carboxyl protective group:
- R 4 to R 6 are defined as mentioned at the outset and Y 'is the hydrogen atom or a carboxyl protective group as defined below, a protective group which may be present subsequently being split off.
- the cyclization is advantageously carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide or tetralin, dimethyl sulfoxide, methylene chloride, chloroform, tetrachloromethane and, for example, at temperatures between 0 and 0 250 ° C, but preferably between 20 and 100 ° C, optionally in the presence of a condensing agent such as phosphorus oxychloride, propanephosphonic acid cycloanhydride, thionyl chloride, sulfuryl chloride,
- a condensing agent such as phosphorus oxychloride, propanephosphonic acid cycloanhydride, thionyl chloride, sulfuryl chloride,
- a base such as, for example, diisopropylethylamine, triethylamine, potassium carbonate, potassium ethylate or potassium tert-butyl.
- the cyclization can also be carried out without a solvent and / or condensing agent.
- Y ' is the hydrogen atom or a carboxyl protective group such as trimethylsilyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te / t-butyl - or benzyl group and X is a hydroxy or represents.
- the first and third reaction steps are carried out by amide formation with an activated carboxylic acid derivative as described under (a).
- a protected carboxylic acid of the general formula VI is converted into a free carboxylic acid of the general formula VII, for example hydrolytically in an aqueous solvent, for example 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, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C or the cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl residue.
- a catalyst such as palladium / carbon in a solvent or solvent mixture such as methanol
- 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 1 to 5 bar.
- 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 1 to 5 bar.
- step (b) The cyclization of a compound of general formula VIII to a compound of general formula I is carried out as described in step (b).
- compounds of the general formula III can also be prepared analogously to those described in patents WO 02/062748, WO 03/000256 or WO 2004/035039.
- any reactive groups present such as hydroxyl, carboxy, amino, alkylamino or imino groups
- the protective radical for a hydroxyl group is the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, ferf-butyl, trityl, benzyl or tetrahydropyranyl group,
- a protective radical for an amino, alkylamino or imino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, te / t-butoxycarbonyl,
- 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 removed by hydrogenolysis, for example using hydrogen in 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 from 1 to 5 bar.
- 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 1 to 5 bar.
- 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 eliminated 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 te / t-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 ether.
- 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 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
- 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 compounds by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6 Wiley Interscience, 1971) of the general formula I with at least two 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 in the enantiomers can be separated.
- the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of 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.
- an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols
- optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
- the optically active alcohol is, for example, (+) - or (-) - menthol and the optically active acyl radical in amides is, for example, the (+) - or _ _ _
- 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.
- suitable acids for this purpose 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 if they contain a carboxy group, can then, if desired, be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
- Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
- the compounds of the general formula I and their tautomers, their enantiomers, their diastereomers and their physiologically tolerable salts have valuable pharmacological properties, in particular an antithrombotic activity, which is preferably based on an action which influences thrombin or factor Xa, for example a thrombin-inhibiting or factor Xa-inhibiting effect, on an effect which prolongs the aPTT time and on an inhibiting effect on related serine proteases such as, for. B. urokinase, factor VIIa, factor IX, factor XI and factor XII.
- the compounds of general formula I obtained which occur in racemates can be obtained by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general formula I with at least two asymmetric carbon atoms due to their physico-chemical 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, can then be separated into the enantiomers as mentioned above.
- 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 obtained in this way, 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.
- suitable acids for this purpose 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 if these contain a carboxy group, if desired subsequently convert them into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
- Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
- the compounds of the general formula I and their tautomers, their enantiomers, their diastereomers and their physiologically tolerable salts have valuable pharmacological properties, in particular an antithrombotic activity, which is preferably based on an action which influences thrombin or factor Xa, for example a thrombin-inhibiting or factor Xa-inhibiting effect, on an effect which prolongs the aPTT time and on an inhibiting effect on related serine proteases such as, for. B. urokinase, factor VIIa, factor IX, factor XI and factor XII.
- 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 enzyme activity (relative to the solvent control) is determined by the test substance concentrations of test substance at different therefrom and the IC 5 o calculated as the concentration which inhibits the factor Xa used by 50%.
- pNA p-nitroaniline
- Tris (hydroxymethyl) aminomethane buffer 100 mmol) and sodium chloride (150 mmol), pH 8.0 plus 1 mg / ml Human Albumin Fraction V, protease-free Factor Xa (Calbiochem), specific activity: 217 lU / mg, final concentration: 7 lU / ml per reaction mixture
- Substrate S 2765 (Chromogenix), final concentration: 0.3 mM / l (1 KM) 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 new compounds and their physiologically compatible salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as the prevention and treatment of deep vein thrombosis, the prevention of reocclusion after bypass surgery or angioplasty (PT ( C) A), as well as occlusion in peripheral arterial diseases, as well as prevention and treatment of pulmonary embolism, disseminated intravascular coagulation, prophylaxis and treatment of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts.
- PT ( C) A angioplasty
- pulmonary embolism disseminated intravascular coagulation
- prophylaxis and treatment of coronary thrombosis prophylaxis of stroke and prevention of occlusion of shunts.
- 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 preventing long-term restenosis after PT (C) A, for the prophylaxis and treatment of ischemic incidents in patients of all forms coronary heart disease, to prevent metastasis and growth of tumors and inflammatory processes, e.g.
- the new compounds and their physiologically tolerable salts can be used therapeutically in combination with acetylsalicylic acid, with platelet aggregation inhibitors such as fibrinogen receptor antagonists (eg abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the coagulation system and their recombinant analogs, for example C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (eg clopidogrel, ticlopidine), with P 2 T receptor antagonists (eg Cangrelor) or with combined thromboxane receptor antagonists / synthetase inhibitors (eg Terbogrel).
- fibrinogen receptor antagonists eg abciximab, eptifibatide, tirofiban, roxifiban
- physiological activators and inhibitors of the coagulation system and their recombinant analogs for example C, TFPI, antithrombin
- the dosage required to achieve a corresponding effect is expediently 0.01 to 3 mg / kg, preferably 0.03 to 1.0 mg / kg for intravenous administration, and 0.03 to 30 mg / kg, preferably 0.1 to 10 mg / kg, each 1 to 1 for oral administration 4 times a day.
- the compounds of 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, e.g. with corn starch, milk sugar, 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, carboxymethyl cellulose or fat-containing substances such as hard fat , work into common galenical preparations such as tablets, coated tablets, capsules, powders, suspensions or suppositories.
- inert customary carriers and / or diluents e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water /
- R f values were determined using ready-made silica gel 60 F 254 TLC plates (E. Merck, Darmstadt, Item No. 1.05714) without chamber saturation.
- the R f values determined under the name Alox were determined using ready-made aluminum oxide 60 F 25 TLC plates (E. Merck, Darmstadt, Item No. 1.05713) without chamber saturation.
- the R f values determined under the name Reversed-Phase-8 were determined using ready-made RP-8 F 254s DC plates (E. Merck, Darmstadt, Article No. 1.15684) without chamber saturation.
- the ratios given for the flow agents relate to volume units of the respective solvents.
- Silica gel from Millipore MATREX TM, 35-70 ⁇ m was used for chromatographic purifications. If further details on the configuration are missing, it remains open whether it is pure stereoisomers or enantiomer / diastereomer mixtures.
- reaction mixture is then poured into water, extracted twice with ethyl acetate, the organic phase is washed with saturated NaCl solution, dried with Na 2 SO 4 and evaporated down in vacuo purified by chromatography (silica gel; eluent: methylene chloride -> methylene chloride / ethanol 97: 3) and triturated with water.
- the white precipitate is filtered off and dried at 40 ° C.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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EP05751720A EP1756068A1 (de) | 2004-06-08 | 2005-06-03 | Benzimidazole, verfahren zu deren herstellung und deren verwendung als arzneimittel |
JP2007526257A JP2008501746A (ja) | 2004-06-08 | 2005-06-03 | ベンズイミダゾール、それらの製造方法、及び医薬としての使用 |
CA002565698A CA2565698A1 (en) | 2004-06-08 | 2005-06-03 | Benzimidazoles, method for producing them and the use thereof as drugs |
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DE102004027821.0 | 2004-06-08 | ||
DE102004027821A DE102004027821A1 (de) | 2004-06-08 | 2004-06-08 | Benzimidazole, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
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WO2005121103A1 true WO2005121103A1 (de) | 2005-12-22 |
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PCT/EP2005/005963 WO2005121103A1 (de) | 2004-06-08 | 2005-06-03 | Benzimidazole, verfahren zu deren herstellung und deren verwendung als arzneimittel |
Country Status (6)
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US (2) | US20050272792A1 (de) |
EP (1) | EP1756068A1 (de) |
JP (1) | JP2008501746A (de) |
CA (1) | CA2565698A1 (de) |
DE (1) | DE102004027821A1 (de) |
WO (1) | WO2005121103A1 (de) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8741890B2 (en) | 2007-11-15 | 2014-06-03 | Boehringer Ingelheim International Gmbh | Substituted amides, manufacturing and use thereof as medicaments |
WO2021255086A1 (en) * | 2020-06-18 | 2021-12-23 | Leo Pharma A/S | Small molecule modulators of il-17 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20040804A1 (es) * | 2002-12-19 | 2004-12-31 | Boehringer Ingelheim Pharma | DERIVADOS DE CARBOXAMIDAS COMO INHIBIDORES DEL FACTOR Xa |
US7371743B2 (en) * | 2004-02-28 | 2008-05-13 | Boehringer Ingelheim International Gmbh | Carboxylic acid amides, the preparation thereof and their use as medicaments |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0442820A1 (de) * | 1990-02-16 | 1991-08-21 | Laboratoires Upsa | Benzimidazo- und Azabenzimidazol-Derivate, Tromboxanrezeptorantagonisten, Verfahren zu deren Herstellung, Herstellungszwischenprodukte, diese enthaltende Zusammenstellungen |
WO2000001704A2 (de) * | 1998-07-04 | 2000-01-13 | Boehringer Ingelheim Pharma Kg | Benzimidazole, deren herstellung und deren verwendung als arzneimittel |
DE10111842A1 (de) * | 2001-03-13 | 2002-09-19 | Boehringer Ingelheim Pharma | Antithrombotische Carbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel |
WO2004056784A1 (de) * | 2002-12-19 | 2004-07-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue carbonsäureamide, deren herstellung und deren verwendung als arzneimittel |
DE10335545A1 (de) * | 2003-08-02 | 2005-06-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Carbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel |
-
2004
- 2004-06-08 DE DE102004027821A patent/DE102004027821A1/de not_active Withdrawn
-
2005
- 2005-06-03 EP EP05751720A patent/EP1756068A1/de not_active Withdrawn
- 2005-06-03 CA CA002565698A patent/CA2565698A1/en not_active Abandoned
- 2005-06-03 WO PCT/EP2005/005963 patent/WO2005121103A1/de not_active Application Discontinuation
- 2005-06-03 JP JP2007526257A patent/JP2008501746A/ja active Pending
- 2005-06-07 US US11/147,471 patent/US20050272792A1/en not_active Abandoned
-
2007
- 2007-09-24 US US11/860,025 patent/US20080015178A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0442820A1 (de) * | 1990-02-16 | 1991-08-21 | Laboratoires Upsa | Benzimidazo- und Azabenzimidazol-Derivate, Tromboxanrezeptorantagonisten, Verfahren zu deren Herstellung, Herstellungszwischenprodukte, diese enthaltende Zusammenstellungen |
WO2000001704A2 (de) * | 1998-07-04 | 2000-01-13 | Boehringer Ingelheim Pharma Kg | Benzimidazole, deren herstellung und deren verwendung als arzneimittel |
DE10111842A1 (de) * | 2001-03-13 | 2002-09-19 | Boehringer Ingelheim Pharma | Antithrombotische Carbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel |
WO2004056784A1 (de) * | 2002-12-19 | 2004-07-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue carbonsäureamide, deren herstellung und deren verwendung als arzneimittel |
US20040220169A1 (en) * | 2002-12-19 | 2004-11-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Carboxylic acid amides, the preparation thereof, and their use as pharmaceutical compositions |
DE10335545A1 (de) * | 2003-08-02 | 2005-06-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Carbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8741890B2 (en) | 2007-11-15 | 2014-06-03 | Boehringer Ingelheim International Gmbh | Substituted amides, manufacturing and use thereof as medicaments |
WO2021255086A1 (en) * | 2020-06-18 | 2021-12-23 | Leo Pharma A/S | Small molecule modulators of il-17 |
Also Published As
Publication number | Publication date |
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DE102004027821A1 (de) | 2006-01-05 |
EP1756068A1 (de) | 2007-02-28 |
CA2565698A1 (en) | 2005-12-22 |
US20050272792A1 (en) | 2005-12-08 |
US20080015178A1 (en) | 2008-01-17 |
JP2008501746A (ja) | 2008-01-24 |
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