EP1173468A1 - Antagonistes recepteurs d'integrine - Google Patents

Antagonistes recepteurs d'integrine

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Publication number
EP1173468A1
EP1173468A1 EP00926971A EP00926971A EP1173468A1 EP 1173468 A1 EP1173468 A1 EP 1173468A1 EP 00926971 A EP00926971 A EP 00926971A EP 00926971 A EP00926971 A EP 00926971A EP 1173468 A1 EP1173468 A1 EP 1173468A1
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EP
European Patent Office
Prior art keywords
gly
bala
bhs
phhs
tolhs
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP00926971A
Other languages
German (de)
English (en)
Inventor
Andreas Kling
Udo Lange
Arnulf Lauterbach
Hervé Geneste
Thomas Subkowski
Johann-Christian Zechel
Claudia Isabella Graef
Wilfried Hornberger
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.)
Abbott GmbH and Co KG
Original Assignee
BASF SE
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Filing date
Publication date
Priority claimed from DE1999119218 external-priority patent/DE19919218A1/de
Priority claimed from DE1999148269 external-priority patent/DE19948269A1/de
Application filed by BASF SE filed Critical BASF SE
Publication of EP1173468A1 publication Critical patent/EP1173468A1/fr
Withdrawn legal-status Critical Current

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    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
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    • 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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    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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Definitions

  • the invention relates to new compounds that bind to integrin receptors, their production and use.
  • Integrins are cell surface glycoprotein receptors that mediate 10 interactions between similar and different cells as well as between cells and extracellular matrix proteins. They are involved in physiological processes such as Embryogenesis, hemostasis, wound healing, immune response and formation / maintenance of tissue architecture are involved. 15
  • disorders in the gene expression of cell adhesion molecules and functional disorders of the receptors can contribute to the pathogenesis of many diseases, such as tumors, thromboembolic events, cardiovascular diseases, lung diseases, 20 diseases of the CNS, the kidney, the gastrointestinal tract or inflammation.
  • Integrins are heterodimers each consisting of an ⁇ and a ⁇ transmembrane subunit, which are non-covalently linked. 25 So far, 16 different ⁇ and 8 different ⁇ subunits and 22 different combinations have been identified.
  • Integrin ⁇ v ß 3 / also called vitronectin receptor mediates the adhesion to a variety of ligands - plasma proteins, extra-
  • cellular matrix proteins cell surface proteins - the majority of which contain the amino acid sequence RGD (Cell, 1986, 44, 517-518; Science 1987, 238, 491-497), such as, for example, Vitronectin, Fibrinogen, Fibronectin, von Willebrand Faktor, Thrombospondin, .Steopontin, laminin, collagen, thrombin,
  • Integrin ⁇ n b ß 3 also called 45 platelet fibrinogen receptor, recognizes fibronectin, vitronectin, thrombospondin, von Willebrand factor and fibrinogen. Integrin ⁇ v ß 3 is expressed, inter alia, on endothelial cells, platelets, monocytes / macrophages, smooth muscle cells, some B cells, fibroblasts, osteoclasts and various tumor cells, such as melanomas, glioblastomas, lung, breast, prostate and bladder carcinomas, Osteosarcomas or neuroblastomas.
  • An increased expression is observed under various pathological conditions, such as in the prothrombotic state, in the case of vascular injury, tumor growth or metastasis or reperfusion and on activated cells, in particular on endothelial cells, smooth muscle cells or macrophages.
  • Integrin 0 v ß 3 has been shown to be involved in the following clinical pictures, among others:
  • Cardiovascular diseases such as atherosclerosis, restenosis after vascular injury, and angioplasty (neointima formation, smooth muscle line migration and proliferation) (J. Vase. Surg. 1994, 19, 125-134; Circulation 1994, 90, 2203-2206),
  • Angiogenesis-associated microangiopathies such as diabetic retinopathy or rheumatic arthritis (Ann. Rev.
  • Cancer such as tumor metastasis or tumor growth (tumor-induced angiogenesis) (Cell 1991, 64, 327-336; Nature 1989, 339, 58-61; Science 1995, 270, 1500-1502),
  • Osteoporosis bone resorption after proliferation, chemotaxis and adhesion of osteoclasts to bone matrix
  • Exp. Cell Res. 1991, 195, 368-375, Cell 1991, 64, 327-336 Hypertension, psoriasis, hyperparathyroism, Paget's disease, malignant hypercalcemia, metastatic osteolytic lesions, inflammation, heart failure, CHF, and in
  • Advantageous O v ß 3 integrin receptor antagonists bind to the integrin 0C v ß 3 receptor with an increased affinity.
  • Particularly advantageous ct v ß 3 integrin receptor antagonists have an increased selectivity compared to the integrin ⁇ v ß 3 and are less effective with respect to the integrin 0Cnß 3 by at least a factor of 10, preferably at least by a factor of 100.
  • WO 9708145 describes meta-guanidino, urea, thiourea or azacyclic aminobenzoic acid derivatives and their use as ⁇ vß 3 integrin receptor antagonists.
  • the object of the invention was to provide new integrin receptor antagonists with advantageous properties. Accordingly, compounds of the formula I were found
  • L is a structural element of the formula I L
  • T is a group of COOH or a radical which can be hydrolyzed to COOH
  • R 2 is hydrogen, NHS0 2 R 21 , NHCOR 21 or NHCOOR 22 ,
  • R 21 is a branched or unbranched, optionally substituted Ci-C ⁇ -alkyl-, C 3 -C 6 -cycloalkyl-,
  • C 1 -C 4 alkyl-C 3 -C 5 cycloalkyl radical C 5 -C 1 bicycloalkyl or Cg-Ci ⁇ -tricycloalkyl radical
  • an aryl, alkylaryl, alkyl heteroaryl radical substituted with up to three identical or different radicals or 3- to 6-membered, saturated, unsaturated or aromatic heterocycle, which can contain up to three different or identical heteroatoms O, N, S, where two radicals together form a fused, saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up to three different ones or may contain identical heteroatoms 0, N, S, and this cycle may optionally be substituted or another, optionally substituted, saturated, unsaturated or aromatic cycle may be fused onto this cycle,
  • R22 is a branched or unbranched, optionally substituted Ci-C ⁇ -alkyl radical or an optionally substituted aryl or alkylaryl
  • R 3 is hydrogen or - (CH 2 ) b - (X) c -R 31 ,
  • R 31 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted Ci-C ⁇ - alkyl, -C-C 4 alkoxy, -O-alkylaryl or -0-
  • R 4 is hydrogen, or a branched or unbranched, optionally substituted C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or C 3 -C 6 cycloalkyl radical,
  • G is a structural element of the formula I G
  • R 5 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted Ci-C ß- alkyl, -C-C 4 alkoxy, -O-alkylaryl or -O-aryl radical, a primary or optionally secondary or tertiary substituted amino radical, a C 2 -C 6 -alkynyl or C 2 -Cg alkenyl radical optionally substituted with C 1 -C 4 alkyl or aryl, a C 5 -C 2 bicycloalkyl, C ⁇ -Cig tricycloalkyl radical or one with up to three same or different
  • Residues substituted, 3- to 6-membered, saturated or unsaturated heterocycle which can contain up to three different or identical heteroatoms 0, N, S, C 3 -Cs cycloalkyl, aryl or hetero aryl radical, two radicals together being one saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up to three different or identical heteroatoms 0, N, S, and the cycle is optionally substituted or another, optionally substituted, saturated, unsaturated or aromatic cycle on this cycle can be condensed, or the side chain of a natural amino acid,
  • R 6 is hydrogen, or a branched or unbranched, optionally substituted C 1 -C 4 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or C 3 -C 6 -cycloalkyl radical,
  • Q is a double-bonded, optionally substituted heteroaryl radical, where two substituents together can represent a saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up to three different or identical heteroatoms 0, N, S, and the cycle optionally substituted or on this cycle a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused on,
  • R i o, R ii independently of one another hydrogen, - (CH 2 ) ⁇ (Y) iR 101 , or both radicals together form a 3 to 8-membered, optionally substituted, saturated, unsaturated or aromatic N-heterocycle of the two additional, identical or can contain different heteroatoms O, N or S,
  • R 101 is a hydroxyl group, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 1 -C 4 alkoxy, -O-alkylaryl or -O-aryl radical, a primary or optionally secondary or tertiary substituted amino radical, one optionally with C 1 -C 4 alkyl or aryl substituted C 2 -C 6 ⁇ alkynyl or C 2 -C 6 alkenyl radical, a C 5 -C 2 bicycloalkyl, C ⁇ -Cig tricycloalkyl radical or one with up to three of the same or different radicals substituted, 3- to 6-membered, saturated or unsaturated heterocycle containing up to three different or identical heteroatoms 0, N, which may contain S, C 3 _ 8 cycloalkyl, aryl or heteroaryl, where two radicals together form an annealed , saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up
  • R 12 is a branched or unbranched, optionally substituted C 1 -C 4 alkyl, alkylaryl, C 3 -C 6 cycloalkyl or C 1 -C 4 alkyl C 3 -C 6 cycloalkyl radical or an optionally substituted aryl radical
  • R 13 is hydrogen, -OH, -CN, -CONH 2 , a branched or unbranched, optionally substituted C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or -OCO-C 4 -C 4 alkyl radical, or an optionally substituted one Alkylaryl, -O-alkylaryl, -OCO-aryl, -OCO-alkylaryl or -OCO-allyl radical,
  • R 14 is hydrogen, a branched or unbranched, optionally substituted C ⁇ -C 4 alkyl, alkylaryl, -C0 2 -C 1 _ 4 alkyl, -C0 2 alkylaryl, -C0 2 allyl, -CO -C ⁇ - 4 alkyl, -CO-alkylaryl or -CO-allyl radical,
  • R 15 is hydrogen, a branched or unbranched, optionally substituted C ⁇ -C 4 alkyl radical or an optionally substituted aryl or alkylaryl radical.
  • R 16 , R 17 independently of one another are -NH 2 , halogen or a branched or unbranched, optionally substituted C 1 -C 4 -alkyl or C 1 -C 4 alkoxy radical or an optionally substituted aryl radical,
  • T is understood to mean a group of COOH or a radical that can be hydrolyzed to COOH.
  • a residue that can be hydrolyzed to COOH is understood to mean a residue which, after hydrolysis, changes into a COOH group.
  • the group O is an example of a radical T which can be hydrolyzed to COOH
  • R 1 has the following meaning:
  • M can be a metal cation, such as an alkali metal cation, such as lithium, sodium, potassium, the equivalent of an alkaline earth metal cation, such as calcium, magnesium and barium, or an environmentally compatible organic ammonium ion such as tertiary C 1 -C 4 -alkylammonium or ammonium ion, such as for example ONa, OK or OLi, b) a branched or unbranched, optionally halogen-substituted Ci-Cs alkoxy radical, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1, 1-dimethylethoxy, especially methoxy, Ethoxy, 1-methylethoxy, pentoxy, hexoxy, heptoxy,
  • a metal cation such as an alkali metal cation, such as lithium, sodium, potassium, the equivalent of an alkaline earth metal cation, such as calcium, magnesium and
  • Octoxy difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1, 2, 2-tetrafluoroethoxy, 2, 2, 2-trifluoroethoxy, 2-chloro-l, 1, 2- trifluoroethoxy or pentafluoroethoxy
  • a branched or unbranched, optionally substituted with halogen -CC 4 alkylthio radical such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio radical
  • R 1 is also a radical - (O) mN (R 18 ) (R 19 ), in which m represents 0 or 1 and R 18 and R 19 , which may be the same or different, have the following meaning:
  • Ci-Cg-alkyl such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1, 1-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1, 2-dimethylbutyl,
  • C 3 -C 6 ⁇ alkenyl such as 2-propenyl, 2-butenyl, 3-butenyl, l-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, l -Methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1, l -Dimethyl-2-propenyl, l, 2-dimethyl-2-propenyl, l-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, l-methyl-2-pentenyl, 2 -Methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-1-3-penteny
  • C 3 -C 6 alkynyl such as 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl, 2-pentynyl, 3-pentynyl,
  • 3-methyl-4-pentynyl 4-methyl-2-pentynyl, 1, l-dimethyl-2-butynyl, 1, l-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2, 2- Dimethyl-3-butynyl, l-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and l-ethyl-l-methyl-2-propynyl, preferably 2-propynyl, 2 -Butinyl, l-methyl-2-propynyl and l-methyl-2-butynyl, especially 2-propynyl,
  • C 3 -C 8 cycloalkyl such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl, where these alkyl, cycloalkyl, alkenyl and alkynyl groups can each be substituted,
  • Phenyl optionally mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C 4 -alkyl, C 4 haloalkyl, C 1 -C 4 -alkoxy, halo-C 4 alkoxy or -CC 4 alkylthio such as 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-dichlorophenyl, 2-methoxy-3-methylphenyl, 2, 4-dimethoxyphenyl, 2-nitro-5-cyanophenyl, 2, 6-difluorophenyl
  • Ci-C ß- alkyl radical under R 21 in structural element L is, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl , 2-methylbutyl, 1,2-dimethylpropyl, 1, 1-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl , 2, 3-dimethylbutyl, 1, 1-dimethylbutyl, 2, 2-dimethylbutyl, 3, 3-dimethylbutyl, 1,1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or l -Ethyl-2-methylpropyl, preferably methyl, ethyl, propy
  • a branched or unbranched C 3 -C 6 cycloalkyl radical is understood as R 21 in structural element L, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • a branched or unbranched C 1 -C 4 alkyl-C 3 -C 6 cycloalkyl radical is understood under R 21 in structural element L to be a C 3 ⁇ C 6 cycloalkyl radical mentioned above which is substituted on a C 4 -C 4 alkyl radical.
  • Ci-C ⁇ -alkyl radicals, C 3 -Cg-cycloalkyl radicals or -C-C 4 alkyl- C 3 -C 6 cycloalkyl radicals can be substituted with up to 5 identical or different radicals selected from the group halogen, aryl or heteroaryl.
  • a C 5 -C 2 bicycloalkyl radical for R 21 is understood to mean, for example, indanyl, norbornyl or camphyl, a C ⁇ - cis tricycloalkyl radical, for example, adamantyl.
  • aryl, alkylaryl, alkylheteroaryl radical which is substituted by up to three identical or different radicals or a 3- to 6-membered saturated, unsaturated or aromatic heterocycle which can contain up to three different or identical heteroatoms 0, N, S and two radicals together a fused, saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up to three different or identical heteroatoms 0, N, S, can represent and the cycle optionally substituted or on this cycle another, optionally substituted, saturated, unsaturated or aromatic cycle can be fused, for R 21 in structural element L for example
  • Aryl radicals such as, for example, phenyl, 1-naphthyl or 2-naphthyl, Alkylaryl radicals, such as, for example, benzyl or homobenzyl,
  • Alkylheteroaryl radicals such as, for example, -CH 2 -2-pyridyl, -CH 2 -3-pyridyl, -CH 2 -4-pyridyl, -CH 2 -2-thienyl, -CH 2 -3-thienyl, -CH 2 -2- Thiazolyl, -CH 2 -4-thiazolyl, CH 2 -5-thiazolyl,
  • Heteroaryl radicals such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5- Thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4- Isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl or 6-pyridazinyl, preferably 2-pyridyl, 3-pyridyl, 4-pyri
  • aryl radicals, alkylaryl radicals, alkylheteroaryl radicals and heteroaryl radicals can be substituted with up to three identical or different radicals, for example selected from the following group:
  • Preferred substituents of the aryl radicals, alkylaryl radicals, Alkylheteroarylreste and heteroaryl for R 21 are C ⁇ -C4 ⁇ alkyl, C 3 -C 6 cycloalkyl, -COOH, -COOMe, -CF3, -CN, C ⁇ -C 4 alkoxy, -SCH 3 , -0-CH 2 -COOH, phenyl, -S0 2 CH 3 , -N0 2 , -OH, -NH 2 , -N-pyrrolidinyl, -N-piperidinyl, -N-morpholinyl, -N-piperazinyl , -NH-C ⁇ -C4 alkyl, -N (C ⁇ -C alkyl) 2, F, Cl, Br or I.
  • Preferred substituents of the aryl radicals, alkylaryl radicals, alkylheteroaryl radicals and heteroaryl radicals for R 21 in which two radicals together represent an fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms 0, N, S and the cycle optionally substituted or a further, optionally substituted cycle may be fused onto this cycle are the following, double-bonded structural elements:
  • Ci-Cs-alkyl radical for R 22 in the structural element L means, for example, the Ci-C ⁇ -alkyl radicals mentioned above for R 21 , preferably 1, 1-dimethylethyl.
  • Aryl radicals for R 22 in structural element L are, for example, phenyl, 1-naphthyl or 2-naphthyl, preferably phenyl;
  • Alkylaryl radicals for R 22 in the structural element L are preferably benzyl or homobenzyl.
  • radical R 3 in the structural element L the index b can be 0, 1, 2 or 3, preferably 0, 1 or 2 and the index c can be 0 or 1.
  • the radical X represents a double bonded radical selected from the group -S0 2 -, -S-, -0-, -CO-, -NH-S0 2 -, -O-CO-, -CO-O-, -NH -CO-, -CO-NH-, -CO-N (R 31 ) -, -N (R 31 ) -CO-, -S0 2 -NH-, -S0 2 -N (R 31 ) - or -N (R 31 ) -S0-.
  • the two R 31 radicals can be the same or different.
  • R 31 in structural element L is, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1, 1-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 1, 1-dimethylbutyl, 2, 2-dimethylbutyl, 3, 3-dimethylbutyl, 1, 1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1- Ethyl-2-methylpropyl, preferably methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylprop
  • R 31 in structural element L is, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy, in particular methoxy, ethoxy or 1-methylethoxy understood.
  • -O-alkylaryl or -O-aryl radicals are, for example, -O-phenyl, -O-1-naphthyl, -0-2-naphthyl or -O-benzyl.
  • Ci-C ß- alkyl, -CC 4 alkoxy radicals of R 31 in structural element L can be substituted with up to five identical or different radicals selected from the group halogen, aryl or heteroaryl.
  • Substituted -O-alkylaryl or -O-aryl radicals are understood to mean, for example, the aforementioned -O-alkylaryl or -O-aryl radicals, it being possible for the aryl part to be substituted with up to three identical or different radicals selected from the following group:
  • a primary or optionally secondary or tertiary substituted amino radical is understood under R 31 in structural element L to mean a primary amino radical -NH, a secondary amino radical -NH (R 311 ) or a tertiary amino radical -N (R 311 ) (R 312 ), where
  • R 311 and R 312 independently of one another are C ⁇ -C 4 -alkyl or C 3 -C ⁇ - Cydoalkyl, as mentioned above, optionally substituted aryl, preferably phenyl, alkylaryl, preferably benzyl, -CO-C ⁇ -C 4 alkyl, can preferably be -C0-CH 3 or -CO-aryl, preferably -CO-phenyl.
  • Preferred amide residues -XR 31 are for example
  • C ⁇ ⁇ C 4 alkyl or aryl C 2 -CG-alkynyl or C 2 -C 6 alkenyl are from R 31 in structural element L, for example, CC 6 -alkynyl, such as ethynyl, 2- Propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-3-butynyl, 2-methyl-1-3-butynyl, l-methyl- 2-butynyl, 1, l-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-2-pentynyl, l-methyl- 2-pentyn
  • Phenyl such as preferably phenylethynyl or phenylethenyl.
  • a C 5 -C ⁇ 2 bicycloalkyl radical for R 31 means, for example, indanyl, norbornyl or camphyl, and a C ß- cis tricycloalkyl radical, for example, adamantyl.
  • 3-6 membered, saturated or unsaturated heterocycle which can contain up to three different or identical heteroatoms 0, N, S, C 3 -C 8 ⁇ cycloalkyl, aryl or Heteroaryl radical, where two radicals together can represent a fused, saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up to three different or identical hetero atoms 0, N, S, and the cycle optionally substituted or a further one on this cycle, optionally substituted, saturated, unsaturated or aromatic cycle can be fused, for R 31 in structural element L for example
  • N 3- to 6-membered, saturated or unsaturated heterocycles which can contain up to three different or identical heteroatoms 0, N, S, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydro-azepinyl, N-morpholinyl or N-piperazinyl, where in the case of heterocycles which carry free amine protons, for example
  • N-piperazinyl the free amine protons by common amine protecting groups such as methyl, benzyl, Boc (ter. -Butoxy- carbonyl), Z (benzyloxycarbonyl), tosyl, -S0 2 -C ⁇ -C 4 alkyl, -S0 -phenyl or -S0 2 -benzyl can be replaced,
  • Aryl radicals such as, for example, phenyl, 1-naphthyl or 2-naphthyl or
  • Heteroaryl radicals such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5- Thiazolyl, 2-oxazolyl, 4-0xazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4- Isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl or 6-pyridazinyl, preferably 2-pyridyl, 3-pyridyl, 4-pyri
  • heterocycles, C 3 -Cs cycloalkyl, aryl and heteroaryl radicals can optionally be substituted with up to three identical or different radicals, for example selected from the following group:
  • Preferred substituents of the heterocycles, C 3 -C 8 cycloalkyl, aryl and heteroaryl radicals for R 31 are C 1 -C 4 -alkyl, -COOH, -COOMe, -CF 3 , -CN, C 1 -C 8 -alkoxy- , -SCH 3 , -O-CH 2 -C0OH, -phenyl, -S0 2 CH 3 , -N0 2 , -OH, -NH 2 , -N-pyrrolidinyl-, -N-piperidinyl, -N-morpholinyl, - N-piperazinyl, -NH--C-C 4 alkyl, -N (-C-C 4 alkyl) 2 , F, Cl, Br or I.
  • Preferred substituents of the heterocycles, C 3 -C 8 -cycloalkyl, aryl and heteroaryl radicals for R 31 in which two radicals together form an fused, saturated, unsaturated or aromatic carbocycle or heterocycle which has up to three different or identical heteroatoms 0, N, S can contain and the cycle can be optionally substituted or a further, optionally substituted cycle can be fused onto this cycle, the following double-bonded structural elements are:
  • Examples of the resulting condensed cycle systems for R 31 are, for example, the corresponding dioxolanyls, benzopyrrolyls, benzofuryls, benzothienyls or fluorenyls.
  • a branched or unbranched, optionally substituted C 1 -C 4 -alkyl radical for R 4 in structural element L is understood to mean, for example, methyl, ethyl, propyl, i-propyl, butyl, t-butyl or i-butyl, preferably methyl.
  • a branched or unbranched, optionally substituted C 3 -C6 cycloalkyl radical for R 4 in structural element L means the radicals mentioned above for R 21 , optionally substituted with up to 5 radicals such as halogen or aryl, preferably cyclohexyl, cyclopentyl or cyclopropyl.
  • C 3 -C 6 alkenyl or C 3 -C 6 alkynyl radicals for R 4 in structural element L mean the radicals mentioned above for R 18 or R 19 , preferably allyl or propargyl.
  • Particularly preferred radicals for R 4 are hydrogen, methyl, cyclopropyl, allyl or propargyl; hydrogen is very particularly preferred.
  • a 1, so that a ⁇ -amino acid represents the preferred basic structure of structural element L.
  • R 5 is hydrogen and independently of R 31 in structural element L, the same radicals as described above for R 31 or a further side chain of a natural amino acid.
  • Preferred radicals R 5 are hydrogen, methyl, ethynyl or ethynyl substituted with methyl, particularly preferred is hydrogen.
  • R 6 is understood independently of R 4 to mean the same radicals as described above for R 4 .
  • Preferred radicals R 6 are hydrogen, methyl, allyl, propargyl or cyclopropyl; hydrogen is particularly preferred.
  • Q is understood to mean a double bonded heteroaryl radical which is optionally substituted with up to three further radicals, where two radicals together form a saturated, unsaturated or aromatic carbocycle or heterocycle which has up to three different or identical heteroatoms 0, N, S can contain, and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused onto this cycle.
  • a heteroaryl radical is preferably a 5- or
  • 6-membered, aromatic heterocycle which may contain up to three different or identical heteroatoms 0, N, S, where heterocycles carry the free amine protons, such as imidazolyl, triazolyl, pyrazolyl or pyrrolyl, the free amine protons by common amine protecting groups, such as for example methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzoxycarbonyl), tosyl, -S0 2 -C ⁇ -C 4 alkyl, -S0 2 -phenyl or -S0-benzyl can be replaced.
  • the following structures are listed as preferred heteroaryl radicals Q, the connecting sites being identified by a dash:
  • the free amine protons of imidazolyl, pyrazole, triazole or pyrrolyl can be protected by common amine protective groups, such as, for example, methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzoxycarbonyl), tosyl , -S0 2 -C ⁇ ⁇ C 4 alkyl, -S0-phenyl or -S0-benzyl to be replaced.
  • common amine protective groups such as, for example, methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzoxycarbonyl), tosyl , -S0 2 -C ⁇ ⁇ C 4 alkyl, -S0-phenyl or -S0-benzyl to be replaced.
  • Preferred substituents of the heteroaryl radicals are independently one or two radicals selected from the group -CN, halogen, preferably Cl or F, -CC 4 alkyl, preferably methyl, -C-haloalkyl, preferably trifluoromethyl, C 1 -C 4 alkoxy , preferably methoxy, -NH-C ⁇ -C 4 alkyl or aryl, preferably phenyl.
  • the structural element A means one of the structural elements of the formula I A 1 to I A 20
  • radicals R 10 and R 11 independently of one another and independently of R 3 are the radicals described above for R 3 in the structural element L, preferably C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkyl-C 3 -C 8 cycloalkyl, aryl, alkylaryl, heteroaryl or Alkylheteroaryl, the aryl, alkylaryl, heteroaryl and alkylheteroaryl radicals, up to three identical or different radicals from the group F, Cl, Br or I, -CC 4 -alkyl, C 3 -C 6 -cycloalkyl, -COOH, -COOMe, -CF 3 , -CN, -C-C 4 -alkoxy-, -SCH 3 , -0-CH 2 -COOH, phenyl, -S0 2 CH 3 , -N0 2 , -OH, -NH 2
  • radicals R 10 and R 11 together form a 3 to 8-membered, optionally substituted, saturated, unsaturated or aromatic N-heterocycle which can additionally contain two further, identical or different heteroatoms 0, N, or S, such as, for example, pyrrolidinyl, piperidinyl, Hexahydroazepinyl, piperazinyl or morpholinyl.
  • R 12 represents a branched or unbranched, optionally substituted C ⁇ -C 4 alkyl, alkylaryl, C 3 -Cg cycloalkyl or C 1 -C 4 alkyl CC 6 cycloalkyl radical or an optionally substituted aryl radical, as above described for R 21 .
  • a branched or unbranched, optionally substituted C 1 -C 4 -alkoxy or -O-alkylaryl radical for R 13 is understood to mean the corresponding radicals as described above for R 31 , preferably methoxy or benzyloxy.
  • -OCO -CC 4 -alkyl-, -OCO-aryl-, -OCO-alkylaryl- or -OCO-allyl- consist of the group -OCO- and the above-described C 31 -C 4 -alkyl- , Aryl, alkylaryl radicals or the allyl radical together.
  • Preferred radicals for R 13 are hydrogen, -OH, -O-benzyl, -OCO-phenyl, -OCO-benzyl, -OCO-allyl, -CN or -C0-NH 2 .
  • Preferred radicals for R 14 are hydrogen, methyl, benzyl, -COO-benzyl, -COO-allyl, -CO-benzyl or -CO-allyl.
  • R 15 denotes hydrogen, a branched or unbranched, optionally substituted C 1 -C 4 -alkyl radical or an optionally substituted aryl or alkylaryl radical, as described above for R 21 or R 4 .
  • Preferred radicals for R 15 are hydrogen, methyl, benzyl or phenyl.
  • R 16, R 17 are independently -NH, halogen, such as Cl, Br, I or F or a branched or unbranched, optionally substituted C ⁇ -C4 alkyl or C ⁇ -C 4 alkoxy or an optionally substituted aryl radical, as described above for R 31 , preferably NH 2 , Cl, F, methyl, methoxy or phenyl.
  • Z 1 ' Z 2 ' Z 3 ' Z 4 independently of one another are CH, C-CH 3 , C-OCH 3 / C-Cl or N, preferably Z 1 and Z 2 or Z 2 and Z 3 or Z 3 and Z 4 are not N at the same time.
  • substituted aryl, alkylaryl, heteroaryl or alkylheteroaryl radicals are understood in the description to mean aryl, alkylaryl, heteroaryl or alkylheteroaryl radicals which have up to three identical or different radicals selected from the group the following group can be substituted:
  • the compounds of the formula I and also the intermediates for their preparation can have one or more asymmetrically substituted carbon atoms.
  • the compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof.
  • the use of an enantiomerically pure compound as the active ingredient is preferred.
  • the compounds of the formula I can also be in the form of physiologically tolerable salts.
  • the compounds of the formula I can also be present as prodrugs in a form in which the compounds of the formula I are released under physiological conditions.
  • group T in structural element L some of which contains groups which can be hydrolyzed to the free carboxylic acid group under physiological conditions.
  • Derivatized structural elements A which release the structural element A under physiological conditions are also suitable.
  • the indices a, e, f and g and the heterocycle Q are chosen so that the distance between the group T and the structural element A is 10 to 14 atomic bonds, preferably 11 to 13 atomic bonds along the shortest possible path along the molecular structure .
  • Particularly preferred compounds of the formula I have the preferred structural elements A of the formula I A 1 , IA 2 / IA 3 , IA / IA 5 »A 8 / I A 10 , or I A 13 and the preferred region of the structural element L, while the Structural elements E and G are widely variable as described above.
  • Further particularly preferred compounds of the formula I have the particularly preferred structural element A of the formula I A 4 and the preferred region of the structural element L, while the structural elements E and G are widely variable as described above. Further particularly preferred compounds of the formula I have the preferred structural element A of the formula I A 4 and the preferred region of the structural element E, while the structural elements L and G are widely variable as described above.
  • Very particularly preferred compounds of the formula I have the preferred structural element A of the formula I A 4 , the preferred region of the structural element E and the preferred region of the structural element L, while the structural element G is widely variable as described above.
  • Extremely preferred compounds of the formula I have the preferred structural element A of the formula I A 4 and the preferred regions of the structural elements E, G and L.
  • 162 ibhs-ithiadiaz-bala-betaanaphth 15
  • 163 bhs-nme35pyr-ala-betameph
  • 251 phhs-25oxaz-bala-beta3quin 5
  • 252 phhs-25methiaz-gly-beta3quin
  • 501 ibhs-ithiadiaz-bala-betathiome 5
  • 502 bim-me24oxaz-leu-zdap
  • bras-oxadiaz-bala-aspaba 598 bras-oxadiaz-bala-betapym
  • 601 ibhs-25oxaz-bala-betafphe 5
  • 602 tolhs-25oxaz-gly-betacbph
  • 630 phhs-ithiadiaz-bala-zdapch 631: phhs-24thiaz-gly-betabediox 632: bhs-nme35pyr-bala-betatos 633: tolhs-25oxaz-bala-betaipr
  • 701 ibhs-25thiaz-gly-beta23meoph 5
  • 702 phhs-25methiaz-gly-betabnaphth
  • 801 bhs-25thiaz-bala-betamesu 5
  • 802 bim-35fur-bala-zdap
  • 901 tolhs-24thioph-bala-betahb 5
  • 902 thazep-24thiaz-gly-betapy

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Abstract

L'invention concerne des composés se liant à des récepteurs d'intégrine, leur fabrication, leur utilisation comme antagonistes récepteurs d'intégrine et pour le traitement de maladies, des préparations pharmaceutiques renfermant ces composés, ainsi que des préparations pharmaceutiques renfermant au moins un autre composé actif.
EP00926971A 1999-04-28 2000-04-17 Antagonistes recepteurs d'integrine Withdrawn EP1173468A1 (fr)

Applications Claiming Priority (5)

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DE1999119218 DE19919218A1 (de) 1999-04-28 1999-04-28 Neue Integrinrezeptorantagonisten
DE19919218 1999-04-28
DE19948269 1999-10-06
DE1999148269 DE19948269A1 (de) 1999-10-06 1999-10-06 Neue Integrinrezeptorantagonisten
PCT/EP2000/003469 WO2000066618A1 (fr) 1999-04-28 2000-04-17 Antagonistes recepteurs d'integrine

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DE10204789A1 (de) * 2002-02-06 2003-08-14 Merck Patent Gmbh Inhibitoren des Integrins alpha¶v¶beta6
KR100759130B1 (ko) * 2005-02-12 2007-09-19 휴메드 주식회사 항 인테그린 항체 코팅스텐트 및 그의 제조방법
WO2008011191A1 (fr) * 2006-07-21 2008-01-24 Replidyne, Inc. Urées hétérocycliques antibactériennes
US8148380B2 (en) 2007-07-23 2012-04-03 Crestone, Inc. Antibacterial amide and sulfonamide substituted heterocyclic urea compounds
WO2009015193A1 (fr) 2007-07-23 2009-01-29 Replidyne, Inc. Composés hétérocycliques d'urée antibactériens substitués par de la sulfone et du sulfoxyde
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SK15342001A3 (sk) 2002-06-04
CA2371604A1 (fr) 2000-11-09
MXPA01010834A (es) 2002-04-24
CN1355811A (zh) 2002-06-26
HUP0202898A2 (hu) 2002-12-28
CZ20013846A3 (cs) 2002-06-12
PL352777A1 (en) 2003-09-08
TR200103090T2 (tr) 2002-05-21
WO2000066618A1 (fr) 2000-11-09
BG106040A (bg) 2002-05-31
BR0010092A (pt) 2002-06-11
RU2001132141A (ru) 2004-03-20
IL146146A0 (en) 2002-07-25
KR20020010618A (ko) 2002-02-04
JP2003500339A (ja) 2003-01-07
NO20015237L (no) 2001-12-21
NO20015237D0 (no) 2001-10-26
AU4551500A (en) 2000-11-17
HK1046692A1 (zh) 2003-01-24

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