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Definitions

• the invention relates to new compounds that bind to integrin receptors, their preparation 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, kidney, 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 24 different combinations have been identified.
• Integrin ⁇ t v ß also called vitronectin receptor, mediates adhesion to a large number 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, from Willebrand factor, thrombospondin, Osteopontin, laminin, collagen, thrombin,
• RGD amino acid sequence RGD
• Integrin 0C ⁇ i b ß 3 also called 45 platelet fibrinogen receptor, recognizes fibronectin, vitronectin, thrombospondin, von Willebrand factor and fibrinogen. Integrin ⁇ v ß 3 is expressed on endothelial cells, platelets, monocytes / macrophages, smooth muscle cells, some B cells, fibroblasts, osteoclasts and various Tuirtor cells, such as melanomas, glioblasto e, lung, breast, prostate and bladder carcinomas , Osteosarcoma or neuroblastoma.
• Increased expression can be observed under various pathological conditions, such as in the prothrombotic state, in the case of vascular injury, tumor growth or tumor formation or reperfusion and on activated cells, in particular on endothelial cells, smooth muscle cells or macrophages.
• Integrin & ß 3 is involved in the following, among others
• Cardiovascular diseases such as atherosclerosis, restenosis after
• Angiogenesis-associated microangiopathies such as diabetic retinopathy or rheumatic arthritis (Ann. Rev. Physiol 1987, 49, 453-464; Int. Ophthalmol. 1987, 11, 41-50; Cell 1994, 79, 1157-1164; J. Biol. Chem. 1992, 267, 10931-10934),
• 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 ßs integrin receptor antagonists bind to the integrin ⁇ v ß 3 receptor with an increased affinity.
• Particularly advantageous ⁇ v ß 3 integrin receptor antagonists have an increased selectivity compared to the integrin f v ß 3 and are less effective with respect to the integrin Otu b ßs by at least a factor of 10, preferably at least by a factor
• ⁇ v ß 3 antagonists with a tricyclic molecular structure are known.
• WO 9915508-A1 WO 9830542-Al and WO 9701540-Al describe di-benzocycloheptane derivatives
• WO 9911626-Al describes dibenzo [1,4] oxazepine derivatives
• WO 9905107-A1 benzocycloheptane derivatives 35 WO 9915508-A1, WO 9830542-Al and WO 9701540-Al describe di-benzocycloheptane derivatives, WO 9911626-Al describes dibenzo [1,4] oxazepine derivatives and WO 9905107-A1 benzocycloheptane derivatives.
• the object of the invention was to provide new integrin receptor antagonists with advantageous properties.
• L is a structural element of the formula I.
• T is a group of COOH or a radical which can be hydrolyzed to COOH and
• R L 1 , R L 2 , R L 3 , R L 4 independently of one another hydrogen, -T, -OH, -NR L 6 R L 7 / -C0-NH, a halogen radical, a branched or unbranched, optionally substituted C ⁇ - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 -
• RL 5 - RL 6 , RL 7 independently of one another hydrogen, a branched or unbranched, optionally substituted
• G is a structural element of the formula I G
• the structural element G can be installed in both orientations and
• Structural element L is connected via X G via a double bond
• Y G CO, CS, C NR G 2 or CR G 3 RG 4 ,
• R G 1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C 1 -C 6 -alkyl or C 1 -C 4 -alkoxy radical,
• RG 2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted Ci-C ⁇ -alkyl, C] _- C 4 alkoxy, C 3 -C cycloalkyl or -0-C 3 -C cycloalkyl radical or an optionally substituted aryl, -O-aryl, arylalkyl or -O-alkylene-aryl radical and
• RG 3 are independently hydrogen or a branched or unbranched, optionally substituted C ⁇ -C 6 alkyl, C -C ⁇ -alkenyl, C 2 -C 6 ⁇ kinyl- Al or C ⁇ -C 4 alkoxy, or both radicals R G 3 and R G 4 together form a cyclic acetal -0-CH 2 -CH -0- or -0-CH 2 -0- or both radicals R G 3 and Rg 4 together form an optionally substituted C 3 -C cycloalkyl, mean
• RG 5 , RG 6 , RG 7 , RG 8 independently of one another are hydrogen, an amino or hydroxyl group, a radical HN-CO-R G 9 , a branched or unbranched, optionally substituted Ci-Cg-alkyl or -C-C 4 - Alkoxy radical, an optionally substituted aryl or arylalkyl radical or, independently of one another, in each case two radicals RQ 5 and R G 6 or RQ 7 and R G 8 together form an optionally substituted, fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle, the can contain up to three different or identical heteroatoms 0, N, S, and
• R G 9 is a branched or unbranched, optionally substituted Ci-C ⁇ alkyl or -CC 4 alkoxy radical or an optionally substituted aryl, hetaryl, arylalkyl or hetarlyalkyl radical
• B is a structural element containing at least one atom which can form hydrogen bonds under physiological conditions as a hydrogen acceptor, at least one hydrogen acceptor atom being at a distance of 4 to 13 atomic bonds from structural element G along the shortest possible path along the structural element framework .
• 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 is an example of a radical T which can be hydrolyzed to COOH
• R 1 has the following meaning: a) OM, where M is 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, for example, primary, secondary, tertiary or quaternary
• M is 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, for example, primary, secondary, tertiary or quaternary
• C 1 -C 4 alkylammonium or ammonium ion such as, for example, ONa, OK or OLi,
• 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, 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
• Ci-Cs alkoxy radical such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1, 1-dimethylethoxy, especially methoxy, Ethoxy, 1-methylethoxy,
• a branched or unbranched, optionally substituted with halogen -CC 4 -alkylthio radical such as methylthio, ethylthio, propylthio, 1-methylethylthio, butyl hio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio radical
• R 1 furthermore a radical - (0) m -N (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-C ⁇ alkyl such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dirnethylpropyl , 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 -Dirnethylbutyl, 3,3-Dirnethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl or the corresponding substituted radicals, preferably methyl, e
• C 2 -C 6 alkynyl such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-3- butynyl, 2-methyl-3-butynyl, l-methyl-2-butynyl, 1, l-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- Hexynyl, l-methyl-2-pentynyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, l-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pent
• C 3 -Cs cycloalkyl such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl or the corresponding substituted radicals,
• a phenyl radical optionally mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C alkyl, C ⁇ -C4 haloalkyl, C ⁇ ⁇ C 4 -alkoxy, C 4 -haloalkoxy or C 1 -C 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,
• R 18 and R 19 together form a, optionally substituted, closed, to form a cycle, for example by
• C 1 -C 4 -Alkyl-substituted C 4 -C 7 -alkylene chain which may contain a hetero atom selected from the group consisting of oxygen, sulfur or nitrogen, such as - (CH 2 ) 4 -, - (CH 2 ) 5 - , - (CH 2 ) 6 -, - (CH 2 ) 7 -, - (CH 2 ) 2 -0- (CH 2 ) 2 -, -CH 2 -S- (CH 2 ) 3 -, - (CH 2 ) 2 -0- (CH 2 ) 3 -, -NH- (CH 2 ) 3 -, -CH 2 -NH- (CH 2 ) 2 -,
• Preferred radicals T are -COOH, -CO-0-C ⁇ -Cs-alkyl or -C0-0- benzyl.
• the rest CR L 1 - the structural element L is linked to the structural element G via a double bond.
• X L preferably denotes the radical CR 3 R L , NR 5 , oxygen or sulfur.
• a halogen radical is understood as R L 1 , R L 2 / R L 3 or R 4 in structural element L, for example F, Cl, Br or I, preferably F.
• Ci-Ce alkyl radical under a branched or unbranched Ci-Ce alkyl radical under R L 1 , R L 2 R L 3 or R L 4 in structural element L, 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 branched or unbranched C 1 -C 4 -alkyl radicals such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, particularly preferably methyl.
• a branched or unbranched C 2 -C 6 alkenyl radical under RL 1 , R 2 / RL 3 or R L 4 in structural element L for example vinyl, 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, 1, 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
• C 2 -C 6 -alkynyl radical for example ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl- under R L 1 , R 2 , R L 3 or R L 4 in structural element L 2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-3-butynyl, 2-methyl-3-butynyl, l-methyl-2-butynyl, 1, l-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, l-methyl-2-pentynyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, l- Methyl
• a branched or unbranched C 3 -C -cycloalkyl radical means RL 1 , RL 2 / RL 3 or R L 4 in structural element L, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
• a branched or unbranched C ⁇ -C 4 alkoxy radical under R 1 , RL 2 , RL 3 or R L 4 in structural element L for example methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy understood.
• residues -CO-NH (-CC 6 alkyl), -CO-N (-C 6 alkyl) 2 represent secondary or tertiary amides and are composed of the amide bond and the corresponding Ci-C ⁇ alkyl radicals as described above for R L 1 , R L 2 / R L 3 or R L 4 together.
• radicals R 1 , R L 2 , R L 3 or R L 4 can also be a radical
• C ⁇ ⁇ C 2 -alkylene-T such as methylene-T or ethylene-T
• C 2 -alkenylene-T such as ethenylene-T or C -alkynylene-T, such as ethinylene-T
• an aryl radical such as phenyl, 1-naphthyl or 2-naphthyl or
• arylalkyl radical such as, for example, benzyl or ethylenephenyl (homobenzyl)
• radicals can be optionally substituted.
• each of two radicals R L 1 and R L 2 or R L 3 and R L 4 or optionally R 1 and RL 3 together can be an optionally substituted 3 to 7-membered saturated or unsaturated carbocycle or heterocycle which can contain up to three different radicals or may contain identical heteroatoms 0, N, S.
• R L 1 , RL 2 / R L 3 or R L 4 can optionally be substituted.
• R L 1 , RL 2 / R L 3 or R L 4 and all further substituted radicals in the description below if the substituents are not specified in more detail, up to 5 substituents, for example selected from the following group, are suitable independently of one another :
• C 1 -C 4 alkyl such as methyl, CF 3 , C 2 Fs or CH 2 F, -CO-0-C ⁇ -C 4 -alkyl-, C 3 -C 6 -cycloalkyl-, C ⁇ -C -alkoxy-, C 1 -C 4 -thioalkyl-, -NH-C0- 0-Cl-C4-alkyl, -0-CH 2 -COO-C ⁇ -C 4 alkyl, -NH-CO-C ⁇ -C 4 alkyl, -CO-NH-C ⁇ -C 4 alkyl, -NH- S0 2 -C-C 4 alkyl, -S0 -NH-C ⁇ -C 4 alkyl, -N (-C-C 4 alkyl
• substituted hetaryl radicals of the description two substituents can form a fused 5- to 7-membered, unsaturated or aromatic carbocycle.
• Preferred radicals RL 1 , R L 2 R L 3 or R L 4 are, independently of one another, hydrogen, halogen, a branched or unbranched, optionally substituted C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, or C 3 -C 7 cycloalkyl radical or the radical -NR L 6 RL 7 •
• radicals R L 1 , R L 2 / R L 3 or R L 4 are independently hydrogen, fluorine or a branched or unbranched, optionally substituted C 1 -C 4 -alkyl radical, preferably methyl.
• radicals R L 5, R L 6, R L 7 i n structural element L are, independently of one another, hydrogen, a branched or unbranched, optionally substituted
• Ci-C ß alkyl for example as described above for R 1 ,
• C0-0 -CC 6 alkyl, S0 -C 6 -alkyl or CO -CC 6 alkyl radical which is selected from the group CO-0, S0 or CO and, for example, from the above for R L 1 described Ci-Cö alkyl residues, or an optionally substituted CO-O-alkylene-aryl, S0 2 -aryl, S0 2 -alkylene-aryl or CO-alkylene-aryl radical, which is selected from the group CO-O, S0 2 , or CO and, for example is composed of the aryl or arylalkyl radicals described above for R L 1 .
• Preferred radicals for R L 6 in structural element L are hydrogen, a branched or unbranched, optionally substituted C 1 -C 4 -alkyl-, CO-0-C ⁇ -C 4 -alkyl-, CO-C ⁇ -C -alkyl- or S0 2 -C ⁇ -C 4 - alkyl radical or an optionally substituted CO-O-benzyl, S0 2 -aryl, S0-alkylene-aryl or CO-aryl radical.
• Preferred radicals for R 7 in structural element L are hydrogen or a branched or unbranched, optionally substituted C 1 -C 4 -alkyl radical.
• Preferred structural elements L are composed of the preferred residues of the structural element.
• Particularly preferred structural elements L are composed of the particularly preferred residues of the structural element.
• G represents a structural element of the formula I G ,
• the structural element G can be installed in both orientations.
• X G is connected to the next structural element via a double bond only applies to the orientation in which the structural element G is connected to structural element L via X G via a double bond.
• the structural element G can be installed in both orientations.
• X G means nitrogen or CRQ 1 -
• X G means carbon.
• R G 1 in structural element G is hydrogen halogen, such as examples game as Cl, F, Br or I, a hydroxy group or a branched or unbranched, optionally substituted Ci-C ⁇ alkyl, preferably C ⁇ -C 4 ⁇ Alkyl or -CC 4 ⁇ alkoxy, for example as described above for R 1 .
• radicals for RQ 1 are hydrogen, methoxy or ethoxy.
• R G 2 in structural element G means hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted Ci-C ⁇ alkyl, C 1 -C 4 alkoxy or C 3 -C cycloalkyl radical, for example as in each case above described for R 1 ,
• an optionally substituted -0-C 3 -C-cycloalkyl group which is composed of an ether group and, for example, the method described above for R 1 is C 3 -C-cycloalkyl group,
• an optionally substituted -O-aryl or -O-alkylene-aryl radical which is composed of a group -0- and, for example, the aryl or arylalkyl radicals described above for R L 1 .
• C 1 -C 6 -alkyl, CC 6 -alkenyl, C 2 -C 6 -alkynyl or C 1 -C 4 -alkoxy radicals for RQ 3 or RQ 4 in structural element G are independent of one another , for example the corresponding radicals described above for R 1 .
• both RQ 3 and RQ 4 together can form a cyclic acetal, such as -0-CH 2 -CH-0- or -0-CH-0-.
• RQ 3 and RQ 4 can together form an optionally substituted C 3 -C 7 cycloalkyl radical.
• Preferred radicals for RQ 3 or RQ 4 are, independently of one another, hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy.
• Ci-C ⁇ -alkyl or -CC 4 alkoxy radicals and optionally substituted aryl or arylalkyl radicals for R G 5 , R G 6 R G 7 or R G 8 in structural element G are understood independently of one another, for example, the corresponding radicals described above for R 1 .
• two radicals RQ 5 and R G 6 or RQ 7 and R G 8 can together form an optionally substituted, fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle which has up to three different or identical heteroatoms 0 , N, S can contain form.
• R G 5 , R G 6 / G 7 or RQ 8 are, independently of one another, hydrogen or optionally substituted aryl radicals, preferably phenyl or arylalkyl radicals, preferably benzyl, and two radicals RQ 5 and RQ 6 or RQ 7 and RQ 8 together, optionally substituted, fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms 0, N, S.
• radicals R G 5 / RG 6 / R G 7 or RG 8 each independently form an optionally substituted, fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle selected from one of the following double-bonded structural formulas:
• a branched or unbranched, optionally substituted C 1 -C 6 -alkyl or C 6 -C 4 -alkoxy radical and an optionally substituted aryl or arylalkyl radical for RQ 9 are understood to mean, for example, the corresponding radicals described above for R L 1 .
• a hetaryl radical for RQ 9 is , for example, radicals such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-0xazolyl, 4-0xazolyl, 5-0xazolyl, 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, 6-pyridazinyl, 3-isoxazole, 4-isox
• Substituted hetaryl radicals for RQ 9 also include fused derivatives of the above-mentioned hetaryl radicals, such as, for example, indazole, indole, benzothiophene, benzofuran, indoline, benzimidazole, benzothiazole, benzoxazole, quinoline or isoquinoline.
• fused derivatives of the above-mentioned hetaryl radicals such as, for example, indazole, indole, benzothiophene, benzofuran, indoline, benzimidazole, benzothiazole, benzoxazole, quinoline or isoquinoline.
• Preferred structural elements G are composed of the preferred residues of the structural element.
• Particularly preferred structural elements G are composed of the particularly preferred residues of the structural element.
• Structural element B is understood to mean a structural element containing at least one atom which can form hydrogen bonds under physiological conditions as a hydrogen acceptor, at least one hydrogen acceptor atom being at a distance of 4 to 13 atomic bonds along the shortest possible path along the structural element framework to structural element G.
• the design of the structural framework of structural element B is widely variable.
• Atoms that can form hydrogen bonds under physiological conditions as hydrogen acceptors are, for example, atoms with Lewis base properties, such as, for example, the heteroatoms nitrogen, oxygen or sulfur.
• Physiological conditions are understood to mean a pH value that prevails at the location in an organism at which the ligands interact with the receptors.
• the physiological conditions have a pH of, for example, 5 to 9.
• the structural element B means a structural element of the formula IB AE- I B
• Z A 2 optionally substituted nitrogen, oxygen or sulfur
• E is a spacer structural element that connects structural element A covalently to structural element G, the number of atomic bonds along the shortest possible path along the structural element framework E being 4 to 12.
• the structural element A means a structural element selected from the group of structural elements of the formulas IA 1 to IA 18 /
• ⁇ are independently hydrogen, CN, halogen, a branched or unbranched, optionally substituted C-C alkyl radical or ß or an optionally substituted aryl, arylalkyl, hetaryl, C 3 -C 7 -cycloalkyl radical or a radical of C0 -0-R A 14 , 0-R A 14 , SR A 14 , RA 15 RA 16 or CO-NR A 15 R A 16 /
• R A 14 is hydrogen, a branched or unbranched, optionally substituted Ci-C ⁇ -alkyl, alkylene, -C-C 4 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or alkylene cycloalkyl radical or an optionally substituted C 3 -C 7 cycloalkyl, aryl, arylalkyl, hetaryl or hetarlyalkyl radical,
• Cx-Ce-alkyl independently of one another hydrogen, a branched or unbranched, optionally substituted Cx-Ce-alkyl, CO-Ci-Ce-alkyl, S0 2 -C ⁇ -C 6 -alkyl-, C00-C ⁇ -C 6 -alkyl-, arylalkyl- , COO-alkylene-aryl, S0 2 -alkylene-aryl or hetarlyalkyl radical or an optionally substituted C 3 -C 7 cycloalkyl radical,
• RA 3 'RA 4 independently of one another hydrogen, - (CH) n - (X A ) JR A 12 / or both radicals together form a 3 to 8-membered, saturated, unsaturated or aromatic N-heterocycle which can additionally contain two further, identical or different heteroatoms 0, N, or S, the cycle optionally being substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle being fused onto this cycle,
• n 0, 1, 2 or 3
• R A 12 is hydrogen, a branched or unbranched, optionally substituted Ci-C ⁇ alkyl, -C-C 4 alkoxy, -O-alkylene-aryl or -O-aryl, a primary or optionally secondary or tertiary substituted amino radical , a C 2 -C 6 -alkynyl or C 2 -C 6 alkenyl radical which is optionally substituted by C 1 -C 4 -alkyl or aryl or one which is substituted by up to three identical or different radicals,
• 3-6 membered, saturated or unsaturated heterocycle which can contain up to three different or identical heteroatoms 0, N, S, C 3 -C 7 cycloalkyl, aryl or heteroaryl radical, where two radicals together form a fused, saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up to three different or identical heteroatoms 0, N, S, and the cycle may optionally be substituted or another, optionally substituted, saturated, unsaturated or aromatic cycle may be fused onto this cycle,
• R A 5 is a branched or unbranched, optionally substituted Ci-C ß- alkyl, arylalkyl, C 3 -C 7 cycloalkyl or -CC 6 alkyl-C 3 -C 7 cycloalkyl radical or an optionally substituted aryl,
• a 7 both radicals R A 6 and R A 6 * together one optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms 0, N, S,
• R A 7 is hydrogen, -OH, -CN, -C0NH 2 / a branched or unbranched, optionally substituted
• R A 8 is hydrogen, a branched or unbranched, optionally substituted C 1 -C 4 -alkyl, CO-C 1 -C 4 -alkyl, S0 2 -C 4 -C 4 -alkyl or CO-0-C 1 -C 4 -Alkylrest or an optionally substituted aryl, CO-aryl, S0 2 aryl, CO-0-aryl, CO-alkylene-aryl, S0 2 -alkylene-aryl, CO-0-alkylene-aryl or alkylene aryl,
• RA 9 , RA 10 independently of one another are hydrogen, -CN, halogen, a branched or unbranched, optionally substituted Ci-Cg-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C 3 -C 7 cycloalkyl radical or a residue C0-0-R A 14 , 0-R A 14 , SR A 14 , NR A 15 R A 16 or CO-NR A 15 RA 16 / or both residues R A 9 and R A 10 together in structural element I.
• a 14 is a 5 to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms 0, N, S and is optionally substituted with up to three identical or different radicals
• R A 11 is hydrogen, CN, halogen, a branched or unbranched, optionally substituted Ci-C ⁇ -alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C 3 -C 7 cycloalkyl radical or a radical CO-0-RA 14 , 0-R A 14 , SR A 14 , NR A 15 RA 16 or CO-NR A 15 R A 16 / R A 17 together in structural element I A 16 both radicals R A 9 and R A 17 together form a 5 to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms 0, N, S and optionally substituted with up to three identical or different radicals, R A
• Z 1 ' Z 2 ' Z 3 ' Z 4 independently of one another nitrogen, CH, C-halogen or a branched or unbranched, optionally substituted C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy radical /
• Halogen for R A 1 or R A 2 in the structural elements I 1 , I A 2 / I A 3 or I A 17 is understood independently of one another to mean fluorine, chlorine, bromine or iodine.
• a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical for R A 1 or R A 2 is understood independently of one another, for example, to be the corresponding radicals described above for R L 1 , preferably methyl or trifluoromethyl.
• the branched or unbranched, optionally substituted CO-Ci-C ⁇ - alkyl radical for R A 1 or R A 2 in the structural elements I A 1 , I A 2 , I A 3 or I A 17 is, for example, from the group CO and the above described for R A 1 or R 2 , branched or unbranched, optionally substituted C 1 -C 6 -alkyl radicals together.
• Optionally substituted aryl, arylalkyl or C 3 -C 7 cycloalkyl radicals for R A 1 or R A 2 are understood independently of one another, for example, to mean the corresponding radicals described above for R L 1 .
• Optionally substituted hetaryl or alkylhetaryl radicals for R A 1 or R A 2 in the structural elements I A 1 , I A 2 I A 3 or I A 17 are understood independently of one another, for example, to mean the corresponding radicals described above for RQ 9 .
• the optionally substituted radicals C0-0-R A 14 , 0-R A 14 , SR A 14 , NR A 15 R A 16 , CO-NR A 15 RA 16 or S0 2 NRA 15 R A 16 stand for R A 1 or R A 2, for example from the groups CO-0, 0, S, N, CO-N or S0 2 -N and the radicals R A 14 R A 15 and R A 16 described in more detail below.
• both radicals R A 1 and R A 2 together can contain an fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group 0, N, or S, form.
• R A 13 and R A 13 * independently of one another denote hydrogen, CN,
• Halogen such as fluorine, chlorine, bromine or iodine
• Ci-C ⁇ -alkyl such as described above for R A 1 R A 2 or, preferably methyl or trifluoromethyl, or
• Ci-Ce-alkyl under a branched or unbranched, optionally substituted Ci-Ce-alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 ⁇ alkenyl or C 2 -C 5 alkynyl radical for R A 14 in structural element A, for example corresponding radicals described above for R L 1 understood.
• a branched or unbranched, optionally substituted alkylene cycloalkyl or alkylene-C ⁇ -C4-alkoxy are understood for R A 14 in structural element A, for example, residues resulting from the above-described R 1, branched or unbranched, optionally substituted Ci- Compose C ⁇ -alkyl radicals and the optionally substituted C 3 -C 7 cycloalkyl radicals or -CC 4 alkoxy radicals.
• Optionally substituted aryl, arylalkyl, hetaryl or alkylhetaryl radicals for R A 14 in structural element A are understood to mean, for example, the corresponding radicals described above for R 1 or R A 2 .
• the branched or unbranched, optionally substituted CO-C 6 alkyl, S0 2 -C 6 C 6 alkyl, COO-C ! -C 6 -alkyl, COO-alkylene aryl or S0-alkylene-aryl radicals or the optionally substituted CO-aryl, S0 2 -aryl or CO-hetaryl radicals are for R A 15 or R A 16, for example, from the corresponding groups -CO-, -S02-, -COO- and the corresponding branched or unbranched, optionally substituted Ci-C ⁇ -alkyl or arylalkyl radicals described above or the corresponding optionally substituted aryl or heteroaryl radicals together.
• a radical - (CH 2 ) n - (X A ) JR A 12 for R A 3 or R A 4 is understood independently of one another to be a radical which is composed of the corresponding radicals - (CH 2 ) n -, (X A ) i and R A 12 together.
• N 0, 1, 2 or 3 and j: 0 or 1.
• X represents a double bonded radical selected from the group -S0 2 -, -S-, -0-, -CO-, -0-C0-, -CO-0-, -C0-N (R A 12 ) - , -N (R A 12 ) -CO-, -N (R A 12 ) -S0 2 - and -S0 2 -N (R A 12 ) -.
• R A 12 means hydrogen
• a primary or optionally secondary or tertiary substituted amino radical such as, for example, -NH 2 , -NH (-CC 6 alkyl) or -N (-C 6 -alkyl) 2, or in the case of a terminal, single-bonded radical R A 12 also, for example, the corresponding cyclic amines such as, for example, N-pyrrolidinyl, N-piperidinyl, N-hexahydro-a-pinyl, N-morpholinyl or N-piperazinyl, where the free amine protons in heterocycles, such as N-piperazinyl, carry the free amine protons by common Amine protecting groups such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, -S0 2 -C ⁇ ⁇ C 4 alkyl, -S0 2 -phenyl or -S0-benzyl can be replaced, a C 2 -C
• N such as 2-pyridyl, 3-pyridyl, 4- Pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-0xazolyl, 4-0xazolyl, 5-0xazolyl, 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, 5-pyrida
• the various residues can form an annealed system as generally described above.
• C 3 -C 7 cycloalkyl, aryl or heteroaryl radical as described, for example, above for R A 13 , where 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, saturated, unsaturated or aromatic cycle can be fused onto this cycle.
• R A 3 and R A 4 may also together form a 3 to 8-membered, saturated, unsaturated or aromatic N-heterocycle which may additionally contain two further, identical or different heteroatoms 0, N, or S, the cycle optionally being substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle may be fused onto this cycle,
• R A 5 represents a branched or unbranched, optionally substituted Ci-C ⁇ -alkyl, arylalkyl or C 3 -C 7 cycloalkyl radical as described for example for R 1 above or a C 1 -C 6 alkyl-C 3 -C cycloalkyl radical which is composed, for example, of the corresponding radicals described above.
• R A 6 and R A 6 * independently of one another denote hydrogen, a branched or unbranched, optionally substituted C 1 -C 4 -alkyl radical, such as optionally substituted methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1, 1-dimethylethyl,
• -CO-0-C 4 -alkyl or -C0-C-C 4 -alkyl radical such as composed, for example, of the group -CO-O- or -CO- and the above-described C 1 -C 4 -alkyl radicals,
• -CO-0-alkylene-aryl or -CO-alkylene-aryl radical such as, for example, composed of the group -CO-O- or -CO- and the arylalkyl radicals described above,
• both radicals R A 6 and R A 6 * in structural element I A 7 together can form an optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S ,
• R A 7 is hydrogen, -OH, -CN, -CONH 2 / a branched or unbranched, optionally substituted C 1 -C 4 -alkyl radical, for example as described above for R A S , -C 4 -alkoxy-, arylalkyl or C 3 -C 7 cycloalkyl, for example as described above for R L 1 , a branched or unbranched, optionally substituted -0-CO -CC 4 -alkyl radical, which is selected from the group -0-C0- and for example composed of the above-mentioned C ⁇ C-alkyl radicals or an optionally substituted -O-alkylene-aryl, -O-CO-aryl, -O-CO-alkylene-aryl or -O-CO-allyl radical resulting from the Groups -0- or -0-C0- and composed for example of the corresponding radicals described above for R L 1 .
• both radicals R A 6 and R A 7 together can form an optionally substituted, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms 0, N, S.
• Halogen for R A 9 or R A 10 is understood independently of one another to mean fluorine, chlorine, bromine or iodine.
• each of R A 9 or R A 10 is independently, for example, the corresponding, radicals described above for R A 14 are understood, preferably methyl or trifluoromethyl.
• NR A 15 R A 16 are each independently understood for R A 9 or R A 10, for example, the corresponding radicals described above for R 13 .
• both radicals R A 9 and R A 10 together in structural element I A 14 can form a 5 to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms 0, N, S and optionally with up to is substituted to three identical or different radicals.
• Halogen means for R A 11, for example, fluorine, chlorine, bromine or iodine.
• Ci-C ⁇ alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C 3 -C cycloalkyl radical or a radical C0-0-R A 14 , 0-R A 14 , SR A 14 , NR A 15 R A 16 or CO-NR A 15 R A 16 are understood for R A 11, for example, the corresponding radicals described above for R A 9 .
• both radicals R A 9 and R A 17 together can form a 5 to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms 0, N, S and optionally with up to three identical or different radicals are formed.
• Z 1 ' Z 2 ' Z 3 ' Z 4 independently of one another are nitrogen, CH, C-halogen, such as CF, C-Cl, C-Br or CI or a branched or unbranched, optionally substituted C 1 -C 4 -C 4 - Alkyl radical which is composed of a carbon radical and, for example, a C 1 -C 4 -alkyl radical described above for R A 6 or a branched or unbranched, optionally substituted C 1 -C 4 -alkoxy radical # which consists of a carbon radical and, for example, a C 1 -C 4 alkoxy radical described above for R A 7 is composed.
• C-halogen such as CF, C-Cl, C-Br or CI or a branched or unbranched
• optionally substituted C 1 -C 4 -C 4 - Alkyl radical which is composed of a carbon radical and, for example, a C 1 -C 4 -alkyl radical described
• Z 5 means oxygen, sulfur or a radical NR A 8 .
• Preferred structural elements A are composed of the preferred residues of the structural element.
• Particularly preferred structural elements A are composed of the particularly preferred residues of the structural element.
• the spacer structural element E is understood to mean a structural element that consists of a branched or unbranched, optionally substituted and heteroatom-containing aliphatic C 2 -C 3u hydrocarbon radical and / or of a 4- to 20-membered, optionally substituted and heteroatom-containing, aliphatic or aromatic mono- or polycyclic hydrocarbon radical.
• Spacer structural element E from two to four partial structural elements, selected from the group E 1 and E 2 together, the order in which the partial structural elements are linked is arbitrary and E 1 and E 2 have the following meaning:
• E 1 is a substructure element of the formula IEI
• CR E 10 CRE I: L , CR E 10 (OR E 12 ) -CRE 1: L , CR E 10 -CR E 11 (OR E 12 ) or an optionally substituted 4 to 11-membered ono- or polycyclic aliphatic or aromatic hydrocarbon containing up to 6 double bonds and up to 6 heteroatoms, selected from the group N, 0, S, can contain
• R E 1, R E 2, R E 4, R E 5, 6 RE / RE 7 are independently hydrogen, halogen, a hydroxy group, a branched or unbranched, optionally substituted Ci-Cg-alkyl,
• w 0, 1, 2, 3 or 4
• R E 3 , R E 8 , R E 9 independently of one another are hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, CO-C 1 -C 6 -alkyl, CO-0-C 1 -C 6 -alkyl or S0-C 1 -C 6 -alkyl radical or an optionally substituted C 3 -C 7 cycloalkyl- , CO-0-alkylene-aryl, CO-alkylene-aryl, CO-aryl, S0 2 -aryl, CO-hetaryl or S0 2 -alkylene-aryl radical,
• R E 12 is hydrogen, a branched or unbranched, optionally substituted -CC 6 alkyl, C 2 -C 6 alkenyl, CC 6 alkynyl or alkylene cycloalkyl radical or an optionally substituted C 3 -C 7 cycloalkyl radical , Aryl, arylalkyl, hetaryl or
• R E 13 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C 1 -C 6 alkyl, C 1 -C alkoxy, arylalkyl, O-alkylene
• C 3 -C 7 cycloalkyl, aryl or heteroaryl radical where two radicals together can represent an fused, saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up to three different or identical heteroatoms 0, N, S, and Cycle optionally substituted or another, optionally substituted, saturated, unsaturated or aromatic cycle may be fused onto this cycle,
• the structural element E is a structural element of the formula I EIE2
• an optionally substituted 4 to 11-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 heteroatoms, selected from the group N, 0, S, E and X are for Q.
• E independently of one another, preferably optionally substituted aryl, such as, for example, optionally substituted phenyl or naphthyl, optionally substituted hetaryl such as, for example, the radicals
• the remnants can be installed in both orientations.
• Z 6 and Z 7 independently of one another represent CH or nitrogen.
• Z 8 means oxygen, sulfur or NH
• Z 9 means oxygen, sulfur or NR E 16 .
• r and t are independently 0, 1, 2 or 3.
• s and u are independently 0, 1 or 2.
• R E 14 and RE 15 independently of one another are hydrogen, -N0 2 , -NH 2 , -CN, -COOH, a hydroxyl group, halogen, a branched or unbranched, optionally substituted Ci-C ⁇ -alkyl-, -C-C -alkoxy- , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or alkylene cycloalkyl radical or an optionally substituted cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, as described in each case above.
• R E 16 independently represents hydrogen, a branched or unbranched, optionally substituted C ⁇ -C6 alkyl, C ⁇ -C 6 alkoxyalkyl, C 3 -C x2 alkynyl, CO-C ⁇ -C 6 alkyl, CO-O-Ci-C ß -alkyl- or S0 2 -C ⁇ -C 6 -alkyl radical or an optionally substituted C 3 -C 7 -cycloalkyl-, aryl, arylalkyl-, CO-O-alkylene-aryl-, CO- alkylene-aryl, CO-aryl, S0 2 aryl, hetaryl, CO-hetaryl or S0 2 -alkylene-aryl group, preferably hydrogen or a branched or unbranched, optionally substituted C-C alkyl ⁇ .
• Preferred radicals for RE 1 are hydrogen, fluorine, chlorine or a radical - (CH 2 ) W -R E 13 , where w is 0, 1, 2, 3 or 4.
• Preferred radicals for RE 2 are hydrogen, halogen, particularly preferably chlorine or fluorine, a hydroxyl group or a branched or unbranched, optionally substituted C 1 -C 6 -alkyl or C 1 -C 4 -alkoxy radical, particularly preferably methyl or ethyl.
• the two radicals R E 1 and R E 2 together form a 3 to 7-membered, optionally substituted, saturated, unsaturated or aromatic carbocycle.
• R E 4 and R E 6 and for R E 5 and R E 7 are each independently the same as the corresponding radicals mentioned above for RE 1 and R E 2 .
• radicals RE 4 and R E 5 or R E 6 and R E 7 together form a 3 to 7-membered, optionally substituted carbocycle.
• Preferred radicals for R E 3 are hydrogen or a branched or unbranched, optionally substituted Ci-C ß- alkyl radical, particularly preferably methyl.
• Preferred radicals for R E 8 and R E 9 are independently hydrogen, a branched or unbranched, optionally substituted C ! -C-alkyl-, C 3 -C 7 -cycloalkyl-, CO-C ⁇ -C 4 -alkyl-, CO-0-alkylene-aryl-, particularly preferably CO-0-benzyl-, CO-alkylene-aryl-, particularly preferably CO-phenyl, CO-OC 1 -C 4 - alkyl, S0 2 -C ⁇ -C 4 alkyl, S0 2 aryl, more preferably tosyl or S0 -alkylene-aryl group.
• Preferred radicals for R 10 and R E E 11 are independently hydrogen, a hydroxy group, a branched or unbranched ter, optionally substituted Ci-C ⁇ -alkyl, particularly preferably C ⁇ -C 4 alkyl, or C ⁇ -C 4 Alkoxy radical or an optionally substituted aryl, arylalkyl, hetaryl or hetarylalkyl radical.
• Preferred radicals for R E 12 are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical or an optionally substituted arylalkyl or hetarylalkyl radical.
• a branched or unbranched Cx-C ß alkyl is under R E 13, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2 -Methylbutyl, 1, 2-Dirnethylpropyl, 1, 1-Dimethylpropyl, 2, 2-Dimethylpropyl, 1-Ethylpropyl, Hexyl, 1-Methylpentyl, 1,2-Dirnethylbutyl, 1, 3-Dirnethylbutyl, 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
• R E 13 is, for example, methoxy, ethoxy, propoxy, 1-methylthoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy, in particular methoxy, Understood ethoxy or 1-methylethoxy.
• -O-alkylene-aryl or -O-aryl radicals are, for example, -O-phenyl, -O-1-naphthyl, -O-2-naphthyl or -O-benzyl.
• Ci-C ß- alkyl, -CC 4 alkoxy radicals of R E 13 can be substituted with up to five identical or different substituents, as described above.
• Substituted -O-alkylene-aryl or -O-aryl radicals are understood to mean, for example, the aforementioned -O-alkylene-aryl or -0-aryl radicals, the aryl part being substituted with up to three identical or different substituents, as described at the outset can.
• a primary amino radical -NH 2 a secondary amino radical -NH (R E 131 ) or a tertiary amino radical -N (R E 131 ) (R E 132 ) is under R E 13 in structural element L. ) understood, whereby
• R E 131 and E 132 R independently C ⁇ -C ⁇ 4 alkyl or C 3 -C 6 -cycloalkyl as mentioned above, optionally substituted aryl, preferably phenyl, arylalkyl, benzyl, -C0-C ⁇ -C 4 preferably - Alkyl, preferably -C0-CH 3 or -CO-aryl, preferably -CO-phenyl.
• R E 13 represents one of the heterocycles described below which is bonded via the ring nitrogen.
• C 2 -C 6 -alkynyl radicals are, for example ethynyl, 2-propynyl , 2-butynyl, 3-butynyl, 1-methyl, 2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-3-butynyl, 2-methyl-3-butynyl, l-methyl- 2-butynyl, 1, l-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, l-methyl-2-pentynyl, l-methyl- 2-pent
• C 2 -C 6 alkenyl such as vinyl, 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, 1,2-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-3-pentenyl, 4-methyl-3-penten
• C 1 -C 4 alkyl radicals or aryl radicals as mentioned above, preferably phenyl, such as preferably phenylethynyl or phenylethenyl.
• a C 5 -C bicycloalkyl radical for R E 13 means, for example, indanyl, norbornyl or camphyl, a Cg-Ci ⁇ -tricycloalkyl radical, for example, adamantyl.
• the residue CO-OR A 14 is composed, as mentioned several times above, from the group CO-O and the residue R A 14 described above for structural element A.
• 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 form a fused,
• 3- to 7-membered, 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 E 13 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 heterocycles carry the free amine protons, such as N-piperazinyl, the free amine protons by common amine protecting groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, -S0 2 -C ⁇ - C 4 alkyl, -S0 2 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, 2-0xazolyl, 4-0xazolyl, 5-0xazolyl, 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-pyri
• heterocycles, C 3 -C 7 cycloalkyl, aryl and heteroaryl radicals can optionally be substituted with up to three identical or different radicals.
• Preferred substituents of the heterocycles, C 3 -Cs-cycloalkyl, aryl and heteroaryl radicals for R E 13 are -C-C-alkyl, -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 , -N-pyrrolidinyl-, -N-piperidinyl, -N-morpholinyl, - N-piperazinyl, -NH--C-C 4 alkyl, -N (-C-C 4 alkyl), F, Cl, Br or I.
• Preferred substituents of the heterocycles, C 3 -C 8 cycloalkyl, aryl and heteroaryl radicals for R E 13 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 E 13 are, for example, the corresponding dioxolanyls, benzopyrrolyls, benzofuryls, benzothienyls or fluorenyls.
• Preferred structural elements E are composed of the preferred radicals for structural element E.
• Preferred structural elements B are composed of the preferred structural elements A and E.
• 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 B or A are also suitable which release the structural element B or A under physiological conditions.
• one of the three structural elements B, G or L has the preferred range, while the remaining structural elements are widely variable.
• two of the three structural elements B, G or L each have the preferred range, while the remaining structural elements are widely variable.
• Preferred compounds of the formula I have, for example, the preferred structural element G, while the structural elements B and L are widely variable.
• the structural elements B and L are widely variable.
• the compounds for example B is replaced by the structural element AE- and the compounds have, for example, the preferred structural element G and the preferred structural element A, while the structural elements E and L are widely variable.
• each line represents a connection.
• the abbreviations in the right column stand for a structural element A, EG and L, separated by a dash, whereby the abbreviations have the following meaning:
• the conversion to III is carried out by hydrogenation of the double bond under standard conditions. Use can also be made of variants which are known per se and are not mentioned here.
• the hydrogenation is preferably carried out in the presence of a noble metal catalyst, such as, for example, Pd on activated carbon, Pt, Pt0 2 , Rh on Al 2 0 3 in an inert solvent at a temperature of 0-150 ° C. and a pressure of 1-200 bar ; the addition of an acid such as acetic acid or hydrochloric acid can be advantageous. Hydrogenation in the presence of 5-10% Pd on activated carbon is particularly preferred.
• solvents for example hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; Glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; Ketones such as acetone, butanone; Amides such as dimethylformamide (DMF), dirthylacetamide or ace
• Compounds of type IV are prepared by reaction with compounds of the general formula AEU E (VI), where the radical U E represents a customary leaving group, for example halogen such as chlorine, bromine, iodine or one, optionally by halogen, alkyl or Haloalkyl-substituted aryl or alkylsulfonyloxy radical, such as, for example, toluenesulfonyloxy, trifluoromethanesulfonyloxy and methylsulfonyloxy or another equivalent leaving group.
• halogen such as chlorine, bromine, iodine or one
• alkyl or Haloalkyl-substituted aryl or alkylsulfonyloxy radical such as, for example, toluenesulfonyloxy, trifluoromethanesulfonyloxy and methylsulfonyloxy or another equivalent leaving group.
• the reaction preferably takes place in an inert solvent with the addition of a suitable base, i.e. a base, which brings about a deprotonation of the intermediate III, takes place in a temperature range from -40 ° C. to the boiling point of the corresponding solvent.
• a suitable base i.e. a base, which brings about a deprotonation of the intermediate III, takes place in a temperature range from -40 ° C. to the boiling point of the corresponding solvent.
• an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, for example sodium or potassium carbonate, an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an alcoholate such as sodium methoxide, potassium tert-butoxide, one organometallic compound such as butyllithium or alkali amides such as lithium diisopropylamide, lithium, sodium or potassium bis (trimethylsilyl) amide are used.
• a carbonate such as alkali metal carbonate, for example sodium or potassium carbonate
• an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide
• an alcoholate such as sodium methoxide, potassium tert-butoxide
• one organometallic compound such as butyllithium or alkali amides such as lithium diisopropylamide, lithium, sodium or potassium bis (trimethylsilyl)
• compounds of type I can also be prepared via V as an intermediate, here too using reaction conditions as are known to the person skilled in the art and are described in standard works.
• Compound V is prepared by reacting compounds of type III with compounds of the general formula D E -EU E (VII) under reaction conditions as have already been described for the preparation of IV.
• U E stands for a suitable leaving group, as described above and D E for CN, or a protected amino or acid function of the general formula NSG 3 or COOSG 2 .
• the fragments D E -E and AE are built up - depending on the actual structure of E - by splitting off the protective groups and coupling the remaining fragments using standard methods, for example amide couplings.
• A is then introduced analogously to the reactions described in Schemes 3-7.
• Type I compounds in which X G represents N can be prepared according to Scheme 2.
• the amide couplings mentioned can be carried out using conventional coupling reagents using suitably protected amino and carboxylic acid derivatives.
• Another method consists in the use of preactivated carboxylic acid derivatives, preferably carboxylic acid halides, symmetrical or mixed anhydrides or so-called active esters, which are usually used for the acylation of amines. These activated carboxylic acid derivatives can also be produced in situ.
• the couplings can generally be carried out in inert solvents in the presence of an acid-binding agent, preferably an organic base such as triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, quinoline; the addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium, can also be favorable.
• an acid-binding agent preferably an organic base such as triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, quinoline
• an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals preferably potassium, sodium, calcium or cesium
• the reaction time is between minutes and 14 days
• the reaction temperature is between -40 ° C and 140 ° C, preferably between -20 ° C and 100 ° C.
• Suitable inert solvents are e.g. Hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert.
• Hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene
• chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane
• Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert.
• Butanol Ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; Glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; Ketones such as acetone, butanone; Amides such as dimethylformamide (DMF), dimethyl acetamide or acetamide; Nitriles such as acetonitrile; Sulfoxides such as dirnethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1, 3-dimethyltetrahydro-2 (IH) pyrimidinone (DMPU), 1, 3-dimethyl-2-imidazolidinone, nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate (ethyl acetate), water; or mixtures of the solvents mentioned
• Protective groups SG which can be used are all of the usual protective groups known to the person skilled in the art from peptide synthesis, as are also described in the above-mentioned standard works.
• the protective groups in the compounds of the formulas IV, V, VI and VII are also split off under conditions known to those skilled in the art and, for example, from Greene and Wuts in "Protective Groups in Organic Synthesis", 2nd Edition, Wiley & Sons, 1991 , are described.
• Protecting groups such as SG 3 are so-called N-terminal amino protecting groups; Boc, Fmoc, benzyloxycarbonyl (Z), acetyl or Mtr are preferred here.
• SGi and SG 2 stand for so-called C-terminal hydroxy protecting groups, preference is given here to C 1 -C 4 -alkyl, such as methyl, ethyl, tert-butyl, or also benzyl or trityl, or polymer-bound protective groups in the form of the commercially available poly- styrene resins such as 2-chlorotrityl chloride resin or Wang resin (Bachern, Novabiochem).
• C 1 -C 4 -alkyl such as methyl, ethyl, tert-butyl, or also benzyl or trityl, or polymer-bound protective groups in the form of the commercially available poly- styrene resins such as 2-chlorotrityl chloride resin or Wang resin (Bachern, Novabiochem).
• acid-labile protective groups e.g. Boc, tert-butyl, Mtr, trityl
• organic acids such as trifluoroacetic acid (TFA), trichloroacetic acid, perchloric acid, triflurethanol; but also inorganic
• Acids such as hydrochloric acid or sulfuric acid, sulfonic acids such as benzene or p-toluenesulfonic acid take place, the acids being generally used in excess.
• sulfonic acids such as benzene or p-toluenesulfonic acid
• trityl the addition of thiols such as e.g. Thioanisole or thiophenol may be beneficial.
• the presence of an additional inert solvent is possible, but not always necessary.
• Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid; Ethers such as THF or dioxane; A ide like DMF or dimethylacetamide; halogenated hydrocarbons such as dichloromethane; Alcohols such as methanol, isopropanol; or water. Mixtures of the solvents mentioned are also suitable.
• the reaction temperature for these reactions is between 10 ° C and 50 ° C, preferably in a range between 0 ° C and 30 ° C.
• Base-labile protective groups such as Fmoc are cleaved as a 5-50% solution in CH 2 C1 2 or DMF by treatment with organic amines such as dirnethylamine, diethylamine, morpholine, piperidine.
• the reaction temperature for these reactions is between 10 ° C and 50 ° C, preferably in a range between 0 ° C and 30 ° C.
• Acid protecting groups such as methyl or ethyl are preferably cleaved by basic hydrolysis in an inert solvent.
• Alkali or alkaline earth metal hydroxides preferably NaOH, KOH or LiOH, are preferably used as bases;
• solvents such as hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene are used as solvents; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert.
• hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene are used as solvents
• chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane
• Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert.
• Protective groups which can be split off hydrogenolytically such as benzyloxycarbonyl (Z) or benzyl can e.g. by hydrogenolysis in the presence of a catalyst (e.g. a noble metal catalyst supported on activated carbon).
• a catalyst e.g. a noble metal catalyst supported on activated carbon.
• Suitable solvents are those given above, in particular alcohols such as methanol, ethanol; Amides such as DMF or dimethylacetamide; Esters such as ethyl acetate.
• Hydrogenolysis is generally carried out at a pressure of 1 to 200 bar and temperatures between 0 ° C and 100 ° C; the addition of an acid such as Acetic acid or hydrochloric acid can be beneficial. 5 to 10% Pd on activated carbon is preferably used as the catalyst.
• Type E blocks are generally constructed using methods known to those skilled in the art; the building blocks used are either commercially available or accessible using methods known from the literature. The synthesis of some of these building blocks is described in the experimental section.
• the radical E can be derived from amino-hetarylcarboxylic acids, amino-hetarylcarboxylic acid esters via compounds of the types VI-VII or nitriles are built up according to methods known and described by the person skilled in the art. A large number of production methods are described in detail in Houben-Weyl's "Methods of Organic Chemistry" (vol. E6: furans, thiophenes, pyrroles, indoles, benzothiophenes, furans, pyrroles; vol. E7: quinolines, pyridines, vol.
• E8 isoxazoles , Oxazoles, thiazoles, pyrazoles, imidazoles and their benzo-fused representatives, and oxadiazoles, thiadiazoles and triazoles;
• Vol. E9 pyridazines, pyrimidines, triazines, azepines and their benzo-fused representatives and purines).
• the sales Depending on the structure of E, these fragments can be linked to E via the amino or acid function by methods which are known to the person skilled in the art.
• W E means COOSG or NSG 3
• Urea or thiourea (AE-1 to AE-3) can be produced using common organic chemistry methods, e.g. by reacting an isocyanate or a thioisocyanate with an amine, optionally in an inert solvent with heating (Houben-Weyl Volume VIII, 157ff.) (Scheme 3).
• Scheme 4 shows an example of the representation of compounds of the type AE-4, e.g. by Blakemoore et al. in Eur.
• Guanidine derivatives of the general formulas AE-5 and AE-6 can be prepared using commercially available or easily accessible reagents, as described, for example, in Synlett 1990, 745, J. Org. Chem. 1992, 57, 2497, Bioorg. Med. Chem. 1996, 6, 1185-1208; Bioorg. Med. Chem. 1998, 1185, or Synth. Comm. 1998, 28, 741-746.
• AE-13 Compounds of the general formula AE-13 can be analogous to Froeyen et al. , Phosphorus Sulfur Silicon Relat. Eggs. 1991, 63, 283-293, AE-14 analogous to Yoneda et al., Heterocycles 1998, 15 N ° -l, Spec. Prepare Issue, 341-344 (Scheme 7). Corresponding connections can also be represented analogously to WO 97/36859.
• the invention further relates to the use of the structural element of the formula IQ L
• the invention further relates to medicaments containing the structural element of the formula I GL -
• the invention further relates to pharmaceutical preparations for oral and parenteral use, containing, in addition to the usual pharmaceutical excipients, at least one compound of the formula I.
• the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intra-perotoneal). It can also be applied with vapors or sprays through the nasopharynx.
• the dosage depends on the age, condition and weight of the patient and on the type of application.
• the daily dose of active substance is between approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.
• the new compounds can be used in the customary pharmaceutical application forms, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
• the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al .: Pharmaceuticals Technology, Thieme-Verlag, Stuttgart, 1991).
• the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
• the invention further relates to the use of the compounds of the formula I for the production of medicaments for the treatment of diseases.
• the compounds of formula I can be used for the treatment of human and animal diseases.
• the compounds of formula I bind to integrin receptors. They are therefore preferably suitable as integrin receptor ligands and for the production of medicaments for the treatment of diseases in which an integrin receptor is involved.
• the compounds of the formula I preferably bind to the ⁇ v ß 3 integrin receptor and can thus be used particularly preferably as ligands of the Otvß integrin receptor and for the treatment of diseases in which the 0Cvß 3 integrin receptor is involved.
• They can preferably be used for the manufacture of medicaments for the treatment of diseases in which, for example, the interaction between the ⁇ vß 3 ⁇ integrin receptor and its natural ligands is excessive.
• the compounds of the formula I are preferably used to influence metabolic processes or regulatory mechanisms which are based on certain diseases, such as, for example, the inhibition of angiogenesis or for the treatment of the following diseases:
• Cardiovascular diseases such as atherosclerosis, restenosis after vascular injury, and angioplasty (neointima formation, smooth muscle line migration and proliferation),
• Angiogenesis-associated microangiopathies such as diabetic retinopathy or rheumatic arthritis
• Cancer such as tumor metastasis or tumor growth (tumor-induced angiogenesis),
• Osteoporosis bone resorption after proliferation, chemotaxis and adhesion of osteoclasts to bone matrix
• Hypertension psoriasis, hyperparathyroism, Paget's disease, malignant hypercalcemia, metastatic osteolytic lesions, inflammation, wound healing, heart failure, CHF, and at
• Methyl [5- (2-tert-butoxy-2-oxoethyl) -6-oxo-6, ll-dihydrosif-di-benzo [b, e] azepin-11-yl] acetate 2 (30.5 g , 77.5 mmol) were taken up in 100 ml of CH 2 C1 2 , 150 ml of TFA were added at 0 ° C. and stirred for about 1 h at 0 ° C and then at RT. After the reaction had ended, the mixture was evaporated, toluene was added twice and the mixture was again evaporated. 33.6 g of a yellowish oil were obtained as the crude product, crystallization from acetone gave 14.8 g of white solid.
• the A in required for further reaction was obtained by cleavage of the Boc group with TFA (under standard conditions); the isolated TFA salts were then used directly in the corresponding couplings.
• the amine required for further reaction was obtained by splitting off the Boc group with TFA (under standard conditions); the isolated TFA salts were then used directly in the corresponding 30 couplings.
• the amine required for further reaction was obtained by splitting off the Boc group with TFA (under standard conditions); the isolated TFA salts were then used directly in the corresponding couplings.
• the amine required for further reaction was obtained by splitting off the Boc group with TFA (under standard conditions); the isolated TFA salts were then used directly in the corresponding couplings.
• the thioamide (6 g; 16.37 mmol) was suspended in 40 ml CH 2 C1 2 , 22.3 g CH 3 I was added and the mixture was stirred at RT overnight. The mixture was then evaporated, taken up in 20 ml of CH 3 OH, 1,2-phenylenediamine (1.95 g; 18.01 mmol) was added and the mixture was stirred again at RT overnight. Concentration of the mixture gave 6 g as a yellow solid.
• the tert-butyl (4-cyanothien-2-yl) methyl carbamate used as starting material was prepared from 5- (aminomethyl) -3-thiophene carbonitrile (WO 98/06741) by standard methods.
• the preparation was carried out analogously to 44 starting from 5- (aminomethyl) thiophene-2-carbonitrile (preparation according to WO 95/23609).
• the crude product obtained after TFA cleavage was dissolved in water, extracted twice with diethyl ether, the aqueous phase brought to pH 10-11 and then extracted twice with ethyl acetate.
• the aqueous phase was saturated with NaCl and extracted again with ethyl acetate.
• DIPEA ethyldiisopropylamine (0.45 g) and after about 2 h (2-pyridinyl) piperazines (0.57 g; 3.54 mmol) were added. The mixture was then stirred at RT.
• Boc-piperazine (1.37 g) was added and the mixture was stirred at 0 ° C. for 1 h and then at RT. For working up, it was diluted with CH 2 C1 2 , with sat. NaCl solution. washed, dried and concentrated. The crude product obtained (3.2 g) was purified by chromatography on silica gel (CH 2 C1 2 / CH 3 0H 1 to 3% + 0.1% acetic acid).
• the methyl ester was saponified analogously to the examples already described in 20 ml of dioxane / H 2 ⁇ 3: 1 with 80 mg of KOH at RT. Processing and purification of the crude product by MPLC (silica gel: Bischoff Prontoprep 60-2540-C18E, 32 ⁇ m; eluent: CH 3 CN / H 2 0 + 0.1% acetic acid) gave 0.22 g of the desired product.
• ESI-MS [M + H +] 537.15;
• Example IB33 35 ⁇ 5- [3- ( ⁇ [4- (ltf-benzimidazol-2-yl) thien-2-yl] methyl ⁇ amino) -3-oxopropyl] -6-oxo-6, ll- dihydro-5H-dibenzo [jb, e] azepin-11-yl ⁇ acetate

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