US20040077638A1 - Novel integrin receptor antagonists - Google Patents

Novel integrin receptor antagonists Download PDF

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US20040077638A1
US20040077638A1 US10/344,449 US34444903A US2004077638A1 US 20040077638 A1 US20040077638 A1 US 20040077638A1 US 34444903 A US34444903 A US 34444903A US 2004077638 A1 US2004077638 A1 US 2004077638A1
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radical
alkyl
optionally substituted
aryl
hydrogen
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Herve Geneste
Andreas Kling
Arnulf Lauterbach
Claudia Graef
Thomas Subkoski
Wilfried Hornberger
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BASF SE
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Priority claimed from PCT/EP2001/009224 external-priority patent/WO2002014320A2/en
Assigned to BASF AKTIENGESELLCHAFT reassignment BASF AKTIENGESELLCHAFT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HORNBERGER, WILFRIED, GRAEF, CLAUDIA ISABELLA, KLING, ANDREAS, LAUTERBACH, ARNULF, SUBKOWSKI, THOMAS, GENESTE, HERVE
Publication of US20040077638A1 publication Critical patent/US20040077638A1/en
Priority to US12/396,698 priority Critical patent/US20100048536A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to novel compounds which bind to integrin receptors, their use as ligands of integrin receptors, in particular as ligands of the ⁇ v ⁇ 3 integrin receptor, and pharmaceutical preparations comprising these compounds.
  • Integrins are cell surface glycoprotein receptors which mediate interactions between identical 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 the tissue architecture.
  • Disturbances in the gene expression of cell adhesion molecules and functional disorders of the receptors can contribute to the pathogenesis of many disorders, such as tumors, thromboembolic events, cardiovascular disorders, lung diseases, disorders of the CNS, the kidney, the gastrointestinal tract or inflammations.
  • Integrins are heterodimers of an ⁇ - and a ⁇ -transmembrane subunit in each case, which are noncovalently bonded.
  • 16 different ⁇ - and 8 different ⁇ -subunits and 22 different combinations have been identified.
  • Integrin ⁇ v ⁇ 3 also called the vitronectin receptor, mediates adhesion to a multiplicity of ligands—plasma proteins, extracellular matrix proteins, cell surface proteins-, of which the majority contain the amino acid sequence RGD (Cell, 1986, 44, 517-518; Science 1987, 238, 491-497), such as vitronectin, fibrinogen, fibronectin, von Willebrand factor, thrombospondin, osteopontin, laminin, collagen, thrombin, tenascin, MMP-2, bone sialoprotein II, various viral, fungal, such as the surface molecules of Candida albicans , parasitic and bacterial proteins, natural integrin antagonists such as disintegrins, neurotoxins—mambin—and blood fluke proteins—decorsin, ornatin—and also some non-RGD ligands, such as Cyr-61 and PECAM-1 (L. Piali, J. Cell Biol. 1995, 130, 451-460; Buckley, J
  • integrin ⁇ IIb ⁇ 3 also called the platelet fibrinogen receptor, recognizes fibronectin, vitronectin, thrombospondin, von Willebrand factor and fibrinogen.
  • Integrin ⁇ v ⁇ 3 is expressed, inter alia, on endothelial cells, blood 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.
  • Increased expression is observed under various pathological conditions, such as in the prothrombotic state, in vascular injury, tumor growth or metastasis or reperfusion and on activated cells, in particular on endothelial cells, smooth muscle cells or macrophages.
  • cardiovascular disorders such as atherosclerosis, restenosis after vascular injury, and angioplasty (neointima formation, smooth muscle cell migration and proliferation) (J. Vasc. Surg. 1994, 19, 125-134; Circulation 1994, 90, 2203-2206),
  • angiogenesis-associated microangiopathies such as diabetic retinopathy or rheumatoid 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),
  • carcinomatous disorders such as in tumor metastasis or in 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
  • pathogenic protein e.g. HIV-1 tat
  • processes e.g. angiogenesis, Kaposi's sarcoma
  • Advantageous ⁇ v ⁇ 3 integrin receptor ligands bind toe the integrin ⁇ v ⁇ 3 receptor with an increased affinity.
  • integrin receptor ligands In contrast to integrin ⁇ v ⁇ 3 , particularly advantageous ⁇ v ⁇ 3 integrin receptor ligands additionally have an increased selectivity and are less active with respect to the integrin ⁇ IIb ⁇ 3 by at least a factor of 10, preferably at least a factor of 100.
  • Antagonists of the ⁇ v ⁇ 3 integrin receptor based on a tricyclic structural element having a heptacycle are described in WO 9906049, WO 9911626 and WO 9701540.
  • EP 889037 describes tricyclic allergy inhibitors.
  • L is a structural element of the formula I L
  • T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and
  • -U- is —(X L ) a —(CR L 1 R L 2 ) b —, —CR L 1 ⁇ CR L 2 —, ethynylene or ⁇ CR L 1 —, where
  • a is 0 or 1
  • b is 0, 1 or 2
  • X L is CR L 3 R L 4 , NR L 5 , oxygen or sulfur,
  • [0045] independently of one another are hydrogen, -T, —OH, —NR L 6 R L 7 , —CO—NH 2 , a halogen radical, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, —CO—NH(C 1 -C 6 -alkyl), —CO—N(C 1 -C 6 -alkyl) 2 or C 1 -C 4 -alkoxy radical, an optionally substituted radical C 1 -C 2 -alkylene-T, C 2 -alkenylene-T or C 2 -alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals R L 1 and R L 2 or R L 3 and R L 4 or optionally R L 1
  • [0047] independently of one another are hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, CO—O—C 1 -C 6 -alkyl, SO 2 —C 1 -C 6 -alkyl or CO—C 1 -C 6 -alkyl radical or an optionally substituted CO—O-alkylenearyl, SO 2 -aryl, CO-aryl, SO 2 -alkylenearyl or Co-alkylenearyl radical,
  • G is a structural element of the formula I G
  • the structural element B is bonded via Ar and the structural element L is bonded via X G to the structural element G by means of a single bond or a double bond and
  • Ar is a fused, aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to'four different or identical heteroatoms O, N, S and is optionally substituted by up to 4 substituents,
  • D G is an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S,
  • X G is CR G 1 or nitrogen, in the case of a single bond to structural element L, or
  • W G is —Y G —N (R G 5 ) or —N(R G 5 )—Y G —,
  • Y G is CO, CS, C ⁇ NR G 2 or CR G 3 R G 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,
  • R G 2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 7 -cycloalkyl or —O—C 3 -C 7 -cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical,
  • R G 3 , R G 4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or C 1 -C 4 -alkoxy radical or both radicals
  • R G 3 and R G 4 together are a cyclic acetal —O—CH 2 —CH 2 —O— or —O—CH 2 —O— or both radicals
  • R G 3 and R G 4 together are an optionally substituted C 3 -C 7 -cycloalkyl radical
  • R G 5 is a radical R G 5A or a radical C 0 -C 6 alkylene-R G 5B , C 2 -C 4 -alkenylene-R G 5B , C 2 -C 4 -alkynylene-R G 5B , C 1 -C 6 -oxoalkylene-R G 5B , C 2 -C 4 -oxoalkenylene-R G 5B , C 2 -C 4 -oxoalkynylene-R G 5B , C 1 -C 4 -aminoalkylene-R G 5B , C 2 -C 4 -aminoalkenylene-R G 5B , C 2 -C 4 -aminoalkynylene-R G 5B , C 2 -C 4 -alkylene-R G 5B , optionally substituted by one or more radicals selected from the group consisting of R G 5A and R G 5C ,
  • R G 5A is a radical COR G 5G , COC(R G 5E ) 2 (R G 5H ), CSR G 5G , S(O) g1 —OR G 5E , S(O) g1 —N(R G 5E )(R G 5F ), PO(OR G 5E ), PO(OR G 5E ) 2 , B(OR G 5E ) 2 , NO 2 or tetrazolyl,
  • R G 5B is hydrogen or an optionally substituted C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloheteroalkyl, aryl or hetaryl radical,
  • R G 5C is hydrogen, halogen, CN, NO 2 , OR G 5D , CF 3 , or a radical N(R G 5E )(R G 5D ), CF 3 S(O) g2 , CO 2 R G 5E , CO—N(R G 5E ) 2 , C 0 -C 6 -alkylene-R G 5B , C 1 -C 6 -oxoalkylene-R G 5B , C 2 -C 4 -alkenylene-R G 5B or C 2 -C 4 -alkynylene-R G 5B ,
  • R G 5D is a radical R G 5E , —CO—R G 5E , CO—OR G 5J , CO—N(R G 5E ) 2 , S(O) g1 —R G 5E or S(O) g1 —N(R G 5E ) 2 ,
  • R G 5E is hydrogen, an optionally substituted C 1 -C 6 -alkyl, aryl-C 0 -C 6 -alkylene, C 3 -C 7 -cycloalkyl-C 0 -C 6 -alkylene, hetaryl or hetarylalkyl radical,
  • R G 5F is a radical R G 5E , CO—R G 5E or CO—OR G 5E ,
  • R G 5G is a radical OR G 5E , N(R G 5E )(R G 5F ), N(R G 5E )—SO 2 R G 5E , N(R G 5E )(OR G 5E ), O—C(R G 5E ) 2 —CO—OR G 5E , O—C(R G 5E ) 2 O—CO—R G 5E , O—N(R G 5E ) 2 or CF 3 ,
  • R G 5H is a radical OR G 5E , CN, S(O) g2 —R G 5E , S(O) g1 —N(R G 5E ) 2 , CO—R G 5E , C(O)N(R G 5E ) 2 or CO 2 —R G 5E ,
  • R G 5J is hydrogen or an optionally substituted C 1 -C 6 -alkyl or aryl-C 0 -C 6 -alkylene radical
  • g1 is 1 or 2 and
  • g2 is 0, 1 or 2
  • m is 1 or 2
  • R G 6 is —OR′, —NR′R′′, —NR′SO 2 R′′′, —NR′OR′, —OCR′ 2 C(O)OR′, —OCR′ 2 OC(O)R′, —OCR′ 2 C(O)NR′ 2 , —CF 3 or —COC(R′) 2 R 7 ,
  • R G 7 is —OR′, —CN, —S(O) r R′, S(O) 2 N(R′) 2 , —C(O)R′C(O)NR′ 2 or —CO 2 R′,
  • r is 0, 1 or 2
  • R′ is hydrogen, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-C 0 -C 4 -alkyl or aryl-C 0 -C 4 -alkyl,
  • R′′ is R′, —C(O)R′ or —C(O)OR G 8 ,
  • R′′′ is C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-C 0 -C 4 -alkyl or aryl-C 0 -C 4 -alkyl,
  • R G 8 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-C 0 -C 4 -alkyl or aryl-C 0 -C 4 -alkyl,
  • B is a structural element containing at least one atom which, under physiological conditions, as a hydrogen acceptor can form hydrogen bridges, where at least one hydrogen, acceptor atom has a distance of 4 to 15 atom bonds to structural element G along the shortest possible route along the structural element skeleton,
  • T is understood as meaning a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH.
  • a radical hydrolyzable to COOH is understood as meaning a radical which changes into a group COOH after hydrolysis.
  • a group which may be mentioned by way of example as a radical T hydrolyzable to COOH is
  • R T 1 has the following meanings:
  • 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 tolerable organic ammonium ion such as primary, secondary, tertiary or quaternary, C 1 -C 4 -alkylammonium or ammonium ion, such as ONa, OK or OLi,
  • an alkali metal cation such as lithium, sodium, potassium
  • an alkaline earth metal cation such as calcium, magnesium and barium
  • an environmentally tolerable organic ammonium ion such as primary, secondary, tertiary or quaternary, C 1 -C 4 -alkylammonium or ammonium ion, such as ONa, OK or OLi
  • an environmentally tolerable organic ammonium ion such as primary, secondary, tertiary or quaternary, C 1 -C 4 -alky
  • a branched or unbranched, optionally halogen-substituted C 1 -C 8 -alkoxy radical such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy., 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, in particular methoxy, thoxy, 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-1,1,2-trifluoroethoxy or pentafluoroethoxy,
  • C 1 -C 8 -alkoxy radical such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy., 1-
  • a branched or unbranched, optionally halogen-substituted C 1 -C 4 -alkylthio radical such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio radical,
  • R T 1 is further a radical —(O) m —N(R 18 )(R 19 ), in which m is 0 or 1 and R 18 and R 19 , which can be identical or different, have the following meanings:
  • C 1 -C 6 -alkyl radical 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, 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 or the corresponding substituted radicals, preferably methyl, ethylbuty
  • C 2 -C 6 -alkenyl radical such as vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pen
  • C 2 -C 6 -alkynyl radical such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 0.2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2
  • C 3 -C 8 -cycloalkyl such as 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 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -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 an optionally substituted, e.g. C 1 -C 4 -alkyl-substituted, C 4 -C 7 -alkylene chain closed to give a cycle, which can contain a heteroatom select d from the group consisting of oxygen, sulfur and nitrogen, such as —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —(CH 2 ) 7 —, —(CH 2 ) 2 —O—(CH 2 ) 2 —, —CH 2 —S—(CH 2 ) 3 —, —(CH 2 ) 2 —O—(CH 2 ) 3 —, —NH—(CH 2 ) 3 —, —CH 2 —NH—(CH 2 ) 2 —, —CH 2 —CH ⁇ CH—CH 2 —, —CH ⁇ CH—(CH 2 ) 3 —, —CO—(CH 2 ) 4 —
  • a radical bioisosteric to COOH is understood as meaning radicals which can replace the function of a group COOH in active compounds by equivalent bond donor/acceptor capabilities or by equivalent charge distribution.
  • Radicals which may be mentioned by way of example as radicals bioisosteric to —COOH are those such as described in “The Practice of Medicinal Chemistry”, Editor: C. G. Wermuth, Academic Press 1996, pages 125 and 216, in particular the radicals —P ⁇ O(OH) 2 , —SO 3 H, tetrazole or acylsulfonamides.
  • Preferred radicals T are —COOH, —CO—O—C 1 -C 8 -alkyl or —CO—O-benzyl.
  • the radical —U— in the structural element L is a spacer selected from the group consisting of —(X L ) a —(CR L 1 R L 2 ) b —, —CR L 1 ⁇ CR L 2 —, ethynylene and ⁇ CR L 1 —.
  • the structural element L is linked to the structural element G via a double bond.
  • X L is a radical CR L 3 R L 4 , NR L 5 , oxygen or sulfur.
  • a halogen radical is understood as meaning, for example, F, Cl, Br or I, preferably F.
  • a branched or unbranched C 1 -C 6 -alkyl radical is understood as meaning, 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,
  • a branched or unbranched C 2 -C 6 -alkenyl radical is understood as meaning, for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pen
  • a branched or unbranched C 2 -C 6 -alkynyl radical is understood as meaning, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-
  • a branched or unbranched C 3 -C 7 -cycloalkyl radical is understood as meaning, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • a branched or unbranched C 1 -C 4 -alkoxy radical is understood as meaning, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.
  • the radicals —CO—NH(C 1 -C 6 -alkyl), —CO—N(C 1 -C 6 -alkyl) 2 are secondary or tertiary amides and are composed of the amide bond and the corresponding C 1 -C 6 -alkyl radicals such as described above for R L 1 , R L 2 , R L 3 or R L 4 .
  • radicals R L 1 , R L 2 , R L 3 or R L 4 can furthermore be a radical
  • C 1 -C 2 -alkylene-T such as methylene-T or ethylene-T
  • C 2 -alkenylene-T such as ethenylene-T or C 2 -alkynylene-T, such as ethynylene-T,
  • an aryl radical such as phenyl, 1-naphthyl or 2-naphthyl or
  • an arylalkyl radical such as benzyl or ethylenephenyl (homobenzyl)
  • two radicals R L 1 and R L 2 , or R L 3 and R L 4 or optionally R L 1 and R L 3 can in each case independently of one another together be an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S.
  • R L 1 , R L 2 , R L 3 or R L 4 can be optionally substituted.
  • suitable substituents if the substituents are not specified in greater detail, are independently of one another up to 5 substituents, for example selected from the following group:
  • R L 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 R L 7 .
  • radicals R L 1 , R L 2 , R L 3 or R L 4 are independently of one another 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 in structural element L are independently of one another hydrogen, a branched or unbranched, optionally substituted
  • CO—O—C 1 -C 6 -alkyl, SO 2 —C 1 -C 6 -alkyl or CO—C 1 -C 6 -alkyl radical which is composed of the group CO—O, SO 2 or CO and, for example, of the C 1 -C 6 -alkyl radicals described above for R L 1 ,
  • CO—O-alkylenearyl, SO 2 -aryl, SO 2 -alkylenearyl or CO-alkylenearyl radical which is composed of the group CO—O, SO 2 or CO and, for example, 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—O—C 1 -C 4 -alkyl, CO—C 1 -C 4 -alkyl or SO 2 —C 1 -C 4 -alkyl radical or an optionally substituted CO—O-benzyl, SO 2 -aryl, SO 2 -alkylenearyl or CO-aryl radical.
  • Preferred radicals for R L 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 radicals of the structural element.
  • Particularly preferred structural elements L are composed of the particularly preferred radicals of the structural element.
  • G is a structural element of the formula I G
  • Ar in structural element G is a fused aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S and is optionally substituted by up to 4 substituents.
  • Ar is a fused aromatic 3- to 6-membered carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to two substituents.
  • Ar is an aromatic 3- to 6-membered carbocycle or heterocycl optionally substituted by up to two substituents and selected from one of the following doubly bonded structural formulae:
  • substitution pattern on Ar relative to the structural element B is not critical.
  • the substitution takes place, in particular in the case of 5- and 6-membered cycles, ortho or meta to W G , when this position is not occupied by a heteroatom.
  • D G in structural element G is an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S.
  • D G is a fused, aromatic or unsaturated 3- to 6-membered carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to two substituents.
  • D G is an optionally substituted, fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle, for example selected from one of the following doubly bonded structural formulae:
  • X G in structural element G is CR G 1 or nitrogen in the case of a single bond to structural element L, or carbon in the case of a double bond to structural element L.
  • X G is CR G 1 in the case of a single bond or carbon in the case of a double bond to structural element L.
  • X G is CR G 1 and is bonded to the structural element L via a single bond.
  • W G in structural element G is the doubly bonded radical —Y G —N(R G 5 )— or —N(R G 5 )—Y G —.
  • Y G in structural element G is CO, CS, C ⁇ NR G 2 or CR G 3 R G 4 , preferably CO, C ⁇ NR G 2 or CR G 3 R G 4 , particularly preferably CO or CR G 3 R G 4 .
  • R G 1 in structural element W G is hydrogen, halogen, such as Cl, F, Br or I, a hydroxyl group or a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical, preferably C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy radical, for example as in each case described above for R L 1 .
  • Preferred radicals for R G 1 are hydrogen, hydroxyl and optionally substituted C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy radicals.
  • radicals for R G 1 are hydrogen and carboxyl-substituted C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy radicals, in particular the radicals —CH 2 COOH or —O—CH 2 COOH.
  • R G 2 in structural element G is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 1 -C 4 -alkoxy or C 3 -C 7 -cycloalkyl radical, for example as in each case described above for R L 1 ,
  • an optionally substituted —O—C 3 -C 7 -cycloalkyl radical which is composed of an ether group and, for example, of the C 3 -C 7 -cycloalkyl radical described above for R L 1 ,
  • an optionally substituted —O-aryl or —O-alkylenearyl radical which is composed of a group —O— and, for example, of the aryl or arylalkyl radicals described above for R L 1 .
  • Preferred radicals R G 2 in structural element G are hydrogen, hydroxyl or a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical, in particular methyl or C 1 -C 4 -alkoxy radical, in particular methoxy.
  • R G 3 and R G 4 are, independently of one another, hydrogen or a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl —C 2 -C 6 -alkynyl or C 1 -C 4 -alkoxy radical or both radicals
  • R G 3 and R G 4 together are a cyclic acetal —O—CH 2 —CH 2 —-O— or —O—CH 2 —O— or both radicals
  • R G 3 and R G 4 together are an optionally substituted C 3 -C 7 -cycloalkyl radical
  • the groups COOH and carbocylic acid ester are excluded as substituents for all radicals R G 3 and R G 4 .
  • Branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or C 1 -C 4 -alkoxy radicals for R G 3 or R G 4 in structural element G independently of one another are understood as meaning, for example, the corresponding radicals in each case described above for R L 1 .
  • both radicals R G 3 and R G 4 can together form a cyclic acetal, such as —O—CH 2 —CH 2 —O— or —O—CH 2 —O—.
  • both radicals R G 3 and R G 4 can together form an optionally substituted C 3 -C 7 -cycloalkyl radical.
  • radicals for R G 3 or R G 4 are independently of one another hydrogen, C 1 -C 6 -alkyl or C 1 -C 4 -alkoxy, and both radicals R G 3 and R G 4 together form a cyclic acetal, such as —O—CH 2 —CH 2 —O— or —O—CH 2 —O—.
  • radicals for R G 3 or R G 4 are independently of one another hydrogen and both radicals R G 3 and R G 4 together form a cyclic acetal, in particular —O—CH 2 —CH 2 —O— or —O—CH 2 —O—.
  • R G 5 is a radical R G 5A or a radical C 0 -C 6 -alkylene-R G 5B , C 2 -C 4 -alkenylene-R G 5B , C 2 -C 4 -alkynylene-R G 5B , C 1 -C 6 -oxoalkylene-R G 5B , C 2 -C 4 -oxoalkenylene-R G 2B , C 2 -C 4 -oxoalkynylene-R G 5B , C 1 -C 4 -aminoalkylene-R G 5B , C 2 -C 4 -aminoalkenylene-R G 5B , C 2 -C 4 -aminoalkynylene-R G 5B , C 2 -C 4 -alkylene-R G 5B , optionally substituted by one or more radicals selected from the group consisting of R G 5A and R G 5 C, where
  • R G 5A is a radical COR G 5G , COC(R G 5E ) 2 (R G 5H ), CSR G 5G , S(O) g1 —OR G 5E , S(O) g1 —N(R G 5E )(R G 5F ), PO(OR G 5E ), PO(OR G 5E ) 2 , B(OR G 5E ) 2 , NO 2 or tetrazolyl,
  • R G 5B is hydrogen or an optionally substituted C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloheteroalkyl, aryl or hetaryl radical,
  • R G 5C is hydrogen, halogen, CN, NO 2 , OR G 5D , CF 3 , or a radical N(R G 5E )(R G 5D ), CF 3 S(O) g2 , CO 2 R G 5E , CO—N(R G 5E ) 2 , C 0 -C 6 -alkylene-R G 5B , C 1 -C 6 -oxoalkylene-R G 5B , C 2 -C 4 -alkenylene —R G 5B or C 2 -C 4 -alkynylene —R G 5B ,
  • R G 5D is a radical R G 5E , —CO-R G 5E , CO—OR G 5J , CO—N(R G 5E ) 2 , S(O) g1 —R G 5E or S(O) g1 —N(R G 5E ) 2 ,
  • R G 5E is hydrogen, an optionally substituted C 1 -C 6 -alkyl, aryl-C 0 -C 6 -alkylene, C 3 -C 7 -cycloalkyl-C 0 -C 6 -alkylene, hetaryl or hetarylalkyl radical,
  • R G 5F is a radical R G 5E , CO—R G 5E or CO—OR G 5E ,
  • R G 5G is a radical OR G 5E , N(R G 5E ) (R G 5F ), N(R G 5E )—SO 2 —R G 5E , N(R G 5E )(OR G 5E ), O—C(R G 5E ) 2 —CO—OR G 5E , O—C(R G 5E ) 2 —O—CO—R G 5E , O—C(R G 5E ) 2 —CO—N(R G 5E ) 2 or CF 3 ,
  • R G 5H is a radical OR G 5E , CN, S(O) g2 R G 5E , S(O) g1 —N(R G 5E ) 2 , CO—R G 5E , C(O)N(R G 5E ) 2 or CO 2 R G 5E ,
  • R G 5J is hydrogen or an optionally substituted C 1 -C 6 -alkyl or aryl-C 0 -C 6 -alkylene radical
  • g1 is 1 or 2 and
  • g2 is 0, 1 or 2
  • m is 1 or 2
  • R G 6 is —OR′, —NR′R′′, —NR′SO 2 R′′′, —NR′OR′, —OCR′ 2 C(O)OR′, —OCR′ 2 OC(O)R′, —OCR′ 2 C(O)NR′ 2 , —CF 3 or —COC(R′) R G 7 ,
  • R G 7 is —OR′, —CN, —S(O) r R′, S(O) 2 N(R′) 2 , —C(O)R′C(O)NR′ 2 or —CO 2 R′,
  • r is 0, 1 or 2
  • R′ is hydrogen, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-C 0 -C 4 -alkyl or aryl-C 0 -C 4 -alkyl,
  • R is R′, —C(O)R′ or —C(O)OR G 8 ,
  • R′′′ is C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-C 0 -C 4 -alkyl or aryl-C 0 -C 4 -alkyl,
  • R G 8 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-C 0 -C 4 -alkyl or aryl-C 0 -C 4 -alkyl.
  • R G 5 if W G ⁇ —N(R G 5 )—Y G — the radical (CH 2 ) m —COR G 6 is also excluded for R G 5 .
  • R G 5 Further preferred radicals for R G 5 are hydrogen,
  • radicals for R G 5 are hydrogen, methyl, ethyl, CH 2 CF 3 , benzyl or homobenzyl, where the phenyl group can optionally be substituted by a C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or C 1 -C 4 -alkylthio radical, CF 3 , OH or halogen.
  • Very particularly preferred radicals for R G 5 are hydrogen, methyl, ethyl or CH 2 CF 3 .
  • Preferred structural elements G are composed of at least one preferred radical of the structural element G, while the remaining radicals are widely variable.
  • Particularly preferred structural elements G are composed of the preferred radicals of the structural element G.
  • Very particularly preferred structural elements G are composed of the particularly preferred radicals of the structural element G.
  • Structural element B is understood as meaning a structural element containing at least one atom which, under physiological conditions, can form hydrogen bridges as a hydrogen acceptor, at least one hydrogen acceptor atom having a distance of 4 to 15 atom bonds from structural element G along the shortest possible route along the structural element skeleton.
  • the arrangement of the structural skeleton of structural element B is widely variable.
  • Suitable atoms which, under physiological conditions, can form hydrogen bridges as hydrogen acceptors are, for example, atoms having Lewis base properties, such as the, heteroatoms nitrogen, oxygen or sulfur.
  • Physiological conditions are understood as meaning a pH which prevails at the site in a body at which the ligands interact with the receptors.
  • the physiological conditions have a pH of, for example, 5 to 9.
  • structural element B is a structural element of the formula I B
  • A is a structural element selected from the group consisting of:
  • a 4- to 8-membered monocyclic saturated, unsaturated or aromatic hydrocarbon which can contain up to 4 heteroatoms selected from the group consisting of O, N and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group consisting of O, N and S is present in the structural element A, or
  • a 9- to 14-membered polycyclic, saturated, unsaturated or aromatic hydrocarbon which can contain up to 6 heteroatoms selected from the group consisting of N, O and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group consisting of O, N and S is present in the structural element A,
  • Z A 1 is oxygen, sulfur or optionally substituted nitrogen and
  • Z A 2 is optionally substituted nitrogen, oxygen or sulfur, or a radical
  • [0214] independently of one another are hydrogen, a branched or unbranched, optionally substituted C 1 -C 8 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 5 -alkylene-C 1 -C 4 -alkoxy, mono- or bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, arylalkyl, C 1 -C 4 -alkyleneheterocycloalkyl, C 1 -C 4 -alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO 2 —R G 11 ,
  • E is a spacer structural element which covalently bonds the structural element A to the structural element G, where the number of atomic [sic] bonds along the shortest possible route along the structural element skeleton E is 3 to 14.
  • the structural element A is a structural element selected from the group consisting of of structural elements of the formulae I A 1 to I A 18 ,
  • [0221] independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl or CO—C 1 -C 6 -alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C 3 -C 7 -cycloalkyl radical or a radical CO—O—R A 14 , O—R A 14 , S—R A 14 , NR A 15 R A 16 , CO—NR A 15 R A 16 or SO 2 NR A 15 R A 16 or both radicals R A 1 and R A 2 together are a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group consisting of O, N and S,
  • [0223] independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C 3 -C 7 -cycloalkyl radical or a radical CO—O—R A 14 , O—R A 14 , S—R A 14 , NR A 15 R A 16 , SO 2 —NR A 15 R A 16 or CO—NR A 15 R A 16 ,
  • R A 14 is hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, alkylene-C 1 -C 4 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or C 1 -C 6 -alkylene-C 3 -C 7 -cycloalkyl radical or an optionally substituted C 3 -C 7 -cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
  • [0227] independently of one another are hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, CO—C 1 -C 6 -alkyl, SO 2 —C 1 -C 6 -alkyl, COO—C 1 -C 6 -alkyl, CO—NH—C 1 -C 6 -alkyl, arylalkyl, COO-alkylenearyl, SO 2 -alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or hetarylalkyl radical or an optionally substituted C 3 -C 7 -cycloalkyl, aryl, CO-aryl, CO—NH-aryl, SO 2 -aryl, hetaryl, CO—NH-hetaryl or CO-hetaryl radical,
  • —(CH 2 ) n —(X A ) j —R A 12 , or both radicals together are a 3- to 8-membered, saturated, unsaturated or aromatic N-heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle is optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle,
  • n 0, 1, 2 or 3
  • X A is —CO—, —CO—N(R X 1 )—, —N(R X 1 )—CO—, —N(R X 1 )—CO—N(R X 1 *)—, —N(R X 1 )—CO—O—, —O—, —S—, —SO 2 —, —SO 2 —N(R X 1 )—, —SO 2 —O—, —CO—O—, —O—CO—, —O—CO—N(R X 1 )—, —N(R X 1 )— or —N(R X 11 )—SO 2 —,
  • R A 12 is hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical, an optionally C 1 -C 4 -alkyl- or aryl-substituted C 2 -C 6 -alkynyl or C 2 -C 6 -alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocycle, substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, a C 3 -C 7 -cycloalkyl, aryl or hetaryl radical, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical R A 12 together with R X 1 or R
  • [0237] independently of one another are hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxyalkyl, C 2 -C 6 -alkenyl, C 2 -C 12 -alkynyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl or SO 2 —C 1 -C 6 -alkyl radical or an optionally substituted C 3 -C 7 -cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO 2 -aryl, hetaryl, CO-hetaryl or SO 2 -alkylenearyl radical,
  • [0239] are hydrogen, a branched or unbranched, optionally substituted C 1 -C 4 -alkyl, —CO—O—C 1 -C 4 -alkyl, arylalkyl, —CO—O-alkylenearyl, —CO—O-allyl, —CO—C 1 -C 4 -alkyl, —CO-alkylenearyl, C 3 -C 7 -cycloalkyl or —CO-allyl radical or in structural element I
  • a 7 both radicals R A 6 and R A 6 * together are 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
  • R A 8 is hydrogen, a branched or unbranched, optionally substituted C 1 -C 4 -alkyl, CO—C 1 -C 4 -alkyl, SO 2 —C 1 -C 4 -alkyl or CO—O—C 1 -C 4 -alkyl radical or an optionally substituted aryl, CO-aryl, SO 2 -aryl, CO—O-aryl, CO-alkylenearyl, SO 2 -alkylenearyl, CO—O-alkylenearyl or alkylenearyl radical,
  • radicals R A 9 and R A 10 together in structural element I A 14 are a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals,
  • R A 11 is hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C 3 -C 7 -cycloalkyl radical or a radical CO—O—R A 14 , O—R A 14 , S—R A 14 , NR A 15 R A 16 , SO 2 —NR A 15 R A 16 or CO—NR A 15 R A 16 ,
  • R A 17 is hydrogen or, in structural element I A 16 , both radicals R A 9 and R A 17 together are 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 O, N, S and is optionally substituted by up to three identical or different radicals,
  • [0248] independently of one another are hydrogen, a branched or unbranched, optionally substituted C 1 -C 8 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 5 -alkylene-C 1 -C 4 -alkoxy, mono- or bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, arylalkyl, C 1 -C 4 -alkyleneheterocycloalkyl, C 1 -C 4 -alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO 2 —R G 11 ,
  • Z 5 is NR A 8 , oxygen or sulfur.
  • the structural element A is a structural element of the formula I A 1 , I A 4 , I A 7 , I A 8 or I A 17 .
  • a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical for R A 1 or R A 2 independently of one another is understood as meaning, for example, the corresponding radicals described above for R G 1 , preferably methyl or trifluoromethyl.
  • the branched or unbranched, optionally substituted radical CO—C 1 -C 6 -alkyl is composed, for example, of the group CO and the branched or unbranched, optionally substituted C 1 -C 6 -alkyl radicals described above for R A 1 or R A 2 .
  • Optionally substituted hetaryl, hetarylalkyl, aryl, arylalkyl or C 3 -C 7 -cycloalkyl radicals for R A 1 or R A 2 independently of one another are understood as meaning, for example, the corresponding radicals described above for R G 7 .
  • R A 1 or R A 2 the optionally substituted radicals CO—O—R A 14 , O—R A 14 , S—R A 14 , NR A 15 R A 16 , CO—NR A 15 R A 16 or SO 2 NR A 15 R A 16 are composed, for example, of the groups CO—O, O, S, N, CO—N or SO 2 —N and the radicals R A 14 , R A 15 or R A 16 described in greater detail below.
  • both radicals R A 1 and R A 2 can together form a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group consisting of O, N and S.
  • R A 13 and R A 13 * are independently of one another hydrogen, CN,
  • halogen such as fluorine, chlorine, bromine or iodine
  • a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical such as described above for R G 1 , preferably methyl or trifluoromethyl or an
  • Preferred radicals for R A 13 and R A 13 * are the radicals hydrogen, F, Cl, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical, optionally substituted aryl or arylalkyl or a radical CO—O—R A 14 , O—R A 14 , NR A 15 R A 16 , SO 2 —NR A 15 R A 16 or CO—NR A 15 R A 16 .
  • a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, alkylenecycloalkyl, alkylene-C 1 -C 4 -alkoxy, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl radical for R A 14 in structural element A is understood as meaning, for example, the corresponding radicals described above for R G 7 .
  • Optionally substituted aryl, arylalkyl, hetaryl or alkylhetaryl radicals for R A 14 in structural element A are understood as meaning, for example, the corresponding radicals described above for R G 7 .
  • Preferred radicals for R A 14 are hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical and optionally substituted benzyl.
  • a branched or unbranched, optionally substituted C 1 -C 6 -alkyl or arylalkyl radical or an optionally substituted C 3 -C 7 -cycloalkyl, aryl, hetaryl or hetarylalkyl radical for R A 15 or R A 16 independently of one another is understood as meaning, for example, the corresponding radicals described above for R A 14 .
  • the branched or unbranched, optionally substituted CO—C 1 -C 6 -alkyl, SO 2 —C 1 -C 6 -alkyl, COO—C 1 -C 6 -alkyl, CO—NH—C 1 -C 6 -alkyl, COO-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or SO 2 ′-alkylenearyl radicals or the optionally substituted CO-aryl, SO 2 -aryl, CO—NH-aryl, CO—NH-hetaryl or CO-hetaryl radicals for R A 15 or R A 16 are composed, for example, of the corresponding groups —CO—, —SO 2 —, —CO—O—, —CO—NH— and the corresponding branched or unbranched, optionally substituted C 1 -C 6 -alkyl, hetarylalkyl or arylalkyl radicals or the
  • a radical (CH 2 ) n —(X A ) j —R A 12 for R A 3 or R A 4 independently of one another is understood as meaning a radical which is composed of the corresponding radicals —(CH 2 ) n —, (X A ) j and R A 12 .
  • n can be: 0, 1, 2, or 3 and j can be: 0 or 1.
  • X A is a doubly bonded radical selected from the group consisting of —CO—, —CO—N(R X 1 )—, —N(R X 1 )—CO—, —N(R X 1 )CO—N(R X 1 *)—, —N(R X 1 )—CO—O—, —O—, —S—, —SO 2 —, —SO 2 —N(R X 1 )—, —SO 2 —O—, —CO—O—, —O—CO—, —O—CO—, —O—CO—N(R X 1 )—, —N(R X 1 )— or —N(R X 1 )—SO 2 —.
  • R A 12 is hydrogen
  • a 3- to 6-membered, saturated or unsaturated heterocycle which is substituted by up to three identical or different radicals and can contain up to three different or identical heteroatoms O, N, S, such as optionally substituted 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-pyridyl,
  • R A 12 and R X 1 or R X 1 * can together form a saturated or unsaturated C 3 -C 7 -heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N.
  • the radical R A 12 together with the radical R X 1 or R X 1 * forms a cyclic amine as the C 3 -C 7 -heterocycle in the case where the radicals are bonded to the same nitrogen atom, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl, where in heterocycles which carry free amine protons, such as N-piperazinyl, the free amine protons can be replaced by customary amine protective groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO 2 —C 1 -C 4 — alkyl, —SO 2 -phenyl or —SO 2 -benzyl.
  • customary amine protective groups such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxy
  • a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 12 -alkynyl, preferably C 2 -C 6 -alkynyl or C 2 -C 6 -alkenyl radical, an optionally substituted C 3 -C 7 -cycloalkyl, aryl, arylalkyl or hetaryl radical for R X 1 and R X 1 * independently of one another is understood as meaning, for example, the corresponding radicals described-above for R G 7 .
  • Preferred branched or unbranched, optionally substituted C 1 -C 6 -alkoxyalkyl for R X 1 and R X 1 * are independently of one another methoxymethylene, ethoxymethylene, t-butoxymethylene, methoxyethylene or ethoxyethylene.
  • Preferred branched or unbranched, optionally substituted radicals CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl, SO 2 —C 1 -C 6 -alkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO 2 -aryl, CO-hetaryl or SO 2 -alkylenearyl are preferably composed of the C 1 -C 6 -alkyl, arylalkyl, aryl or hetaryl radicals and the radicals —CO—, —O—, —SO 2 — described above.
  • Preferred radicals for R X 1 and R X 1 * are independently of one another hydrogen, methyl, cyclopropyl, allyl and propargyl.
  • R A 3 and R A 4 can further together form a 3- to 8-membered saturated, unsaturated or aromatic N heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle can be optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle,
  • R A 5 is a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, arylalkyl, C 1 -C 4 -alkyl-C 3 -C 7 -cycloalkyl or C 3 -C 7 -cycloalkyl radical or an optionally substituted aryl, hetaryl, heterocycloalkyl or heterocycloalkenyl radical, such as described above for R G 7 .
  • R A 6 and R A 6* are independently of one another 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—O-alkylenearyl or —CO-alkylenearyl radical such as 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 can together 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 6 , C 1 -C 4 -alkoxy, arylalkyl or C 3 -C 7 -cycloalkyl radical, for example as described above for R L 14 , a branched or unbranched, optionally substituted —O—CO—C 1 -C 4 -alkyl radical, which is composed of the group —O—CO— and, for example, of the C 1 -C 4 -alkyl radicals mentioned above or an optionally substituted —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical which is composed of the groups —O— or —O—CO— and, for example, of the corresponding radicals described above for R G 7
  • both radicals R A 6 and R A 7 can together 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 O, N, S.
  • a branched or unbranched, optionally substituted C 1 -C 4 -alkyl radical or an optionally substituted aryl or arylalkyl radical is understood as meaning, for example, the corresponding radicals described above for R A 15 , where the radicals CO—C 1 -C 4 -alkyl, SO 2 —C 1 -C 4 -alkyl, CO—O—C 1 -C 4 -alkyl, CO-aryl, SO 2 -aryl, CO—O-aryl, CO-alkylenearyl, SO 2 -alkylenearyl or CO—O-alkylenearyl are composed analogously to the other composed radicals of the group consisting of CO, SO 2 and COO and, for example, of the corresponding C 1 -C 4 -alkyl, aryl or arylalkyl radicals described above for R A 15 , and these radicals can be optionally substituted.
  • a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl or C 3 -C 7 -cycloalkyl radical independently of one another is understood as meaning, for example, the corresponding radicals described above for R A 14 , preferably methyl or trifluoromethyl.
  • R A 9 or R A 10 a radical CO—O—R A 14 , O—R A 14 , S—R A 14 , SO 2 —NR A 15 R A 16 , NR A 15 R A 16 or CO—NR A 15 R A 16 independently of one another is understood as meaning, for example, the corresponding radicals described above for R A 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 O, N, S and is optionally substituted by up to three identical or different radicals.
  • Substituents in this case are in particular understood as meaning halogen, CN, a branched or unbranched, optionally substituted C 1 -C 4 -alkyl radical, such as methyl or trifluoromethyl, or the radicals O—R A 14 , S—R A 14 , NR A 15 R A 16 , CO—NR A 15 R A 16 or —((R A 8 )HN)C ⁇ N—R A 7 .
  • a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C 3 -C 7 -cycloalkyl radical or a radical CO—O—R A 14 , O—R A 14 , S—R A 14 , NR A 15 R A 16 , SO 2 —NR A 15 R A 16 or CO—NR A 15 R A 16 for R A 11 is understood, for example, as meaning 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 O, N, S and is optionally substituted by up to three identical or different radicals.
  • Z 1 , Z 2 , Z 3 , Z 4 are independently of one another nitrogen, C—H, C-halogen, such as C—F, C—Cl, C—Br or C—I or a branched or unbranched, optionally substituted C—C 1 -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—C 1 -C 4 -alkoxy radical which is composed of a carbon radical and, for example, a C 1 -C 4 -alkoxy radical described above for R A 7 .
  • C-halogen such as C—F, C—Cl, C—Br or C—I or a branched or unbranched
  • optionally substituted C—C 1 -C 4 -alkyl radical which is composed of a carbon radical and, for example, a C 1 -C 4 -alky
  • Z 5 is oxygen, sulfur or a radical NR A 8 .
  • Preferred structural elements A are composed of at least one preferred radical of the radicals belonging to the structural element A, while the remaining radicals are widely variable.
  • Particularly preferred structural elements A are composed of the preferred radicals of the structural element A.
  • the spacer structural element E is understood as meaning a structural element that consists of a branched or unbranched aliphatic C 2 -C 30 -hydrocarbon radical which is optionally substituted and contains heteroatoms and/or of a 4- to 20-membered aliphatic or aromatic mono- or polycyclic hydrocarbon radical which is optionally substituted and contains heteroatoms.
  • the spacer structural element E is composed of two to four substructural elements, selected from the group consisting of E 1 and E 2 , where the sequence of linkage of the substructural elements is arbitrary and E 1 and E 2 have the following meanings:
  • E 1 is a substructural element of the formula I E1
  • E 2 is a substructural element of the formula I E2
  • [0315] independently of one another are 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 identical or different heteroatoms selected from the group consisting of N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted,
  • x is 0, 1, 2, 3 or 4,
  • z is 0 or 1
  • W E is —CO—, —CO—N(R W 2 )—, —N(R W 2 )—CO—, —N(R W 2 )—CO—N(R W 2 *)—, —N(R W 2 )—CO—O—, —O—, —S—, —SO 2 —, —SO 2 —N(R W 2 )—, —SO 2 —O—, —CO—O—, —O—CO—, —O—CO—N(R W 2 )—, —N(R W 2 )— or —N(R W 2 )—SO 2 —,
  • [0324] independently of one another are hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 8 -alkynyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl or SO 2 -C 1 -C 6 -alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C 3 -C 7 -cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO 2 -aryl, CO-hetaryl or SO 2 -alkylenearyl radical,
  • R E 17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical, an optionally substituted C 3 -C 7 -cycloalkyl, aryl, hetaryl or arylalkyl radical, a C 2 -C 6 -alkynyl or C 2 -C 6 -alkenyl radical optionally substituted by C 1 -C 4 -alkyl or aryl, an optionally substituted C 6 -C 12 -bicycloalkyl, C 1 -C 6 -alkylene-C 6 -C 12 -bicycloalkyl, C 7 -C 20 -tricycloalkyl or C 1 -C 6 -alkylene-C 7 -C 20 -tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different
  • [0327] independently of one another are hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxyalkyl, C 2 -C 6 -alkenyl, C 2 -C 12 -alkynyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl, CO—NH—C 1 -C 6 -alkoxyalkyl, —CO—NH—C 1 -C 6 -alkyl or SO 2 —C 1 -C 6 -alkyl radical or an optionally substituted hetaryl, arylalkyl, C 3 -C 7 -cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO 2 -aryl, —CO-hetaryl, SO 2
  • R E 12 is hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 8 -alkynyl radical, an optionally substituted C 3 -C 7 -cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—R E 16 , COOR E 16 or SO 2 —R E 16 ,
  • R E 15 is hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or alkylenecycloalkyl radical or an optionally substituted C 3 -C 7 -cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
  • R E 16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or C 1 -C 5 -alkylene-C 1 -C 4 -alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, arylalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -heterocycloalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -heterocycloalkenyl or hetarylalkyl radical.
  • the coefficient c is preferably 0 or 1
  • the coefficient d is preferably 1 or 2
  • the coefficients f, g, h independently of one another are preferably 0 or 1
  • k 6 is preferably 0.
  • 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 identical or different heteroatoms selected from the group consisting of N, O, S, where the ring carbons or ring nitrogens can optionally be substituted, for Q E and X E independently of one another is preferably understood as meaning optionally substituted arylene, such as optionally substituted phenylene or naphthylene, or optionally substituted hetarylene such as the radicals
  • Aliphatic hydrocarbons are understood as meaning, for example, saturated and unsaturated hydrocarbons.
  • Z 6 and Z 7 are independently of one another CH or nitrogen.
  • Z 8 is oxygen, sulfur or NH
  • Z 9 is oxygen, sulfur or NR E 20 .
  • r1, r2, r3 and t are independently of one another 0, 1, 2 or 3.
  • s and u are independently of-one another 0, 1 or 2.
  • X E and Q E independently of one another are optionally substituted phenylene, a radical
  • R E 18 and R E 19 are independently of one another hydrogen, —NO 2 , —NH 2 , —CN, —COOH, a hydroxyl group, halogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 1 -C 4 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or alkylenecycloalkyl radical or an optionally substituted C 3 -C 7 -cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, as in each case described above.
  • R E 20 is, independently of one another, hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxyalkyl, C 3 -C 12 -alkynyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl or SO 2 —C 1 -C 6 -alkyl radical or an optionally substituted C 3 -C 7 -cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO 2 -aryl, hetaryl, CO-hetaryl or SO 2 -alkylenearyl radical, preferably hydrogen or a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical.
  • Y E and Z E are independently of one another CO, —N(R E 11 )—, CO—NR E 12 , NR E 12 —CO, sulfur, SO, SO 2 , SO 2 —NR E 12 , NR E 12 —SO 2 , CS, CS—NR E 12 , NR E 12 —CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, C(R E 13 )(CR E 14 ) CR E 13 —O—CR E 14 , C( ⁇ CR E 13 R E 14 ), CR E 13 ⁇ CR E 14 , —CR E 13 (OR E 15 )—CHR E 14 — or —CHR E 13 —CR E 14 (OR E 15 )—,
  • oxygen preferably oxygen, —N(R E 11 )—, —C(R E 13 )(CR E 14 )-, CO—NR E 12 , NR E 12 —CO, SO 2 —NR E 12 , NR E 12 —SO 2 or CR E 13 CR E 14 ,
  • oxygen particularly preferably oxygen, —N(R E 11 )—, —C(R E 13 )(CR E 14 )—, CO—NR E 12 or NR E 12 —CO.
  • R E 12 is hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 8 -alkynyl radical or an optionally substituted C 3 -C 7 -cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical, such as correspondingly described above for R G 7 or a radical CO—R E 16 , COOR E 16 or SO 2 —R E 16 , preferably hydrogen, methyl, allyl, propargyl and cyclopropyl.
  • a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl radical or an optionally substituted C 3 -C 7 -cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for R E 13 , R E 14 or R E 15 independently of one another is understood as meaning, for example, the corresponding radicals described above for R G 7 .
  • a branched or unbranched, optionally substituted C 1 -C 4 -alkoxy radical for R E 13 or R E 14 independently of on another is understood as meaning, for example, the C 1 -C 4 -alkoxy radicals described above for R A 14 .
  • Preferred alkylenecycloalkyl radicals for R E 13 , R E 14 or R E 15 independently of one another are, for example, the C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl radicals described above for R G 7 .
  • a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or alkylenecycloalkyl radical or an optionally substituted C 3 -C 7 -cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for R E 1 , R E 2 R E 3 , R E 4 , R E 5 , R E 6 , R E 7 , R E 8 , R E 9 or R E 10 independently of one another is understood as meaning, for example, the corresponding radicals mentioned above for R G 7 .
  • two radicals R E 3 and R E 4 or R E 5 and R E 6 or R E 7 and R E 8 or R E 9 and R E 10 can in each case independently of one another together form a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocycle which can contain up to three heteroatoms from the group consisting of O, N and S.
  • the radical —(CH 2 ) x —(W E ) z —R E 17 is composed of a C 0 -C 4 -alkylene radical, optionally a bonding element W E selected from the group consisting of
  • [0359] independently of one another are hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 8 -alkynyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl or SO 2 —C 1 -C 6 -alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C 3 -C 7 -cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO 2 -aryl, CO-hetaryl or SO 2 -alkylenearyl radical, preferably independently of on another are hydrogen, methyl, cyclopropyl, allyl, propargyl, and
  • [0361] is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical, an optionally substituted C 3 -C 7 -cycloalkyl, aryl, hetaryl or arylalkyl radical, a C 2 -C 6 -alkynyl or C 2 -C 6 -alkenyl radical optionally substituted by C 1 -C 4 -alkyl or aryl, an optionally substituted C 6 -C 12 -bicycloalkyl, C 1 -C 6 -alkylene-C 6 -C 12 -bicycloalkyl, C 7 -C 20 -tricycloalkyl or C 1 -C 6 -alkylene-C 7 -C 20 -tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals
  • R E 17 and R W 2 or R W 2 * can together form a saturated or unsaturated C 3 -C 7 -heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N.
  • the radicals R E 17 and R W 2 or R W 2 * together form a cyclic amine as the C 3 -C 7 -heterocycle in the case where the radicals are bonded to the same nitrogen atom, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl where in heterocycles which carry free amine protons, such as N-piperazinyl, the free amine protons can be replaced by customary amine protective groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO 2 —C 1 -C 4 -alkyl, —SO 2 -phenyl or —SO 2 -benzyl.
  • customary amine protective groups such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl),
  • Preferred radicals for R E 1 , R E 2 , R E 3 , R E 4 , R E 5 , R E 6 , R E 7 , R E 8 , R E 9 or R E 10 are independently of one another hydrogen, halogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl radical, optionally substituted aryl or the radical —(CH 2 ) x —(W E ) z —R E 17 .
  • radicals for R E 1 , R E 2 , R E 3 , R E 4 , R E 5 , R E 6 , R E 7 , R E 8 , R E 9 or R E 10 are independently of one another hydrogen, F, a branched or unbranched, optionally substituted C 1 -C 4 -alkyl radical, in particular methyl.
  • a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxyalkyl, C 2 -C 6 alkenyl, C 2 -C 2 -alkynyl or arylalkyl radical or an optionally substituted aryl, hetaryl or C 3 -C 7 -cycloalkyl for R E 11 and R E 11* in structural element E independently of one another is understood as meaning, for example, the corresponding radicals described above for R G 7 .
  • the branched or unbranched, optionally substituted radicals CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl, CO—NH—C 1 -C 6 -alkoxyalkyl, CO—NH—C 1 -C 6 -alkyl or SO 2 —C 1 -C 6 -alkyl radical or the optionally substituted radicals CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO 2 -aryl, CO-hetaryl, SO 2 -alkylenearyl, SO 2 -hetaryl or SO 2 -alkylenehetaryl for R E 11 and R E 11 * independently of one another are composed, for example, of the corresponding groups CO, COO, CONH or SO 2 and the corresponding radicals mentioned above.
  • Preferred radicals for R E 11 or R E 11 * are independently of one another hydrogen, a branched or unbranched, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 12 -alkynyl or arylalkyl radical, or an optionally substituted hetaryl or C 3 -C 7 -cycloalkyl radical.
  • radicals for R E 11 or R E 11 * are hydrogen, methyl, cyclopropyl, allyl or propargyl.
  • structural element E 1 is a radical —CH 2 —CH 2 —CO—, —CH 2 —CH 2 —CH 2 —CO— or a C 1 -C 5 -alkylene radical.
  • the spacer structural element E used is a structural element of the formula I E1E2
  • Preferred structural elements E are composed of at least one preferred radical of the radicals belonging to structural element E, while the remaining radicals are widely variable.
  • Particularly preferred structural elements E are composed of th preferred radicals of structural element E.
  • Preferred structural elements B are composed either of the preferred structural element A, whiled E is widely variable or of the preferred structural element E, while A is widely variable.
  • the compounds of the formula I, and also the intermediates for their preparation, can have one or more asymmetric substituted carbon atoms.
  • the compounds can be present as pure enantiomers or pure diastereomers or as a mixture thereof.
  • the use of an enantiomerically pure compound as the active compound is preferred.
  • the compounds of the formula I can also be present 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 liberated under physiological conditions.
  • group T in structural element L which in some cases contains groups which are hydrolyzable to the free carboxylic acid group under physiological conditions.
  • derivatized structural elements B or A which liberate the structural element B or A respectively under physiological conditions.
  • Preferred compounds of the formula I contain, for example, the preferred structural element G, while the structural elements B and L are widely variable.

Abstract

The invention relates to novel compounds which bind to integrin receptors, their use as ligands of integrin receptors, in particular as ligands of the αvβ3 integrin receptor, and pharmaceutical preparations comprising these compounds.

Description

  • The present invention relates to novel compounds which bind to integrin receptors, their use as ligands of integrin receptors, in particular as ligands of the α[0001] vβ3 integrin receptor, and pharmaceutical preparations comprising these compounds.
  • Integrins are cell surface glycoprotein receptors which mediate interactions between identical 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 the tissue architecture. [0002]
  • Disturbances in the gene expression of cell adhesion molecules and functional disorders of the receptors can contribute to the pathogenesis of many disorders, such as tumors, thromboembolic events, cardiovascular disorders, lung diseases, disorders of the CNS, the kidney, the gastrointestinal tract or inflammations. [0003]
  • Integrins are heterodimers of an α- and a β-transmembrane subunit in each case, which are noncovalently bonded. Up to now, 16 different α- and 8 different β-subunits and 22 different combinations have been identified. [0004]
  • Integrin α[0005] vβ3 also called the vitronectin receptor, mediates adhesion to a multiplicity of ligands—plasma proteins, extracellular matrix proteins, cell surface proteins-, of which the majority contain the amino acid sequence RGD (Cell, 1986, 44, 517-518; Science 1987, 238, 491-497), such as vitronectin, fibrinogen, fibronectin, von Willebrand factor, thrombospondin, osteopontin, laminin, collagen, thrombin, tenascin, MMP-2, bone sialoprotein II, various viral, fungal, such as the surface molecules of Candida albicans, parasitic and bacterial proteins, natural integrin antagonists such as disintegrins, neurotoxins—mambin—and blood fluke proteins—decorsin, ornatin—and also some non-RGD ligands, such as Cyr-61 and PECAM-1 (L. Piali, J. Cell Biol. 1995, 130, 451-460; Buckley, J. Cell Science 1996, 109, 437-445, J. Biol. Chem. 1998, 273, 3090-3096).
  • A number of integrin receptors show cross-reactivity with ligands which contain the RGD motif. Thus integrin α[0006] IIbβ3, also called the platelet fibrinogen receptor, recognizes fibronectin, vitronectin, thrombospondin, von Willebrand factor and fibrinogen.
  • Integrin α[0007] vβ3 is expressed, inter alia, on endothelial cells, blood 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.
  • Increased expression is observed under various pathological conditions, such as in the prothrombotic state, in vascular injury, tumor growth or metastasis or reperfusion and on activated cells, in particular on endothelial cells, smooth muscle cells or macrophages. [0008]
  • An involvement of integrin α[0009] vβ3 has been demonstrated, inter alia, in the following syndromes:
  • cardiovascular disorders such as atherosclerosis, restenosis after vascular injury, and angioplasty (neointima formation, smooth muscle cell migration and proliferation) (J. Vasc. Surg. 1994, 19, 125-134; Circulation 1994, 90, 2203-2206), [0010]
  • acute kidney failure (Kidney Int. 1994, 46, 1050-1058; Proc. Natl. Acad. Sci. 1993, 90, 5700-5704; Kidney Int. 1995, 48, 1375-1385), [0011]
  • angiogenesis-associated microangiopathies such as diabetic retinopathy or rheumatoid 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), [0012]
  • arterial thrombosis, [0013]
  • stroke (phase II studies with ReoPro, Centocor Inc., 8th annual European Stroke Meeting), [0014]
  • carcinomatous disorders, such as in tumor metastasis or in tumor growth (tumor-induced angiogenesis) (Cell 1991, 64, 327-336; Nature 1989, 339, 58-61; Science 1995, 270, 1500-1502), [0015]
  • osteoporosis (bone resorption after proliferation, chemotaxis and adhesion of osteoclasts to bone matrix) (FASEB J. 1993, 7, 1475-1482; Exp. Cell Res. 1991, 195, 368-375, Cell 1991, 64, 327-336), [0016]
  • high blood pressure (Am. J. Physiol. 1998, 275, H1449-H1454), [0017]
  • psoriasis (Am. J. Pathol. 1995, 147, 1661-1667), [0018]
  • hyperparathyroidism, [0019]
  • Paget's disease (J. Clin. Endocrinol. Metab. 1996, 81, 1810-1820), [0020]
  • malignant hypercalcemia (Cancer Res. 1998, 58, 1930-1935), [0021]
  • metastatic osteolytic lesions (Am. J. Pathol. 1997, 150, 1383-1393), [0022]
  • pathogenic protein (e.g. HIV-1 tat)-induced processes (e.g. angiogenesis, Kaposi's sarcoma) (Blood 1999, 94, 663-672) [0023]
  • inflammation (J. Allergy Clin. Immunol. 1998, 102, 376-381), [0024]
  • cardiac insufficiency, CHF, and also in [0025]
  • antiviral, antiparasitic, antifungal or antibacterial therapy and prophylaxis (adhesion and internalization) (J. Infect. Dis. 1999, 180, 156-166; J. Virology 1995, 69, 2664-2666; Cell 1993, 73, 309-319). [0026]
  • On account of their key role, pharmaceutical preparations which contain low-molecular weight integrin α[0027] vβ3 ligands are of high therapeutic or diagnostic benefit, inter alia, in the indications mentioned.
  • Advantageous α[0028] vβ3 integrin receptor ligands bind toe the integrin αvβ3 receptor with an increased affinity.
  • In contrast to integrin α[0029] vβ3, particularly advantageous αvβ3 integrin receptor ligands additionally have an increased selectivity and are less active with respect to the integrin αIIbβ3 by at least a factor of 10, preferably at least a factor of 100.
  • For a multiplicity of compounds, such as anti-α[0030] vβ3 monoclonal antibodies, peptides which contain thee RGD binding sequence, natural, RGD-containing proteins (e.g. disintegrins) and low-molecular weight compounds, an integrin αvβ3 antagonistic action has been shown and a positive in vivo effect demonstrated (FEBS Letts 1991, 291, 50-54; J. Biol. Chem. 1990, 265, 12267-12271; J. Biol. Chem. 1994, 269, 20233-20238; J. Cell Biol 1993, 51, 206-218; J. Biol. Chem. 1987, 262, 17703-17711; Bioorg. Med. Chem. 1998, 6, 1185-1208).
  • Antagonists of the α[0031] vβ3 integrin receptor based on a tricyclic structural element having a heptacycle are described in WO 9906049, WO 9911626 and WO 9701540.
  • EP 889037 describes tricyclic allergy inhibitors. [0032]
  • U.S. Pat. No. 54,290,123 describes tricyclic antagonists of the endothelin receptor. [0033]
  • It is an object of the present invention to make available novel integrin receptor ligands having advantageous properties. [0034]
  • Accordingly, we have found that this object is achieved by compounds of the formula I [0035]
  • B-G-L  I
  • where B, G and L have the following meanings: [0036]
  • L is a structural element of the formula I[0037] L
  • —U-T  IL
  • where [0038]  
  • T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and [0039]
  • -U- is —(X[0040] L)a—(CRL 1RL 2)b—, —CRL 1═CRL 2—, ethynylene or ═CRL 1—, where
  • a is 0 or 1, [0041]
  • b is 0, 1 or 2, [0042]
  • X[0043] L is CRL 3RL 4, NRL 5, oxygen or sulfur,
  • R[0044] L 1, RL 2, RL 3, RL 4
  • independently of one another are hydrogen, -T, —OH, —NR[0045] L 6RL 7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals RL 1 and RL 2 or RL 3 and RL 4 or optionally RL 1 and RL 3 together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S,
  • R[0046] L 5, RL 6, RL 7
  • independently of one another are hydrogen, a branched or unbranched, optionally substituted C[0047] 1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or Co-alkylenearyl radical,
  • G is a structural element of the formula I[0048] G
    Figure US20040077638A1-20040422-C00001
  • where [0049]  
  • the structural element B is bonded via Ar and the structural element L is bonded via X[0050] G to the structural element G by means of a single bond or a double bond and
  • Ar is a fused, aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to'four different or identical heteroatoms O, N, S and is optionally substituted by up to 4 substituents, [0051]
  • D[0052] G is an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S,
  • X[0053] G is CRG 1 or nitrogen, in the case of a single bond to structural element L, or
  • carbon, in the case of a double bond to structural element L, [0054]
  • W[0055] G is —YG—N (RG 5) or —N(RG 5)—YG—,
  • Y[0056] G is CO, CS, C═NRG 2 or CRG 3RG 4,
  • R[0057] G 1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical,
  • R[0058] G 2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical,
  • R[0059] G 3, RG 4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG 3 and RG 4 together are a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG 3 and RG 4 together are an optionally substituted C3-C7-cycloalkyl radical,
  • with the proviso that, as substituents of the C[0060] 1-C6-alkyl radicals, the groups COOH and carboxylic acid ester are excluded,
  • R[0061] G 5 is a radical RG 5A or a radical C0-C6alkylene-RG 5B, C2-C4-alkenylene-RG 5B, C2-C4-alkynylene-RG 5B, C1-C6-oxoalkylene-RG 5B, C2-C4-oxoalkenylene-RG 5B, C2-C4-oxoalkynylene-RG 5B, C1-C4-aminoalkylene-RG 5B, C2-C4-aminoalkenylene-RG 5B, C2-C4-aminoalkynylene-RG 5B, C2-C4-alkylene-RG 5B, optionally substituted by one or more radicals selected from the group consisting of RG 5A and RG 5C,
  • R[0062] G 5A is a radical CORG 5G, COC(RG 5E)2(RG 5H), CSRG 5G, S(O)g1—ORG 5E, S(O)g1—N(RG 5E)(RG 5F), PO(ORG 5E), PO(ORG 5E)2, B(ORG 5E)2, NO2 or tetrazolyl,
  • R[0063] G 5B is hydrogen or an optionally substituted C3-C7-cycloalkyl, C3-C7-cycloheteroalkyl, aryl or hetaryl radical,
  • R[0064] G 5C is hydrogen, halogen, CN, NO2, ORG 5D, CF3, or a radical N(RG 5E)(RG 5D), CF3S(O)g2, CO2RG 5E, CO—N(RG 5E)2, C0-C6-alkylene-RG 5B, C1-C6-oxoalkylene-RG 5B, C2-C4-alkenylene-RG 5B or C2-C4-alkynylene-RG 5B,
  • R[0065] G 5D is a radical RG 5E, —CO—RG 5E, CO—ORG 5J, CO—N(RG 5E)2, S(O)g1—RG 5E or S(O)g1—N(RG 5E)2,
  • R[0066] G 5E is hydrogen, an optionally substituted C1-C6-alkyl, aryl-C0-C6-alkylene, C3-C7-cycloalkyl-C0-C6-alkylene, hetaryl or hetarylalkyl radical,
  • R[0067] G 5F is a radical RG 5E, CO—RG 5E or CO—ORG 5E,
  • R[0068] G 5G is a radical ORG 5E, N(RG 5E)(RG 5F), N(RG 5E)—SO2RG 5E, N(RG 5E)(ORG 5E), O—C(RG 5E)2—CO—ORG 5E, O—C(RG 5E)2O—CO—RG 5E, O—N(RG 5E)2 or CF3,
  • R[0069] G 5H is a radical ORG 5E, CN, S(O)g2—RG 5E, S(O)g1—N(RG 5E)2, CO—RG 5E, C(O)N(RG 5E)2 or CO2—RG 5E,
  • R[0070] G 5J is hydrogen or an optionally substituted C1-C6-alkyl or aryl-C0-C6-alkylene radical,
  • g1 is 1 or 2 and [0071]
  • g2 is 0, 1 or 2, [0072]
  • with the proviso that if W[0073] G═—YG—N(RG 5)— the radical (CH2)m—CORG 6 is excluded for RG 5, where
  • m is 1 or 2, [0074]
  • R[0075] G 6 is —OR′, —NR′R″, —NR′SO2R′″, —NR′OR′, —OCR′2C(O)OR′, —OCR′2OC(O)R′, —OCR′2C(O)NR′2, —CF3 or —COC(R′)2R7,
  • R[0076] G 7 is —OR′, —CN, —S(O)rR′, S(O)2N(R′)2, —C(O)R′C(O)NR′2 or —CO2R′,
  • r is 0, 1 or 2, [0077]
  • R′ is hydrogen, C[0078] 1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
  • R″ is R′, —C(O)R′ or —C(O)OR[0079] G 8,
  • R′″ is C[0080] 1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
  • R[0081] G 8 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
  • B is a structural element containing at least one atom which, under physiological conditions, as a hydrogen acceptor can form hydrogen bridges, where at least one hydrogen, acceptor atom has a distance of 4 to 15 atom bonds to structural element G along the shortest possible route along the structural element skeleton, [0082]
  • and the physiologically tolerable salts, prodrugs and the enantiomerically pure or diastereomerically pure and tautomeric forms. [0083]
  • In the structural element L, T is understood as meaning a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH. [0084]
  • A radical hydrolyzable to COOH is understood as meaning a radical which changes into a group COOH after hydrolysis. [0085]
  • A group which may be mentioned by way of example as a radical T hydrolyzable to COOH is [0086]
    Figure US20040077638A1-20040422-C00002
  • in which R[0087] T 1 has the following meanings:
  • a) OM, where 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 tolerable organic ammonium ion such as primary, secondary, tertiary or quaternary, C[0088] 1-C4-alkylammonium or ammonium ion, such as ONa, OK or OLi,
  • b) a branched or unbranched, optionally halogen-substituted C[0089] 1-C8-alkoxy radical, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy., 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, in particular methoxy, thoxy, 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-1,1,2-trifluoroethoxy or pentafluoroethoxy,
  • c) a branched or unbranched, optionally halogen-substituted C[0090] 1-C4-alkylthio radical such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio radical,
  • d) an optionally substituted —O-alkylenearyl radical, such as —O-benzyl, [0091]
  • e) R[0092] T 1 is further a radical —(O)m—N(R18)(R19), in which m is 0 or 1 and R18 and R19, which can be identical or different, have the following meanings:
  • hydrogen, [0093]
  • a branched or unbranched, optionally substituted [0094]
  • C[0095] 1-C6-alkyl radical, 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, 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 or the corresponding substituted radicals, preferably methyl, ethyl, propyl, butyl or i-butyl,
  • C[0096] 2-C6-alkenyl radical., such as vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl-1-1-methyl-ethyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl or the corresponding substituted radicals,
  • C[0097] 2-C6-alkynyl radical, such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 0.2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl or the corresponding substituted radicals,
  • C[0098] 3-C8-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl or the corresponding substituted radicals,
  • or a phenyl radical, optionally mono- or polysubstituted, for example mono- to trisubstituted, by halogen, nitro, cyano, C[0099] 1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-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,
  • or R[0100] 18 and R19 together form an optionally substituted, e.g. C1-C4-alkyl-substituted, C4-C7-alkylene chain closed to give a cycle, which can contain a heteroatom select d from the group consisting of oxygen, sulfur and nitrogen, such as —(CH2)4—, —(CH2)5—, —(CH2)6—, —(CH2)7—, —(CH2)2—O—(CH2)2—, —CH2—S—(CH2)3—, —(CH2)2—O—(CH2)3—, —NH—(CH2)3—, —CH2—NH—(CH2)2—, —CH2—CH═CH—CH2—, —CH═CH—(CH2)3—, —CO—(CH2)2—CO— or —CO— (CH2)3—CO—.
  • A radical bioisosteric to COOH is understood as meaning radicals which can replace the function of a group COOH in active compounds by equivalent bond donor/acceptor capabilities or by equivalent charge distribution. [0101]
  • Radicals which may be mentioned by way of example as radicals bioisosteric to —COOH are those such as described in “The Practice of Medicinal Chemistry”, Editor: C. G. Wermuth, Academic Press 1996, pages 125 and 216, in particular the radicals —P═O(OH)[0102] 2, —SO3H, tetrazole or acylsulfonamides.
  • Preferred radicals T are —COOH, —CO—O—C[0103] 1-C8-alkyl or —CO—O-benzyl.
  • The radical —U— in the structural element L is a spacer selected from the group consisting of —(X[0104] L)a—(CRL 1RL 2)b—, —CRL 1═CRL 2—, ethynylene and ═CRL 1—. In the case of the radical ═CRL 1—, the structural element L is linked to the structural element G via a double bond.
  • X[0105] L is a radical CRL 3RL 4, NRL 5, oxygen or sulfur.
  • Preferred radicals —U— are the radicals —CR[0106] L 1═CRL 2—, ethynylene or —(XL)a—(CRL 1RL 2)b—, where XL is preferably CRL 3RL 4 (a=0 or 1) or oxygen (a=1).
  • Particularly preferred radicals —U— are the radicals —(X[0107] L)a—(CRL 1RL 2)b—, where XL is preferably CRL 3RL 4 (a=0 or 1) or oxygen (a=1).
  • Under R[0108] L 1, RL 2, RL 3 or RL 4 in structural element L, a halogen radical is understood as meaning, for example, F, Cl, Br or I, preferably F.
  • Under R[0109] L 1, RL 2, RL 3 or RL 4 in structural element L, a branched or unbranched C1-C6-alkyl radical is understood as meaning, 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 C1-C4-alkyl-radicals such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, particularly preferably methyl.
  • Under R[0110] L 1, RL 2, RL 3 or RL 4 in structural element L, a branched or unbranched C2-C6-alkenyl radical is understood as meaning, for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl.
  • Under R[0111] L 1, RL 2, RL 3 or RL 4 in structural element L, a branched or unbranched C2-C6-alkynyl radical is understood as meaning, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably ethynyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl.
  • Under R[0112] L 1, RL 2, RL 3 or RL 4 in structural element L, a branched or unbranched C3-C7-cycloalkyl radical is understood as meaning, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Under R[0113] L 1, RL 2, RL 3 or RL 4 in structural element L, a branched or unbranched C1-C4-alkoxy radical is understood as meaning, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.
  • The radicals —CO—NH(C[0114] 1-C6-alkyl), —CO—N(C1-C6-alkyl)2 are secondary or tertiary amides and are composed of the amide bond and the corresponding C1-C6-alkyl radicals such as described above for RL 1, RL 2, RL 3 or RL 4.
  • The radicals R[0115] L 1, RL 2, RL 3 or RL 4 can furthermore be a radical
  • C[0116] 1-C2-alkylene-T, such as methylene-T or ethylene-T,
  • C[0117] 2-alkenylene-T, such as ethenylene-T or C2-alkynylene-T, such as ethynylene-T,
  • an aryl radical, such as phenyl, 1-naphthyl or 2-naphthyl or [0118]
  • an arylalkyl radical, such as benzyl or ethylenephenyl (homobenzyl), [0119]
  • where the radicals can optionally be substituted. [0120]
  • Furthermore, two radicals R[0121] L 1 and RL 2, or RL 3 and RL 4 or optionally RL 1 and RL 3 can in each case independently of one another together be an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S.
  • All radicals for R[0122] L 1, RL 2, RL 3 or RL 4 can be optionally substituted. For the radicals RL 1, RL 2, RL 3 or RL 4 and all further substituted radicals of the description below, suitable substituents, if the substituents are not specified in greater detail, are independently of one another up to 5 substituents, for example selected from the following group:
  • —NO[0123] 2, —NH2, —OH, —CN, —COOH, —O—CH2—COOH, halogen, a branched or unbranched, optionally substituted C1-C4-alkyl radical, such as methyl, CF3, C2F5 or CH2F, —CO—O—C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, C1-C4-thioalkyl, —NH—CO—O—C1-C4-alkyl, —O—CH2—COO—C1-C4-alkyl, —NH—CO—C1-C4-alkyl, —CO—NH—C1-C4-alkyl, —NH—SO2—C1-C4-alkyl, —SO2—NH—C1-C4-alkyl, —N(C1-C4-alkyl)2, —NH—C1-C4-alkyl, or —SO2—C1-C4-alkyl radical, such as —SO2—CF3, an optionally substituted —NH—CO-aryl, —CO—NH-aryl, —NH—CO—O-aryl, —NH—CO—O-alkylenearyl, —NH—SO2-aryl, —SO2—NH-aryl, —CO—NH-benzyl, —NH—SO2-benzyl or —SO2—NH-benzyl radical, an optionally substituted radical —SO2—NRS 2RS 3 or —CO—NRS 2RS 3 where the radicals RS 2 and RS 3 independently of one another can have the meaning RL 5 as below or both radicals RS 2 and RS 3 together can be a 3- to 6-membered, optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three further different or identical heteroatoms O, N, S, and optionally two radicals substituted on this heterocycle can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can be optionally substituted or a further, optionally substituted cycle can be fused to this cycle.
  • If not specified in greater detail, in all terminally bonded, substituted hetaryl radicals of the description, two substituents can form a fused 5- to 7-membered, unsaturated or aromatic carbocycle. [0124]
  • Preferred radicals R[0125] L 1, RL 2, RL 3 or RL 4 are independently of one another hydrogen, halogen, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy or C3-C7-cycloalkyl radical or the radical —NRL 6RL 7.
  • Particularly preferred radicals R[0126] L 1, RL 2, RL 3 or RL 4 are independently of one another hydrogen, fluorine or a branched or unbranched, optionally substituted C1-C4-alkyl radical, preferably methyl.
  • The radicals R[0127] L 5, RL 6, RL 7 in structural element L are independently of one another hydrogen, a branched or unbranched, optionally substituted
  • C[0128] 1-C6-alkyl radical, for example as described above for RL 1,
  • C[0129] 3-C7-cycloalkyl radical, for example as described above for RL 1,
  • CO—O—C[0130] 1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical, which is composed of the group CO—O, SO2 or CO and, for example, of the C1-C6-alkyl radicals described above for RL 1,
  • or an optionally substituted CO—O-alkylenearyl, SO[0131] 2-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, which is composed of the group CO—O, SO2 or CO and, for example, of the aryl or arylalkyl radicals described above for RL 1.
  • Preferred radicals for R[0132] L 6 in structural element L are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—O—C1-C4-alkyl, CO—C1-C4-alkyl or SO2—C1-C4-alkyl radical or an optionally substituted CO—O-benzyl, SO2-aryl, SO2-alkylenearyl or CO-aryl radical.
  • Preferred radicals for R[0133] L 7 in structural element L are hydrogen or a branched or unbranched, optionally substituted C1-C4-alkyl radical.
  • Preferred structural elements L are composed of the preferred radicals of the structural element. [0134]
  • Particularly preferred structural elements L are composed of the particularly preferred radicals of the structural element. [0135]
  • G is a structural element of the formula I[0136] G
    Figure US20040077638A1-20040422-C00003
  • where the structural element B is bonded via Ar and the structural element L is bonded via X[0137] G to the structural element G by means of a single bond or a double bond.
  • Ar in structural element G is a fused aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S and is optionally substituted by up to 4 substituents. [0138]
  • Preferably, Ar is a fused aromatic 3- to 6-membered carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to two substituents. [0139]
  • Particularly preferably, Ar is an aromatic 3- to 6-membered carbocycle or heterocycl optionally substituted by up to two substituents and selected from one of the following doubly bonded structural formulae: [0140]
    Figure US20040077638A1-20040422-C00004
  • in particular selected from one of the following, doubly bonded structural formulae: [0141]
    Figure US20040077638A1-20040422-C00005
  • The substitution pattern on Ar relative to the structural element B is not critical. Preferably, the substitution takes place, in particular in the case of 5- and 6-membered cycles, ortho or meta to W[0142] G, when this position is not occupied by a heteroatom.
  • D[0143] G in structural element G is an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S.
  • Preferably, D[0144] G is a fused, aromatic or unsaturated 3- to 6-membered carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to two substituents.
  • Particularly preferably, D[0145] G is an optionally substituted, fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle, for example selected from one of the following doubly bonded structural formulae:
    Figure US20040077638A1-20040422-C00006
  • in particular selected from one of the following doubly bonded structural formulae: [0146]
    Figure US20040077638A1-20040422-C00007
  • X[0147] G in structural element G is CRG 1 or nitrogen in the case of a single bond to structural element L, or carbon in the case of a double bond to structural element L.
  • Preferably, X[0148] G is CRG 1 in the case of a single bond or carbon in the case of a double bond to structural element L.
  • Particularly preferably, X[0149] G is CRG 1 and is bonded to the structural element L via a single bond.
  • W[0150] G in structural element G is the doubly bonded radical —YG—N(RG 5)— or —N(RG 5)—YG—.
  • Y[0151] G in structural element G is CO, CS, C═NRG 2 or CRG 3RG 4, preferably CO, C═NRG 2 or CRG 3RG 4, particularly preferably CO or CRG 3RG 4.
  • R[0152] G 1 in structural element WG is hydrogen, halogen, such as Cl, F, Br or I, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl radical, preferably C1-C4-alkyl or C1-C4-alkoxy radical, for example as in each case described above for RL 1.
  • Preferred radicals for R[0153] G 1 are hydrogen, hydroxyl and optionally substituted C1-C4-alkyl or C1-C4-alkoxy radicals.
  • Particularly preferred radicals for R[0154] G 1 are hydrogen and carboxyl-substituted C1-C4-alkyl or C1-C4-alkoxy radicals, in particular the radicals —CH2COOH or —O—CH2COOH.
  • R[0155] G 2 in structural element G is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy or C3-C7-cycloalkyl radical, for example as in each case described above for RL 1,
  • an optionally substituted —O—C[0156] 3-C7-cycloalkyl radical, which is composed of an ether group and, for example, of the C3-C7-cycloalkyl radical described above for RL 1,
  • an optionally substituted aryl or arylalkyl radical, for example as in each case described above for R[0157] L 1 or
  • an optionally substituted —O-aryl or —O-alkylenearyl radical, which is composed of a group —O— and, for example, of the aryl or arylalkyl radicals described above for R[0158] L 1.
  • Preferred radicals R[0159] G 2 in structural element G are hydrogen, hydroxyl or a branched or unbranched, optionally substituted C1-C6-alkyl radical, in particular methyl or C1-C4-alkoxy radical, in particular methoxy.
  • Possible substituents are, for example, the above-mentioned substituents. [0160]
  • R[0161] G 3 and RG 4 are, independently of one another, hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl —C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG 3 and RG 4 together are a cyclic acetal —O—CH2—CH2—-O— or —O—CH2—O— or both radicals RG 3 and RG 4 together are an optionally substituted C3-C7-cycloalkyl radical,
  • with the proviso that, as substituents of the C[0162] 1-C6-alkyl radicals, the groups COOH and carboxylic acid ester are excluded.
  • In a preferred embodiment, the groups COOH and carbocylic acid ester are excluded as substituents for all radicals R[0163] G 3 and RG 4.
  • Branched or unbranched, optionally substituted C[0164] 1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radicals for RG 3 or RG 4 in structural element G independently of one another are understood as meaning, for example, the corresponding radicals in each case described above for RL 1.
  • Further, both radicals R[0165] G 3 and RG 4 can together form a cyclic acetal, such as —O—CH2—CH2—O— or —O—CH2—O—.
  • Furthermore, both radicals R[0166] G 3 and RG 4 can together form an optionally substituted C3-C7-cycloalkyl radical.
  • Preferred radicals for R[0167] G 3 or RG 4 are independently of one another hydrogen, C1-C6-alkyl or C1-C4-alkoxy, and both radicals RG 3 and RG 4 together form a cyclic acetal, such as —O—CH2—CH2—O— or —O—CH2—O—.
  • Particularly-preferred radicals for R[0168] G 3 or RG 4 are independently of one another hydrogen and both radicals RG 3 and RG 4 together form a cyclic acetal, in particular —O—CH2—CH2—O— or —O—CH2—O—.
  • R[0169] G 5 is a radical RG 5A or a radical C0-C6-alkylene-RG 5B, C2-C4-alkenylene-RG 5B, C2-C4-alkynylene-RG 5B, C1-C6-oxoalkylene-RG 5B, C2-C4-oxoalkenylene-RG 2B, C2-C4-oxoalkynylene-RG 5B, C1-C4-aminoalkylene-RG 5B, C2-C4-aminoalkenylene-RG 5B, C2-C4-aminoalkynylene-RG 5B, C2-C4-alkylene-RG 5B, optionally substituted by one or more radicals selected from the group consisting of RG 5A and RG 5C, where
  • R[0170] G 5A is a radical CORG 5G, COC(RG 5E)2(RG 5H), CSRG 5G, S(O)g1—ORG 5E, S(O)g1—N(RG 5E)(RG 5F), PO(ORG 5E), PO(ORG 5E)2, B(ORG 5E)2, NO2 or tetrazolyl,
  • R[0171] G 5B is hydrogen or an optionally substituted C3-C7-cycloalkyl, C3-C7-cycloheteroalkyl, aryl or hetaryl radical,
  • R[0172] G 5C is hydrogen, halogen, CN, NO2, ORG 5D, CF3, or a radical N(RG 5E)(RG 5D), CF3S(O)g2, CO2RG 5E, CO—N(RG 5E)2, C0-C6-alkylene-RG 5B, C1-C6-oxoalkylene-RG 5B, C2-C4-alkenylene —RG 5B or C2-C4-alkynylene —RG 5B,
  • R[0173] G 5D is a radical RG 5E, —CO-RG 5E, CO—ORG 5J, CO—N(RG 5E)2, S(O)g1—RG 5E or S(O)g1—N(RG 5E)2,
  • R[0174] G 5E is hydrogen, an optionally substituted C1-C6-alkyl, aryl-C0-C6-alkylene, C3-C7-cycloalkyl-C0-C6-alkylene, hetaryl or hetarylalkyl radical,
  • R[0175] G 5F is a radical RG 5E, CO—RG 5E or CO—ORG 5E,
  • R[0176] G 5G is a radical ORG 5E, N(RG 5E) (RG 5F), N(RG 5E)—SO2—RG 5E, N(RG 5E)(ORG 5E), O—C(RG 5E)2—CO—ORG 5E, O—C(RG 5E)2—O—CO—RG 5E, O—C(RG 5E)2—CO—N(RG 5E)2 or CF3,
  • R[0177] G 5H is a radical ORG 5E, CN, S(O)g2RG 5E, S(O)g1—N(RG 5E)2, CO—RG 5E, C(O)N(RG 5E)2 or CO2 RG 5E,
  • R[0178] G 5J is hydrogen or an optionally substituted C1-C6-alkyl or aryl-C0-C6-alkylene radical,
  • g1 is 1 or 2 and [0179]
  • g2 is 0, 1 or 2 [0180]
  • with the proviso that if W[0181] G═YG—N(RG 5)— the radical —(CH2)m—CORG 6 is excluded for RG 5, where
  • m is 1 or 2, [0182]
  • R[0183] G 6 is —OR′, —NR′R″, —NR′SO2R′″, —NR′OR′, —OCR′2C(O)OR′, —OCR′2OC(O)R′, —OCR′2C(O)NR′2, —CF3 or —COC(R′) RG 7,
  • R[0184] G 7 is —OR′, —CN, —S(O)rR′, S(O)2N(R′)2, —C(O)R′C(O)NR′2 or —CO2R′,
  • r is 0, 1 or 2 [0185]
  • R′ is hydrogen, C[0186] 1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
  • R is R′, —C(O)R′ or —C(O)OR[0187] G 8,
  • R′″ is C[0188] 1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
  • R[0189] G 8 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl.
  • In a preferred embodiment of R[0190] G 5, if WG═—N(RG 5)—YG— the radical (CH2)m—CORG 6 is also excluded for RG 5.
  • Further preferred radicals for R[0191] G 5 are hydrogen,
  • C[0192] 1-C6-alkyl, C3-C7cycloalkyl, aryl or arylalkyl such as described above for RL 1,
  • a radical COO—C[0193] 1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl which is composed of the group consisting of COO, SO2 or CO and the C1-C6-alkyl radicals described above,
  • a radical COO—C[0194] 1-C4-alkylene aryl, SO2-aryl, CO-aryl, CO-hetaryl, SO2—C1-C4-alkylene-aryl or CO—C1-C4-alkylene-aryl.
  • Particularly preferred radicals for R[0195] G 5 are hydrogen, methyl, ethyl, CH2CF3, benzyl or homobenzyl, where the phenyl group can optionally be substituted by a C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkylthio radical, CF3, OH or halogen.
  • Very particularly preferred radicals for R[0196] G 5 are hydrogen, methyl, ethyl or CH2CF3.
  • Preferred structural elements G are composed of at least one preferred radical of the structural element G, while the remaining radicals are widely variable. [0197]
  • Particularly preferred structural elements G are composed of the preferred radicals of the structural element G. [0198]
  • Very particularly preferred structural elements G are composed of the particularly preferred radicals of the structural element G. [0199]
  • Structural element B is understood as meaning a structural element containing at least one atom which, under physiological conditions, can form hydrogen bridges as a hydrogen acceptor, at least one hydrogen acceptor atom having a distance of 4 to 15 atom bonds from structural element G along the shortest possible route along the structural element skeleton. The arrangement of the structural skeleton of structural element B is widely variable. [0200]
  • Suitable atoms which, under physiological conditions, can form hydrogen bridges as hydrogen acceptors are, for example, atoms having Lewis base properties, such as the, heteroatoms nitrogen, oxygen or sulfur. [0201]
  • Physiological conditions are understood as meaning a pH which prevails at the site in a body at which the ligands interact with the receptors. In the present case, the physiological conditions have a pH of, for example, 5 to 9. [0202]
  • In a, preferred embodiment, structural element B is a structural element of the formula I[0203] B
  • A-E-  IB
  • where A and E have the following meanings: [0204]
  • A is a structural element selected from the group consisting of: [0205]
  • a 4- to 8-membered monocyclic saturated, unsaturated or aromatic hydrocarbon which can contain up to 4 heteroatoms selected from the group consisting of O, N and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group consisting of O, N and S is present in the structural element A, or [0206]
  • a 9- to 14-membered polycyclic, saturated, unsaturated or aromatic hydrocarbon which can contain up to 6 heteroatoms selected from the group consisting of N, O and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group consisting of O, N and S is present in the structural element A, [0207]
  • a radical [0208]
    Figure US20040077638A1-20040422-C00008
  • where [0209]  
  • Z[0210] A 1 is oxygen, sulfur or optionally substituted nitrogen and
  • Z[0211] A 2 is optionally substituted nitrogen, oxygen or sulfur, or a radical
    Figure US20040077638A1-20040422-C00009
  • where [0212]  
  • R[0213] A 18, RA 19
  • independently of one another are hydrogen, a branched or unbranched, optionally substituted C[0214]   1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG 11, —CO—ORG 11, —CO—NG 11RG 11* or —CO—RG 11, and
  • E is a spacer structural element which covalently bonds the structural element A to the structural element G, where the number of atomic [sic] bonds along the shortest possible route along the structural element skeleton E is 3 to 14. [0215]
  • In a particularly preferred embodiment, the structural element A is a structural element selected from the group consisting of of structural elements of the formulae I[0216] A 1 to IA 18,
    Figure US20040077638A1-20040422-C00010
    Figure US20040077638A1-20040422-C00011
  • where [0217]
  • m, p, q [0218]
  • independently of one another are 1, 2 or 3, [0219]
  • R[0220] A 1, RA 2
  • independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C[0221] 1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C3-C7-cycloalkyl radical or a radical CO—O—RA 14, O—RA 14, S—RA 14, NRA 15RA 16, CO—NRA 15RA 16 or SO2NRA 15RA 16 or both radicals RA 1 and RA 2 together are a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group consisting of O, N and S,
  • R[0222] A 13, RA 13*
  • independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C[0223] 1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA 14, O—RA 14, S—RA 14, NRA 15RA 16, SO2—NRA 15RA 16 or CO—NRA 15RA 16,
  • where [0224]  
  • R[0225] A 14 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or C1-C6-alkylene-C3-C7-cycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
  • R[0226] A 15, RA 16,
  • independently of one another are hydrogen, a branched or unbranched, optionally substituted C[0227] 1-C6-alkyl, CO—C1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, arylalkyl, COO-alkylenearyl, SO2-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or hetarylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, CO-aryl, CO—NH-aryl, SO2-aryl, hetaryl, CO—NH-hetaryl or CO-hetaryl radical,
  • R[0228] A 3, RA 4
  • independently of one another are hydrogen, [0229]
  • —(CH[0230] 2)n—(XA)j—RA 12, or both radicals together are a 3- to 8-membered, saturated, unsaturated or aromatic N-heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle is optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle,
  • where [0231]
  • n is 0, 1, 2 or 3, [0232]
  • j is 0.0 or 1, [0233]
  • X[0234] A is —CO—, —CO—N(RX 1)—, —N(RX 1)—CO—, —N(RX 1)—CO—N(RX 1*)—, —N(RX 1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX 1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX 1)—, —N(RX 1)— or —N(RX 11)—SO2—,
  • R[0235] A 12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally C1-C4-alkyl- or aryl-substituted C2-C6-alkynyl or C2-C6-alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocycle, substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, a C3-C7-cycloalkyl, aryl or hetaryl radical, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RA 12 together with RX 1 or RX 1*, forms a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N,
  • R[0236] X 1, RX 1*
  • independently of one another are hydrogen, a branched or unbranched, optionally substituted C[0237] 1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical,
  • R[0238] A 6, RA 6*
  • are hydrogen, a branched or unbranched, optionally substituted C[0239] 1-C4-alkyl, —CO—O—C1-C4-alkyl, arylalkyl, —CO—O-alkylenearyl, —CO—O-allyl, —CO—C1-C4-alkyl, —CO-alkylenearyl, C3-C7-cycloalkyl or —CO-allyl radical or in structural element IA 7 both radicals RA 6 and RA 6* together are 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[0240] A 7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted
  • C[0241] 1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—CO—C1-C4-alkyl radical, or an optionally substituted arylalkyl, —O-alkylenearyl, —O—CO-aryl, O—CO-alkylenearyl or —O—CO-allyl radical, or both radicals RA 6 and RA 7 together are an optionally substituted, 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[0242] A 8 is hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—C1-C4-alkyl, SO2—C1-C4-alkyl or CO—O—C1-C4-alkyl radical or an optionally substituted aryl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl, CO—O-alkylenearyl or alkylenearyl radical,
  • R[0243] A 9, RA 10
  • independently of one another are hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C[0244] 1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, —C3-C7-cycloalkyl radical or a radical CO—O—RA 14, O—RA 14, S—RA 14, NRA 15RA 16, SO2—NRA 15RA 16 or CO—NRA 15RA 16, or both radicals RA 9 and RA 10 together in structural element IA 14 are a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals,
  • R[0245] A 11 is hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA 14, O—RA 14, S—RA 14, NRA 15RA 16, SO2—NRA 15RA 16 or CO—NRA 15RA 16,
  • R[0246] A 17 is hydrogen or, in structural element IA 16, both radicals RA 9 and RA 17 together are 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 O, N, S and is optionally substituted by up to three identical or different radicals,
  • R[0247] A 19, RA 19
  • independently of one another are hydrogen, a branched or unbranched, optionally substituted C[0248] 1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG 11, —CO—ORG 11, —CO—NRG 11RG 11* or —CO—RG 11 which is independent of RG 11
  • Z[0249] 1, Z2, Z3, Z4,
  • independently of one another are nitrogen, C H, C-halogen or a branched or unbranched, optionally substituted C—C[0250] 1-C4-alkyl or C—C1-C4-alkoxy radical,
  • Z[0251] 5 is NRA 8, oxygen or sulfur.
  • In a further very particularly preferred embodiment, the structural element A is a structural element of the formula I[0252] A 1, IA 4, IA 7, IA 8 or IA 17.
  • A branched or unbranched, optionally substituted C[0253] 1-C6-alkyl radical for RA 1 or RA 2 independently of one another is understood as meaning, for example, the corresponding radicals described above for RG 1, preferably methyl or trifluoromethyl.
  • For R[0254] A 1 or RA 2 in the structural-elements IA 1, IA 2, IA 3 and IA 17, the branched or unbranched, optionally substituted radical CO—C1-C6-alkyl is composed, for example, of the group CO and the branched or unbranched, optionally substituted C1-C6-alkyl radicals described above for RA 1 or RA 2.
  • Optionally substituted hetaryl, hetarylalkyl, aryl, arylalkyl or C[0255] 3-C7-cycloalkyl radicals for RA 1 or RA 2 independently of one another are understood as meaning, for example, the corresponding radicals described above for RG 7.
  • For R[0256] A 1 or RA 2, the optionally substituted radicals CO—O—RA 14, O—RA 14, S—RA 14, NRA 15RA 16, CO—NRA 15RA 16 or SO2NRA 15RA 16 are composed, for example, of the groups CO—O, O, S, N, CO—N or SO2—N and the radicals RA 14, RA 15 or RA 16 described in greater detail below.
  • Further, both radicals R[0257] A 1 and RA 2 can together form a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group consisting of O, N and S.
  • R[0258] A 13 and RA 13* are independently of one another hydrogen, CN,
  • halogen, such as fluorine, chlorine, bromine or iodine, [0259]
  • a branched or unbranched, optionally substituted C[0260] 1-C6-alkyl radical, such as described above for RG 1, preferably methyl or trifluoromethyl or an
  • optionally substituted aryl, arylalkyl, hetaryl or C[0261] 3-C7-cycloalkyl radical or a radical CO—O—RA 14, O—RA 14, S—RA 14, NRA 15RA 16, SO2NRA 15RA 16 or CO—NRA 15RA 16 as in each case described above for RA 1.
  • Preferred radicals for R[0262] A 13 and RA 13* are the radicals hydrogen, F, Cl, a branched or unbranched, optionally substituted C1-C6-alkyl radical, optionally substituted aryl or arylalkyl or a radical CO—O—RA 14, O—RA 14, NRA 15RA 16, SO2—NRA 15RA 16 or CO—NRA 15RA 16.
  • A branched or unbranched, optionally substituted C[0263] 1-C6-alkyl, C3-C7-cycloalkyl, alkylenecycloalkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl or C2-C6-alkynyl radical for RA 14 in structural element A is understood as meaning, for example, the corresponding radicals described above for RG 7.
  • Optionally substituted aryl, arylalkyl, hetaryl or alkylhetaryl radicals for R[0264] A 14 in structural element A are understood as meaning, for example, the corresponding radicals described above for RG 7.
  • Preferred radicals for R[0265] A 14 are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical and optionally substituted benzyl.
  • A branched or unbranched, optionally substituted C[0266] 1-C6-alkyl or arylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or hetarylalkyl radical for RA 15 or RA 16 independently of one another is understood as meaning, for example, the corresponding radicals described above for RA 14.
  • The branched or unbranched, optionally substituted CO—C[0267] 1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, COO-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or SO2′-alkylenearyl radicals or the optionally substituted CO-aryl, SO2-aryl, CO—NH-aryl, CO—NH-hetaryl or CO-hetaryl radicals for RA 15 or RA 16 are composed, for example, of the corresponding groups —CO—, —SO2—, —CO—O—, —CO—NH— and the corresponding branched or unbranched, optionally substituted C1-C6-alkyl, hetarylalkyl or arylalkyl radicals or the corresponding optionally substituted aryl or hetaryl radicals described above.
  • A radical (CH[0268] 2)n—(XA)j—RA 12 for RA 3 or RA 4 independently of one another is understood as meaning a radical which is composed of the corresponding radicals —(CH2)n—, (XA)j and RA 12. Here, n can be: 0, 1, 2, or 3 and j can be: 0 or 1.
  • X[0269] A is a doubly bonded radical selected from the group consisting of —CO—, —CO—N(RX 1)—, —N(RX 1)—CO—, —N(RX 1)CO—N(RX 1*)—, —N(RX 1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX 1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX 1)—, —N(RX 1)— or —N(RX 1)—SO2—.
  • R[0270] A 12 is hydrogen,
  • a branched or unbranched, optionally substituted C[0271] 1-C6-alkyl radical, as described above for RG 7,
  • a C[0272] 2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl,
  • or a 3- to 6-membered, saturated or unsaturated heterocycle which is substituted by up to three identical or different radicals and can contain up to three different or identical heteroatoms O, N, S, such as optionally substituted 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, 6-pyridazinyl, 2-(1,3,4-thiadiazolyl), 2-(1,3,4)-oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, triazinyl. [0273]
  • Further, R[0274] A 12 and RX 1 or RX 1* can together form a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N.
  • Preferably, the radical R[0275] A 12 together with the radical RX 1 or RX 1* forms a cyclic amine as the C3-C7-heterocycle in the case where the radicals are bonded to the same nitrogen atom, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl, where in heterocycles which carry free amine protons, such as N-piperazinyl, the free amine protons can be replaced by customary amine protective groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO2—C1-C4— alkyl, —SO2-phenyl or —SO2-benzyl.
  • A branched or unbranched, optionally substituted C[0276] 1-C6-alkyl, C2-C12-alkynyl, preferably C2-C6-alkynyl or C2-C6-alkenyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl or hetaryl radical for RX 1 and RX 1* independently of one another is understood as meaning, for example, the corresponding radicals described-above for RG 7.
  • Preferred branched or unbranched, optionally substituted C[0277] 1-C6-alkoxyalkyl for RX 1 and RX 1* are independently of one another methoxymethylene, ethoxymethylene, t-butoxymethylene, methoxyethylene or ethoxyethylene.
  • Preferred branched or unbranched, optionally substituted radicals CO—C[0278] 1-C6-alkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl are preferably composed of the C1-C6-alkyl, arylalkyl, aryl or hetaryl radicals and the radicals —CO—, —O—, —SO2— described above.
  • Preferred radicals for R[0279] X 1 and RX 1* are independently of one another hydrogen, methyl, cyclopropyl, allyl and propargyl.
  • R[0280] A 3 and RA 4 can further together form a 3- to 8-membered saturated, unsaturated or aromatic N heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle can be optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle,
  • R[0281] A 5 is a branched or unbranched, optionally substituted C1-C6-alkyl, arylalkyl, C1-C4-alkyl-C3-C7-cycloalkyl or C3-C7-cycloalkyl radical or an optionally substituted aryl, hetaryl, heterocycloalkyl or heterocycloalkenyl radical, such as described above for RG 7.
  • R[0282] A 6 and RA 6* are independently of one another hydrogen, a branched or unbranched, optionally substituted
  • C[0283] 1-C4-alkyl radical, such as optionally substituted methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl,
  • —CO—O—C[0284] 1-C4-alkyl or —CO—C1-C4-alkyl radical such as composed of the group —CO—O— or —CO— and the C1-C4-alkyl radicals described above,
  • arylalkyl radical, as described above for R[0285] G 7,
  • —CO—O-alkylenearyl or —CO-alkylenearyl radical such as composed of the group —CO—O— or —CO— and the arylalkyl radicals described above, [0286]
  • —CO—O-allyl or —CO-allyl radical, [0287]
  • or C[0288] 3-C7-cycloalkyl radical, such as described above for RG 7.
  • Further, both radicals R[0289] A 6 and RA 6* in structural element IA 7 can together 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[0290] A 7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl radical, for example as described above for RA 6, C1-C4-alkoxy, arylalkyl or C3-C7-cycloalkyl radical, for example as described above for RL 14, a branched or unbranched, optionally substituted —O—CO—C1-C4-alkyl radical, which is composed of the group —O—CO— and, for example, of the C1-C4-alkyl radicals mentioned above or an optionally substituted —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical which is composed of the groups —O— or —O—CO— and, for example, of the corresponding radicals described above for RG 7.
  • Further, both radicals R[0291] A 6 and RA 7 can together 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 O, N, S.
  • For R[0292] A 8 in structural element A, a branched or unbranched, optionally substituted C1-C4-alkyl radical or an optionally substituted aryl or arylalkyl radical is understood as meaning, for example, the corresponding radicals described above for RA 15, where the radicals CO—C1-C4-alkyl, SO2—C1-C4-alkyl, CO—O—C1-C4-alkyl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl or CO—O-alkylenearyl are composed analogously to the other composed radicals of the group consisting of CO, SO2 and COO and, for example, of the corresponding C1-C4-alkyl, aryl or arylalkyl radicals described above for RA 15, and these radicals can be optionally substituted.
  • In each case, for R[0293] A 9 or RA 10, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl or C3-C7-cycloalkyl radical independently of one another is understood as meaning, for example, the corresponding radicals described above for RA 14, preferably methyl or trifluoromethyl.
  • In each case, for R[0294] A 9 or RA 10, a radical CO—O—RA 14, O—RA 14, S—RA 14, SO2—NRA 15RA 16, NRA 15RA 16 or CO—NRA 15RA 16 independently of one another is understood as meaning, for example, the corresponding radicals described above for RA 13.
  • Further, both radicals R[0295] A 9 and RA 10 together in structural element IA 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 O, N, S and is optionally substituted by up to three identical or different radicals.
  • Substituents in this case are in particular understood as meaning halogen, CN, a branched or unbranched, optionally substituted C[0296] 1-C4-alkyl radical, such as methyl or trifluoromethyl, or the radicals O—RA 14, S—RA 14, NRA 15RA 16, CO—NRA 15RA 16 or —((RA 8)HN)C═N—RA 7.
  • A branched or unbranched, optionally substituted C[0297] 1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA 14, O—RA 14, S—RA 14, NRA 15RA 16, SO2—NRA 15RA 16 or CO—NRA 15RA 16 for RA 11 is understood, for example, as meaning the corresponding radicals described above for RA 9.
  • Further, in structural element I[0298] A 16, both radicals RA 9 and RA 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 O, N, S and is optionally substituted by up to three identical or different radicals.
  • A branched or unbranched, optionally substituted C[0299] 1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical SO2-RG 11, —CO—ORG 11, —CO—NRG 11RG 11* or —CO—RG 11 for RA 18 and RA 19 independently of one another is understood as meaning, for example, the radicals described above for RG 12, preferably hydrogen or a branched or unbranched, optionally substituted C1-C8-alkyl radical.
  • Z[0300] 1, Z2, Z3, Z4 are independently of one another nitrogen, C—H, C-halogen, such as C—F, C—Cl, C—Br or C—I or a branched or unbranched, optionally substituted C—C1-C4-alkyl radical which is composed of a carbon radical and, for example, a C1-C4-alkyl radical described above for RA 6 or a branched or unbranched optionally substituted C—C1-C4-alkoxy radical which is composed of a carbon radical and, for example, a C1-C4-alkoxy radical described above for RA 7.
  • Z[0301] 5 is oxygen, sulfur or a radical NRA 8.
  • Preferred structural elements A are composed of at least one preferred radical of the radicals belonging to the structural element A, while the remaining radicals are widely variable. [0302]
  • Particularly preferred structural elements A are composed of the preferred radicals of the structural element A. [0303]
  • In a preferred embodiment, the spacer structural element E is understood as meaning a structural element that consists of a branched or unbranched aliphatic C[0304] 2-C30-hydrocarbon radical which is optionally substituted and contains heteroatoms and/or of a 4- to 20-membered aliphatic or aromatic mono- or polycyclic hydrocarbon radical which is optionally substituted and contains heteroatoms.
  • In a further preferred embodiment, the spacer structural element E is composed of two to four substructural elements, selected from the group consisting of E[0305] 1 and E2, where the sequence of linkage of the substructural elements is arbitrary and E1 and E2 have the following meanings:
  • E[0306] 1 is a substructural element of the formula IE1
  • —(YE)k1—(CRE 1RE 2)c—(QE)k2—(CRE 3RE 4)d—  IE1
  • and [0307]  
  • E[0308] 2 is a substructural element of the formula IE2
  • (NRE 11)k3—(CRE 5RE 6)f-(ZE)k4—(CRE 7RE 8)g—(XE)k5—(CRE 9RE 10)h—(NRE 11*)k6—  IE2,
  • where [0309]
  • c, d, f, g, h [0310]
  • independently of one another are 0, 1 or 2, [0311]
  • k1, k2, k3, k4, k5, k6 [0312]
  • independently of one another are 0 or 1, [0313]
  • X[0314] E, QE
  • independently of one another are 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 identical or different heteroatoms selected from the group consisting of N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, [0315]
  • Y[0316] E, ZE
  • independently of one another are CO, —N(R[0317] E 11)—, CO—NRE 12, NRE 12—CO, sulfur, SO, SO2, SO2—NRE 12, NRE 12—SO2, CS, CS—NRE 12, —C(RE 13)(CRE 14)—, NRE 12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE 13—O—CRE 14, C(═CRE 13RE 14), CRE 13═CRE 14, —CRE 13(ORE 15)—CHRE 14— or —CHRE 13—CRE 14(ORE 15)—,
  • R[0318] E 1, RE 2, RE 3, RE 4, RE 5, RE 6, RE 7, RE 8, RE 9, RE 10
  • independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C[0319] 1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE 17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical or independently of one another in each case two radicals RE 1 and RE 2 or RE 3 and RE 4 or RE 5 and RE 6 or RE 7 and RE 8 or RE 9 and RE 10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocycle or heterocycle which can contain up to three heteroatoms selected from the group consisting of O, N and S,
  • x is 0, 1, 2, 3 or 4, [0320]
  • z is 0 or 1, [0321]
  • W[0322] E is —CO—, —CO—N(RW 2)—, —N(RW 2)—CO—, —N(RW 2)—CO—N(RW 2*)—, —N(RW 2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW 2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW 2)—, —N(RW 2)— or —N(RW 2)—SO2—,
  • R[0323] W 2, RW 2*
  • independently of one another are hydrogen, a branched or unbranched, optionally substituted C[0324] 1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2-C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical,
  • R[0325] E 17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE 17 forms, together with RW 2 or RW 2* a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N,
  • R[0326] E 11, RE 11*
  • independently of one another are hydrogen, a branched or unbranched, optionally substituted C[0327] 1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, —CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, —CO-hetaryl, SO2-alkylenearyl, —SO2-hetaryl or SO2-alkylenehetaryl radical,
  • R[0328] E 12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl radical, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE 16, COORE 16 or SO2—RE 16,
  • R[0329] E 13, RE 14
  • independently of one another-are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C[0330] 1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
  • R[0331] E 15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
  • R[0332] E 16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical.
  • The coefficient c is preferably 0 or 1, the coefficient d is preferably 1 or 2, the coefficients f, g, h independently of one another are preferably 0 or 1 and k[0333] 6 is preferably 0.
  • 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 identical or different heteroatoms selected from the group consisting of N, O, S, where the ring carbons or ring nitrogens can optionally be substituted, for Q[0334] E and XE independently of one another is preferably understood as meaning optionally substituted arylene, such as optionally substituted phenylene or naphthylene, or optionally substituted hetarylene such as the radicals
    Figure US20040077638A1-20040422-C00012
  • and their substituted or fused derivatives, or radicals of the formulae I[0335] E 1 to IE 11,
    Figure US20040077638A1-20040422-C00013
    Figure US20040077638A1-20040422-C00014
  • where the incorporation of the radicals can take place in both orientations. Aliphatic hydrocarbons are understood as meaning, for example, saturated and unsaturated hydrocarbons. [0336]
  • Z[0337] 6 and Z7 are independently of one another CH or nitrogen.
  • Z[0338] 8 is oxygen, sulfur or NH,
  • Z[0339] 9 is oxygen, sulfur or NRE 20.
  • r1, r2, r3 and t are independently of one another 0, 1, 2 or 3. [0340]
  • s and u are independently of-one another 0, 1 or 2. [0341]
  • Particularly preferably, X[0342] E and QE independently of one another are optionally substituted phenylene, a radical
    Figure US20040077638A1-20040422-C00015
  • and their substituted or fused derivatives, or radicals of the formulae I[0343] E 1, IE 2, IE 3, IE 4 and IE 7, where the incorporation of the radicals can take place in both orientations.
  • R[0344] E 18 and RE 19 are independently of one another hydrogen, —NO2, —NH2, —CN, —COOH, a hydroxyl group, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, as in each case described above.
  • R[0345] E 20 is, independently of one another, hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C3-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical, preferably hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl radical.
  • Y[0346] E and ZE are independently of one another CO, —N(RE 11)—, CO—NRE 12, NRE 12—CO, sulfur, SO, SO2, SO2—NRE 12, NRE 12—SO2, CS, CS—NRE 12, NRE 12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, C(RE 13)(CRE 14) CRE 13—O—CRE 14, C(═CRE 13RE 14), CRE 13═CRE 14, —CRE 13(ORE 15)—CHRE 14— or —CHRE 13—CRE 14(ORE 15)—,
  • preferably oxygen, —N(R[0347] E 11)—, —C(RE 13)(CRE 14)-, CO—NRE 12, NRE 12—CO, SO2—NRE 12, NRE 12—SO2 or CRE 13CRE 14,
  • particularly preferably oxygen, —N(R[0348] E 11)—, —C(RE 13)(CRE 14)—, CO—NRE 12 or NRE 12—CO.
  • R[0349] E 12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl or C2-C8-alkynyl radical or an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical, such as correspondingly described above for RG 7 or a radical CO—RE 16, COORE 16 or SO2—RE 16, preferably hydrogen, methyl, allyl, propargyl and cyclopropyl.
  • A branched or unbranched, optionally substituted C[0350] 1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for RE 13, RE 14 or RE 15 independently of one another is understood as meaning, for example, the corresponding radicals described above for RG 7.
  • A branched or unbranched, optionally substituted C[0351] 1-C4-alkoxy radical for RE 13 or RE 14 independently of on another is understood as meaning, for example, the C1-C4-alkoxy radicals described above for RA 14.
  • Preferred alkylenecycloalkyl radicals for R[0352] E 13, RE 14 or RE 15 independently of one another are, for example, the C1-C4-alkylene-C3-C7-cycloalkyl radicals described above for RG 7.
  • A branched or unbranched, optionally substituted C[0353] 1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical for RE 16 is understood as meaning, for example, the corresponding radicals described above for RG 11.
  • A branched or unbranched, optionally substituted C[0354] 1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for RE 1, RE 2 RE 3, RE 4, RE 5, RE 6, RE 7, RE 8, RE 9 or RE 10 independently of one another is understood as meaning, for example, the corresponding radicals mentioned above for RG 7.
  • Further, two radicals R[0355] E 3 and RE 4 or RE 5 and RE 6 or RE 7 and RE 8 or RE 9 and RE 10 can in each case independently of one another together form a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocycle which can contain up to three heteroatoms from the group consisting of O, N and S.
  • The radical —(CH[0356] 2)x—(WE)z—RE 17 is composed of a C0-C4-alkylene radical, optionally a bonding element WE selected from the group consisting of
  • —CO—, —CO—N(R[0357] W 2)—, —N(RW 2)—CO—, —N(RW 2)—CO—N(RW 2*)—, —N(RW 2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW 2)—, —SO2—O—, —CO—O, —O—CO—, —O—CO—N(RW 2)—, —N(RW 2)— and —N(RW 2)—SO2—, preferably selected from the group consisting of —CO—N(RW 2)—, —N(RW 2)—CO—, —O—, —SO2N(RW 2), —N(RW 2)— and —N(RW 2)—SO2—, and the radical RE 17, where
  • R[0358] W 2 and RW 2*
  • independently of one another are hydrogen, a branched or unbranched, optionally substituted C[0359] 1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, preferably independently of on another are hydrogen, methyl, cyclopropyl, allyl, propargyl, and
  • R[0360] E 17
  • is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C[0361] 1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, such as optionally substituted 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, 6-pyridazinyl 2-(1,3,4-thiadiazolyl), 2-(1,3,4)-oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl or triazinyl.
  • Further, R[0362] E 17 and RW 2 or RW 2* can together form a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N.
  • Preferably, the radicals R[0363] E 17 and RW 2 or RW 2* together form a cyclic amine as the C3-C7-heterocycle in the case where the radicals are bonded to the same nitrogen atom, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl where in heterocycles which carry free amine protons, such as N-piperazinyl, the free amine protons can be replaced by customary amine protective groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO2—C1-C4-alkyl, —SO2-phenyl or —SO2-benzyl.
  • Preferred radicals for R[0364] E 1, RE 2, RE 3, RE 4, RE 5, RE 6, RE 7, RE 8, RE 9 or RE 10 are independently of one another hydrogen, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, optionally substituted aryl or the radical —(CH2)x—(WE)z—RE 17.
  • Particularly preferred radicals for R[0365] E 1, RE 2, RE 3, RE 4, RE 5, RE 6, RE 7, RE 8, RE 9 or RE 10 are independently of one another hydrogen, F, a branched or unbranched, optionally substituted C1-C4-alkyl radical, in particular methyl.
  • A branched or unbranched, optionally substituted C[0366] 1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6alkenyl, C2-C2-alkynyl or arylalkyl radical or an optionally substituted aryl, hetaryl or C3-C7-cycloalkyl for RE 11 and RE 11* in structural element E independently of one another is understood as meaning, for example, the corresponding radicals described above for RG 7.
  • The branched or unbranched, optionally substituted radicals CO—C[0367] 1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or the optionally substituted radicals CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl for RE 11 and RE 11* independently of one another are composed, for example, of the corresponding groups CO, COO, CONH or SO2 and the corresponding radicals mentioned above.
  • Preferred radicals for R[0368] E 11 or RE 11* are independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C12-alkynyl or arylalkyl radical, or an optionally substituted hetaryl or C3-C7-cycloalkyl radical.
  • Particularly preferred radicals for R[0369] E 11 or RE 11* are hydrogen, methyl, cyclopropyl, allyl or propargyl.
  • In a particularly preferred embodiment of structural element E[0370] 1, structural element E1 is a radical —CH2—CH2—CO—, —CH2—CH2—CH2—CO— or a C1-C5-alkylene radical.
  • In a particularly preferred embodiment of structural element E, the spacer structural element E used is a structural element of the formula I[0371] E1E2
  • -E2-E1-  IE1E2
  • where the structural elements E[0372] 2 and E1 have the meanings described above.
  • Preferred structural elements E are composed of at least one preferred radical of the radicals belonging to structural element E, while the remaining radicals are widely variable. [0373]
  • Particularly preferred structural elements E are composed of th preferred radicals of structural element E. [0374]
  • Preferred structural elements B are composed either of the preferred structural element A, whiled E is widely variable or of the preferred structural element E, while A is widely variable. [0375]
  • The compounds of the formula I, and also the intermediates for their preparation, can have one or more asymmetric substituted carbon atoms. The compounds can be present as pure enantiomers or pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as the active compound is preferred. [0376]
  • The compounds of the formula I can also be present in other tautomeric forms. [0377]
  • The compounds of the formula I can also be present in the form of physiologically tolerable salts. [0378]
  • The compounds of the formula I can also be present as prodrugs in a form in which the compounds of the formula I are liberated under physiological conditions. By way of example, reference may be made here to the group T in structural element L, which in some cases contains groups which are hydrolyzable to the free carboxylic acid group under physiological conditions. Also suitable are derivatized structural elements B or A which liberate the structural element B or A respectively under physiological conditions. [0379]
  • In preferred compounds of the formula I, in each case one of the three structural elements B, G or L has the preferred range, while the remaining structural elements are widely variable. [0380]
  • In particularly preferred compounds of the formula I, in each case two of the three structural elements B, G or L have the preferred range, while the remaining structural elements are widely variable. [0381]
  • In very particularly preferred compounds of th formula I, in each case all three structural elements B, G or L have the preferred range, while the remaining structural element is widely variable. [0382]
  • Preferred compounds of the formula I contain, for example, the preferred structural element G, while the structural elements B and L are widely variable. [0383]
  • In particularly preferred compounds of the formula I, for example, B is replaced by the structural element A-E- and the compounds contain, for example, the preferred structural element G and the preferred structural element A, while the structural elements E and L are widely variable. [0384]
  • Further particularly preferred compounds of the formula I contain, for example, the preferred structural element G and the preferred structural element A, while the structural elements E and L are widely variable. [0385]
  • Very particularly preferred compounds of the formula I in which A-E- is B- are listed below, the number before the text block being the number of an individualized compound of the formula I, and in the text block A-E-G-L the abbreviations being separated by a bonding dash in each case for an individual structural element A, E, G or L and the meaning of the abbreviations of the structural elements being explained after the table. [0386]
  • No. A-E-G-L [0387]
  • 1 bhs-but-noh-es [0388]
  • 2 im-ampap-noh-as [0389]
  • 3 bhs-n3o-cmh-gs [0390]
  • 4 bim-n4o-npy-ps [0391]
  • 5 mam2py-ampip-npy-es [0392]
  • 6 mam2py-ampap-cmh-as [0393]
  • 7 bim-ediao-nm-as [0394]
  • 8 bhs-ampip-cmm-ps [0395]
  • 9 mam2py-n5o-nm-as [0396]
  • 10 mam2py-pro-nmtf-as [0397]
  • 11 mam2py-pipeme2-cmm-es [0398]
  • 12 mam2py-apam-nmom-es [0399]
  • 13 bhs-n4o-cmm-gs [0400]
  • 14 bhs-n4o-npy-gs [0401]
  • 15 bhs-n3o-nom-ps [0402]
  • 16 dhim-but-nmtf-es [0403]
  • 17 mam2py-but-npy-as [0404]
  • 18 2py-ampip-noh-gs [0405]
  • 19 mam2py-pipa2-cmm-es [0406]
  • 20 bhs-n5o-nmtf-gs [0407]
  • 21 bhs-pipeme2-ncll-ps [0408]
  • 22 2py-but-npy-es [0409]
  • 23 mam2py-pipeme2-cmm-ps [0410]
  • 24 mam2py-ampap-noh-es [0411]
  • 25 bim-pipeme2-nm1-gs [0412]
  • 26 2py-ampip-cmm-es [0413]
  • 27 mam2py-ampap-nm-es [0414]
  • 28 2py-eam-nm-es [0415]
  • 29 bhs-penta-noh-ps [0416]
  • 30 bhs-n4o-nmom-gs [0417]
  • 31 mam2py-n4o-nomm-ps [0418]
  • 32 bim-pipeme2-cmm-as [0419]
  • 33 2py-ampip-cmm-gs [0420]
  • 34 2py-a2o2o-cmh-as [0421]
  • 35 2py-42thiaz2-nm-es [0422]
  • 36 2py-42thiaz2-cmm-es [0423]
  • 37 mam2py-pipeme2-nm-as [0424]
  • 38 2py-n3o-nomm-ps [0425]
  • 39 bhs-n4o-nm-as [0426]
  • 40 bim-apam-nomm-gs [0427]
  • 41 bim-42thiaz2-noh-es [0428]
  • 42 bhs-but-nomm-ps [0429]
  • 43 mam2py-apam-nomm-ps [0430]
  • 44 bhs-pipeme2-cmh-gs [0431]
  • 45 dhpyrr-n3o-nomm-ps [0432]
  • 46 bim-pipa2-cmh-gs [0433]
  • 47 bhs-42thiaz2-cmm-ps [0434]
  • 48 2py-n4o-npy-ps [0435]
  • 49 bim-pipeme2-cotf-gs [0436]
  • 50 bim-n5o-nmtf-gs [0437]
  • 51 2py-pipeme2-nm-es [0438]
  • 52 bim-pipeme2-cmh-es [0439]
  • 53 mam2py-n3o-nomm-as [0440]
  • 54 2py-ampap-nm-gs [0441]
  • 55 bhs-ampap-nm-as [0442]
  • 56 bhs-ampip-npy-gs [0443]
  • 57 mam2py-n3o-nm-gs [0444]
  • 58 2py-a2o2o-nm-es [0445]
  • 59 bhs-eam-cmm-ps [0446]
  • 60 bhs-penta-nm-es [0447]
  • 61 bim-n5o-cmh-es [0448]
  • 62 mam2py-apam-cmm-ps [0449]
  • 63 bim-ampap-noh-ps [0450]
  • 64 bim-penta-npy-es [0451]
  • 65 dhpyrr-but-nomm-gs [0452]
  • 66 bim-n3o-npy-as [0453]
  • 67 bim-n3o-noh-ps. [0454]
  • 68 mam2py-but-nm-gs, [0455]
  • 69 bhs-apam-cmm-as [0456]
  • 70 bim-42thiaz2-nomm-ps [0457]
  • 71 bhs-penta-nomm-es [0458]
  • 72 2py-penta-cmh-as [0459]
  • 73 bhs-apam-nmtf-as [0460]
  • 74 bhs-n3o-noh-ps [0461]
  • 75 2py-42thiaz2-cmh-as. [0462]
  • 76 bhs-mam3o-noh-as [0463]
  • 77 mam2py-ampip-nomm-gs [0464]
  • 78 2py-n3o-cmm-as [0465]
  • 79 bim-but-nmtf-ps [0466]
  • 80 mam2py-n4o-nth-es [0467]
  • 81 mam2py-n4o-cmh-as [0468]
  • 82 bim-but-run-es [0469]
  • 83 mam2py-n5o-noh-es [0470]
  • 84 2py-penta-npy-gs [0471]
  • 85 2py-apam-cmh-ps [0472]
  • 86 2py-but-cmh-as [0473]
  • 87 2py-apam-cmm-gs [0474]
  • 88 bim-but-nonum-es [0475]
  • 89 bhs-hexa-noh-as [0476]
  • 90 2py-penta-nom-as [0477]
  • 91 2py-ediao-npy-ps [0478]
  • 92 mam2py-ampap-nmtf-gs, [0479]
  • 93 mam2py-n4o-npy-ms [0480]
  • 94 bhs-ampip-cmh-as [0481]
  • 95 2py-ampip-nm-ps [0482]
  • 96 mam2py-but-cmm-as [0483]
  • 97 2py-n3o-cmh-as [0484]
  • 98 bim-n4o-cmh-gs [0485]
  • 99 mam2py-apam-noh-as [0486]
  • 100 bhs-but-cmh-as [0487]
  • 101 bhs-n3o-npy-es [0488]
  • 102 2py-apam-nm-ms [0489]
  • 103 mam2py-ampip-nomm-as [0490]
  • 104 bim-but-cmh-ps [0491]
  • 105 bim-but-cmm-ps [0492]
  • 106 bhs-but-npy-ps [0493]
  • 107 bhs-ampip-nmtf-gs [0494]
  • 108 bim-ampip-nm-ms [0495]
  • 109 2py-n4o-cmh-gs [0496]
  • 110 2py-ampap-cmm-gs [0497]
  • 111 mam2py-n5o-nomm-gs [0498]
  • 112 mam2py-pipeme2-cmh-ps [0499]
  • 113 bim-ampip-nm-ps [0500]
  • 114 mam2py-apam-npy-ps [0501]
  • 115 bhs-but-nomm-es [0502]
  • 116 mam2py-n4o-nom-es [0503]
  • 117 mam2py-n3o-cmm-ps [0504]
  • 118 bim-penta-noh-es [0505]
  • 119 bhs-n3o-noh-es [0506]
  • 120 2py-mea3-cmh-as [0507]
  • 121 mam2py-n2am-nomm-gs [0508]
  • 122 bhs-hexa-nm-gs [0509]
  • 123 mam2py-apam-cmh-es [0510]
  • 124 2py-n4o-nomm-gs [0511]
  • 125 bim-n3o-nmtf-as [0512]
  • 126 2py-apam-nomm-ps [0513]
  • 127 mam2py-apam-cmh-as [0514]
  • 128 bhs-ampap-cmm-gs [0515]
  • 129 bhs-n3o-cmh-es [0516]
  • 130 2py-pipeme2-cmh-as [0517]
  • 131 2py-penta-cmm-gs [0518]
  • 132 mam2py-n5o-npy-as [0519]
  • 133 bim-n5o-cmm-gs [0520]
  • 134 bim-ampip-npy-es [0521]
  • 135 2py-pipeme2-cmm-gs [0522]
  • 136 mam2py-n5o-cmm-es [0523]
  • 137 2py-n4o-nm-gs [0524]
  • 138 bhs-ampip-nomm-gs [0525]
  • 139 mam2py-ampmp-cmtf gs [0526]
  • 140 bhs-penta-nmtf-es [0527]
  • 141 bhs-n5o-cmh-ps [0528]
  • 142 mam2py-n4o-noh-ps [0529]
  • 143 2py-but-cmm-gs [0530]
  • 144 bim-apam-npy-as [0531]
  • 145 bim-n5o-cmm-ps [0532]
  • 146 bhs-penta-noh-es [0533]
  • 147 bhs-pipeme2-npy-es [0534]
  • 148 bim-pipeme2-cmm-ps [0535]
  • 149 mam2py-ampap-npy-gs [0536]
  • 150 mam2py-mam3o-cmm-es [0537]
  • 151 bim-mam-nomm-ps [0538]
  • 152 mam2py-pipeme2-cmh-gs [0539]
  • 153 bim-n4o-nm-as [0540]
  • 154 2py-diao-nomm-gs [0541]
  • 155 2py-but-cmm-as [0542]
  • 156 2py-apam-cmm-s [0543]
  • 157 2py-n3o-nmtf-as [0544]
  • 158 bhs-but-noh-ps [0545]
  • 159 2py-but-nm-es [0546]
  • 160 bim-n5am-nmtf-es [0547]
  • 161 bim-n4o-nmtf-es [0548]
  • 162 mam2py-but-noh-ps [0549]
  • 163 2py-penta-nmtf-as [0550]
  • 164 bim-pipeme2-nrtf-as [0551]
  • 165 bim-n3o-cmh-gs [0552]
  • 166 2py-pipeme2-cmh-ps [0553]
  • 167 mampy-a2o2o-nomm-gs [0554]
  • 168 2py-but-nm-as [0555]
  • 169 bim-ampap-nomm-gs [0556]
  • 170 mam2py-ampip-nmtf-gs [0557]
  • 171 bim-apam-nomm-as [0558]
  • 172 bhs-n4o-npy-ps [0559]
  • 173 bim-but-noh-ps [0560]
  • 174 bhs-penta-cmm-es [0561]
  • 175 bhs-aaf-cmm-ps [0562]
  • 176 2py-ampip-cmm-as [0563]
  • 177 bim-n5o-noh-ms [0564]
  • 178-2py-n5o-npy-es [0565]
  • 179 mam2py-pipeme2-nm-gs [0566]
  • 180 bhs-but-nm-ps [0567]
  • 181 thpym-n5o-npy-ps [0568]
  • 182 bhs-ampap-noh-as [0569]
  • 183 bim-n3o-npy-ps [0570]
  • 184 2py-ampap-npy-es [0571]
  • 185 mam2py-n5o-cmh-as [0572]
  • 186 bhs-penta-cmh-es [0573]
  • 187 bhs-ampip-npy-ps [0574]
  • 188 2py-n5o-cmh-gs [0575]
  • 189 bim-but-cmh-es [0576]
  • 190 mam2py-n3o-cmm-as [0577]
  • 191 bim-but-nm-gs [0578]
  • 192 mam2py-pipeme2-npy-as [0579]
  • 193 mam2py-penta-cmh-as [0580]
  • 194 bhs-ampip-nm-as [0581]
  • 195 bim-pipeme2-nmom-gs [0582]
  • 196 2py-penta-nm-ps [0583]
  • 197 bhs-n3o-ncll-ps [0584]
  • 198 2py-mea3-nm-es [0585]
  • 199 2py-ampip-nmtf-es [0586]
  • 200 2py-but-noh-as [0587]
  • 201 mam2py-penta-npy-ps [0588]
  • 202 bim-ampap-cmm-gs [0589]
  • 203 bim-n5o-nmtf-ps [0590]
  • 204 2py-n5o-nomm-es [0591]
  • 205 bhs-ampap-cmh-es [0592]
  • 206 bim-ampip-nth-as [0593]
  • 207 bim-n5o-noh-es [0594]
  • 208 bhs-n4o-npy-as [0595]
  • 209 2py-n3o-nm-as [0596]
  • 210 mam2py-but-cmh-as [0597]
  • 211 bim-n3o-nomm-ms [0598]
  • 212 bhs-pipeme2-nm-es [0599]
  • 213 mam2py-ampip-nm-es [0600]
  • 214 2py-but-cmm-es [0601]
  • 215 bim-ampap-nm-ps [0602]
  • 216 bhs-ampap-cmh-as [0603]
  • 217 bhs-but-nmtf-gs [0604]
  • 218 bhs-mam3o-nmtf-ps [0605]
  • 219 bhs-pipeme2-nm-as [0606]
  • 220 2py-n5o-nmtf-as [0607]
  • 221 2py-n5o-noh-gs [0608]
  • 222 bim-n2am-nm-as [0609]
  • 223 bhs-n5o-cmm-as [0610]
  • 224 bhs-ampip-nmtf-as [0611]
  • 225 2py-n5o-npy-gs [0612]
  • 226 im-but-nomm-gs [0613]
  • 227 bim-ampip-npy-gs [0614]
  • 228 bhs-ampip-nm-es [0615]
  • 229 bim-n4o-npy-gs [0616]
  • 230 bim-apam-nmtf-ps [0617]
  • 231 2py-penta-npy-as [0618]
  • 232 bim-penta-npy-gs [0619]
  • 233 bim-n5o-noh-as [0620]
  • 234 bim-aaf-nomm-ps [0621]
  • 235 2py-apam-nmtf-gs [0622]
  • 236 bim-n5o-npy-as [0623]
  • 237 2py-n4o-nmtf-gs [0624]
  • 238 bim-ampip-nmtf-ps [0625]
  • 239 bim-penta-npy-as [0626]
  • 240 2py-n4o-cmm-ps [0627]
  • 241 bhs-pipeme2-noh-ps [0628]
  • 242 2py-n5o-nomm-as [0629]
  • 243 bhs-pro-nm-gs [0630]
  • 244 2py-but-npy-as [0631]
  • 245 2py-ampip-nomm-ps [0632]
  • 246 mam2py-n5o-npy-ps [0633]
  • 247 bim-ampap-cmh-ps [0634]
  • 248 bim-mam3o-nm-as [0635]
  • 249 bim-ampap-cmh-as [0636]
  • 250 bim-n5o-nmtf-es [0637]
  • 251 2py-pipeme2-nm-as [0638]
  • 252 am2py-n4o-npy-es [0639]
  • 253 bim-apamr-nmtf-as [0640]
  • 254 2py-ampip-nomm-gs [0641]
  • 255 mam2py-n4o-noh-as [0642]
  • 256 bhs-penta-nm-as [0643]
  • 257 2py-n4o-nomm-es [0644]
  • 258 impy-penta-cmh-as [0645]
  • 259 bhs-n3am-nm-gs [0646]
  • 260 2py-penta-npy-es [0647]
  • 261 2py-ampap-npy-gs [0648]
  • 262 bim-n3o-npy-es [0649]
  • 263 bim-but-nomm-ps [0650]
  • 264 2py-penta-noh-as [0651]
  • 265 bim-n3o-nml-ps [0652]
  • 266 2py-n4o-nmtf-es [0653]
  • 267 bim-n4o-cmm-es [0654]
  • 268 am2py-n5o-noh-es [0655]
  • 269 pippy-apam-cmm-es [0656]
  • 270 2py-ampip-nmtf-gs [0657]
  • 271 2py-ampap-cmm-as [0658]
  • 272 bim-ampip-nomm-ps [0659]
  • 273 mam2py-pipeme2-nmtf-es [0660]
  • 274 impy-n3o-rumtf-ps [0661]
  • 275 bim-ampip-rm-as [0662]
  • 276 bim-n5am-nm-as [0663]
  • 277 bhs-n3o-cmm-as [0664]
  • 278 2py-n3o-cmh-es [0665]
  • 279 mam2py-n4o-nmtf-es [0666]
  • 280 bhs-ampap-cmh-gs [0667]
  • 281 bhs-ampip-noh-gs [0668]
  • 282 bhs-n5o-nomm-es [0669]
  • 283 2py-n5o-noh-ps [0670]
  • 284 2py-ampap-noh-ps [0671]
  • 285 bim-n4o-cmm-as. [0672]
  • 286 2py-ampap-nmtf-gs [0673]
  • 287 2py-edia2-npy-ps [0674]
  • 288 mam2py-penta-nmtf-ps [0675]
  • 289 bim-pipeme2-nmo-gs [0676]
  • 290 bhs-n3o-nm-es [0677]
  • 291 2py-n5o-cmm-es [0678]
  • 292 bhs-apam-cmh-as [0679]
  • 293 bim-diam-nomm-ps [0680]
  • 294 2py-pipeme2-nmtf-as. [0681]
  • 295 bhs-penta-npy-es [0682]
  • 296 bhs-n5o-npy-es [0683]
  • 297 bim-n5o-cmh-gs [0684]
  • 298 bhs-apam-noh-as [0685]
  • 299 2py-but-cotf-gs [0686]
  • 300 2py-n3o-noh-gs [0687]
  • 301 mam2py-penta-noh-ps [0688]
  • 302 bhs-n5o-nmtf-es [0689]
  • 303 mam2py-apam-cmm-es [0690]
  • 304 2py-n3o-nmtf-gs [0691]
  • 305 mam2py-but-nmtf-gs [0692]
  • 306 bim-n3o-cmm-ps [0693]
  • 307 bhs-ampip-cmh-gs [0694]
  • 308 bim-ampip-noh-es [0695]
  • 309 mam2py-penta-nmtf-ms [0696]
  • 310 bhs-n2am-nmtf-ps [0697]
  • 311 mam2py-n3o-nmtf-as [0698]
  • 312 thpym-apam-cmm-es [0699]
  • 313 2py-penta-cmh-ps [0700]
  • 314 bhs-diam-cmm-ps [0701]
  • 315 bim-but-cmm-gs [0702]
  • 316 mam2py-ampap-nom-gs [0703]
  • 317 bim-but-nmtf-gs [0704]
  • 318 bhs-pipeme2-nomm-gs [0705]
  • 319 2py-ampip-npy-es [0706]
  • 320 im-apam-cmm-es [0707]
  • 321 bhs-penta-cmh-as [0708]
  • 322 2py-n4o-nm-es [0709]
  • 323 mam2py-ampap-noh-gs [0710]
  • 324 mam2py-apam-nmtf-as [0711]
  • 325 2py-eam-cmh-as [0712]
  • 326 bim-but-cmh-gs [0713]
  • 327 2py-n5o-npy-ms [0714]
  • 328 2py-apam-noh-gs [0715]
  • 329 2py-mam3o-nomm-gs [0716]
  • 330 2py-n3o-npy-ps [0717]
  • 331 2py-n5o-cmm-ps [0718]
  • 332 bim-n3o-cotf-ps [0719]
  • 333 mam2py-ediao-nmtf-as [0720]
  • 334 bim-n5o-nm-es [0721]
  • 335 bhs-ampap-noh-nms [0722]
  • 336 2py-pipeme2-noh-es [0723]
  • 337 bim-aaf-noh-es [0724]
  • 338 mam2py-diam-npy-es [0725]
  • 339 bim-pipeme2-nm-gs [0726]
  • 340 2py-but-nmom-gs [0727]
  • 341 mam2py-pipeme2-cmm-as [0728]
  • 342 2py-n5o-cmm-gs [0729]
  • 343 bhs-apam-nm-ps [0730]
  • 344 bim-n3o-nm-gs [0731]
  • 345 bhs-diam-nmtf-ps [0732]
  • 346 pippy-pipeme2-cmh-gs [0733]
  • 347 bhs-but-nmtf-es [0734]
  • 348 am2py-pipeme2-cmm-ps [0735]
  • 349 mam2py-n5o-npy-es [0736]
  • 350 bhs-ampap-nomm-es [0737]
  • 351 bim-n3o-nmo-ps [0738]
  • 352 bhs-n4o-noh-as [0739]
  • 353 bim-mea3-nomm-ps [0740]
  • 354 bhs-penta-cmm-ps [0741]
  • 355 bim-n3am-nomm-ps [0742]
  • 356 2py-n3am-cmm-es [0743]
  • 357 dhim-ampap-nomm-gs [0744]
  • 358 mam2py-n4o-npy-as [0745]
  • 359 bim-ampip-nom-as [0746]
  • 360 2py-n3o-nmtf-es [0747]
  • 361 mam2py-pipeme2-cmm-gs [0748]
  • 362 2py-pro-nomm-gs [0749]
  • 363 2py-penta-nm-gs [0750]
  • 364 mam2py-penta-nmo-as [0751]
  • 365 bhs-ampap-nmtf-gs [0752]
  • 366 2py-but-nm-ps [0753]
  • 367 2py-n5am-nm-es [0754]
  • 368 2py-penta-nmtf-gs [0755]
  • 369 bim-n3am-nm-as [0756]
  • 370 2py-penta-cmh-ms [0757]
  • 371 bhs-n5o-nm-es [0758]
  • 372 mam2py-n3o-nmtf-ps [0759]
  • 373 bhs-n5am-nmtf-ps [0760]
  • 374 bim-4o-nm-gs [0761]
  • 375 bhs-n5o-nm-as [0762]
  • 376 bim-chex2-cmh-gs [0763]
  • 377 mam2py-penta-nm-gs [0764]
  • 378 2py-n5o-nm-gs [0765]
  • 379 2py-pipeme2-npy-ps [0766]
  • 380 mam2py-apam-nm-as [0767]
  • 381 mam2py-ampip-npy-as [0768]
  • 382 bim-a2o2o-nomm-ps [0769]
  • 383 mam2py-ampap-noh-ps [0770]
  • 384 bim-pipeme2-npy-es [0771]
  • 385 bhs-pipeme2-npy-gs [0772]
  • 386 mam2py-ampap-cmh-ps [0773]
  • 387 bhs-ampap-nomm-gs [0774]
  • 388 bim-apam-cmh-es [0775]
  • 389 bhs-apam-cmh-es [0776]
  • 390 thpym-n4o-nm-gs [0777]
  • 391 2py-apam-cmh-as [0778]
  • 392 im-ampip-nm-as [0779]
  • 393 bhs-n3o-nomm-ps [0780]
  • 394 mam2py-pipeme2-nomm-gs [0781]
  • 395 bim-ampap-nomm-as [0782]
  • 396 bim-penta-noh-gs [0783]
  • 397 bim-a2o2o-noh-es [0784]
  • 398 bim-pro-cmh-gs [0785]
  • 399 mam2py-hexa-nmtf-as [0786]
  • 400 bhs-ampip-npy-as [0787]
  • 401 2py-pipeme2-noh-gs [0788]
  • 402 2py-n3am-nomm-gs [0789]
  • 403 bhs-apam-nmtf-ps [0790]
  • 404 bim-n3am-cmh-gs [0791]
  • 405 bim-pipeme2-nm-es [0792]
  • 406 bim-n4o-nomm-gs [0793]
  • 407 mam2py-but-cmm-ps [0794]
  • 408 bim-n4o-nomm-as [0795]
  • 409 bim-pipeme2-cmm-gs [0796]
  • 410 bim-ampip-noh-gs [0797]
  • 411 mam2py-n3o-npy-es [0798]
  • 412 mam2py-ampip-noh-ps [0799]
  • 413 bhs-penta-cmm-as [0800]
  • 414 mam2py-penta-nomm-ps [0801]
  • 415 bhs-penta-nomm-as [0802]
  • 416 bhs-hexa-nmtf-ps [0803]
  • 417 mam2py-n3o-cmh-ps [0804]
  • 418 bhs-n4o-cmh-gs [0805]
  • 419 bim-n5o-nm-ps [0806]
  • 420 gua-penta-cmh-as. [0807]
  • 421 bhs-apam-cmh-ps [0808]
  • 422 mam2py-pipeme2-cmh-es [0809]
  • 423 2py-penta-cmh-gs [0810]
  • 424 bim-n3o-nm-as [0811]
  • 425 2py-pipeme2-nomm-ps [0812]
  • 426 gua-but-nmtf-es [0813]
  • 427 2py-ampap-npy-ps [0814]
  • 428 2py-ampip-cmm-ms [0815]
  • 429 bhs-but-cmm-es [0816]
  • 430 2py-ampap-nomm-ps [0817]
  • 431 bim-apam-nm-es [0818]
  • 432 2py-chex2-npy-ps [0819]
  • 433 bhs-ampip-nomm-as [0820]
  • 434 mam2py-ampip-nomm-ps [0821]
  • 435 bim-but-npy-ps [0822]
  • 436 mam2py-pipeme2-nomm-es [0823]
  • 437 mam2py-n3o-cmm-es [0824]
  • 438 2py-mam-npy-ps [0825]
  • 439 mam2py-edia2-cmm-es [0826]
  • 440 bhs-n3o-nmtf-es [0827]
  • 441 2py-n4o-npy-gs [0828]
  • 442 2py-pipeme2-cmm-ps [0829]
  • 443 bim-n5o-cmm-es. [0830]
  • 444 dhim-n5o-noh-es [0831]
  • 445 gua-n5o-noh-es [0832]
  • 446 mam2py-penta-cotf-as [0833]
  • 447 2py-diam-cmm-es [0834]
  • 448 mam2py-mea3-npy-es [0835]
  • 449 bhs-apam-nomm-ps [0836]
  • 450 mam2py-apam-nomm-as [0837]
  • 451 bhs-ampap-nm-gs [0838]
  • 452 mam2py-n5o-nmtf-es [0839]
  • 453 mam2py-ampap-nm-gs [0840]
  • 454 2py-n4o-cmh-es [0841]
  • 455 bhs-pipeme2-nmtf-as [0842]
  • 456 2py-ampap-cmm-ps [0843]
  • 457 mam2py-n3o-nomm-es [0844]
  • 458 bim-n5o-nomm-as [0845]
  • 459 2py-ampip-cotf-es [0846]
  • 460 2py-n3o-nm-gs [0847]
  • 461 2py-but-nmtf-es [0848]
  • 462 bhs-n4o-nomm-es. [0849]
  • 463 mam2py-ediao-cmm-es [0850]
  • 464 mam2py-penta-nmtf-gs [0851]
  • 465 bhs-pipeme2-cmh-ps [0852]
  • 466 bim-penta-noh-as [0853]
  • 467 2py-apam-nmtf-as [0854]
  • 468 2py-n4o-npy-es [0855]
  • 469 mam2py-apam-nomm-es [0856]
  • 470 mam2py-ampap-nomm-es [0857]
  • 471 bhs-apam-npy-es [0858]
  • 472 mam2py-ampap-nomm-es [0859]
  • 473 mam2py-but-nm-es [0860]
  • 474 mam2py-pro-cmm-es [0861]
  • 475 mam2py-ampap-npy-ps [0862]
  • 476 pippy-n4o-nm-gs [0863]
  • 477 bhs-pipa2-noh-as [0864]
  • 478 bhs-n56-nm-ps [0865]
  • 479 mam2py-n3am-nmtf-as [0866]
  • 480 bim-n5o-nomm-ps [0867]
  • 481 bim-n4o-ran-es [0868]
  • 482 bhs-n5o-cmm-es [0869]
  • 483 bhs-penta-npy-gs [0870]
  • 484 bhs-ampip-npy-es [0871]
  • 485 bim-penta-cmh-es [0872]
  • 486 bhs-apam-npy-as [0873]
  • 487 bhs-n4o-cmh-es [0874]
  • 488 bhs-n3o-noh-gs [0875]
  • 489 bim-pipeme2-nmtf-s [0876]
  • 490 2py-chex2-nomm-gs [0877]
  • 491 bim-penta-nmtf-ps [0878]
  • 492 bim-n4o-npy-as [0879]
  • 493 bim-ampap-nmtf-gs [0880]
  • 494 bim-ampip-npy-as [0881]
  • 495 2py-n3o-nomm-es [0882]
  • 496 bim-ampap-cmh-gs [0883]
  • 497 impy-ampap-nomm-gs [0884]
  • 498 bim-apam-nomm-es [0885]
  • 499 2py-n4o-noh-ps [0886]
  • 500 bhs-n5o-cmh-gs [0887]
  • 501 bhs-penta-nmtf-gs [0888]
  • 502 dhpyrr-ampip-cmm-es [0889]
  • 503 2py-apam-nm-gs [0890]
  • 504 mam2py-ampap-nomm-ms [0891]
  • 505 2py-ampip-nm-as [0892]
  • 506 bhs-but-cmh-gs [0893]
  • 507 mam2py-apam-nmtf-es [0894]
  • 508 2py-n5o-nomm-gs [0895]
  • 509 bim-ampap-nmtf-es [0896]
  • 510 bhs-a2o2o-cmm-ps [0897]
  • 511 mam2py-but-noh-es [0898]
  • 512 2py-n3o-nm-es [0899]
  • 513 bim-but-cmtf-es [0900]
  • 514 2py-but-nmtf-gs [0901]
  • 515 2py-pipeme2-nomm-gs [0902]
  • 516 mam2py-ampap-nm-ps [0903]
  • 517 2py-n5o-nmo-ps [0904]
  • 518 2py-n3o-noh-ps [0905]
  • 519 2py-apam-cmm-as [0906]
  • 520 bhs-ampap-nmo-as [0907]
  • 521 bim-mam-cmh-gs [0908]
  • 522 2py-ampip-nmom-es [0909]
  • 523 2py-apam-cmh-gs [0910]
  • 524 bhs-n3o-npy-as [0911]
  • 525 bim-but-noh-es [0912]
  • 526 bhs-n5o-cmh-es [0913]
  • 527 bhs-n5o-nomm-gs [0914]
  • 528 bhs-penta-nm-ps [0915]
  • 529 bhs-ampap-cmm-ps [0916]
  • 530 bim-ediao-cmh-gs [0917]
  • 531 mam2py-apam-nmtf-ps [0918]
  • 532 2py-apam-nth-es [0919]
  • 533 am2py-apam-nm-es [0920]
  • 534 am2py-n3o-npy-gs [0921]
  • 535 2py-n3o-npy-es [0922]
  • 536 bim-n3o-cmh-es [0923]
  • 537 bim-pipeme2-noh-es [0924]
  • 538 mam2py-penta-cmm-ps [0925]
  • 539 bhs-pipa2-nm-gs [0926]
  • 540 bhs-ampap-cotf-as [0927]
  • 541 mam2py-but-npy-ps [0928]
  • 542 bhs-n5o-npy-ps [0929]
  • 543 dhpyrr-penta-nmtf-as [0930]
  • 544 bhs-ampap-nmtf-as [0931]
  • 545 mam2py-ampip-cmh-es [0932]
  • 546 bim-apam-nm-gs [0933]
  • 547 mam2py-ampap-cmm-as [0934]
  • 548 2py-n5o-nmtf-ps [0935]
  • 549 im-n3o-nomm-ps [0936]
  • 550 bim-penta-nmtf-as [0937]
  • 551 bim-n4o-nmtf-as [0938]
  • 552 2py-apam-noh-es [0939]
  • 553 bim-pipeme2-nomm-as [0940]
  • 554 2py-n5o-nm-es [0941]
  • 555 2py-penta-nomm-ps [0942]
  • 556 bhs-ampap-cmh-ps [0943]
  • 557 mam2py-mam-nmtf-as [0944]
  • 558 bhs-penta-nm-gs [0945]
  • 559 bim-ampip-npy-ps [0946]
  • 560 2py-ampip-nm-gs [0947]
  • 561 bim-mam3o-cmh-gs [0948]
  • 562 mam2py-pipeme2-nomm-ps [0949]
  • 563 bhs-n3o-cmh-as [0950]
  • 564 bhs-pipeme2-nmtf-ps [0951]
  • 565 2py-but-nmo-gs [0952]
  • 566 bim-ampip-cmtf-as [0953]
  • 567 bhs-ampap-noh-es [0954]
  • 568 bim-pipeme2-npy-ps [0955]
  • 569 mam2py-pipeme2-nmtf-gs [0956]
  • 570 mam2py-ampap-nth-gs [0957]
  • 571 bhs-apam-npy-gs [0958]
  • 572 2py-penta-nm-as [0959]
  • 573 am2py-eam-nomm-gs [0960]
  • 574 bhs-ampip-noh-as [0961]
  • 575 2py-but-noh-es [0962]
  • 576 dhim-n3o-nmtf-ps [0963]
  • 577 mam2py-n4o-cmm-as [0964]
  • 578 bim-eam-nmtf-es [0965]
  • 579 bim-but-npy-as [0966]
  • 580 bim-but-cmh-as [0967]
  • 581 2py-ampip-noh-es [0968]
  • 582 mam2py-pipeme2-noh-gs [0969]
  • 583 bim-ampip-ncl1-as [0970]
  • 584 mam2py-ampip-nm-gs [0971]
  • 585 2py-n5o-nm-ps [0972]
  • 586 2py-pipeme2-npy-gs [0973]
  • 587 bim-ampap-noh-gs [0974]
  • 588 2py-ampap-nomm-es [0975]
  • 589 2py-apam-nmtf-ps [0976]
  • 590 bhs-penta-cmh-gs [0977]
  • 591 bim-penta-cmm-ps [0978]
  • 592 bim-pipeme2-nomm-es [0979]
  • 593 bhs-but-cmm-as [0980]
  • 594 2py-ampap-nmtf-as [0981]
  • 595 2py-ampap-cmm-es [0982]
  • 596 bhs-n3o-cmm-ps [0983]
  • 597 bim-n5o-noh-gs [0984]
  • 598 mam2py-n4o-nmtf-gs [0985]
  • 599 bim-pipeme2-cmh-ms [0986]
  • 600 2py-n4o-nm-as [0987]
  • 601 bhs-n4o-noh-gs [0988]
  • 602 thpym-pipeme2-cmh-gs [0989]
  • 603 bim-apam-noh-as [0990]
  • 604 bhs-ampip-nmtf-ps [0991]
  • 605 bhs-ampap-npy-gs [0992]
  • 606 mam2py-ampap-nmtf-ps [0993]
  • 607 2py-ampip-noh-ps [0994]
  • 608 mam2py-n3am-cmm-es [0995]
  • 609 2py-ampap-nm-ps [0996]
  • 610 mam2py-apam-cotf-es [0997]
  • 611 bhs-penta-npy-as [0998]
  • 612 mam2py-n4o-npy-gs, [0999]
  • 613 mam2py-penta-nmtf-es [1000]
  • 614 mam2py-n3o-cmh-es [1001]
  • 615 bim-n3o-nomm-as [1002]
  • 616 2py-ampip-cmh-gs [1003]
  • 617 2py-n4o-noh-es [1004]
  • 618 bhs-but-npy-as [1005]
  • 619 bim-ampip-cmm-gs [1006]
  • 620 am2py-ampap-nomm-gs [1007]
  • 621 2py-ampap-nmtf-es [1008]
  • 622 bim-n3o-noh-gs [1009]
  • 623 bim-eam-nm-as [1010]
  • 624 bim-n4o-cmm-gs [1011]
  • 625 bhs-penta-nmtf-ps [1012]
  • 626 2py-ampip-cmh-es [1013]
  • 627 bim-but-npy-es [1014]
  • 628 bhs-pipeme2-cmtf-ps [1015]
  • 629 bhs-ampap-cmm-as [1016]
  • 630 bim-ampap-nomm-es [1017]
  • 631 bim-ampip-cmh-ps [1018]
  • 632 2py-apam-ncl1-es [1019]
  • 633 mam2py-n3o-cmm-gs [1020]
  • 634 mam2py-apam-nm-es [1021]
  • 635 bhs-n5o-cmm-ps [1022]
  • 636 pippy-n5o-npy-ps [1023]
  • 637 bhs-n5o-nmtf-as [1024]
  • 638 mam2py-n5o-nomm-as [1025]
  • 639 bim-edia2-cmh-gs [1026]
  • 640 bim-ampip-cmh-es [1027]
  • 641 mam2py-pipeme2-nomm-as [1028]
  • 642 bim-n5o-nomm-gs [1029]
  • 643 bhs-n3o-nm-as [1030]
  • 644 2py-pipeme2-cmm-as [1031]
  • 645 bhs-pipeme2-nmtf-gs [1032]
  • 646 mam2py-penta-npy-gs [1033]
  • 647 mam2py-n5o-cmm-ps [1034]
  • 648 bim-n4o-nomm-ps [1035]
  • 649 bhs-n4o-nomm-ps [1036]
  • 650 2py-n3o-cmm-ps [1037]
  • 651 2py-ampip-nmtf-ps [1038]
  • 652 bhs-ediao-nm-gs [1039]
  • 653 bim-ampap-nomm-ps [1040]
  • 654 2py-ampap-nomm-gs [1041]
  • 655 mam2py-ampip-noh-as [1042]
  • 656 2py-ampap-nm-es [1043]
  • 657 2py-apam-nomm-es [1044]
  • 658 bim-n5o-ncl1-es [1045]
  • 659 mam2py-ampip-npy-ps [1046]
  • 660 2py-n5o-cmh-as [1047]
  • 661 bhs-ampap-nmom-as [1048]
  • 662 bim-n5o-nomm-es [1049]
  • 663 mam2py-n4o-cmh-ps [1050]
  • 664 dhim-penta-cmh-as [1051]
  • 665 bim-apam-cmh-as [1052]
  • 666 2py-penta-noh-ps [1053]
  • 667 bim-hexa-nm-as [1054]
  • 668 2py-but-nomm-gs [1055]
  • 669 bhs-n3o-nm-ps [1056]
  • 670 mam2py-chex2-nmtf-as [1057]
  • 671 bhs-edia2-nm-gs [1058]
  • 672 bim-ampap-nmtf-ps [1059]
  • 673 mam2py-n3o-nm-as [1060]
  • 674 bim-pipeme2-noh-as [1061]
  • 675 bhs-pipeme2-nm-gs [1062]
  • 676 bim-apam-cmm-as [1063]
  • 677 impy-n4o-npy-es [1064]
  • 678 bim-n4o-nomm-es [1065]
  • 679 bim-ampip-nmtf-es [1066]
  • 680 2py-ampap-cmh-as [1067]
  • 681 mampy-aaf-nomm-gs [1068]
  • 682 bhs-apam-noh-es [1069]
  • 683 bhs-ampip-nomm-ps [1070]
  • 684 bhs-n3o-nomm-gs [1071]
  • 685 bhs-apam-nmtf-es [1072]
  • 686 bim-n4o-noh-ps [1073]
  • 687 2py-mam3o-npy-ps [1074]
  • 688 bim-ampap-npy-ps [1075]
  • 689 im-n4o-nm-gs [1076]
  • 690 bim-but-nom-es [1077]
  • 691 bhs-ampip-cmh-es [1078]
  • 692 bhs-but-cmh-ps [1079]
  • 693 2py-ampap-cmh-es [1080]
  • 694 bhs-n5o-noh-as [1081]
  • 695 2py-but-nomm-as [1082]
  • 696 2py-n5o-cmh-ps [1083]
  • 697 mam2py-ampap-ncl1-gs [1084]
  • 698 bim-apam-nomm-ps [1085]
  • 699 2py-penta-cmh-es [1086]
  • 700 bim-penta-nm-gs [1087]
  • 701 bim-n56-npy-gs [1088]
  • 702 bhs-n3o-npy-ps [1089]
  • 703 bhs-n3o-nmtf-ms [1090]
  • 704 bhs-mam-nm-gs [1091]
  • 705 2py-ampip-npy-ps [1092]
  • 706 dhim-n4o-npy-es [1093]
  • 707 2py-n4o-cmm-gs [1094]
  • 708 impy-but-nmtf-es [1095]
  • 709 bhs-n5o-nm-gs [1096]
  • 710 2py-pipeme2-nmtf-es [1097]
  • 711 bhs-ediao-noh-as [1098]
  • 712 bim-n3o-nomm-ps [1099]
  • 713 bim-n4o-noh-as [1100]
  • 714 mam2py-n4o-nmtf-ps [1101]
  • 715 2py-pipeme2-npy-es [1102]
  • 716 bhs-penta-noh-as [1103]
  • 717 2py-pipeme2-noh-ps [1104]
  • 718 2py-pipa2-cmm-es [1105]
  • 719 bhs-but-cmh-es [1106]
  • 720 2py-apam-npy-es [1107]
  • 721 bhs-pipeme2-cmh-as [1108]
  • 722 bhs-pipeme2-cmm-gs [1109]
  • 723 am2py-ampip-nm-as [1110]
  • 724 bim-ampip-nm-gs [1111]
  • 725 2py-hexa-nomm-gs [1112]
  • 726 bim-n3o-cmm-gs [1113]
  • 727 bhs-penta-npy-ps [1114]
  • 728 bhs-pipeme2-nomm-ps [1115]
  • 729 2py-penta-cmtf-as [1116]
  • 730 bim-ampap-noh-as [1117]
  • 731 bhs-ampap-nomm-ps [1118]
  • 732 bim-apam-cmm-ps [1119]
  • 733 2py-diam-cmh-as [1120]
  • 734 bim-ampip-nomm-gs [1121]
  • 735 mam2py-ampip-noh-gs [1122]
  • 736 bim-but-nm-ps [1123]
  • 737 mam2py-but-nmtf-ps [1124]
  • 738 bhs-n36-nm-gs [1125]
  • 739 bim-penta-nomm-ps [1126]
  • 740 bim-n3o-noh-as [1127]
  • 741 2py-apam-nm-ps [1128]
  • 742 mam2py-but-nm-as [1129]
  • 743 bim-ampip-noh-as [1130]
  • 744 bim-ampip-nmtf-as [1131]
  • 745 bhs-ampip-nomm-es [1132]
  • 746 mam2py-n5o-nm-gs [1133]
  • 747 mam2py-ampip-cmm-as [1134]
  • 748 mam2py-n4o-cmh-gs [1135]
  • 749 2py-apam-cmm-ps [1136]
  • 750 2py-n3o-nmtf-ps [1137]
  • 751 dhpyrr-ampap-noh-as [1138]
  • 752 bhs-apam-npy-ps [1139]
  • 753 mam2py-n3o-npy-as [1140]
  • 754 2py-n5am-cmh-as [1141]
  • 755 mam2py-pipa2-nmtf-as [1142]
  • 756 bhs-n3o-npy-gs [1143]
  • 757 2py-n5o-cmh-es [1144]
  • 758 bim-ampap-cmh-es [1145]
  • 759 bhs-apam-nm-gs [1146]
  • 760 mam2py-apam-noh-es [1147]
  • 761 bim-apam-npy-gs [1148]
  • 762 mam2py-n3o-noh-es [1149]
  • 763 bhs-but-nomm-gs [1150]
  • 764 bim-apam-cmm-es [1151]
  • 765 mam2py-ampip-cmh-ps [1152]
  • 766 mam2py-n4o-nm-es [1153]
  • 767 bhs-but-npy-gs [1154]
  • 768 2py-n4o-nomm-ps [1155]
  • 769 mam2py-ampip-nmtf-ps [1156]
  • 770 2py-diam-nm-es [1157]
  • 771 mam2py-n5o-noh-gs [1158]
  • 772 bhs-pipeme2-npy-ps, [1159]
  • 773 bim-ampap-nm-s [1160]
  • 774 bim-apam-nm-ps [1161]
  • 775 bim-ampip-noh-ps [1162]
  • 776 2py-penta-cmm-ps [1163]
  • 777 mam2py-mam3o-nmtf-as [1164]
  • 778 bhs-chex2-nm-gs [1165]
  • 779 bim-apam-nmtf-es [1166]
  • 780 bhs-ampap-nmtf-ps [1167]
  • 781 bhs-n5o-nomm-ps [1168]
  • 782 bim-n5o-nm-as [1169]
  • 783 mam2py-penta-noh-es [1170]
  • 784 2py-n3o-npy-gs [1171]
  • 785 bhs-pipeme2-nom-ps [1172]
  • 786 bim-pipeme2-nomm-gs [1173]
  • 787 bhs-n4o-cotf-gs [1174]
  • 788 mam2py-apam-nml-es [1175]
  • 789 bhs-but-ran-es [1176]
  • 790 gua-apam-nm-es [1177]
  • 791 bim-pipeme2-noh-gs [1178]
  • 792 bim-pipeme2-nm-ps [1179]
  • 793 bim-but-nm-as [1180]
  • 794 2py-n4o-cmh-as [1181]
  • 795 bhs-apam-cmh-gs [1182]
  • 796 2py-ampip-cmh-as [1183]
  • 797 bhs-ampip-noh-ps [1184]
  • 798 pippy-but-nomm-gs [1185]
  • 799 2py-a2o2o-cmm-es [1186]
  • 800 bim-apam-npy-es [1187]
  • 801 bim-apam-noh-gs [1188]
  • 802 bhs-n4o cmm-as [1189]
  • 803 2py-but-nomm-es [1190]
  • 804 2py-apam-nomm-gs [1191]
  • 805 mam2py-n4o-noh-gs [1192]
  • 806 2py-n5o-noh-es [1193]
  • 807 bhs-chex2-noh-as [1194]
  • 808 bhs-n5o-npy-gs [1195]
  • 809 bhs-n3o-nmtf-ps [1196]
  • 810 im-pipeme2-cmh-gs [1197]
  • 811 2py-apam-noh-ps [1198]
  • 812 bim-mea3-noh-es [1199]
  • 813 mam2py-but-nomm-gs [1200]
  • 814 bhs-ampap-nomm-as [1201]
  • 815 mam2py-a2o2o-npy-es [1202]
  • 816 2py-pipeme2-cmh-gs [1203]
  • 817 2py-hexa-npy-ps [1204]
  • 818 mam2py-n4o-cmh-es [1205]
  • 819 bim-ampip-cmh-as [1206]
  • 820 dhim-ampip-nm-as [1207]
  • 821 bim-n5o-cmh-ps [1208]
  • 822 mam2py-penta-nmtf-as [1209]
  • 823 bhs-pipeme2-cmm-ps [1210]
  • 824 bim-n5o-noh-ps [1211]
  • 825 bim-penta-noh-ps [1212]
  • 826 bim-ampap-npy-gs [1213]
  • 827 mam2py-penta-nm-as [1214]
  • 828 dhpyrr-apam-cmm-es [1215]
  • 829 bim-n3o-npy-gs [1216]
  • 830 2py-n3o-cmh-gs [1217]
  • 831 mam2py-but-nmtf-as [1218]
  • 832 2py-ampip-nmtf-as [1219]
  • 833 bhs-ampap-noh-gs [1220]
  • 834 mam2py-apam-npy-es [1221]
  • 835 bim-but-nmtf-es [1222]
  • 836 bhs-ampap-npy-ps [1223]
  • 837 bim-ampap-cmm-es [1224]
  • 838 bhs-ampip-cmm-es [1225]
  • 839 mam2py-ampap-nomm-gs [1226]
  • 840 mam2py-pipeme2-nm-ps [1227]
  • 841 bim-penta-nomm-es [1228]
  • 842 bim-n3o-nomm-es [1229]
  • 843 bim-but-nmtf-as [1230]
  • 844 bim-penta-nomm-as [1231]
  • 845 bhs-pipeme2-cmm-ms [1232]
  • 846 bim-but-nomm-gs [1233]
  • 847 mam2py-penta-nm-ps [1234]
  • 848 bim-but-npy-gs [1235]
  • 849 mam2py-n5o-npy-gs [1236]
  • 850 2py-n3o-cmm-es [1237]
  • 851 mam2py-but-noh-gs [1238]
  • 852 bim-apam-noh-ps [1239]
  • 853 bhs-pipeme2-nomm-es [1240]
  • 854 mam2py-apam-cmh-gs [1241]
  • 855 bim-apam-cmm-gs [1242]
  • 856 2py-n4o-nmtf-as [1243]
  • 857 bim-penta-npy-ps [1244]
  • 858 bhs-n3o-cmm-gs [1245]
  • 859 bhs-ampip-noh-es [1246]
  • 860 mam2py-n5o-nm-ps [1247]
  • 861 2py-n4o-noh-gs [1248]
  • 862 mam2py-n4o-noh-es [1249]
  • 863 bim-n5o-cmm-as [1250]
  • 864 bhs-penta-cmh-ps [1251]
  • 865 mam2py-ampap-nm-as [1252]
  • 866 2py-but-noh-gs [1253]
  • 867 2py-pipeme2-nm-gs [1254]
  • 868 bhs-n4o-nmtf-s [1255]
  • 869 2py-ampip-cmm-ps [1256]
  • 870 2py-n4o-noh-as [1257]
  • 871 bim-n4o-nmtf-gs [1258]
  • 872 2py-ampap-nm-as [1259]
  • 873 2py-but-nomm-ms [1260]
  • 874 mam2py-apam-nmo-es [1261]
  • 875 mam2py-n4o-nomm-as [1262]
  • 876 bhs-n4o-nmtf-as [1263]
  • 877 2py-ampip-nmo-es [1264]
  • 878 2py-penta-cmm-es [1265]
  • 879 mam2py-pipeme2-npy-ps [1266]
  • 880 mam2py-ampap-nmtf-es [1267]
  • 881 2py-n2am-nm-es [1268]
  • 882 thpym-n3o-nomm-ps [1269]
  • 883 bim-n4o-noh-es [1270]
  • 884 mam2py-n4o-npy-es [1271]
  • 885 bim-n2am-noh-es [1272]
  • 886 bim-penta-cmh-ass [1273]
  • 887 bhs-penta-nomm-ps [1274]
  • 888 mam2py-n5o-noh-as [1275]
  • 889 bhs-ampap-nml-as [1276]
  • 890 2py-pipeme2-nmtf-ps [1277]
  • 891 2py-pipeme2-nmtf-gs [1278]
  • 892 mam2py-but-cmh-gs [1279]
  • 893 2py-n5o-nomm-ps [1280]
  • 894 mam2py-pipeme2-nmtf-as [1281]
  • 895 mam2py-penta-cmh-ps [1282]
  • 896 bhs-ampap-npy-as [1283]
  • 897 2py-but-cmm-ps [1284]
  • 898 bhs-n3o-nmtf-as [1285]
  • 899 2py-ampip-nomm-as [1286]
  • 900 bim-n5o-nmtf-as [1287]
  • 901 mam2py-but-cmh-ps [1288]
  • 902 mam2py-ampap-cmm-gs [1289]
  • 903 bhs-but-noh-gs [1290]
  • 904 bhs-n5o-nmtf-ps [1291]
  • 905 bhs-apam-noh-ps [1292]
  • 906 bim-n5o-nth-es [1293]
  • 907 mam2py-42thiaz2-nomm-gs [1294]
  • 908 mam2py-n3o-noh-gs [1295]
  • 909 mam2py-n4o-cmm-ps [1296]
  • 910 bim-penta-nmtf-es [1297]
  • 911 bhs-n5o-noh-gs [1298]
  • 912 bim-pipeme2-noh-ps [1299]
  • 913 mam2py-n5o-nmtf-gs [1300]
  • 914 mam2py-aaf-npy-es [1301]
  • 915 bim-n5am-noh-es [1302]
  • 916 2py-ampip-nml-es [1303]
  • 917 mam2py-but-cmh-es [1304]
  • 918 bhs-but-nmtf-ps [1305]
  • 919 bim-hexa-cmh-gs [1306]
  • 920 bim-penta-nm-as [1307]
  • 921 bim-n3o-nm-es [1308]
  • 922 2py-but-npy-gs [1309]
  • 923 bim-pipeme2-cmm-es [1310]
  • 924 mam2py-ampip-cmh-gs [1311]
  • 925 bhs-n3o-nth-ps [1312]
  • 926 dhim-apam-nm-es [1313]
  • 927 mam2py-ampip-nmtf-as [1314]
  • 928 2py-apam-nm-es [1315]
  • 929 2py-apam-nm-as [1316]
  • 930 mam2py-n4o-nm-gs [1317]
  • 931 2py-but-nmtf-ps [1318]
  • 932 2py-n3o-noh-as [1319]
  • 933 dhpyrr-n5o-npy-ps [1320]
  • 934 bim-apam-npy-ps [1321]
  • 935 mam2py-n3o-noh-as [1322]
  • 936 mam2py-pipeme2-noh-ps [1323]
  • 937 bim-42thiaz2-nmtf-es [1324]
  • 938 2py-penta-nmtf-es [1325]
  • 939 bhs-apam-nmtf-gs [1326]
  • 940 2py-ampap-nmtf-ps [1327]
  • 941 bim-apam-noh-es [1328]
  • 942 bhs-penta-cmm-gs [1329]
  • 943 bhs-apam-noh-gs [1330]
  • 944 bim-but-nomm-as [1331]
  • 945 dhim-pipeme2-cmm-ps [1332]
  • 946 2py-apam-nomm-as [1333]
  • 947 2py-but-nm-gs [1334]
  • 948 2py-n5o-nmtf-gs [1335]
  • 949 mam2py-apam-cmm-gs [1336]
  • 950 bhs-but-npy-es [1337]
  • 951 pippy-ampip-cmm-es [1338]
  • 952 bhs-n3am-noh-as [1339]
  • 953 bim-n3o-cmh-ps [1340]
  • 954 2py-penta-nomm-es [1341]
  • 955 thpym-ampap-noh-as [1342]
  • 956 am2py-but-npy-gs [1343]
  • 957 2py-pipeme2-nomm-as [1344]
  • 958 2py-n3o-noh-es [1345]
  • 959 bim-n3o-cmm-es [1346]
  • 960 pippy-penta-nmtf-as [1347]
  • 961 2py-n4o-cmm-as [1348]
  • 962 bhs-n4o-nmtf-ps [1349]
  • 963 bim-pipeme2-npy-as [1350]
  • 964 bim-ampap-nm-gs [1351]
  • 965 bhs-ampip-cmm-as [1352]
  • 966 bim-penta-nm-ps [1353]
  • 967 bhs-mam3o-nm-gs [1354]
  • 968 mam2py-ampip-cmm-gs [1355]
  • 969 bhs-n5o-cmh-as [1356]
  • 970 bhs-apam-cmm-ps [1357]
  • 971 mam2py-apam-npy-gs [1358]
  • 972 bim-ampip-nomm-es [1359]
  • 973 2py-n3am-npy-ps [1360]
  • 974 mam2py-n3o-npy-ps [1361]
  • 975 bim-apam-nmtf-gs [1362]
  • 976 bhs-ampip-nm-ps [1363]
  • 977 am2py-n3o-nmtf-ps [1364]
  • 978 2py-ampap-cmh-ps [1365]
  • 979 mam2py-n4o-nm-as [1366]
  • 980 impy-apam-nm-es [1367]
  • 981 2py-penta-noh-gs [1368]
  • 982 2py-ampap-npy-as [1369]
  • 983 bhs-apam-nomm-es [1370]
  • 984 bim-n3o-nomm-gs [1371]
  • 985 dhpyrr-pipeme2-cmh-gs [1372]
  • 986 bhs-n4o-nm-es [1373]
  • 987 mam2py-n5o-nmtf-ps [1374]
  • 988 mam2py-n3o-nomm-gs [1375]
  • 989 bim-penta-cmm-as [1376]
  • 990 mam2py-but-noh-as [1377]
  • 991 2py-n5o-npy-as [1378]
  • 992 bhs-ampap-noh-ps [1379]
  • 993 mam2py-eam-npy-es [1380]
  • 994 2py-ampip-nm-es [1381]
  • 995 mam2py-ampap-cmm-es [1382]
  • 996 mam2py-penta-nm-es [1383]
  • 997 bhs-ediao-nmtf-ps [1384]
  • 998 mam2py-mam-cmm-es [1385]
  • 999 bim-edia2-nomm-ps [1386]
  • 1000 2py-n4o-cmh-ps [1387]
  • 1001 bhs-n3o-cmm-es [1388]
  • 1002 2py-but-cmh-es [1389]
  • 1003 2py-but-nmtf-as [1390]
  • 1004 2py-pipeme2-cmm-es [1391]
  • 1005 bim-aaf-nmtf-es [1392]
  • 1006 bhs-n5o-nomm-as [1393]
  • 1007 bim-ampap-cmm-ps [1394]
  • 1008 mam2py-apam-nmtf-gs [1395]
  • 1009 bhs-ampip-cmm-gs [1396]
  • 1010 2py-n5o-cotf-ps [1397]
  • 1011 mam2py-penta-cmm-gs [1398]
  • 1012 bhs-pro-noh-as [1399]
  • 1013 gua-ampap-nomm-gs [1400]
  • 1014 2py-n2am-cmh-as [1401]
  • 1015 2py-n5o-noh-as [1402]
  • 1016 2py-ampip-cmh-ps [1403]
  • 1017 mam2py-mea3-nomm-gs [1404]
  • 1018 pippy-n3o-nomm-ps [1405]
  • 1019 mam2py-ampap-noh-as [1406]
  • 1020 mam2py-n5o-cmm-gs [1407]
  • 1021 bhs-apam-nm-as [1408]
  • 1022 bhs-edia2-noh-as [1409]
  • 1023 bhs-ampap-npy-es [1410]
  • 1024 mam2py-ampap-nomm-as [1411]
  • 1025 bim-n5o-nm-gs [1412]
  • 1026 bim-n5o-cmtf-es [1413]
  • 1027 mam2py-penta-nomm-gs [1414]
  • 1028 bim-n3o-nm-ps [1415]
  • 1029 2py-apam-cmh-es [1416]
  • 1030 mam2py-pipeme2-npy-es [1417]
  • 1031 mam2py-pipeme2-nm-es [1418]
  • 1032 gua-pipeme2-cmm-ps [1419]
  • 1033 2py-apam-npy-ps [1420]
  • 1034 mam2py-n3o-nm-es [1421]
  • 1035 2py-penta-cmm-as [1422]
  • 1036 mam2py-ampap-npy-es [1423]
  • 1037 bhs-but-nm-as [1424]
  • 1038 bhs-apam-nomm-gs [1425]
  • 1039 2py-n5o-nml-ps [1426]
  • 1040 mam2py-n3o-nomm-ps [1427]
  • 1041 bim-but-cmm-as [1428]
  • 1042 2py-n3o-nm-ps [1429]
  • 1043 am2py-but-nmtf-es [1430]
  • 1044 2py-apam-npy-as [1431]
  • 1045 mam2py-n5o-cmm-as [1432]
  • 1046 mam2py-pipeme2-noh-es [1433]
  • 1047 bhs-but-nmtf-as [1434]
  • 1048 am2py-n3o-nm-ps [1435]
  • 1049 2py-mea3-cmm-es [1436]
  • 1050 2py-n3o-cmm-gs [1437]
  • 1051 mam2py-ampap-nomm-ps [1438]
  • 1052 bhs-ampap-nmtf-es [1439]
  • 1053 bhs-n3o-nomm-as [1440]
  • 1054 2py-mam-nomm-gs [1441]
  • 1055 bhs-but-cmm-ps [1442]
  • 1056 bim-penta-nm-es [1443]
  • 1057 2py-n3o-nomm-as [1444]
  • 1058 mam2py-apam-cmm-ms [1445]
  • 1059 2py-aaf-nm-es [1446]
  • 1060 bhs-eam-nmtf-ps [1447]
  • 1061 2py-apam-nom-es [1448]
  • 1062 mam2py-n4o-nmtf-as [1449]
  • 1063 bhs-ampap-nm-es [1450]
  • 1064 mam2py-n2am-npy-es [1451]
  • 1065 2py-edia2-nomm-gs [1452]
  • 1066 bhs-n3o-cmh-ps [1453]
  • 1067 bhs-n4o-cmm-es [1454]
  • 1068 dhpyrr-ampip-nm-as [1455]
  • 1069 dhpyrr-n4o-nm-gs [1456]
  • 1070 bim-diam-nmtf-es [1457]
  • 1071 bhs-mam-noh-as [1458]
  • 1072 mam2py-42thiaz2-npy-es [1459]
  • 1073 bim-ampap-cmm-as [1460]
  • 1074 mam2py-n4o-nomm-gs [1461]
  • 1075 bhs-but-cmm-gs [1462]
  • 1076 mam2py-n4o-nomm-es [1463]
  • 1077 bhs-n3o-nmtf-gs [1464]
  • 1078 2py-n3o-nomm-gs [1465]
  • 1079 mam2py-pipeme2-cmh-as [1466]
  • 1080 mam2py-n5o-cmh-es [1467]
  • 1081 2py-penta-ncl1-as [1468]
  • 1082 2py-n3o-cmh-ps [1469]
  • 1083 bhs-n5o-npy-as [1470]
  • 1084 bim-n4o-cmm-ps [1471]
  • 1085 bhs-pro-nmtf-ps [1472]
  • 1086 bim-ampap-noh-es [1473]
  • 1087 bhs-apam-cmm-es [1474]
  • 1088 bhs-n4o-nml-gs [1475]
  • 1089 mam2py-n3o-noh-ps [1476]
  • 1090 mampy-ampip-cmh-as [1477]
  • 1091 2py-apam-npy-gs [1478]
  • 1092 2py-n4o-npy-as [1479]
  • 1093 bhs-n4o-noh-es [1480]
  • 1094 mam2py-ampap-npy-as [1481]
  • 1095 bim-n3o-cmm-as [1482]
  • 1096 2py-but-npy-ps [1483]
  • 1097 mam2py-penta-npy-es [1484]
  • 1098 bim-ampip-cmm-ps [1485]
  • 1099 bim-ampip-cmm-as [1486]
  • 1100 gua-ampip-cmm-es [1487]
  • 1101 2py-n4o-nmtf-ps [1488]
  • 1102 mam2py-penta-cmm-es [1489]
  • 1103 2py-n4o-nm-ps [1490]
  • 1104 bim-apam-nm-as [1491]
  • 1105 2py-pipeme2-cmh-es [1492]
  • 1106 bim-n3o-nmom-ps [1493]
  • 1107 gua-n3o-nmtf-ps [1494]
  • 1108 bim-pipeme2-cmh-gs [1495]
  • 1109 mam2py-n3o-nmtf-es [1496]
  • 1110 2py-but-cmh-gs [1497]
  • 1111 2py-apam-noh-as [1498]
  • 1112 mam2py-n5o-cmh-ps [1499]
  • 1113 bhs-n4o-nomm-as [1500]
  • 1114 bhs-penta-nmtf-as [1501]
  • 1115 bhs-n2am-cmm-ps [1502]
  • 1116 bhs-pipeme2-nomm-as [1503]
  • 1117 bim-apam-cmh-ps [1504]
  • 1118 bhs-n3o-nomm-es [1505]
  • 1119 2py-but-nml-gs [1506]
  • 1120 bim-a2o2o-nmtf-es [1507]
  • 1121 bim-pipeme2-nm-as [1508]
  • 1122 bim-pipeme2-nmtf-ps [1509]
  • 1123 mam2py-n5o-cmh-gs [1510]
  • 1124 bim-apam-cmh-gs [1511]
  • 1125 bim-pipeme2-cmh-ps [1512]
  • 1126 mam2py-ampip-nomm-es [1513]
  • 1127 thpym-penta-nmtf-as [1514]
  • 1128 bhs-pipeme2-noh-as [1515]
  • 1129 bim-ampap-npy-es [1516]
  • 1130 2py-ampap-nomm-as [1517]
  • 1131 mam2py-but-nomm-es [1518]
  • 1132 mam2py-n4o-npy-ps [1519]
  • 1133 2py-n5o-cmm-as [1520]
  • 1134 2py-penta-nth-as [1521]
  • 1135 mam2py-n5am-nomm-gs [1522]
  • 1136 mam2py-n4o-ncll-es [1523]
  • 1137 bim-ampap-npy-as [1524]
  • 1138 2py-ampap-noh-es [1525]
  • 1139 2py-n4o-nomm-as [1526]
  • 1140 bhs-ampip-nmtf-es [1527]
  • 1141 mam2py-but-cmm-es [1528]
  • 1142 bhs-pipeme2-cmh-es [1529]
  • 1143 bhs-ampip-nm-gs [1530]
  • 1144 2py-but-noh-ps [1531]
  • 1145 bhs-n4o-noh-ps [1532]
  • 1146 2py-apam-cmtf-es [1533]
  • 1147 mam2py-ampip-cmm-ps [1534]
  • 1148 bhs-pipeme2-noh-es [1535]
  • 1149 mam2py-pipeme2-npy-gs [1536]
  • 1150 2py-pipeme2-nomm-es [1537]
  • 1151 mam2py-n4o-cmtf-es [1538]
  • 1152 mam2py-n3o-cmh-gs [1539]
  • 1153 bim-pipa2-nomm-ps [1540]
  • 1154 bhs-n5o-noh-es [1541]
  • 1155 mam2py-chex2-cmm-es [1542]
  • 1156 2py-penta-npy-ps [1543]
  • 1157 bhs-apam-nm-es [1544]
  • 1158 bim-penta-nmtf-gs [1545]
  • 1159 mam2py-ampip-cmm-es [1546]
  • 1160 2py-n5o-nmtf-es [1547]
  • 1161 bhs-n4o-cmh-as [1548]
  • 1162 thpym-but-nomm-gs [1549]
  • 1163 mam2py-penta-noh-as [1550]
  • 1164 bim-n4o-cmh-as [1551]
  • 1165 mam2py-penta-cmh-es [1552]
  • 1166 bim-penta-cmh-ps [1553]
  • 1167 2py-apam-nmtf-es [1554]
  • 1168 bhs-pipeme2-nm-ps [1555]
  • 1169 bhs-n5o-cmm-gs [1556]
  • 1170 mam2py-apam-cmh-ps [1557]
  • 1171 2py-ampap-noh-as [1558]
  • 1172 bim-diam-noh-es [1559]
  • 1173 2py-pipeme2-nm-ps [1560]
  • 1174 bhs-n3o-noh-as [1561]
  • 1175 mam2py-pipeme2-nmtf-ps [1562]
  • 1176 bim-n3o-nmtf-es [1563]
  • 1177 bhs-but-noh-as [1564]
  • 1178 mam2py-penta-nomm-as [1565]
  • 1179 bim-n5o-cmh-as [1566]
  • 1180 2py-ampip-noh-as [1567]
  • 1181 bim-but-nth-es [1568]
  • 1182 bim-n4o-nmtf-ps [1569]
  • 1183 2py-pro-npy-ps [1570]
  • 1184 mam2py-n5o-nmtf-as [1571]
  • 1185 bhs-n4o-nmtf-gs [1572]
  • 1186 2py-n5o-npy-ps [1573]
  • 1187 mam2py-ampap-cmh-gs [1574]
  • 1188 mam2py-penta-nmom-as [1575]
  • 1189 2py-n3o-npy-as [1576]
  • 1190 bim-n5o-npy-es [1577]
  • 1191 bhs-pipeme2-noh-gs [1578]
  • 1192 bhs-ampap-nm-ps [1579]
  • 1193 bhs-apam-cmm-gs [1580]
  • 1194 bim-pipeme2-nomm-ps [1581]
  • 1195 pippy-ampap-noh-as [1582]
  • 1196 mam2py-n5o-noh-ps [1583]
  • 1197 bhs-but-nm-gs [1584]
  • 1198 mam2py-edia2-nmtf-as [1585]
  • 1199 mam2py-n3o-nmtf-gs [1586]
  • 1200 mam2py-n5o-nm-es [1587]
  • 1201 bim-penta-nomm-gs [1588]
  • 1202 bim-n2am-nmtf-es [1589]
  • 1203 mam2py-n4o-cmm-es [1590]
  • 1204 bim-pipeme2-npy-gs [1591]
  • 1205 mam2py-diam-nomm-gs [1592]
  • 1206 bhs-pipeme2-nth-ps [1593]
  • 1207 2py-penta-nomm-gs [1594]
  • 1208 bhs-ampap-cmm-es [1595]
  • 1209 mam2py-ampip-nm-as [1596]
  • 1210 bim-ampip-cmh-gs [1597]
  • 1211 mam2py-apam-noh-gs [1598]
  • 1212 bim-n4o-noh-gs [1599]
  • 1213 bhs-n5am-cmm-ps [1600]
  • 1214 bim-n5o-npy-ps [1601]
  • 1215 mam2py-apam-nm-ps [1602]
  • 1216 bhs-n5o-noh-ps [1603]
  • 1217 bim-but-cmm-es [1604]
  • 1218 bhs-n3o-cmtf-ps [1605]
  • 1219 bhs-n4o-nm-ms [1606]
  • 1220 bim-n4o-cmh-es [1607]
  • 1221 2py-aaf-cmm-es [1608]
  • 1222 bim-but-ncll-es [1609]
  • 1223 mam2py-but-nomm-as [1610]
  • 1224 bhs-pipeme2-npy-as [1611]
  • 1225 bim-ampip-nmtf-gs [1612]
  • 1226 bhs-mea3-cmm-ps [1613]
  • 1227 mam2py-penta-cmm-as [1614]
  • 1228 bim-ampap-nmtf-as [1615]
  • 1229 bim-but-noh-gs [1616]
  • 1230 mam2py-hexa-cmm-es [1617]
  • 1231 mam2py-n5am-npy-es [1618]
  • 1232 bim-ampap-nm-as [1619]
  • 1233 im-n5o-npy-ps [1620]
  • 1234 mam2py-penta-cmh-gs [1621]
  • 1235 mam2py-n5o-nomm-ps [1622]
  • 1236 2py-penta-noh-es [1623]
  • 1237 2py-n4o-cmm-es [1624]
  • 1238 2py-but-nomm-ps [1625]
  • 1239 mam2py-ampip-nmtf-es [1626]
  • 1240 bhs-penta-nomm-gs [1627]
  • 1241 bim-n4o-nm-ps [1628]
  • 1242 2py-pipeme2-npy-as [1629]
  • 1243 bim-ampip-nomm-as [1630]
  • 1244 bim-pipeme2-nmtf-gs [1631]
  • 1245 bim-ampip-cmm-es [1632]
  • 1246 mam2py-penta-noh-gs [1633]
  • 1247 mam2py-penta-nml-as [1634]
  • 1248 bim-mea3-nmtf-es [1635]
  • 1249 2py-penta-nmtf-ps [1636]
  • 1250 bim-n5o-nom-es [1637]
  • 1251 2py-edia2-cmm-es [1638]
  • 1252 bhs-but-nomm-as [1639]
  • 1253 bim-but-noh-as [1640]
  • 1254 2py-aaf-cmh-as [1641]
  • 1255 bhs-n4o-nm-ps [1642]
  • 1256 mam2py-pipeme2-noh-as [1643]
  • 1257 mam2py-n4o-nm-ps [1644]
  • 1258 2py-n5o-nmom-ps [1645]
  • 1259 bim-pro-nm-as [1646]
  • 1260 bim-penta-cmh-gs [1647]
  • 1261 2py-ampap-noh-gs [1648]
  • 1262 mam2py-ampap-nmtf-as [1649]
  • 1263 bhs-apam-nomm-as [1650]
  • 1264 im-penta-nmtf-as [1651]
  • 1265 bhs-pipeme2-nmtf-es [1652]
  • 1266 2py-n5o-nm-as [1653]
  • 1267 bim-ampip-nm-es [1654]
  • 1268 bim-pipeme2-cmh-as [1655]
  • 1269 mam2py-ampap-cmm-ps [1656]
  • 1270 mam2py-penta-nomm-es [1657]
  • 1271 mam2py-but-nm-ps [1658]
  • 1272 mam2py-ampip-npy-gs [1659]
  • 1273 bhs-pipeme2-cmm-as [1660]
  • 1274 bim-n4o-npy-es [1661]
  • 1275 bhs-ampip-cmh-ps [1662]
  • 1276 bhs-n4o-nm-gs [1663]
  • 1277 bhs-n4o-nmo-gs [1664]
  • 1278 2py-pipa2-nomm-gs [1665]
  • 1279 mam2py-n5o-nomm-es [1666]
  • 1280 mam2py-apam-npy-as [1667]
  • 1281 bim-eam-noh-es [1668]
  • 1282 am2py-penta-cmh-as [1669]
  • 1283 mam2py-but-npy-es [1670]
  • 1284 bhs-penta-noh-gs [1671]
  • 1285 bim-n3o-noh-es [1672]
  • 1286 bim-n3o-nmtf-gs [1673]
  • 1287 bim-n3o-cmh-as [1674]
  • 1288 mam2py-ampip-noh-es [1675]
  • 1289 bhs-n4o-cmm-ps [1676]
  • 1290 bhs-chex2-nmtf-ps [1677]
  • 1291 mam2py-but-nmtf-es [1678]
  • 1292 bhs-n4o-cmh-ps [1679]
  • 1293 2py-pipa2-npy-ps [1680]
  • 1294 impy-pipeme2-cmm-ps [1681]
  • 1295 mam2py-apam-noh-ps [1682]
  • 1296 2py-ampap-cmh-gs [1683]
  • 1297 2py-but-cmh-ps [1684]
  • 1298 mam2py-ampip-nm-ps [1685]
  • 1299 2py-penta-nm-es [1686]
  • 1300 mam2py-apam-cmm-as [1687]
  • 1301 2py-mam-cmm-es [1688]
  • 1302 mam2py-but-cmm-gs [1689]
  • 1303 bim-but-nmtf-ms [1690]
  • 1304 mam2py-apam-nomm-gs [1691]
  • 1305 bim-penta-cmm-es [1692]
  • 1306 mam2py-but-nomm-ps [1693]
  • 1307 bhs-n4o-npy-es [1694]
  • 1308 2py-ampip-npy-as [1695]
  • 1309 gua-n4o-npy-es [1696]
  • 1310 mam2py-n4o-cmm-gs [1697]
  • 1311 bim-chex2-nm-as [1698]
  • 1312 thpym-ampip-cmm-es [1699]
  • 1313 2py-pipeme2-noh-as [1700]
  • 1314 impy-n5o-noh-es [1701]
  • 1315 bim-n3o-nmtf-ps [1702]
  • 1316 mam2py-n36-cmh-as [1703]
  • 1317 2py-ampip-npy-gs [1704]
  • 1318 bhs-n4o-nomm-gs [1705]
  • 1319 mam2py-ampap-cmh-es [1706]
  • 1320 mam2py-penta-npy-as [1707]
  • 1321 bim-penta-cmm-gs [1708]
  • 1322 bhs-pipeme2-cmm-es [1709]
  • 1323 mam2py-apam-nm-gs [1710]
  • 1324 2py-penta-nomm-as [1711]
  • 1325 bim-n4o-cmh-ps [1712]
  • In the above list, the following abbreviations are used for the structural units A, E, G and L. [1713]
    A = Abbreviation A = Abbreviation
    Figure US20040077638A1-20040422-C00016
         		2py
    Figure US20040077638A1-20040422-C00017
         		thpym
    Figure US20040077638A1-20040422-C00018
         		dhim
    Figure US20040077638A1-20040422-C00019
         		pippy
    Figure US20040077638A1-20040422-C00020
         		bim
    Figure US20040077638A1-20040422-C00021
         		am2py
    Figure US20040077638A1-20040422-C00022
         		bhs
    Figure US20040077638A1-20040422-C00023
         		dhpyrr
    Figure US20040077638A1-20040422-C00024
         		gua
    Figure US20040077638A1-20040422-C00025
         		im
    Figure US20040077638A1-20040422-C00026
         		impy
    Figure US20040077638A1-20040422-C00027
         		mam2py
    E = Abbreviation E = Abbreviation
    Figure US20040077638A1-20040422-C00028
         		edia2
    Figure US20040077638A1-20040422-C00029
         		n2am
    Figure US20040077638A1-20040422-C00030
         		mam
    Figure US20040077638A1-20040422-C00031
         		n5am
    Figure US20040077638A1-20040422-C00032
         		pipa2
    Figure US20040077638A1-20040422-C00033
         		eam
    Figure US20040077638A1-20040422-C00034
         		ampip
    Figure US20040077638A1-20040422-C00035
         		n3o
    Figure US20040077638A1-20040422-C00036
         		n4o
    Figure US20040077638A1-20040422-C00037
         		n3am
    Figure US20040077638A1-20040422-C00038
         		daim
    Figure US20040077638A1-20040422-C00039
         		penta
    Figure US20040077638A1-20040422-C00040
         		ediao
    Figure US20040077638A1-20040422-C00041
         		a2o2o
    Figure US20040077638A1-20040422-C00042
         		n5o
    Figure US20040077638A1-20040422-C00043
         		hexa
    Figure US20040077638A1-20040422-C00044
         		aaf
    Figure US20040077638A1-20040422-C00045
         		mam3o
    Figure US20040077638A1-20040422-C00046
         		42thiaz2
    Figure US20040077638A1-20040422-C00047
         		pipeme2
    Figure US20040077638A1-20040422-C00048
         		chex2
    Figure US20040077638A1-20040422-C00049
         		mean3
    Figure US20040077638A1-20040422-C00050
         		ampap
    Figure US20040077638A1-20040422-C00051
         		pro
    Figure US20040077638A1-20040422-C00052
         		apam
    Figure US20040077638A1-20040422-C00053
         		but
    The bond to the structural unit L = as should be understood as meaning a single or double bond for X = C.
    G = Abbreviation G = Abbreviation
    Figure US20040077638A1-20040422-C00054
         		nmo
    Figure US20040077638A1-20040422-C00055
         		cmm
    Figure US20040077638A1-20040422-C00056
         		nomm
    Figure US20040077638A1-20040422-C00057
         		nm
    Figure US20040077638A1-20040422-C00058
         		cmtf
    Figure US20040077638A1-20040422-C00059
         		nmtf
    Figure US20040077638A1-20040422-C00060
         		nm1
    Figure US20040077638A1-20040422-C00061
         		ncl1
    Figure US20040077638A1-20040422-C00062
         		nmom
    Figure US20040077638A1-20040422-C00063
         		nth
    Figure US20040077638A1-20040422-C00064
         		cotf
    Figure US20040077638A1-20040422-C00065
         		npy
    Figure US20040077638A1-20040422-C00066
         		cmh
    Figure US20040077638A1-20040422-C00067
         		nom
    Figure US20040077638A1-20040422-C00068
         		noh
    L = Abbreviation L = Abbreviation
    Figure US20040077638A1-20040422-C00069
         		es
    Figure US20040077638A1-20040422-C00070
         		ps
    Figure US20040077638A1-20040422-C00071
         		gs
    Figure US20040077638A1-20040422-C00072
         		ms
    Figure US20040077638A1-20040422-C00073
         		as
  • The compounds of the formula I and the starting substances used for their preparation can generally be prepared by methods of organic chemistry known to the person skilled in the art, such as are described in standard works such as Houben-Weyl, “[1714] Methoden der Organischen, Chemie” [Methods of Organic Chemistry], Thieme-Verlag, Stuttgart, or March “Advanced Organic Chemistry”, 4th Edition, Wiley & Sons. Further preparation methods are also described in R. Larock, “Comprehensive Organic Transformations”, Weinheim 1989, in particular the preparation of alkenes, alkynes, halides, amines, ethers, alcohols, phenols, aldehydes, ketones, nitrites, carboxylic acids, esters, amides and acid chlorides. The selection of suitable protective groups for functional groups and the introduction or removal of the protective groups is described, for example, in Greene and Wats in “Protective Groups in Organic Synthesis”, 2nd Edition, Wiley & Sons, 1991. The synthesis of compounds of the formula I can either be carried out in solution or on a polymer support, in each case reaction conditions being used such as are known and are suitable for the respective reactions. Use can also be made in this case of variants which are known per se, but not mentioned here.
  • The general synthesis of compounds of the formula I, where, as described above, A-E- can be the structural element B- and -U-T can be the structural element -L, is described in Schemes 1-10. If not stated otherwise, all starting materials and reagents are commercially available, or can be prepared from commercially obtainable precursors according to customary methods. [1715]
  • Structural units of the formula III (for X[1716] G=carbon) are either known or can be prepared by known methods starting from appropriately fused 1H-azepine-2,5-diones. (II), as is described in an exemplary manner, for example, in J. Med. Chem. 1986, 29, 1877-1888 or DE 1568217. 1H-Azepine-2,5-diones (II), which are used for the preparation of compounds of the formula I, are either commercially available or can be prepared according to the following publications:
  • 5H-dibenzo[b,e]azepine-6,11-dione or substituted variants according to J. Med. Chem. 1965, 8, 74, or Gazz. Chim. Ital. 1953, 83, 533 and 1954, 84, 1135; 5H-pyrido[3,2-c][1]benzazepine-5,11(6H)-dione according to Liebigs Ann. Chem. 1989, 469-476; 4H-thieno[3,2-c][1]benzazepine-4,10(5H)-dione according to Eur. J. Med. Chem. Ther. 1981, 16, 391-398. [1717]
  • Further examples and their access are described in the following references: J. Heterocycl. Chem. 1991, 28, 379-384; Eur. J. Med. 1993, 28, 439-445; J. Med. Chem. 1965, 8, 74; J. Med. Chem. 1989, 32, 1033-1038; Synth. Commun. 1996, 26, 1839-1847; Indian J. Chem. Sect. B 1984, 23, 163-164; J. Heterocycl. Chem. 1982, 19, 689-690; J. Chem. Soc. Perkin Trans. 1 1976, 1279-1285; J. Chem. Res. 1984, 350-351; Synth. Commun. 1990, 20, 1379-1385; J. Chem. Soc. C 1969, 1321; J. Pharm. Soc. 1994, 83, 137-142; Arch. Pharm. 1979, 312, 662-669; J. Heterocycl. Chem. 1998, 35, 675-686; J. Med. Chem. 1981, 24, 1097-1099. [1718]
  • The conversion into compounds of the formula III is generally carried out by methods known to the person skilled in the art, such as are described in Larock, “Comprehensive Organic Transformations”, Weinheim 1989, p. 167 ff, where methods which are not mentioned can also be used here. Preferably, compounds of the general formula III are prepared by reaction of the ketones II with a phosphonic ester of the general formula (EtO)[1719] 2P(═O)—(XL)a—(CRL 1RL 2)b—COO-PG1 in the presence of a base. PG1 is understood as meaning an acid protective group.
  • The reaction preferably takes place in a polar aprotic solvent, such as tetrahydrofuran, dioxane; dimethylformamide (DMF), dimethylacetamide or acetamide; dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone; in a temperature range—depending on the nature of the solvent used—from −40° C. up to the boiling point of the corresponding solvent. [1720]
  • The base used can be an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an alkoxide such as sodium methoxide, potassium tert-butoxide, an organometallic compound such as butyllithium or alkali metal amides such as lithium diisopropylamide and lithium, sodium or potassium bis(trimethylsilyl)amide. [1721]
  • The reaction to give IV is carried out by hydrogenation of the double bond under standard conditions. Here too, use can be made of variants known per se which are not mentioned. Preferably, the hydrogenation is carried out in the presence of a noble metal catalyst, such as Pd on active carbon, Pt, PtO[1722] 2, Rh on Al2O3 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. The hydrogenation is particularly preferably carried out in the presence of 5-10% Pd on active carbon.
  • Solvents which can be used are all customary inert solvents, such as hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 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), dimethylacetamide or acetamide; sulfoxides such as dimethyl sulfoxide, sulfolane; pyridine, N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone; water or mixtures of the solvents mentioned. [1723]
    Figure US20040077638A1-20040422-C00074
  • Compounds of type V are prepared by reaction with compounds of the general formula A-E′-U[1724] E (VI), where the radical UE is OH, COOH, NH2 or a customary leaving group, for example halogen such as chlorine, bromine, iodine or aryl or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl, trifluoromethanesulfonyl and methylsulfonyl or another equivalent leaving group, and MR, for example, is Br, Cl, I, OH, COOPG2, NHPG3 and E′ is a subfragment of E defined such that M-E′ is equal to E or E′ is equal to E if MR=Hal.
  • The introduction of the side chain in compounds of the formula V depends on the radical M on th aromatic ring Ar (formulae II to IV). The following description of the preparation of the compounds of the formula V is by way of example and is non-limiting for the possible synthesis. In this case, use can also be made of methods for the preparation of substituted aromatic rings, which are known per se, but not mentioned here. [1725]
    Figure US20040077638A1-20040422-C00075
  • If MR=OH, a method for the formation of carbon-oxygen bonds can be used for the ether bond to be produced. Analogous methods can be used in the synthesis of amine or sulfide linkages. Phenol (1) in Scheme 2 is reacted with an alcohol HO-E′-A in a Mitsunobu-like coupling (Organic Reactions 1992, 42, 335-656; Synthesis 1981, 1-28) to give the product (2). The reaction proceeds via the adduct of DEAD and triphenylphosphine and is carried out in an aprotic solvent such as THF, CH[1726] 2Cl2 or DMF.
  • Compounds of the formula V can also be prepared by other methods known to the person skilled in the art. Ether bonding in formula V can be obtained, for example, by the reaction of the hydroxy function with compounds which contain a leaving group such as chloride, bromide or iodide. [1727]
  • If MR=OMe, the methoxy group in (3) can be converted into the hydroxy function by the action of BBr[1728] 3 in an inert solvent such as CH2Cl2 or alternatively by reaction with ethanethiol and AlCl3 in an inert solvent, preferably CH2Cl2. Other methods for the cleavage of the methoxy function are described in Greene's “Protective Groups in Organic Synthesis” (Wiley).
  • The phenol (1) can be converted into the corresponding triflate (4) by reacting it with trifluoromethanesulfonic anhydride (Tf[1729] 2O) in the presence of a suitable base such as 2,6-lutidine in an inert solvent such as CH2Cl2. The triflate (4) can in turn be converted into the carboxylic acid (5, MR=COOH) in the presence of potassium acetate, 1,1′-bis(diphenylphosphino)ferrocene (dppf) and a palladium catalyst such as palladium-II acetate (Pd(OAc)2) in a solvent such as DMSO according to the general method of Cacchi and Lupi (Tetrahedron Lett. 33 (1992) 3939) using CO. Alternatively, the same reaction, is possible starting from the bromide (6) or the corresponding iodide, or any functional group which can be converted into the triflate, the bromide or the iodide.
  • Derivatives such as (5) can be coupled, for example, with amines to give compounds of the formula V. Such coupling methods are generally known, as described in the following, for example in Bodansky's “The Practice of Peptide Synthesis” (Springer, Berlin 1984). [1730]
  • Further methods for the reaction of carboxylic acids to give amides can also be read up in Standard reference works such as “Compendium of Organic Synthetic Methods”, Vol I-VI (Wiley). If the amine component employed for the reaction contains a protective group, this can be removed before or alternatively after the hydrolysis of the ester. Cleavage methods are described in Greene's “Protective Groups in Organic Synthesis”. When using the Boc protective group, this, can be removed under acidic conditions, e.g. by the action of 4N HCl in dioxane or trifluoroacetic acid. [1731]
  • For MR=Br, Cl or I, an acetylene unit can be introduced by means of a coupling method for the formation of carbon-carbon bonds, e.g. a Stille coupling of aromatic triflates or organostannanes with palladium catalysis, preferably (PPh[1732] 3)2PdCl2, in the presence of LiCl in an inert solvent such as DMF or dioxane (J. Am. Chem. Soc. 1987, 109, 5478-86). The triple bond can be converted into the double or single bond according to known methods by the choice of suitable reduction conditions.
  • Removal of the protective group PG[1733] 1 according to standard conditions (see below) leads to the compounds of the general formula I. If PG1 is equal to C1-C4-alkyl or benzyl, the compounds of the general formula V correspond directly to th compounds of the type I.
  • Alternatively to this synthesis strategy, compounds of type I can also be prepared via VII as an intermediate, where here too reaction conditions are used such as are known to the person skilled in the art and described in standard works. [1734]
  • Compound V is prepared by reaction of compounds of the type IV with radicals of the general formula D[1735] E-E′-XE (VIII) under reaction conditions such as have already been described above for the preparation of V (from IV+VI). XE is a suitable leaving group, such as has likewise already been described, and DE is CN, or a protected amino or acid function of the general formula NHPG3 or COOPG2. The synthesis of the fragments DE-E′ or A-E′ is carried out—depending on the actual structure of E—by removal of the protective groups and coupling of the residual fragments according to standard methods, e.g. amide couplings.
  • The introduction of A is then carried out analogously to the reactions described in Schemes 6-10. [1736]
  • Generally, however, syntheses of the compounds of the formula II are possible in all sorts of ways. [1737]
  • An alkylation of the nitrogen (WG′ corresponds to WG, if R[1738] G 5 is equal to hydrogen) can take place either after the cyclization (IX to II, Scheme 3) or before the cyclization (X to XI, Scheme 3). The cyclization of XI to II can be carried out, for example, by use of polyphosphoric acid (Procter et al., J. Chem. Soc. (C) 1969, 1000). Alternatively, XI can be converted by methods known to the person skilled in the art into the acid chloride XII, which is then cyclized to II by activators such as AlCl3 or SnCl4 according to Friedel-Craft.
  • Use can also be made of other preactivated carboxylic acid derivatives XII: symmetrical or mixed anhydrides or “active esters” which are customarily used for the acylation of amines. These activated carboxylic acid derivatives (COQ) can also be prepared in situ. It is to be taken into account in this connection that, for example, when using AlCl[1739] 3 a methoxy group (M-R=OMe, X) is converted into the hydroxy function (M-R′=OH, II), which is why it can be the case that R is not equal to R′.
    Figure US20040077638A1-20040422-C00076
  • In many cases (e.g. if MR=OH), the hydrogenation of the compounds III to IV (Scheme 1) is carried out after protection of the function (Scheme 4). One possibility is acetylation. The protective group (PG in compound XIII) is introduced by known methods and removed by known-methods after the hydrogenation (see Greene “Protective Groups in Organic Synthesis”, Wiley). [1740]
    Figure US20040077638A1-20040422-C00077
  • Another possibility consists in carrying out the hydrogenation only after the introduction of the side chain (XV to VII, Scheme 4), according to methods such as have already been described for compounds of the formula V. [1741]
  • Compounds of the formula I in which X[1742] G is equal to N can be prepared according to Scheme 5.
    Figure US20040077638A1-20040422-C00078
  • The starting point of the synthesis are compounds of the type XVI, which are either known or are accessible by methods known to the person skilled in the art, such as are described, for example, in Pharmazie 45 (8), 1990, 555-559. [1743]
  • Alkylation with a compound of the general formula XIX (U[1744] L=customary leaving group) under customary reaction conditions leads to XVII. The further reactions to give I then proceed via XVIII analogously to Scheme 1.
  • The coupling of the individual fragments and the removal of the protective groups can be carried out according to known processes (see Larock, “Comprehensive Organic Transformations”; protective groups: Greene, T., “Protective Groups in Organic Synthesis”, New York 1991), in the case of amide bonds also analogously to the methods of peptide synthesis, such as are described in standard works, e.g. in Bodanszky “The Practice of Peptide Synthesis”, 2nd Edition, Springer-Verlag 1994, and Bodanszky “Principles of Peptide Synthesis”, Springer-Verlag 1984. A general survey of the customary methods for peptide synthesis and a listing of suitable reagents is furthermore to be found in NOVABIOCHEM 1999 “Catalog and Peptide Synthesis Handbook”. [1745]
  • The amide couplings mentioned can be carried out with the aid of customary coupling reagents using suitably protected amino and carboxylic acid derivatives. Another method consists in the use of preactivated carboxylic acid derivatives, preferably of carboxylic acid halides, symmetrical or mixed anhydrides or “active esters”, which are customarily used for the acylation of amines. These activated carboxylic acid derivatives can also be prepared in situ. As a rule, the couplings can be carried out in inert solvents in the presence of an acid-binding agent, preferably of an organic base such as triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, quinoline; the addition of an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogencarbonate or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or cesium, can also be favorable. [1746]
  • Depending on the conditions used, the reaction time is between [lacuna] minutes and 14 days; the reaction temperature between −40° C. and 140° C., preferably between −20° C. and 100° C. [1747]
  • Suitable inert solvents are, for example, hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 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), dimethylacetamide or acetamide; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; water; or mixtures of the solvents mentioned. [1748]
  • Protective groups PG which can be used are all protective groups known and customary from peptide synthesis to the person skilled in the art, such as are also described in the above-mentioned standard works. The removal of the protective groups in the compounds of the formulae V, VII and XVIII is likewise carried out according to conditions such as are known to the person skilled in the art and are described, for example, by Greene and. Wuts in “Protective Groups in Organic Synthesis”, 2nd Edition, Wiley & Sons, 1991. [1749]
  • Protective groups such as PG[1750] 3 are “N-terminal amino protective groups”; Boc, Fmoc, benzyloxycarbonyl (Z), acetyl and. Mtr are preferred here.
  • PG[1751] 1 and PG2 are “C-terminal hydroxy protective groups”; C1-4-alkyl such as methyl, ethyl, tert-butyl, or alternatively benzyl or trityl, or polymer-bound protective groups in the form of the commercially available polystyrene resins such as 2-chlorotrityl chloride resin or Wang resin (Bachem, Novabiochem) are preferred here.
  • The removal of acid-labile protective groups (e.g. Boc, tert-butyl, Mtr, trityl) can be carried out, depending on the protective group used, using organic acids such as trifluoroacetic acid (TFA), trichloroacetic acid, perchloric acid, trifluoroethanol, sulfonic acids such as benzene- or p-toluenesulfonic acid but also inorganic acids such as hydrochloric acid or sulfuric acid, the acids generally being employed in an excess. [1752]
  • In the case of trityl, the addition of thiols such as thioanisole or thiophenol can be advantageous. 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, amides such as 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 the reactions are carried out in a range between 0° C. and 30° C. [1753]
  • Base-labile protective groups such as Fmoc are cleaved by treatment with organic amines such as dimethylamine, diethylamine, morpholine, piperidine as 5-50% solutions in CH[1754] 2Cl2 or DMF. The reaction temperature for these reactions is between 10° C. and. 50° C. and the reactions are preferably carried out in a range between 0° C. and 30° C.
  • Acid protective groups such as methyl or ethyl are preferably cleaved by basic hydrolysis in an inert solvent. The bases used are preferably alkali metal or alkaline earth metal hydroxides, preferably NaOH, KOH or LiOH. The solvents used are all customary inert solvents such as hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene, chlorinated hydrocarbons such as trichloroethylene, 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 ac tone, butanone, amides such as dimethylformamide (DMF), dimethylacetamide or acetamide, nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, nitro compounds such as nitromethane or nitrobenzene, water or mixtures of the solvents mentioned. The addition of a phase-transfer catalyst can be advantageous depending on the solvent or solvent mixture used. The reaction temperature for these reactions is generally between −10° C. and 100° C. [1755]
  • Hydrogenolytically removable protective groups such as benzyloxycarbonyl (Z) or benzyl can be removed, for example, by hydrogenolysis in the presence of a catalyst (e.g. of a noble metal catalyst on active carbon as a support). Suitable solvents are those indicated above, in particular alcohols such as methanol or ethanol, amides such as DMF or dimethylacetamide, esters such as ethyl acetate. As a rule, the hydrogenolysis is carried out at a pressure of 1-200 bar and at temperatures between 0 and 100° C.; the addition of an acid such as acetic acid or hydrochloric acid may be advantageous. The catalyst used is preferably 5 to 10% Pd on active carbon. [1756]
  • The synthesis of structural units of Type E (or E′) is generally carried out by methods known to the person skilled in the art. The structural units used are either commercially available or accessible by methods known from the literature. The synthesis of some of these structural units is described by way of example in the example section. [1757]
  • In the case in which the fragments Q[1758] E or XE contained in the compounds of the type VI and VIII are a hetaryl radical, the structural units used are either commercially available or accessible by methods known to the person skilled in the art. A large number of preparation methods are described in detail in Houben-Weyl's “Methoden der. organischen Chemie” [Methods of Organic Chemistry (Vol. E6: furans, thiophenes, pyrroles, indoles, benzothiophenes, benzofurans, benzopyrroles; Vol. E7: quinolines, pyridines; Vol. E8: isoxazoles, oxazoles, thiazoles, pyrazoles, imidazoles and their benzo-fused representatives, and also oxadiazoles, thiadiazoles and triazoles; Vol. E9: pyridazines, pyrimidines, triazines, azepines and their benzo-fused representatives, and purines). The linkage of these fragments to E can also take place, depending on the structure of E, via the amino or acid function by methods which are known to the person skilled in the art.
  • The synthesis of structures of the general formula A-E′-D[1759] E is carried out by methods known to the person skilled in the art, such as are described in WO 97/08145. Examples of these are the conversion of compounds of the general formula:
  • HNRE 12-EA1-DE  (XX)
  • NC-EA2-DE  (XXI)
  • into compounds-of the general formula: [1760]
  • A-NRE 12-EA1-DE  (XXII)
  • A-E′-DE  (XXIII)
  • The groups E[1761] A1 and EA2 in the formulae XX-XXII are structural fragments which after the appropriate modification, e.g. the reaction with suitable reagents or coupling with appropriate structural units, form the structural fragment A-E in totality. These structural units can then be reacted either directly—in the case of the corresponding free amines or carboxylic acids or after removal of the protective groups—to give compounds of the-general formula I (Schemes 1 and 5). In principle, A, however, can also be introduced, as described in Scheme 1, into compounds of type IV, where the reaction conditions mentioned can be used exactly as variants not described here.
  • In Schemes 6-10, a number of the methods for the introduction of A are described by way of example, where in each case reaction conditions were used such as are known and suitable for the respective reactions. Use can also be made in this case of variants which are known per se, but not mentioned here. [1762]
  • Ureas and thioureas (AE-1 to AE-3) can be prepared by customary methods of organic chemistry, e.g. by reaction of an isocyanate or of an thioisocyanate with an amine, if appropriate in an inert solvent, with warming (Houben-Weyl Volume VIII, 157ff.) (Scheme 6) [1763]
    Figure US20040077638A1-20040422-C00079
  • Scheme 7 shows, by way of example, the preparation of compounds of the type AE-4, such as is described, for example, by Blakemoore et al. in Eur. [1764] J. Med. Chem. 1987 (22) 2, 91-100, or von Misra et al. in Bioorg. Med. Chem. Lett. 1994 4 (18), 2165-2170. The pyridine N-oxide-can be converted into the corresponding pyridines under the conditions of a transfer hydrogenation (e.g. Pd catalyst such as Pd/active carbon; inert solvent such as methanol, ethanol, isopropanol) using, for example, cyclohexene, 1,4-cyclohexadiene, formic acid or formates.
    Figure US20040077638A1-20040422-C00080
  • Unsubstituted or cyclic guanidine derivatives of the general formula AE-5 and AE-6 can be prepared by means of commercially available or readily accessible reagents, such as are described, for example, in [1765] 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.
  • The preparation of compounds of the general formula AE-7 can be carried out analogously to U.S. Pat. No. 3,202,660, compounds of the formula AE-9, AE-10, AE-11 and AE-12 analogously to WO 97/08145. Compounds of the formula AE-8 can be prepared, as shown in Scheme 5, for example, according to the method described by Perkins et al., [1766] Tetrahedron Lett. 1999, 40, 1103-1106. Scheme 8 gives a general survey of the synthesis of the compounds mentioned.
    Figure US20040077638A1-20040422-C00081
    Figure US20040077638A1-20040422-C00082
    Figure US20040077638A1-20040422-C00083
  • Compounds of the general formula AE-13 can be prepared analogously to Froeyen et al., [1767] Phosphorus Sulfur Silicon Relat. Elem. 1991, 63, 283-293, AE-14 analogously to Yoneda et al., Heterocycles 1998, 15 N′-1, Spec., Issue, 341-344 (Scheme 9). The preparation of corresponding compounds can also be carried out analogously to WO 97/36859:
    Figure US20040077638A1-20040422-C00084
  • Compounds of the general formula AE-15 can be prepared as in Synthesis 1981, 963-965 and Synth. Comm. 1997, 27 (15), 2701-2707, AE-16 analogously to J. Org. Chem. 1991, 56 (6), 2260-2262 (Scheme 10). [1768]
    Figure US20040077638A1-20040422-C00085
  • Structural units of the type I[1769] A 17 (see sketch on p. 24, naphthyridine derivatives) can be prepared analogously to WO 00/09503.
  • The invention further relates to the use of the structural element of the formula, I[1770] GL
  • -G-L  IGL
  • for the preparation of compounds which bind to integrin receptors. [1771]
  • The invention further relates to drugs comprising the structural element of the formula I[1772] GL.
  • The invention further relates to pharmaceutical preparations, comprising at least one compound of the formula I in addition to the customary pharmaceutical excipients. [1773]
  • The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in the customary manner. Administration can also be carried out through the nasopharynx using vapors or sprays. Further, the compounds according to the invention can be introduced by direct contact with the affected tissue. [1774]
  • The dose depends on the age, condition and weight of the patient and on the manner of administration. As a rule, the daily dose of active compound is between approximately 0.5 and 50 mg/kg of body weight in the case of oral administration and between approximately 0.1 and 10 mg/kg. of body weight in the case of parenteral administration. [1775]
  • The novel compounds can be administered in solid or liquid form in the customary pharmaceutical administration forms, e.g. as tablets, film-coated tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointments, creams or sprays. These are prepared in a customary manner. The active compounds can in this case be processed using the customary pharmaceutical excipients such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-delaying agents, antioxidants and/or propellants (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-verlag, Stuttgart, 1991). The administration forms thus obtained normally contain the active compound in an amount from 0.1 to 90% by weight. [1776]
  • The invention further relates to the use of the compounds of the formula I for the production of drugs for the treatment-of diseases. The compounds of the formula I can be used for treating human and animal diseases. The compounds of the formula I bind to integrin receptors. They are therefore preferably suitable as integrin receptor ligands and for the production of drugs for treating diseases in which an integrin receptor is involved, in particular for the treatment of diseases in which the interaction between integrins and their natural ligands is dysregulated, i.e. excessive or reduced. [1777]
  • Integrin receptor ligands are understood as meaning agonists and antagonists. [1778]
  • An excessive or decreased interaction is understood as meaning either an excessive or decreased expression of the natural ligand and/or of the integrin receptor and thus an excessive or decreased amount of natural ligand and/or integrin receptor or an increased or decreased affinity of the natural ligand for the integrin receptor. [1779]
  • The interaction between integrins and their natural ligands is dysregulated compared with the normal state, i.e. excessive or decreased, if this dysregulation does not correspond to the physiological state. An increased or decreased interaction can lead to pathophysiological situations. [1780]
  • The level of dysregulation-which leads to a pathophysiological situation is dependent on the individual organism and, on the site and nature of the disorder. [1781]
  • Preferred integrin receptors for which the compounds of the formula I according to the invention can be-used are the α[1782] 5β1, α4β1, gpIIbβ3, αvβ5 and αvβ3 integrin receptors.
  • The compounds of the formula I particularly preferably bind to the α[1783] vβ3 integrin receptor and can thus be particularly preferably used as ligands of the αvβ3 integrin receptor and for the treatment of diseases in which the interaction between αvβ3 integrin receptor and its natural ligands is excessive or decreased.
  • The compounds of the formula I are preferably used for the treatment of the following diseases: [1784]
  • cardiovascular disorders such as atherosclerosis, restenosis after vascular injury or stent implantation, and angioplasty (neointima formation, smooth muscle cell migration and proliferation), [1785]
  • acute kidney failure, [1786]
  • angiogenesis-associated microangiopathies such as diabetic angiopathies or retinopathy or rheumatoid arthritis, [1787]
  • blood platelet-mediated vascular occlusion, arterial thrombosis, [1788]
  • stroke, reperfusion damage after myocardial infarct or stroke, [1789]
  • carcinomatous-disorders, such as in tumor metastasis or in tumor growth (tumor-induced angiogenesis), [1790]
  • osteoporosis (bone resorption after chemotaxis and adhesion of osteoclasts to the bone matrix), [1791]
  • high blood pressure, psoriasis, hyperparathyroidism, Paget's disease, malignant hypercalcemia, metastatic osteolytic lesions, inflammation, wound healing, cardiac insufficiency, congestive heart failure CHF, as well as in [1792]
  • antiviral, antimycotic, antiparasitic or antibacterial therapy and prophylaxis (adhesion and internalization), in particular in mycotically mediated disorders., in particular infections by [1793] Candida albicons.
  • Advantageously, the compounds of the formula I can be administered in combination with at least one further compound in order to achieve an improved curative action in a number of indications. These further compounds can have the same or a different mechanism of action as/from the compounds of the formula I. [1794]
  • In addition to the compounds of the formula I and the customary pharmaceutical excipients, the pharmaceutical preparations can therefore contain at least one further compound, depending on the indication, in each case selected from one of the 10 groups below. [1795]
  • Group 1: [1796]
  • inhibitors of blood platelet adhesion, activation or aggregation, such as acetylsalicylic acid, lysine acetylsalicylate, piracetam, dipyridamol, abciximab, thromboxane antagonists, fibrinogen antagonists, such as tirofiban, or inhibitors of ADP-induced aggregation such as ticlopidine or clopidogrel, [1797]
  • anticoagulants which prevent thrombin activity or formation, such as inhibitors of IIa, Xa, XIa, IXa or VIIa, [1798]
  • antagonists of blood platelet-activating compounds and selectin antagonists [1799]
  • for the treatment of blood platelet-mediated vascular occlusion or thrombosis, or [1800]
  • Group 2: [1801]
  • inhibitors of blood platelet activation or aggregation, such as GPIIb/IIIa antagonists, thrombin or factor Xa inhibitors or ADP receptor antagonists, [1802]
  • serine protease inhibitors, [1803]
  • fibrinogen-lowering compounds, [1804]
  • selectin antagonists, [1805]
  • antagonists of ICAM-1 or VCAM-1 [1806]
  • inhibitors of leukocyte adhesion [1807]
  • inhibitors of vascular wall transmigration, [1808]
  • fibrinolysis-modulating compounds, such as streptokinase, tPA, plasminogen-activating stimulants, TAFI inhibitors, XIa inhibitors or PAI-1 antagonists, [1809]
  • inhibitors of complement factors, [1810]
  • endothelin receptor antagonists, [1811]
  • tyrosine kinase inhibitors, [1812]
  • antioxidants and [1813]
  • interleukin 8 antagonists [1814]
  • for the treatment of myocardial infarct or stroke, or [1815]
  • Group 3: [1816]
  • endothelin antagonists, [1817]
  • ACE inhibitors, [1818]
  • angiotensin receptor antagonists, [1819]
  • endopeptidase inhibitors, [1820]
  • beta-blockers, [1821]
  • calcium channel antagonists, [1822]
  • phosphodiesterase inhibitors and [1823]
  • caspase inhibitors [1824]
  • for the treatment of congestive heart failure, or [1825]
  • Group 4: [1826]
  • thrombin inhibitors, [1827]
  • inhibitors of factor Xa, [1828]
  • inhibitors of the coagulation pathway which leads to thrombin formation, such as heparin or low-molecular weight heparins, inhibitors of blood platelet adhesion, activation or aggregation, such as GPIIb-IIIa antagonists or antagonists of the blood platelet adhesion and activation mediated by vWF or GPIb, [1829]
  • endothelin receptor antagonists, [1830]
  • nitrogen oxide synthase inhibitors, [1831]
  • CD44 antagonists, [1832]
  • selectin antagonists, [1833]
  • MCP-1 antagonists, [1834]
  • inhibitors of signal transduction in proliferating cells, [1835]
  • antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF and [1836]
  • antioxidants [1837]
  • for the treatment of restenosis after vascular injury or stent implantation, or [1838]
  • Group 5: [1839]
  • antagonists of the cell response-mediated by EGF, PDGF, VEGF or bFGF, [1840]
  • heparin or low-molecular weight heparins or further GAGs, [1841]
  • inhibitors of MMPS, [1842]
  • selectin antagonists, [1843]
  • endothelin antagonists, [1844]
  • ACE inhibitors, [1845]
  • angiotensin receptor antagonists and [1846]
  • glycosylation inhibitors or AGE formation inhibitors or AGE breakers and antagonists of their receptors, such as RAGE, [1847]
  • for the treatment of diabetic angiopathies or [1848]
  • Group 6: [1849]
  • lipid-lowering compounds, [1850]
  • selectin antagonists, [1851]
  • antagonists of ICAM-1 or VCAM-1 [1852]
  • heparin or low-molecular weight heparins or further GAGs, [1853]
  • inhibitors of MMPs, [1854]
  • endothelin antagonists, [1855]
  • apolipoprotein Al antagonists, [1856]
  • cholesterol antagonists, [1857]
  • HMG CoA reductase inhibitors, [1858]
  • ACAT inhibitors, [1859]
  • ACE inhibitors, [1860]
  • angiotensin receptor antagonists, [1861]
  • tyrosine kinase inhibitors, [1862]
  • protein kinase C inhibitors, [1863]
  • calcium channel antagonists, [1864]
  • LDL receptor function stimulants, [1865]
  • antioxidants [1866]
  • LCAT mimetics and [1867]
  • free radical scavengers [1868]
  • for the treatment of atherosclerosis or [1869]
  • Group 7: [1870]
  • cytostatic or antineoplastic compounds, [1871]
  • compounds which inhibit proliferation, such as kinase inhibitors and [1872]
  • heparin or low-molecular weight heparins or further GAGs [1873]
  • for the treatment of cancer, preferably for the inhibition of tumor growth or metastasis, or [1874]
  • Group 8: [1875]
  • compounds for antiresorptive therapy, [1876]
  • compounds for hormone exchange therapy, such as estrogen or progesterone antagonists, [1877]
  • recombinant human growth hormone, [1878]
  • bisphosphonates, such as alendronates [1879]
  • compounds for calcitonin therapy, [1880]
  • calcitonin stimulants, [1881]
  • calcium channel antagonists, [1882]
  • bone formation stimulants, such as growth factor agonists, [1883]
  • interleukin-6 antagonists and [1884]
  • Src tyrosine kinase inhibitors [1885]
  • for the treatment of osteoporosis or [1886]
  • Group 9: [1887]
  • TNF inhibitors, such as TNF antibodies, in particular the human antibody D[1888] 2E7,
  • antagonists of VLA4 or VCAM-1, [1889]
  • antagonists of LFA-1, Mac-1 or ICAMs, [1890]
  • complement inhibitors, [1891]
  • immunosuppressants, [1892]
  • interleukin-1, -5 or -8 antagonists and [1893]
  • dihydrofolate reductase inhibitors [1894]
  • for the treatment of rheumatoid arthritis or [1895]
  • Group 10: [1896]
  • collagenase, [1897]
  • PDGF antagonists and [1898]
  • mmps [1899]
  • for improved wound healing. [1900]
  • A pharmaceutical preparation comprising at least one compound of the formula I, if appropriate pharmaceutical excipients and at least one further compound, depending on the indication, in each case selected from one of the above groups, is understood as meaning a combined administration of at least one of the compounds of the formula I with at least one further compound in each case selected from one of the groups described above and, if appropriate, pharmaceutical excipients. [1901]
  • Combined administration can be carried out by means of a substance mixture comprising at least one compound of the formula I, if appropriate pharmaceutical excipients and at least one further compound, depending on the indication, in each case selected from one of the above groups, but also spatially and/or chronologically separate. [1902]
  • In the case of the spatially and/or chronologically separate administration, the administration of the components of the pharmaceutical preparation, the compounds of the formula I and the compounds selected from one of the abovementioned groups takes place spatially and/or chronologically separately. [1903]
  • For the treatment of restenosis after vascular injury or stenting, the administrations of the compounds of the formula I can be carried out locally at the affected sites, on their own or in combination with at least one compound selected from group 4. It may also be advantageous to coat the stents with these compounds. [1904]
  • For the treatment of osteoporosis, it may be advantageous to carry out the administration of the compounds of the formula I in combination with antiresorptive or hormone replacement therapy. [1905]
  • The invention accordingly relates to the use of the abovementioned pharmaceutical preparations for the production of drugs for the treatment of diseases. [1906]
  • In a preferred embodiment, the invention relates to the use of the abovementioned combined pharmaceutical preparations for the production of drugs for treating [1907]
  • blood platelet-mediated vascular occlusion or thrombosis [1908]
  • when using compounds of group 1, [1909]
  • myocardial infarct or stroke [1910]
  • when using compounds of group 2, [1911]
  • congestive heart failure [1912]
  • when using compounds of group 3, [1913]
  • restenosis after vascular injury or stent implantation [1914]
  • when using compounds of group 4, [1915]
  • diabetic angiopathies [1916]
  • when using compounds of group 5, [1917]
  • atherosclerosis [1918]
  • when using compounds of group 6, [1919]
  • cancer [1920]
  • when using compounds of group 7, [1921]
  • osteoporosis [1922]
  • when using compounds of group 8, [1923]
  • rheumatoid arthritis [1924]
  • when using compounds of group 9, [1925]
  • wound healing [1926]
  • when using compounds of group 10. [1927]
  • The following examples illustrate the invention, the selection of these examples being non-limiting.[1928]
    • I. SYNTHESIS EXAMPLES
  • I.A Precursors [1929]
  • 4-[(1-oxido-2-pyridinyl)amino]-1-butanol (1) [1930]
  • A mixture of 2-chloropyridine N-oxide (70.0 mmol, 11.0 g), 4-aminobutanol (130 mmol, 11.5 g) and NaHCO[1931] 3 (340.0 mmol, 28.9 g) in tert-amyl alcohol (500 ml) was heated underreflux for 24 h. After dilution with CH2Cl2, the suspension was filtered and the filtrate was concentrated in a rotary evaporator. Chromatography on silica gel (CH2Cl2/MeOH 0 to 20%) afforded 6.9 g of target product; ESI-MS [2M+H+]=365.1, [M+H+]=183.05, 83.2;
  • [1932] 1H-NMR (270 MHz, CDCl3) δ ppm: 8.11 (d, 1H), 7.23 (t, 1H), 6.86 (s br., 1H), 6.66-6.47 (m, 2H), 3.69 (t, 2H), 3.32 (q, 2H), 2.53 (s br., 1H), 1.90-1.54 (m, 4H).
  • 3-[(1-Oxido-2-pyridinyl)amino]-1-propanol (2) [1933]
  • A mixture of 2-chloropyridine N-oxide (7.70 mmol, 997.5 mg), 3-aminopropanol (15.0 mmol, 1.1-g) and NaHCO[1934] 3 (40.0 mmol, 3.4 g) in tert-amyl-alcohol (80 ml) was heated under reflux for 21 h. After dilution with CH2Cl2, the suspension was filtered and the filtrate was concentrated in a rotary evaporator. Chromatography on silica gel (CH2C2/MeOH 0 to 20%) afforded 1 g of target product; ESI-MS [2M+H+]=337.1, [M+H+]=169.15;
  • [1935] 1H-NMR (270 MHz, DMSO) δ ppm: 8.07 (d, 1H), 7.26-7.08 (m, 1H), 6.78 (d, 1H), 6.56 (t, 1H), 4.61 (s br., 1H), 3.60-3.13 (m, incl. DMSO), 1.69 (quint., 2H).
  • N-[4-(aminomethyl)phenyl]-1H-benzimidazol-2-amine (hydrochloride) (3) [1936]
  • a), 20 g of tert-butyl 4-aminobenzyl carbamate (89.97 mmol) dissolved in 100 ml of CH[1937] 3CN were added dropwise at 0° C. to a solution of 24.5 g of thiocarbonyldiimidazole and 1.56 g of imidazole in 600 ml of CH3CN and the mixture was stirred at RT overnight. 19.5 g of 1,2-phenylenediamine were then added and the mixture was again stirred at RT for 2 h. For the work-up, the reaction mixture was evaporated in vacuo, the residue was taken up in CH2Cl2, and the solution was washed 7× with 10% citric acid and 2× with satd. NaCl solution, dried over Na2SO4, filtered and concentrated. The crude product thus obtained (31.78 g; brown foam) was reacted directly without further purification; ESI-MS [M+H+]=373.15;
  • [1938] 1H-NMR (360 MHz, DMSO) δ ppm: 9.5 and 9.05 (each s, 1H), 7.45 (d, 2H), 7.35 (m, 1H), 7.20 (d, 1H), 7.15, 6.95, 6.75, 6.60 (each m, 1H), 4.85 (s, 2H), 4.10 (d, 2H), 1.35 (s, 9H).
  • b) Crude product 3a was dissolved in 750 ml of ethanol together with 36.7 g of HgO (yellow) and 0.4 g of sulfur and the solution was heated to reflux for 2 h. The reaction mixture was then filtered twice through Celite and evaporated to dryness; 20.7 g ESI-MS [M+H[1939] +]=339.15.
  • c) 7 g of the crude product 3b were introduced into 70 ml of CH[1940] 2Cl2, 35 ml of HCl in diethyl ether (satd. at 0°C.) and stirred at RT for 2 h. The resulting precipitate was filtered off with suction, washed with CH2Cl2 and dried; 6.7 g of brown amorphous solid; ESI-MS [M+H+]=239.15;
  • [1941] 1H-NMR (360 MHz, DMSO) δ ppm: 11.6 (s broad, 1H), 8.4 (s broad, 3H), 8.25 (s broad, 1H), 7.65 and 7.55 (each d, 2H), 7.45 and 7.3 (each m, 2H), 4.19 (m, 2H).
  • N[1942] 1-Pyridin-2-ylpropane-1,3-diamine (4)
  • 2-Bromopyridine (100 g; 0.633 mol) and 1,3-diaminopropane (234.5 g; 3.16 mol) were heated to reflux for 7 h. After reaction was complete, the mixture was evaporated. Distillation in an oil pump vacuum of the residue which remained afforded 43 g of the desired product; ESI-MS [M+H[1943] +]=152.15;
  • [1944] 1H-NMR (360 MHz, CDCl3) δ (ppm): 8.05 (d, 1H), 7.36 (t, 1H), 6.51 (t, 1H), 6.36 (d, 1H), 4.98 (s, 1H), 3.35 (s, 2H), 2.82 (t, 2H), 1.73 (m, 1H), 1.32 (s, 2H).
  • 2-[(3-Methoxyanilino)carbonyl]benzoic Acid (5) [1945]
  • A solution of 3-methoxyaniline (80.0 mmol, 9.9 g) was added dropwise at 10° C. to a solution of phthalic anhydride (80.0 mmol, 11.9 g) in THF (80 ml). The mixture was stirred overnight and treated with water (1.2 l). The precipitate was filtered off with suction, washed with ice-cold water and also with acetone and pentane and then dried in vacuo. Yield: 19.5 g; mp 168.4 to 168.9° C.; ESI-MS: [2M+Na[1946] +]=565.2, [M+K+]=310.0, [M+H+]=272.05;
  • [1947] 1H-NMR (400 MHz; DMSO-d6): δ (ppm) 13.01 (s br., 1H), 10.31 (s br., 1H), 7.87 (d, 1H), 7.69-7.49 (m, 3H), 7.39 (s, 1H), 7.26-7.19 (m, 2H), 6.69-6.62 (m, 1H), 3.73 (s, 3H).
  • Methyl 2-{[3-methoxy(methyl)anilino]carbonyl}benzoate (6) [1948]
  • 2-[(3-Methoxyanilino)carbonyl]benzoic acid (5, 36.9 mmol 10.0 g) was introduced at 10° C. into a suspension of 5.3 g of NaH (60%; freed from oil using pentane) in DMSO (110.0 ml). The mixture was stirred at RT for 1 h until the evolution of H[1949] 2 was complete. Methyl iodide (169.6 mmol, 24.1 g) was added dropwise and the mixture was stirred further overnight. For the work-up, water (100 ml) was added dropwise and the solution was extracted with ethyl acetate. The combined organic phases were washed with an aq. saturated NaCl solution. Drying and concentration of the organic phase afforded 11.2 g of yellow residue; ESI-MS: [2M+Na+]=621.3, [M+K+]=338.0, [M+H+]=300.15;
  • [1950] 1H-NMR (400 MHz; CDCl3): δ (ppm) 7.78 (d, 1H), 7.32 (t, 1H), 7.28-7.21 (m, 1H), 7.17 (d, 1H), 7.04 (t, 1H), 6.74-6.64 (m, 2H), 6.61 (d, 1H), 3.92 (s, 3H), 3.63 (s, 3H), 3.51 (s, 3H).
  • 2-{[3-Methoxy(methyl)anilino]carbonyl}benzoic Acid (7) [1951]
  • LiOH (73.5 mmol, 1.8 g) in water (250 ml) was added dropwise to a solution of methyl 2-{[3-methoxy(methyl)anilino]carbonyl}benzoate (6, 36.8 mmol, 11.0 g) in methanol (250 ml). The mixture was stirred at 40° C. overnight. The mixture was acidified to pH 4.1 (using 2 N HCl) at 0° C. and the suspension was concentrated. The residue was dissolved using CH[1952] 2Cl2 and extracted by shaking with water. Drying and concentration of the organic phase afforded 9.8 g of foam; ESI-MS: [2M+Na+]=593.3, [M+K+]=324.0, [M+H+]=286.15; 1H-NMR (270 MHz; DMSO-d6): δ (ppm) 13.13 (s br., 1H), 7.68 (d, 1H), 7.42-7.24 (m, 2H), 7.18 (d, 1H), 7.07 (t, 1H), 6.92-6.73 (m, 2H), 6.64 (d, 1H), 3.59 (s, 3H).
  • 2-{[3-Methoxy(methyl)anilino]carbonyl}benzoyl chloride (8) [1953]
  • Thionyl chloride (56.6 mmol, 6.7 g) was added at 5° C. to absolution of 2-{[3-methoxy(methyl)anilinolcarbonyl}benzoic acid (7, 33.3 mmol, 9.5 g) in THF (180 ml). The mixture was warmed to 40° C. for 2 h and then codistilled a number of times with toluene. It was possible to react the residual brown oil (10.4 g) further without purification. [1954]
  • 3-Hydroxy-5-methyl-5H-dibenzo[b,e]azepine-6,11-dione (9) [1955]
  • 2-{[3-Methoxy(methyl)anilino]carbonyl}benzoyl chloride (8, 10.4 g) was heated to 180*C with a mixture of AlCl[1956] 3 (701.9 mmol, 93.6 g) and NaCl (391.0 mmol, 23.0 g) and the black melt was stirred for 15 min. For the work-up, the cooled melt was poured onto ice/water and the deposited precipitate was filtered off with suction. The precipitate was washed by stirring with heptane and filtered and purified by means of chromatography on silica gel (eluent: gradient of hexane/CH2Cl2 50 to 100% to CH2Cl2/MeOH 0 to 5%): 2.8 g; ESI-MS: [M+K+]=292.0, [M+H+]=254.1;
  • [1957] 1H-NMR (270 MHz; DMSO-d6): δ (ppm) 10.59 (s br., 1H), 8.08-7.99 (m, 1H), 7.81-7.69 (m, 2H), 7.69-7.59 (m, 1H), 7.41 (d, 1H), 6.86 (d, 1H), 6.73 (dd, 1H), 3.50 (s, 3H).
  • Methyl (2 E,Z)-(3-hydroxy-5-methyl-6-oxo-5,6-dihydro-1H-dibenzo-[b,e]azepin-11-ylidene)ethanoate (10) [1958]
  • A solution of methyl diethylphosphonoacetate (23.7 mmol, 5.0 g) and lithium methoxide (23.7 mmol, 0.9 g) in DMF (50 ml) was added dropwise at 0° C. under N[1959] 2 to 3-hydroxy-5-methyl-5H-dibenzo[b,e]azepine-6,11-dione (9, 7.9 mmol, 2.0 g) and lithium methoxide (7.9 mmol, 0.3 g) in DMF (50 ml). The mixture was warmed to 60° C. overnight. The solution was treated at 0° C. with 2 N HCl and extracted with ethyl acetate. The combined organic phases were extracted by shaking with aq. saturated NaCl solution. Drying, concentration and chromatography on silica gel (CH2Cl2/MeOH 0 to 100%) afforded 2.0 g as a cis:trans mixture; ESI-MS: [M+K+]=348.0, [M+H+]=310.05.
  • Methyl (2 E,Z)-(3-acetyloxy-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo-[b,e]azepin-11-ylidene)ethanoate (11) [1960]
  • Acetyl chloride (2.23 mmol, 0.18 g) and then pyridine (4.46 mmol, 0.35 g) were injected at 0° C. into a solution of methyl (2 E,Z)-(3-hydroxy-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo[b,]azepin-11-ylidene)ethanoate (10, 0.74 mmol, 0.23 g) in DMF (10 ml). The mixture was stirred overnight at RT and, for the work-up, poured onto 20 ml of ice/water. The mixture was acidified and extracted with diethyl ether. Drying and concentration of the organic phase afforded 0.26 g; ESI-MS: [M+K[1961] +]=390.0, [M+H+]=352.0.
  • Methyl [3-acetyloxy-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-11-yl)acetate (12) [1962]
  • Methyl [2 E,Z)-(3-acetyloxy-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo-[b,e]azepin-11-ylidene)ethanoate (11, 0.68 mmol, 0.24 g) and Pd/carbon (40 mg) in MeOH (24 ml)/ethyl acetate (24 ml) were treated with H[1963] 2 gas at 50° C., 120 bar for 21 h. Filtering through Celite and concentration afforded 0.25 g; ESI-MS: [M+K+]=392.0, [M+H+]=354.15.
  • Methyl [3-hydroxy-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-11-yl)acetate (13) [1964]
  • K[1965] 2CO3 was added at 5° C. to a solution of methyl [3-acetyloxy-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (12, 0.71 mmol, 0.25 g) in MeOH (9 ml). The mixture was stirred at RT for 5 h. The solution was neutralized using aq. NH4Cl and extracted with CH2Cl2. Drying and concentration afforded 0.18 g of white residue; ESI-MS: [2M+Na+]=645.2, [M+K+] 350.0, [M+H+]=312.05.
  • Methyl (5-methyl-3-{4-[[1-oxido-2-pyridinyl)amino]butoxy}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (14) [1966]
  • A solution of 4-[(1-oxido-2-pyridinyl)amino]-1-butanol (1) (0.40 mmol, 0.07 g) and diethyl azodicarboxylate (0.40 mmol, 0.08 g) in DMF (2 ml) was added dropwise to methyl[3-Hydroxy-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (13, 0.16 mmol, 0.05 g) and triphenylphosphine (0.43 mmol, 0.11 g) in DMF (5 ml) under argon. The mixture was stirred overnight at 40° C. Concentration, codistillation with xylene and chromatography on silica gel (heptane/CH[1967] 2Cl2 0 to 100% to CH2Cl2/MeOH 0 to 100%) afforded 24.00 mg (purity 90%).
  • Methyl {5-methyl-6-oxo-3-{4-(2-pyridinylamino)butoxy]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetate (15) [1968]
  • The suspension of methyl (5-methyl-3-{4-[[1-oxido-2-pyridinyl)amino]-butoxy}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-11-yl)acetate (14, 0.05 mmol, 24.0 mg), cyclohexene (4.93 mmol, 0.50 ml) and Pd/carbon (30.0 mg) was stirred under reflux overnight. After filtration through Celite and concentration, the residue was taken up in water and the mixture was extracted with diethylether. Concentration afforded 6.70 mg. [1969]
  • Methyl (2 E,Z)-(5-methyl-3-{3-[(1-oxido-2-pyridinyl)amino]-propoxy}-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)-ethanoate (16) [1970]
  • A solution of 3-[(1-oxido-2-pyridinyl)amino]-1-propanol (2, 0.81 mmol, 0.14 g) and diethyl azodicarboxylate (0.81 mmol, 0.17 g) was added dropwise to a solution of methyl (2 E,Z)-(3-hydroxy-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)ethanoate (10, 0.32 mmol, 0.10 g) and triphenylphosphine (0.87 mmol, 0.23 g) under argon. The mixture was stirred at RT overnight. Concentration, codistillation with xylene and filtration through silica gel afforded 0.12 g; ESI-MS: [M+K[1971] +]=498.1, [M+H+]=460.15, 230.6.
  • Methyl (2 E,Z)-(5-methyl-6-oxo-3-{3-(2-pyridinylamino)-propoxy]-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)ethanoate (17) [1972]
  • The suspension of methyl (2 E,Z)-(5-methyl-3-{3-[(1-oxido-2-pyridinyl)-amino]propoxy}-6-oxo-5,6-dihydro-11H-dibenzo[b,e]-azepin-11-ylidene)ethanoate (16, 0.11 mmol, 50.0 mg), cyclohexene (4.93 mmol, 0.50 ml) and Pd/carbon (50.0 mg) was stirred under reflux for 2 d. Filtration through Celite, chromatography on silica gel (heptane/CH[1973] 2Cl2 0 to 100%, CH2Cl2/MeOH 0 to 100%) afforded 31.80 mg; ESI-MS: [M+K+]=482.1, [M+H+]=444.15, 222.6.
  • Methyl {5-methyl-6-oxo-3-[3-(2-pyridinylamino)propoxy]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (18) [1974]
  • Methyl (2 E,Z)-(5-methyl-6-oxo-3-{3-(2-pyridinylamino)-propoxy]-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)ethanoate (17, 0.12 mmol, 55.0 mg) and Pd/carbon (5 mg) in MeOH (4 ml/ethyl acetate (4 ml) were treated with H[1975] 2 gas at 50° C., 120 bar for 21 h. Filtration through Celite, concentration and column chromatography afforded 22.0 mg; ESI-MS: [M+K+]=484.1, [M+Na+]=468.0, [M+H+]=446.15, 223.6.
  • Methyl (5-methyl-6-oxo-3-{[(trifluoromethyl)sulfonyl]oxy}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (19) [1976]
  • Trifluoromethanesulfonic anhydride (1.15 mmol, 326.2 mg) was added at −78° C. under argon to a solution of [3-hydroxy-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (13, 0.58 mmol, 180.0 mg) and 2,6-dimethylpyridine (1.16 mmol, 123.9 mg) in CH[1977] 2Cl2 (6 ml). The mixture was stirred at −78° C. for 30 min and then at RT overnight. The excess of triflate was removed in a high vacuum. The oily residue was taken up in CH2Cl2, washed with HCl (1N), buffered with aq. NaHCO3 and washed with sat. aq. NaCl. Drying and concentration afforded 250.0 mg of brownish oil, which was reacted further without additional purification.
  • 11-(2-Methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepine-3-carboxylic Acid (20) [1978]
  • Carbon monoxide was passed through a suspension of methyl (5-methyl-6-oxo-3-{[(trifluoromethyl)sulfonyl]oxy}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (19, 0.56 mmol, 250.0 mg), potassium acetate (2.26 mmol, 221.3 mg, 1,1′-bis(diphenylphosphino)ferrocene (0.11 mmol, 64.8 mg) and palladium acetate (0.03 mmol, 6.4 mg) in DMSO (9 ml). The mixture was then heated at 70° C. for 3 h, a CO-filled balloon guaranteeing a CO atmosphere over the reaction mixture going into solution. For the work-up, the solution was diluted with water (40 ml), brought to pH 8 using aq. NaHCO[1979] 3 and extracted with diethyl ether. The aq. phase was then acidified with HCl (1N) at 0° C. and extracted with CH2Cl2. In order to remove DMSO, the CH2Cl2 phases were washed a number of times with water. Drying and concentration afforded 120.0 mg of yellow oil; ESI-MS: [M+H+]=340.11.
  • Methyl [3-({[4-(1H-benzimidazol-2-ylamino)benzyl]amino}-carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate (21) [1980]
  • Diisopropylethylamine (0.4 mmol, 51.4 mg) and EDCI*HCl (0.19 mmol, 36.71 mg) were added at 0° C. to a solution of 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepine-3-carboxylic acid (20, 0.15 mmol, 50.0 mg) in CH[1981] 2Cl2 (2 ml)/DMF (1 ml). The mixture was then stirred at 0° C. for 1 h before adding N-[4-(aminomethyl)phenyl]-1H-benzimidazol-2-amine (hydrochloride) (3) (0.16 mmol, 44.5 mg) dissolved in DMF. The mixture was stirred at 0° C. for 1 hour and at RT overnight. Concentration and chromatography (CH2Cl2/MeOH 0 to 100%) afforded 16.0 mg of target product; ESI-MS: [M+H+]=560.15, 280.65.
  • Methyl (5-methyl-6-oxo-3-({[3-(2-pyridinylamino)propyl]amino}-carbonyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate (22) [1982]
  • Diisopropylethylamine (0.2 mmol, 25.3 mg) and EDCI*HCl (0.19 mmol, 36.71 mg) were added at 0° C. to a solution of 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-3-carboxylic acid (20, 0.15 mmol, 50.0 mg) in CH[1983] 2Cl2 (2 ml)/DMF (1 ml). The mixture was then stirred at 0° C. for 1 h before adding N1-pyridin-2-ylpropane-1,3-diamine (4) (0.15 mmol, 22.7 mg) dissolved in DMF. The mixture was stirred at 0° C. for 1 hour and at RT overnight. Concentration and chromatography. (CH2Cl2/MeOH 0 to 100%) afforded 15.0 mg of target product; ESI-MS: [M+H+]=473.15, 237.1.
  • Methyl (2 E,Z)-(5-methyl-6-oxo-3-{[(trifluoromethyl)sulfonyl]-oxy}-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)ethanoate (23) [1984]
  • Trifluoromethanesulfonic anhydride (4.20 mmol, 1.2 g) was added at −78° C. under argon to a solution of methyl (2 E,Z)-(3-hydroxy-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)-ethanoate (10, 3.23 mmol, 1.0 g) and 2,6-dimethylpyridine (6.47 mmol, 0.69 g) in CH[1985] 2Cl2 (30 ml). The mixture was stirred at −78° C. for 30 min and then at RT overnight. The excess of triflate was removed in a high vacuum. The oily residue was taken up in CH2Cl2, washed with HCl (1N), buffered with aq. NaHCO3 and washed with sat. aq. NaCl. Drying and concentration of the organic phase afforded 1.1 g of brownish oil, which was reacted further without additional purification.
  • (11 E,Z)-11-(2-Methoxy-2-oxoethylidene)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepine-3-carboxylic Acid (24) [1986]
  • Carbon monoxide was passed through a suspension of methyl (2 E,Z)-(5-methyl-6-oxo-3-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-11H-dibenzo-[b,e]azepin-11-ylidene)ethanoate (23, 2.54 mmol, 1.1 g), potassium acetate (10.15 mmol, 1.0 g), 1,1′-bis(diphenylphosphino)ferrocene (0.51 mmol, 0.29 g), palladium acetate (0.13 mmol, 28.5 mg) in DMSO (40 ml). The mixture was then heated at 70° C. for 3 h, a CO-filled balloon guaranteeing a CO atmosphere over the reaction mixture going into solution. For the work-up, the solution was diluted with water (50 ml), brought to pH 7 to 8 using aq. NaHCO[1987] 3 and extracted with diethyl ether. The aq. phase was then acidified with HCl (1N) at 0° C. and extracted with combined CH2Cl2. In order to remove DMSO, the combined CH2Cl2 phases were washed a number of times with water. Drying and concentration afforded 200.0 mg of yellow oil; ESI-MS: [M+K+]=376.0, [M+H+]=338.05, 102.15.
  • N[1988] 1-(1H-Benzimidazol-2-yl)pentane-1,5-diamine (hydrochloride) (25)
  • Preparation was carried out analogously to the synthesis of 3 starting from 7 g of N-Boc-1,5-diaminopentane hydrochloride (29.3 mmol). After reaction analogously to 3a, 10.3 g of N-Boc-5-{[(2-aminoanilino)-carbothioyl]amino}pentan-1-amine were obtained; ESI-MS [M+H[1989] +]=353.25. Cyclodesulfurization and subsequent removal of the Boc group using TFA afforded an oily crude product, which was taken up in CH3OH and converted into the corresponding hydrochloride using 250 ml of ethereal HCl (saturated at 0° C.). Stirring the obtained solid with a mixture of CH3OH/methyl tert-butyl ether afforded 1.8 g of a reddish amorphous solid.
  • [1990] 1H-NMR (360 MHz, DMSO) δ ppm: 9.30 (t, 1H), 8.15 (s broad, 3H), 7.40 and 7.25 (each m, 2H), 3.35 (m, 2H superimposed with H20 peak), 2.80 (m, 2H), 1.65 (m, 4H), 1.45 (m, 2H).
  • tert-Butyl 1H-benzimidazol-2-ylmethylcarbamate (26) [1991]
  • 3.32 g of 30% NaOCH[1992] 3 soln were added to tert-butyl cyanomethylcarbamate (3 g; 19.21 mmol) in 20 ml of CH3OH and the mixture was stirred at room temperature for 1 h. After addition of 3.4 g of 1,2-phenylenediamine bishydrochloride, the reaction mixture was stirred further overnight, then added to 100 ml of H2O, filtered and the solid thus obtained was dried in vacuo. 3.45 g; ESI-MS [M+H+]=248.15
  • [1993] 1H-NMR (270 MHz; DMSO-d6) δ (ppm) 12.60 (s, 1H), 7.30-7.15 (m 3H). 7.05 (m 2H), 4.15 (d, 2H), 1.29 (s, 9H).
  • 1H-Benzimidazol-2-ylmethanamine (trifluoroacetate) (27) [1994]
  • 3 g of the Boc compound 26 were suspended in 15 ml of CH[1995] 2Cl2, 25 ml of TFA were added and the mixture was stirred at RT for 3 h. The mixture was then concentrated and the residue obtained was stirred with n-pentane (5.8 g); ESI-MS [M+H+]=148.05.
  • Methyl [3-({[5-(1H-benzimidazol-2-ylamino)pentyl]amino}carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate (28) [1996]
  • TOTU (0.24 mmol, 77.3 mg) was added in portions at 0° C. to a solution of N[1997] 1-(1H-benzimidazol-2-yl)pentane-1,5-diamine (hydrochloride) (25, 0.24 mmol, 60.1 mg), 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepine-3-carboxylic acid (20, 0.24 mmol, 80.0 mg) and N-methylmorpholine (0.49 mmol, 50.1 mg) in DMF (5 ml). The mixture was stirred at 0° C. for 2 h and concentrated in a rotary evaporator. The residue was taken up in ethyl acetate (20 ml), and washed with H2O, a 5% aq. K2CO3 solution and subsequently a 5% aq. NaCl solution. The org. phase was dried over Na2SO4 and concentrated. Chromatography on silica gel (CH2Cl2/MeOH 0 to 100%) afforded 23.0 mg of target product; ESI-MS: [M+H+]=540.42.
  • Methyl(3-{(1H-benzimidazol-2-ylmethyl)amino]carbonyl}-5methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (29) [1998]
  • Diisopropylethylamine (0.24 mmol, 30.5 mg) and EDCI*HCl (0.28 mmol, 54.1 mg) were added at 0° C. to a solution of 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo [b,e]azepine-3-carboxylic acid (20, 0.24 mmol, 80.0 mg) in CH[1999] 2Cl2 (1.5 ml)/DMF (0.5 ml). The mixture was then, stirred at RT for 1 h before adding 1H-benzimidazol-2-ylmethanamine (trifluoroacetate) (27) (0.24 mmol, 88.4 mg) and diisopropylethylamine (0.47 mmol, 60.9 mg) dissolved in DMF. The mixture then was stirred at 0° C. for 1 hour and at RT for 6 h. Concentration and chromatography (CH2Cl2/MeOH 0 to 100%) afforded 37.0 mg of target product; ESI-MS: [M+H+]=469.15.
  • 7-(4-Aminobutyl)-1,2,3,4-tetrahydro[1,8]naphthyridine (bistrifluoroacetate) (30) [2000]
  • a.) A solution of 5-tert-butoxycarbonylaminovaleric acid (50.0 mmol, 10.86 g), O,N-dimethylhydroxylamine hydrochloride (50 mmol, 4.88 g), N-methylmorpholine (0.30 mol, 30.35 g), HOBT (53.90 mmol, 8.42 g) and EDCI*HCl (55.0 mmol, 10.54 g) in CH[2001] 3CN (200 ml)+was stirred at RT for 2 days. The mixture was concentrated and the residue was taken up in ethyl acetate and washed successively with water, a 10% strength KHSO4 solution, a saturated aqueous NaHCO3 solution and a saturated aqueous NaCl solution. Drying and concentration of the organic phase gave 6.96 g of a yellowish oil; ESI-MS: [2M+Na+]=543.3, [M+Na+]=283.1, 205.1, 161.1.
  • [2002] 1H-NMR (270 MHz, CDCl3) δ (ppm): 4.63 (1H, s. br.), 3.68 (3H, s), 3.21-3.05 (3+2H, m), 2.44 (2H, t), 1.76-1.48 (2+2H, m), 1.43 (9H, s).
  • b.) At 0° C., methylmagnesium bromide (60.0 mmol, 17.30 ml of a 3M solution in Et[2003] 2O) was added dropwise to a solution of tert-butyl 5-[methoxy(methyl)amino]-5-oxopentylcarbamate (30a, 30.0 mmol, 6.9 g) in THF (120 ml). The reaction mixture was stirred at 0° C. for 5 h and then carefully acidified with a 10% strength KHSO4 solution and extracted with ethyl acetate, and the organic phase was then washed with a saturated aqueous NaHCO3 solution and a saturated aqueous NaCl solution, dried and concentrated: 5.5 g of a yellowish oil; ESI-MS: [M-BOC+H+]=116.15.
  • c.) A mixture of tert-butyl 5-oxohexylcarbamate (30b, 9.29 mmol, 2.0 g), 2-aminonicotinaldehyde (Heterocycl. 1993, 36, 2518; 11.20 mmol, 1.37 g) and KOH (0.37 ml of a 20% strength aqueous solution) was refluxed for 8 h. Concentration and column chromatography gave 1.60 g of the target product; ESI-MS: [M+H[2004] +]=302.15.
  • d.) A suspension of tert-butyl 4-[1,8]naphthyridin-2-yl butylcarbamate (30c, 5.31 mmol, 1.60 g) and Pd/C (10%, 1.5 g) in ethanol (40 ml) was stirred under an H[2005] 2 atmosphere overnight and then filtered through Celite and washed with ethanol. Column chromatography gave 290 mg; ESI-MS: [M+H+]=306.25.
  • [2006] 1H-NMR (360 MHz, CDCl3) δ (ppm): 7.04 (1H, d), 6.29 (1H, d), 4.97 (1H, s. br.), 4.81 (1H, s. br.), 3.37. (2H, m sym.), 3.12 (2H, q br.), 2.65 (2H, t), 2.53 (2H, t), 1.89 (2H, quint.), 1.67 (2H, quint.), 1.51 (2H, quint.), 1.43 (9H, s).
  • e.) TFA (18.30 mmol, 2.09 g) was added to a solution of tert-butyl 4-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl) butylcarbamate (30d, 0.92 mmol, 0.28 g) in CH[2007] 2Cl2 (8 ml); the solution was stirred for 20 h and concentrated: 380 mg; ESI-MS: 206.1, 130.7.
  • [2008] 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.07 (1H, d), 6.31 (1H, d), 5.58 (1H, s. br.), 3.39 (2H, m sym.), 2.96 (2H, s. br.), 2.76 (2H, t), 2.68 (2H, t), 2.56 (2H, t), 1.88 (2H, quint.), 1.69 (2H, quint.), 1.51 (2H, quint.).
  • trans-N-{[4-Aminomethyl)cyclohexyl]methyl}-1H-benzimidazol-2-amine (dihydrochloride) (31) [2009]
  • The preparation was carried out similarly to that of compound 3 starting with 10 g of benzyl {4-[(tert-butoxycarbonyl)amino]cyclohexyl}methylcarbamate (EP 669317) by removing the Boc group using 4N HCl in dioxane, synthesis of the benzimidazole and subsequent hydrogenolysis. 3.6 g of white dihydrochloride were isolated; FAB-MS [M+H[2010] +]: 245.
  • 5-(5,6,7,8-Tetrahydro[1,8]naphthyridin-2-yl)-1-pentanaminium chloride (32) [2011]
  • a.) The coupling of 6-tert-butoxycarbonylaminocaproic acid (129.7 mmol, 30.00 g) and O,N-dimethylhydroxylamine hydrochloride (155.65 mmol, 15.18 g) was carried out similarly to the method used for 30a. Drying and concentration of the organic phase gave 29.70 g of a yellowish oil; ESI-MS: [M+Na[2012] +]=297.1, [M-tBu+H+]=219.1, [M-Boc+H+]=175.15.
  • b.) Similarly to the method used for 30b and using the starting material tert-butyl 6-[methoxy(methyl)amino]-6-oxohexylcarbamate (32a, 110.0 mmol, 29.5 g), 20.70 g of tert-butyl 6-oxoheptylcarbamate were prepared; ESI-MS: [M+Na[2013] +]=252.1, [M-BOC+H+]=130.15.
  • c.) At −95° C., a solution of tert-butyl 6-oxoheptylcarbamate (32b, 15.26 mmol, 3.50 g) in THF was added dropwise to a solution of LDA (30.52 mmol) in THF (500 ml), and the mixture was stirred at −95° C. for 30 min. 2-Aminonicotinaldehyde (Heterocycl. 1993, 36, 2518; 15.26 mmol, 1.86 g), dissolved in THF, was added dropwise and the mixture was stirred at −95° C. for 5 h and allowed to warm to RT overnight. A saturated aqueous NH[2014] 4Cl solution was added, the mixture was extracted with ethyl acetate and the organic phase was washed with a 2% strength aqueous citric acid solution, with water and finally with a 5% strength NaHCO3 solution and again with water; drying and concentration of the organic phase gave 4.75 g of impure target product which was reacted further as a crude mixture.
  • d.) 32c (5.10 g) was hydrogenated similarly to 30c. Column chromatography (CH[2015] 2Cl21MeOH 0-5%) gave 30.00 g of tert-butyl 5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentylcarbamate; ESI-MS: [M+H+]=321.2, 320.25. 1H-NMR (360 MHz, CDCl3) δ (ppm): 7.02 (1H, d), 6.28 (1H, d), 4.81 (1H, s. br.), 4.66 (1H, s. br.), 3.36 (2H, m), 3.08 (2H, q br.), 2.68 (2H, t), 2.51 (2H, t), 1.89 (2H, quint.), 1.64 (2H, quint.), 1.47 (2H, quint.), 1.42 (9H, s), 1.32 (2H, quint.).
  • e.) TFA (7.78 mmol, 0.89 g) was added to absolution of 32d (0.78 mmol, 0.25 g) in CH[2016] 2Cl2 (20 ml) and the solution was stirred for 20 h, concentrated and converted into the hydrochloride using a 1M methanolic HCl solution; 250 mg; ESI-MS: 221.15, 220.15, 110.7; 1H-NMR (400 MHz, DMSO) δ (ppm): 8.16 (1H, s), 8.00 (2H, s. br.), 7.60 (1H, d), 6.59 (1H, d), 2.81-2.69 (4H, m), 2.63 (2H, t), 1.82 (2H, quint.), 1.68 (2H, quint.), 1.58 (2H, quint.), 1.32 (2H, quint.).
  • N[2017] 1-(1H-Benzimidazol-2-yl)butane-1,4-diamine (trifluoroacetate) (33)
  • The preparation was carried out similarly to that of compound 3 using 9.87 g of N-Boc-1,4-diaminobutan (52.3 mmol) as starting material. Reaction similarly to that of 3a gave 17.08 g of N-Boc-4-{[(2-aminoanilino)carbothioyl]amino}butane-1-amine; ESI-MS [M+H[2018] +]=338.99.
  • Subsequent cyclodesulfurization and removal of Boc using TFA gave a brown solid which was repeatedly triturated with n-pentane and then recrystallized from a mixture of CH[2019] 3OH/methyl tert-butyl ether; 14.35 g, ESI-MS [M+H+]=205.15.
  • [2020] 1H-NMR (360 MHz, DMSO) δ ppm: 9.20 (t, 1H), 7.80 (s broad, 3H), 7.35 and 7.20 (each m, 2H), 3.40 (m, 2H partially obscured by H2O peak), 2.80 (m, 2H), 1.65 (m, 4H).
  • I.B. Compounds of the Formula I [2021]
    • EXAMPLE I
  • {5-Methyl-6-oxo-3-{4-(2-pyridinylamino)butoxy]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetic Acid [2022]
  • NaOH (0.01 mmol, 138.7 mg) was added to a solution of methyl {5-methyl-6-oxo-3-{4-(2-pyridinylamino)-butoxy]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetate (15, 0.0.1 mmol, 6.7 mg) in water (3 ml/MeOH (3 ml). The mixture was stirred at 60° C. overnight. After concentration, water was added and the solution was extracted with CH[2023] 2Cl2. The aqueous phase was concentrated in a rotary evaporator. Lyophilization afforded 3.10 mg; ESI-MS: [M+H+]=445.
    • EXAMPLE II
  • Sodium [2024]
  • {5-methyl-6-oxo-3-[3-(2-pyridinylamino)propoxy]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate [2025]
  • NaOH (0.01 mmol, 106.4 mg) was added to a solution of. {5-methyl-6-oxo-3-[3-(2-pyridinylamino)-propoxy]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (18, 0.01 mmol, 5.0 mg) in water (2 ml)/MeOH (2 ml). The mixture was stirred at 60° C. overnight. After concentration, water was added and the solution was extracted with CH[2026] 2Cl2. The aqueous phase was concentrated in a rotary evaporator. Lyophilization afforded 3.16 mg; ESI-MS: [M+K+]=470.0, [M+H+]=432.15, 216.6.
    • EXAMPLE III
  • Sodium [3-({[4-(1H-benzimidazol-2-ylamino)benzyl]amino}-carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate [2027]
  • Methyl [3-({[4-(1H-benzimidazol-2-ylamino)benzyl]amino}-carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate (21, 0.03 mmol, 15.0 mg) dissolved in water. (6 ml)/MeOH (6 ml) was treated at 0° C. with NaOH (0.03 mmol, 254.6 mg) and stirred at RT overnight. After concentrating in a rotary evaporator the residue was taken up in water/CH[2028] 2Cl2, and extracted a number of times with CH2Cl2 and diethyl ether. Lyophilization afforded 9.2 mg of white salt; ESI-MS: [M+K+]=584.2, [M+H+]=546.15, 273.65, 118.9.
    • EXAMPLE IV
  • Sodium (5-methyl-6-oxo-3-({[3-(2-pyridinylamino)propyl]-amino}carbonyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate [2029]
  • Methyl (5-methyl-6-oxo-3-({[3-(2-pyridinylamino propyl]-amino}-carbonyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate (22, 0.03 mmol, 14.0 mg) dissolved in water (6 ml)/MeOH (6 ml) was treated at 0° C. with NaOH (0.03 mmol, 0.28 ml of 0.1 N ag. soln) and stirred at RT overnight. After concentrating in a rotary evaporator, the residue was taken up in water/CH[2030] 2Cl2, and extracted a number of times with CHCl3 and diethyl ether. Lyophilization afforded 5.1 mg of-salt; ESI-MS: [M+H+]=459.15, 230.1.
    • EXAMPLE V
  • Methyl (2 E,Z)-[3-({[4-(1H-benzimidazol-2-ylamino)benzyl]amino}-carbonyl)-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene]ethanoate [2031]
  • Diisopropylethylamine (0.30 mmol, 38.3 mg) and HATU (0.36 mmol, 51.50 mg) were added at 0° C. to a solution of (11 E,Z)-11-(2-methoxy-2-oxoethylidene)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepine-3-carboxylic acid (24, 0.30 mmol, 0.1 g) in CH[2032] 2Cl2 (5 ml)/DMF (2 ml). The mixture was then stirred at 0° C. for 1 h before injecting N-[4-(aminomethyl)phenyl]-1H-benzimidazol-2-amine (hydrochloride) (3) (0.33 mmol, 89.6 mg) and diisopropylethylamine (0.30 mmol, 38.3 mg) dissolved in DMF. The mixture was stirred at 0° C. for 30 min and at RT for 5 h. After concentration, the residue was taken up using CH2Cl2/water, washed with aq. NaHCO3 and then with a 5% solution of citric acid, buffered with aq. NaHCO3 and finally washed with aq. saturated NaCl solution. Concentration and column chromatography (heptane/CH2Cl2 0 to 100% CH2Cl2/MeOH 0 to 100%) afforded 70.0 mg of target product; ESI-MS: [M+K+]=596.2, [M+H+]=558.25, 279.65.
    • EXAMPLE VI
  • (2 E,Z)-[3({[4-(1H-Benzimidazol-2-ylamino)benzyl]amino}-carbonyl)-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene]ethanoic Acid [2033]
  • Aq. LiOH (0.34 mmol, 8.3 mg) was added dropwise at 5° C. to methyl (2 E,Z)-[3-({[4-(1H-benzimidazol-2-ylamino)benzyl]amino}-carbonyl)-5-methyl-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene]ethanoate (Example V, 0.04 mmol, 20.0 mg) dissolved in water (3 ml)/EtOH (3 ml) and the mixture was stirred at RT overnight. After concentrating in a rotary evaporator, the residue was taken up in water/CH[2034] 2Cl2, and extracted a number of times with CHCl3 and diethyl ether. The water phase was adjusted to pH 4 to 5 at 0° C. Filtration and drying of the deposited precipitate afforded 15.0 mg of target product; ESI-MS: [M+H+]=544.05,. 272.6, 130.1.
    • EXAMPLE VII
  • Sodium (2 E,Z)-{5-methyl-6-oxo-3-[3-(2-pyridinylamino)propoxy)-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene}ethanoate [2035]
  • Methyl (2 E,Z)-(5-methyl-6-oxo-3-{3-(2-pyridinylamino)propoxy]-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)ethanoate (17, 0.03 mmol, 15.0 mg) dissolved in water (6 ml)/MeOH (6 ml) was treated at 5° C. with NaOH (0.03 mmol, 321.1 mg) and the mixture was heated at 60° C. for 6 h. After concentrating in a rotary evaporator, the residue was taken up in water/CH[2036] 2Cl2 and extracted a number of times with CHCl3 and diethyl ether. Lyophilization of the water phase afforded 5.2 mg of white salt;. ESI-MS: [M+K+]=468.1, [M+H+]=430.15, 215.6, 101.1.
    • EXAMPLE VIII
  • Sodium [3-({[5-(1H-benzimidazol-2-ylamino)pentyl]amino}-carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate [2037]
  • Methyl [3-({[5-(1H-benzimidazol-2-ylamino)pentyl]amino}-carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate (28, 0.04 mmol, 20.0 mg) dissolved in water (7 ml)/MeOH (7 ml) was treated at 5° C. with NaOH (0.03 mmol, 333.9 mg) and the mixture was heated at 40° C. for 4 h. After concentrating in a rotary evaporator, the residue was taken up in water/CH[2038] 2Cl2 and extracted a number of times with CHCl3 and diethyl ether. Lyophilization of the water phase afforded 14.6 mg of salt; ESI-MS: [M+H+]=526,25.
    • EXAMPLE IX
  • Sodium (3-{[(1H-benzimidazol-2-ylmethyl)amino]carbonyl}-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate [2039]
  • Methyl (3-{[(1H-benzimidazol-2-ylmethyl)amino]carbonyl}-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl) acetate (29, 0.08 mmol, 37.0 mg) dissolved in water (10 ml)/MeOH (10 ml) was treated at 5° C. with NaOH (0.07 mmol, 711.0 mg) and the mixture was heated at 40° C. for 6 h. After concentrating in a rotary evaporator, the residue was taken up in water/CH[2040] 2Cl2 and extracted a number of times with CHCl3 and diethyl ether. Lyophilization of the water phase afforded 28.6 mg of salt; ESI-MS: [M+H+]=455.15.
    • EXAMPLE X
  • Methyl [5-methyl-6-oxo-3-({[4-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)butyl]amino}carbonyl)-6,11-dihydro-5H-dibenzo [b,e]azepin-11-yl] acetate [2041]
  • At 0° C., ethyldiisopropylamine (0.29 mmol, 114.27 mg) and HATU (0.35 mmol, 134.45 mg) were added to a solution of 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo [b,e]azepine-3-carboxylic acid (20) (0.29 mmol, 100.00, mg) in CH[2042] 2Cl2 (15 ml), the mixture was then stirred at 0° C. for 1 h, and 7-(4-aminobutyl)-1,2,3,4-tetrahydro[1,8]naphthyridin (bistrifluoroacetate) (30) (0.41 mmol, 131.75 mg) and ethyldiisopropylamine (0.64 mmol, 251.39 mg) were added. The mixture was stirred at 0° C. for 1 h and at RT overnight and then concentrated. The residue was taken up in ethyl acetate/water, the pH was adjusted to 6.5 using a 5% strength aqueous NH4Cl solution and the mixture was extracted with ethyl acetate. Concentration and silica gel chromatography (CH2Cl2/CH3OH 0-100%) gave 71.80 mg of target product; ESI-MS [M+H+]; 527.25.
    • EXAMPLE XI
  • Sodium [5-methyl-6-oxo-3-({[4-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)butyl]amino}carbonyl)-6,11-dihydro-5H-dibenzo [b,e]azepin-11-yl]acetate [2043]
  • The methyl ester (Example X) was hydrolyzed similarly to Example II; 44.00 mg of target product; ESI-MS: [M+H[2044] +]=513.25.
    • EXAMPLE XII
  • Methyl {3-[({[4-(1H-benzimidazol-2-ylamino)cyclohexyl]methyl}amino)carbonyl]-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo [b,e]azepin-11-yl}acetate [2045]
  • Preparation similar to Example X starting with 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo [b,e]azepine-3-carboxylic acid (20) (0.29 mmol, 100.00 mg) and trans-N-{[4-(aminomethyl)cyclohexyl]methyl}-1H-benzimidazol-2-amine (dihydrochloride) (31) (0.32 mmol, 102.85 mg). 90.90 mg of target product; ESI-MS: [M+H[2046] +]=566.25, 283.65.
    • EXAMPLE XIII
  • {3-[({[4-(1H-Benzimidazol-2-ylamino)cyclohexyl]methyl}amino) carbonyl]-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetic Acid [2047]
  • The methyl ester (Example XII) was hydrolyzed similarly to Example II; 9.50 mg of target product; ESI.-MS: [M+H[2048] +]=552.35, 276.55.
    • EXAMPLE XIV
  • Methyl [5-methyl-6-oxo-3-({[5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl) pentyl]amino}carbonyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate [2049]
  • Preparation similar to Example X starting with 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo [b,e]azepine-3-carboxylic acid (20). (0.29 mmol, 100.00 mg) and 5-(5,6,7,8-tetrahydro[118]naphthyridin-2-yl)-1-pentanaminium chloride (32) (0.41 mmol, 105.54 mg). 102.00 mg of target product; ESI-MS [M+H[2050] +]: 541.25.
    • EXAMPLE XV
  • [5-Methyl-6-oxo-3-({[5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl) pentyl]amino}carbonyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic Acid [2051]
  • The methyl ester (Example XIV) was hydrolyzed similarly to Example II; 49.20 mg of target product (about 95% pure according to HPLC); ESI-MS: [M+H[2052] +]=527.25, 264.1.
    • EXAMPLE XVI
  • Methyl [3-({[4-(1H-benzimidazol-2-ylamino)butyl]amino}carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate [2053]
  • Coupling of 11-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-3-carboxylic acid (20) (0.29 mmol, 100.00 mg) with N[2054] 1-(1H-benzimidazol-2-yl)butane-1,4-diamine (trifluoroacetate) (33) (0.32 mmol, 103.18) similarly to 21 and purification by silica gel chromatography (ethyl acetate/CH3OH 0-100%) gave 39.50 mg of target product; ESI-MS [M+H+]: 526.25, 263.6.
    • EXAMPLE XVII
  • [3-({[4-1H-Benzimidazol-2-ylamino)butyl]amino}carbonyl)-5-methyl-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic Acid [2055]
  • The methyl ester (Example XIV) was hydrolyzed similarly to Example II; 18.70 mg of target product; ESI-MS: [M+H[2056] +]=512.15.
    • II. BIOLOGICAL EXAMPLES EXAMPLE 1
  • Integrin α[2057] vβ3 Assay
  • For the identification and assessment of integrin α[2058] vβ3 ligands, a test system was used which was based on competition between the natural integrin αvβ3 ligand vitronectin and the test substance for binding to solid phase-bound integrin αvβ3.
  • Procedure [2059]
  • Microtiter plates coated with 250 ng/ml of integrin α[2060] vβ3 in 0.05 M NaHCO3 pH 9.2; 0.1 ml/well;
  • saturation with 1% powdered milk/assay buffer; 0.3 ml/well; 0.5 h/RT [2061]
  • 3× washing with 0.05% Tween 20/assay buffer [2062]
  • test substance in 0.1% powdered milk/assay buffer, 50 μl/well+0 μl/ml or 2 μg/ml of human vitronectin (Boehringer Ingelheim T007) in 0.1% powdered milk/assay buffer, 50 μl/well; 1 h/RT [2063]
  • 3× washing with 0.05% Tween 20/assay buffer [2064]
  • 1 μg/ml of anti human vitronectin antibody coupled to peroxidase (Kordia SAVN-APHRP) in 0.1% powdered milk/assay buffer; 0.1 ml/well; 1 h/RT [2065]
  • 3× washing with 0.05% Tween 20/assay buffer [2066]
  • 0.1 ml/well of peroxidase substrate [2067]
  • stop reaction with 0.1 ml/well of 2 M H[2068] 2SO4
  • measurement of the absorption at 450 nm [2069]
  • Integrin α[2070] vβ3: Human placenta is solubilized with Nonidet and integrin αvβ3 affinity-purified on a GRGDSPK matrix (elution with EDTA). Impurities due to integrin αIIbβ3 and human serum albumin, and the detergent and EDTA are removed by anion-exchange chromatography.
  • Assay buffer: 50 mM tris pH 7.5; 100 mM NaCl; 1 mM CadC[2071] 2; 1 mM MgCl2; 10 μM MnCl2
  • Peroxidase substrate: mix 0.1 ml of TMB solution (42 mM TMB in DMSO) and 10 ml of substrate buffer (0.1 M sodium acetate pH 4.9), then add 14.7 μl of 3% H[2072] 2O2.
  • Various dilutions of the test substances are employed in the assay and the IC[2073] 50 values are determined (concentration of the ligand at which 50% of the ligand is displaced). The compound from Example I showed the best result here.
    • EXAMPLE 2
  • Integrin α[2074] IIbβ3 Assay
  • The assay is based on competition between the natural integrin α[2075] IIbβ3 ligand fibrinogen and the test substance for binding to integrin αIIbβ3.
  • Procedure [2076]
  • Coat microtiter plates with 10 μg/ml of fibrinogen (Calbiochem 341578) in 0.05 M NaHCO[2077] 3 pH 9.2; 0.1 ml/well;
  • saturate with 1% BSA/PBS; 0.3 ml/well; 30 min/RT [2078]
  • 3× washing with 0.05% Tween 20/PBS [2079]
  • test substance in 0.1% BSA/PBS; 50 μl/well+200 μl/ml of integrin α[2080] IIbβ3 (Kordia) in 0.1% BSA/PBS; 50 μl/well; 2 to 4 h/RT
  • 3× washing as above [2081]
  • biotinylated anti-integrin α[2082] IIbβ3 antibody (Dianova CBL 130 B); 1:1000 in 0.1% BSA/PBS; 0.1 ml/well; 2 to 4 h/RT
  • 3× washing as above [2083]
  • streptavidin-peroxidase complex (B.M. 1089153) 1:10,000 in 0.1% BSA/PBS; 0.1 ml/well; 30 min/RT [2084]
  • 3× washing as above [2085]
  • 0.1 ml/well of peroxidase substrate [2086]
  • stop reaction using 0.1 ml/well of 2 M H[2087] 2SO4
  • measurement of the absorption at 450 nm [2088]
  • Peroxidase substrate: mix 0.1 ml of TMB solution (42 mM TMB in DMSO) and 10 ml of substrate buffer (0.1 M Na acetate pH 4.9), then add 14.7 μl of 3% H[2089] 2O2
  • Various dilutions of the test substances are employed in the assay and the IC[2090] 50 values are determined (concentration of the antagonists at which 50% of the ligand is displaced). By comparison of the IC50 values in the integrin αIIbβ3 and integrin αvβ3 assay, the selectivity of the substances can be determined.
    • EXAMPLE 3
  • CAM Assay [2091]
  • The CAM (chorioallantoic membrane) assay serves as a generally recognized model for the assessment of the in vivo activity of integrin α[2092] vβ3 antagonists. It is based on the inhibition of angiogenesis and neovascularization of tumor tissue (Am. J. Pathol. 1975, 79, 597-618; Cancer Res. 1980, 40, 2300-2309; Nature 1987, 329, 630). The procedure is carried out analogously to the prior art. The growth of the chicken embryo blood vessels and of the transplanted tumor tissue can be readily monitored and assessed.
    • EXAMPLE 4
  • Rabbit Eye Assay [2093]
  • In this in-vivo model, the inhibition of angiogenesis and neovascularization in the presence of integrin α[2094] vβ3 antagonists can be monitored and assessed analogously to Example 3. The model is generally recognized and is based on the growth of rabbit blood vessels starting from the edge in th corn a of the eye (Proc. Natl. Acad. Sci. USA. 1994, 91, 4082-4085; Science 1976, 193, 70-72). The procedure is carried out analogously to the prior art.

Claims (34)

We claim:
1. A compound of the formula I
B-G-L  I
where B, G and L have the following meanings:
L is a structural element of the formula IL
-U-T  IL
where
T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and
-U- is (XL)a—(CRL 1RL 2)b—, —CRL 1═CRL 2—, ethynylene or ═CRL 1—, where
a is 0 or 1,
b is 0, 1 or 2,
XL is CRL 3RL 4, NRL 5, oxygen or sulfur,
RL 1, RL 2, RL 3, RL 4
independently of one another are hydrogen, -T, —OH, —NRL 6RL 7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals RL 1 and RL 2 or RL 3 and RL 4 or optionally RL 1 and RL 3 together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S,
RL 5, RL 6, RL 7
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical,
G is a structural element of the formula IG
Figure US20040077638A1-20040422-C00086
 where
the structural element B is bonded via Ar and the structural element L is bonded via XG to the structural element G by means of a single bond or a double bond and
Ar is a fused, aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to four different or identical heteroatoms O, N, S and is optionally substituted by up to 4 substituents,
DG is an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S,
XG is CRG 1 or nitrogen, in the case of a single bond to structural element L, or
carbon, in the case of a double bond to structural element L,
WG is —YG—N(RG 5)— or —N(RG 5)—YG—,
YG is CO, CS, C═NRG 2 or CRG 3RG 4,
RG 1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical
RG 2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or O-alkylenearyl radical,
RG 3, RG 4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG 3 and RG 4 together are a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG 3 and RG 4 together are an optionally substituted C3-C7-cycloalkyl radical,
with the proviso that, as substituents of the C1-C6-alkyl radicals, the groups COOH and carboxylic acid ester are excluded,
RG 5 is a radical RG 5A or a radical C0-C6-alkylene-RG 5B, C2-C4-alkenylene-R5B, C2-C4-alkynylene-R5B, C1-C6-oxoalkylene-RG 5B, C2-C4-oxoalkenylene-RG 5B, C2-C4-oxoalkynylene-RG 5B, C1-C4-aminoalkylene-RG 5B, C2-C4-aminoalkenylene-RG 5B, C2-C4-aminoalkynylene-RG 5B, C2-C4-alkylene-RG 5B, optionally substituted by one or more radicals selected from the group consisting of RG 5A and RG 5C,
RG 5A is a radical CORG 5G, COC(RG 5E)2(RG 5H), CSRG 5G, S(O)g1—ORG 5E, S(O)g1—N(RG 5E)(RG 5F), PO(ORG 5E), PO(ORG 5E)2, B(ORG 5E)2, NO2 or tetrazolyl,
RG 5B is hydrogen or an optionally substituted C1-C7-cycloalkyl, C3-C7-cycloheteroalkyl, aryl or hetaryl radical,
RG 5C is hydrogen, halogen, CN, NO2, ORG 5D, CF3, or a radical N(RG 5E) (RG 5D), CF3S(O)g2, CO2RG 5E, CO—N(RG 5E)2, C0-C6-alkylene-RG 5B, C1-C6oxoalkylene-RG 5B, C2-C4-alkenylene-RG 5B or C2-C4-alkynylene-RG 5B,
RG 5D is a radical RG 5E, —CO—RG 5E, CO—ORG 5J, CO—N (RG 5E)2, S(O)g1—RG 5E or S(O)g1—N(RG 5E)2,
RG 5E is hydrogen, an optionally substituted C1-C6-alkyl, aryl-C0-C6-alkylene, C3-C7-cycloalkyl-C0-C6-alkylene, hetaryl or hetarylalkyl radical,
RG 5F is a radical RG 5E, CO—RG 5E or CO—ORG 5E,
RG 5G is a radical ORG 5E, N(RG 5E) (RG 5F), N(RG 5E)—SO2—RG 5E, N(RG 5E)(ORG 5E), O—C(RG 5E)2—CO—ORG 5E, O—C(RG 5E)2O—CO—NRG 5E, O—C(RG 5E)2—CO—N(RG 5E)2 or CF3,
RG 5H is a radical ORG 5E, CN, S(O)g2—RG 5E, S(O)g1—N(RG 5E)2, CO—RG 5E, C(O)N(RG 5E)2 or CO2—RG 5E,
RG 5J is hydrogen or an optionally substituted C1-C6-alkyl or aryl-C0-C6-alkylene radical,
g1 is 1 or 2 and
g2 is 0, 1 or 2,
with the proviso that if WG═YG—N(RG 5)— the radical —(CH2)m—CORG 6 is excluded for RG 5, where
m is 1 or 2,
RG 6 is —OR′, —NR′R″, —NR′SO2R′″, —NR′OR′, —OCR′2C(O)OR′, —OCR′2OC(O)R′, —OCR′2C(O)NR′2, —CF3 or —COC(R′)2RG 7,
RG 7 is —OR′, —CN, S(O)rR′, S(O)2N(R′)2, —C(O)R′C(O)NR′2 or —CO2R′,
r is 0, 1 or 2,
R′ is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
R″ is R′, —C(O)R′ or —C(O)ORG 8,
R′″ is C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
RG 8 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
B is a structural element containing at least one atom which, under physiological conditions, can form hydrogen bridges as a hydrogen acceptor, where at least one hydrogen acceptor atom has a distance of 4 to 15 atom bonds from structural element G along the shortest possible route along the structural element skeleton,
or the physiologically tolerable salts, prodrugs and the enantiomerically pure or diastereomerically pure and tautomeric forms.
2. A compound as claimed in claim 1, wherein the structural element B is a structural element of the formula IB
A-E-  IB
where A and E have the following meanings:
A is a structural element selected from the group consisting of:
a 4- to 8-membered monocyclic saturated, unsaturated or aromatic hydrocarbon which can contain up to 4 heteroatoms selected from the group consisting of O, N and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group consisting of O, N and S is present in the structural element A, and
a 9- to 14-membered polycyclic, saturated, unsaturated or aromatic hydrocarbon which can contain up to 6 heteroatoms selected from the group consisting of N, O and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group consisting of O, N and S is present in th structural element A,
a radical
Figure US20040077638A1-20040422-C00087
 where
ZA 1 is oxygen, sulfur or optionally substituted nitrogen and
ZA 2 is optionally substituted nitrogen, oxygen or sulfur, or a radical
Figure US20040077638A1-20040422-C00088
 where
RA 18, RA 19
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG 11, —CO—ORG 11, —CO—NRG 11RG 11* or —CO—RG 11, and
E is a spacer structural element which covalently bonds the structural element A to the structural element G, where the number of atomic bonds along the shortest possible route along the structural element skeleton E is 3 to 14.
3. A compound as claimed in on of claims 1 and 2, wherein the structural element A used is a structural element selected from the group consisting of structural elements of the formulae IA 1 to IA 18,
Figure US20040077638A1-20040422-C00089
Figure US20040077638A1-20040422-C00090
where
m, p, q
independently of one another are 1, 2 or 3,
RA 1, RA 2
independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C3-C7-cycloalkyl radical or a radical CO—O—RA 14, O—RA 14, S—RA 14, NRA 15RA 16, CO—NRA 15RA 16 or SO2NRA 15RA 16 or both radicals RA 1 and RA 2 together are a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group consisting of O, N and S,
RA 13, RA 13*
independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA 14, O-RA 14, S-RA 14, NRA 15RA 16, SO2—NRA 15RA 16 or CO—NRA 15RA 16,
 where
RA 14 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or C1-C6-alkylene-C3-C7-cycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
RA 15, RA 16,
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, CO—C1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, arylalkyl, COO-alkylenearyl, SO2-alkylenearyl, C0-NH-alkylenearyl, CO—NH-alkylenehetaryl or hetarylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, CO-aryl, CO—NH-aryl, SO2-aryl, hetaryl, CO—NH-hetaryl or CO-hetaryl radical,
RA 3 RA 4
independently of one another are hydrogen, —(CH2)n—(XA)j—RA 12, or both radicals together are a 3- to 8-membered, saturated, unsaturated or aromatic N-heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle is optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle,
 where
n is 0, 1, 2 or 3,
j is 0 or 1,
XA is —CO—, —CO—N(RX 1)—, —N(RX 1)—CO—, —N(RX 1)—CO—N(RX 1*)—, —N(RX 1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX 1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX 1)—, —N(RX 1)— or —N(RX 1)—SO2—,
RA 12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally C1-C4-alkyl- or aryl-substituted C2-C6-alkynyl or C2-C6-alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocycle, substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, a C3-C7-cycloalkyl, aryl or hetaryl radical, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RA 12, together with RX 1 or RX 1* forms a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N,
RX 1, RX 1*
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical,
RA 6, RA 6*
are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, —CO—O—C1-C4-alkyl, arylalkyl, —CO—O-alkylenearyl, —CO—O-allyl, —CO—C1-C4-alkyl, —CO-alkylenearyl, C3-C7-cycloalkyl or —CO-allyl radical or, in structural element IA 7, both radicals RA 6 and RA 6* together are 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,
RA 7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—CO—C1-C4-alkyl radical, or an optionally substituted arylalkyl, —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical, or both radicals RA 6 and RA 7 together are an optionally substituted, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S,
RA 8 is hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—C1-C4-alkyl, SO2—C1-C4-alkyl or CO—O—C1-C4-alkyl radical or an optionally substituted aryl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl, CO—O-alkylenearyl or alkylenearyl radical,
RA 9, RA 10
independently of one another are hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA 14, O—RA 14, S—RA 14, NRA 15RA 16, SO2—NRA 15RA 16 or CO—NRA 15RA 16, or both radicals RA 9 and RA 10 together in structural element IA 14 are a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals,
RA 11 is hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA 14, O—RA 14, S—RA 14, NRA 15RA 16, SO2—NRA 15RA 16 or CO—NRA 15RA 16,
RA 17 is hydrogen or, in structural element IA 16, both radicals RA 9 and RA 17 together are 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 O, N, S and is optionally substituted by up to three identical or different radicals,
RA 18, RA 19
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG 4, —CO—ORG 4, —CO—NRG 4RG 4* or —CO-RG 4
Z1, Z2, Z3, Z4
independently of one-another are nitrogen, C—H, C-halogen or a branched or unbranched, optionally substituted C—C1-C4?-alkyl or C—C1-C4-alkoxy radical,
Z5 is NRA 8, oxygen or sulfur.
4. A compound as claimed in one of claims 1 to 3, wherein the spacer structural element E is composed of two to four substructural elements, selected from the group consisting of E1 and E2, where the sequence of linkage of the substructural elements is arbitrary and E1 and E2 have the following meanings:
E1 is a substructural element of the formula IE1
—(YE)k1—(CRE 1RE 2)c—(QE)k2—(CRE 3RE 4)d—  IE1
 and
E2 is a substructural element of the formula IE2
(NRE 11)k3—(CRE 5RE 6)f—(ZE)k4—(CRE 7RE 8)g—(XE)k5—(CRE 9RE 10)h—(NRE 11*)k6—  IE2,
 where
C, d, f, g, h
independently of one another are 0, 1 or 2,
k1, k2, k3, k4, k5, k6
independently of one another are 0 or 1,
XE, QE
independently of one another are 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 identical or different heteroatoms selected from the group consisting of N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted,
YE, ZE
independently of one another are CO, —N(RE 11)—, CO—NRE 12, NRE 12—CO, sulfur, SO, SO2, SO2—NRE 12, NRE 12—SO2, CS, CS—NRE 12, —C(RE 13)(CRE 14)—, NRE 12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE 13—O—CRE 14, C(═CRE 13RE 14), CRE 13═CRE 14, —CRE 13(ORE 15)—CHRE 14— or —CHRE 13—CRE 14 (ORE 15)—,
RE 1, RE 2, RE 3, RE 4, RE 5, RE 6, RE 7, RE 8, RE 9, RE 10
independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE 17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical or independently of one another in each case two radicals RE 1 and RE 2 or RE 3 and RE 4 or RE 5 and RE 6 or RE 7 and RE 8 or RE 9 and RE 10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocycle or heterocycle which can contain up to three heteroatoms selected from the group consisting of O, N and S
x is 0, 1, 2, 3 or 4,
z is 0 or 1,
WE is —CO—, —CO—N(RW 2)—, —N(RW 2)—CO—, —N(RW 2)—CO—N(RW 2*)—, —N(RW 2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW 2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW 2)—, —N(RW 2)— or —N(RW 2)—SO2—,
RW 2, RW 2*
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, Co-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical,
RE 17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE 17 forms, together with RW 2 or RW 2*, a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N,
RE 11, RE*
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical,
RE 12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl radical, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE 16, COORE 16 or SO2—RE 16,
RE 13, RE 14
independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
RE 15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
RE 16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical.
5. A compound as claimed in one of claims 1 to 4, wherein the spacer structural element E used is a structural element of the formula IE1E2
-E2-E1-  IE1E2
and E1 and E2 have the following meanings:
E1 is a substructural element of the formula IE1
—(YE)k1—(CRE 1RE 2)c—(QE)k2—(CRE 3RE 4)d—  IE1
 and
E2 is a substructural element of the formula IE2
—(NRE 11)k3—(CRE 5RE 6)f—(ZE)k4—(CRE 7RE 8)g—(XE)k5—(CRE 9RE 10)h—(NRE 11*)k6—  IE2,
 where
c, d, f, g, h
independently of one another are 0, 1 or 2,
k1, k2, k3, k4, k5, k6
independently of one another are 0 or 1,
XE, QE
independently of one another are 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 identical or different heteroatoms selected from the group consisting of N, O, and S, where the ring carbons and/or the ring nitrogens, can optionally be substituted,
YE, ZE
independently of one another are CO, —N(RE 11)—, CO—NRE 12, NRE 12—CO, sulfur, SO, SO2, SO2—NRE 12, NRE 12—SO2, CS, CS—NRE 12, —C(RE 13)(CRE 14)—, NRE 12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE 13—O—CRE 14, C(═CRE 13RE 14), CRE 13═CRE 14, —CRE 13(ORE 15)—CHRE 14— or —CHRE 13—CRE 14(ORE 15)—,
RE 1, RE 2, RE 3, RE 4, RE 5, RE 6 RE 7, RE 8, RE 9, RE 10
independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x— (WE)z—RE 17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical or independently of one another are-in each case two radicals RE 1 and RE 2 or RE 3 and RE 4 or RE 5 and RE 6 or RE 7 and RE 8 or RE 9 and RE 10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocycle, which can contain up to three heteroatoms selected from the group consisting of O, N and S,
x is 0, 1, 2, 3 or 4,
z is 0 or 1,
WE is —CO—, —CO—N(RW 2)—, —N(RW 2)—CO—, —N(RW 2)—CO—N(RW 2*)—, —N(RW 2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW 2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW 2)—, —N(RW 2)— or —N(RW 2)—SO2—,
RW 2, RW 2*
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical,
RE 17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle, which is substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE 17 forms together with RW 2 or RW 2* a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N,
RE 11, RE 11*
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NR—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical,
RE 12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO-RE 16, COORE 16 or SO2—RE 16,
RE 13, RE 14
independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
RE 15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
RE 16 is hydrogen, a hydroxyl group, a branched or unbranched optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical.
6. The use of the structural element of the formula IGL
-G-L  IGL
for the preparation of compounds which bind to integrin receptors,
where G and L have the following meanings:
L is a structural element of the formula IL
-U-T  IL
 where
T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and
-U- is (XL)a—(CRL 1RL 2)b—, —CRL 1═CRL 2—, ethynylene or ═CRL 1—, where
a is 0 or 1,
b is 0, 1 or 2,
XL is CRL 3RL 4, NRL 5, oxygen or sulfur,
RL 1, RL 2, RL 3, RL 4
independently of one another are hydrogen, -T, —OH, —NRL 6RL 7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or independently of one another in each case two radicals RL 1 and RL 2 or RL 3 and RL 4 or optionally RL 1 and RL 3 together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S,
RL 5, RL 6, RL 7
independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical,
G is a structural element of the formula IG
Figure US20040077638A1-20040422-C00091
 where
the structural element B is bonded via Ar and the structural elements L is bonded via XG to the structural element G by means of a single bond or a double bond and
Ar is a fused, aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to four different or identical heteroatoms O, N, S and is optionally substituted by up to 4 substituents,
DG is an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S,
XG is CRG 1 or nitrogen, in the case of a single bond to structural element L or
carbon, in the case of a double bond to structural element L,
WG is —YG—N(RG 5)— or —N(RG 5)—YG—,
YG is CO, CS, C═NRG 2 or CRG 3RG 4,
RG 1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched; optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical,
RG 2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or
 —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl- or —O-alkylene aryl radical,
RG 3 RG 4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG 3 and RG 4 together are, a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG 3 and RG 4 together are an optionally substituted C3-C7-cycloalkyl radical,
with the proviso that, as substituents of the C1-C6-alkyl radicals, the groups COOH and carboxylic acid ester are excluded,
RG 5 is a radical RG 5A or a radical CO—C6-alkylene-RG 5B, C2-C4-alkenylene-RG 5B, C2-C4-alkynylene-RG 5B, C1-C6-oxoalkylene-RG 5B, C2-C4-oxoalkenylene-RG 5B, C2-C4-oxoalkynylene-RG 5B, C1-C4-aminoalkylene-RG 5B, C2-C4-aminoalkenylene-RG 5B, C2-C4-aminoalkynylene-RG 5B, C2-C4-alkylene-RG 5B, optionally substituted by one or more radicals selected from the group consisting of RG 5A and RG 5C,
RG 5A is a radical CORG 5G, COC(RG 5E)2(RG 5H), CSRG 5G, S(O)g1—ORG 5E, S(O)g1—N(RG 5E)(RG 5F), PO(ORG 5E), PO(ORG 5E)2, B(ORG 5E)2, NO2 or tetrazolyl,
RG 5B is hydrogen or an optionally substituted C3-C7-cycloalkyl, C3-C7-cycloheteroalkyl, aryl or hetaryl radical,
RG 5C is hydrogen, halogen, CN, NO2, ORG 5D, CF3, or a radical N(RG 5E)(RG 5D), CF3S(O)g2, CO2RG 5E, CO—N(RG 5E)2, C0-C6-alkylene-RG 5B, C1-C6-oxoalkylene-RG 5B, C2-C4-alkenylene-RG 5B or C2-C4-alkynylene-RG 5B,
RG 5D is a radical RG 5E, —CO—RG 5E, CO—ORG 5J, CO—N(RG 5E)2, S(O)g1—RG 5E or S(O)g1N((RG 5E)2,
RG 5E is hydrogen, an optionally substituted C1-C6-alkyl, aryl-C0-C6-alkylene, C3-C7-cycloalkyl-C0-C6-alkylene, hetaryl or hetarylalkyl radical,
RG 5F is a radical RG 5E, CO—RG 5E or CO—ORG 5E,
RG 5G is a radical ORG 5E, N(RG 5E)(RG 5F), N(R5E)—SO2—RG 5E, N(RG 5E)(ORG 5E), O—C(RG 5E)2—CO—ORG 5E, O—C(RG 5E)2—O—CO—RG 5E, O—C(RG 5E)2—CO—N (RG 5E)2 or CF3,
RG 5H is a radical ORG 5E, CN, S(O)g2—RG 5E, S(O)g1—N(RG 5E)2, CO—RG 5E, C(O)N(RG 5E)2 or CR2—RG 5E,
RG 5J is hydrogen or an optionally substituted C1-C6-alkyl or aryl-C0-C6-alkylene radical,
g1 is 1 or 2 and
g2 is 0, 1 or 2,
with the proviso that if WG═—YG—N(RG 5)— the radical —(CH2)m—CORG 6 is excluded for RG 5, where
m is 1 or 2,
RG 6 is —OR′, —NR′R″, —NR′SO2R′″, —NR′OR′, —OCR′2C(O)OR′, —OCR′2OC(O)R′, —OCR′2C(O)NR′2, —CF3 or —COC(R′)2 RG 7,
RG 7 is —OR′, —CN, —S(O)rR′, S(O)2N(R′)2, —C(O)R′C(O)NR′2 or —CO2R′,
r is 0, 1 or 2
R′ is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
R″ is R′, —C(O)R′ or —C(O)ORG 8,
R′″ is C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
RG 8 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl.
7. A drug containing the structural element of the formula IGL
-G-L  IGL
where G and L have the following meanings:
L is a structural element of the formula IL
-U-T  IL
 where
T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and
-U- is (XL)a—(CRL 1RL 2)b—, —CRL 1═CRL 2—, ethynylene or ═CRL 1—, where
a is 0 or 1,
b is 0, 1 or 2,
XL is CRL 3RL 4, NRL 5, oxygen or sulfur,
RL 1, RL 2, RL 3, RL 4
independently of one another are hydrogen, -T, —OH, —NRL 6RL 7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or independently of one another in each case two radicals RL 1 and RL 2 or RL 3 and RL 4 or optionally RL 1 and RL 3 together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S,
RL 5, RL 6, RL 7
independently of one another are hydrogen, a branched or unbranched, optionally, substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical,
G is a structural element of the formula IG
Figure US20040077638A1-20040422-C00092
 where
the structural element B is bonded via Ar and the structural element L is bonded via XG to the structural element G by means of a single bond or a double bond and
Ar is a fused, aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to four different or identical heteroatoms O, N, S and is optionally substituted by up to 4 substituents,
DG is an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to 4 different or identical heteroatoms O, N, S,
XG is CR 1 or nitrogen, in the case of a single bond to structural element L or
carbon, in the case of a double bond to structural element L,
WG is —YG—N(RG 5)— or —N(RG 5)—YG—,
YG is CO, CS, C═NRG 2, or CRG 3RG 4,
RG 1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical,
RG 2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical,
RG 3, RG 4
independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals R3 and RG 4 together are a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG 3 and RG 4 together are an optionally substituted C3-C7-cycloalkyl radical,
with the proviso that, as substituents of the C1-C6-alkyl radicals, the groups COOH and carboxylic acid ester are excluded,
RG 5 is a radical RG 5A or a radical CO—C6-alkylene-RG 5B, C2-C4-alkenylene-RG 5B, C2-C4-alkynylene-R5B, C1-C6-oxoalkylene-RG 5B, C2-C4-oxoalkenylene-R5B, C2-C4-oxoalkynylene-RG 5B, C1-C4-aminoalkylene-RG 5B, C2-C4-aminoalkenylene-RG 5B, C2-C4-aminoalkynylene-RG 5B, C2-C4-alkylene-RG 5B, optionally substituted by one or more radicals selected from the group consisting of RG 5A and RG 5C,
RG 5A is a radical CORG 5G, COC(RG 5E)2(RG 5H), CSRG 5G, S(O)g1—ORG 5E,
 S(O)g1—N(RG 5E) (RG 5F), PO(ORG 5E), PO(ORG 5E)2, B(ORG 5E)2, NO2 or tetrazolyl,
RG 5B is hydrogen or an optionally substituted C3-C7-cycloalkyl, C3-C7-cycloheteroalkyl, aryl or hetaryl radical,
RG 5C is hydrogen, halogen, CN, NO2, ORG 5D, CF3, or a radical N(RG 5E)(RG 5D), —CF3S(O)g2, CO2RG 5E, CO—N(RG 5E)2, CO—C6-alkylene-RG 5B, C1-C6-oxoalkylene-RG 5B, C2-C4-alkenylene-RG 5B or C2-C4-alkynylene-RG 5B,
RG 5D is a radical RG 5E, —CO—RG 5E, CO—ORG 5J, CON(RG 5E)2, S(O)g1—RG 5E or S(O)g1N(RG 5E)2,
RG 5E is hydrogen, an optionally substituted C1-C6-alkyl, aryl-C0-C6-alkylene, C3-C7-cycloalkyl-C0-C6-alkylene, hetaryl or hetarylalkyl radical,
RG 5F is a radical RG 5E, CO—RG 5E or CO—ORG 5E,
RG 5G is a radical ORG 5E, N(RG 5E) (RG 5F), N(RG 5E)-SO2—RG 5E, N(RG 5E)(ORG 5E), O—C(RG 5E)2—CO—ORG 5E, O—C (RG 5E)2—O—CO—RG 5E, O—C(RG 5E)2—CO—N (RG 5E)2 or CF3,
RG 5H is a radical ORG 5E, CN, S(O)g2—RG 5E, S(O)g1—N(RG 5E)2, CO—RG 5E, C(O)N(RG 5E)2 or CO2—RG 5E,
RG 5J is hydrogen or an optionally substituted C1-C6-alkyl or aryl-C0-C6-alkylene radical,
g1 is 1 or 2 and
g2 is 0, 1 or 2,
with the proviso that if WG═—YG—N(RG 5)— the radical —(CH2)m—CORG 6 is excluded for RG 5,
m is 1 or 2,
RG 6 is —OR′, —NR′R″, —NR′SO2R′″, —NR′OR′, —OCR′2C(O)OR′, —OCR′2OC(O)R′, —OCR′2C(O)NR′2, —CF3 or —COC(R′)2RG 7,
RG 7 is —OR′, _CN, —S(O)rR′, S(O)2N(R′)2, —C(O)R′C(O)NR′2 or —CO2R′,
r is 0, 1 or 2
R′ is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
R″ is R1, —C(O)R′ or —C(O)ORG 8,
R′″ is C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl,
RG 8 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl-C0-C4-alkyl or aryl-C0-C4-alkyl.
8. A pharmaceutical preparation, comprising at least one compound as claimed in any of claims 1 to 5 in addition to the customary pharmaceutical excipients.
9. The use of a compound as claimed in any of claims 1 to 5 for the production of drugs for the treatment of diseases.
10. The use of a compound as claimed in any of claims 1 to 5 as integrin receptor ligands.
11. The use of a compound as claimed in any of claims 1 to 5 as claimed in claim 10 as ligands of the αvβ3 integrin receptor.
12. The use of a compound as claimed in any of claims 1 to 5 as claimed in claim 9 for the production of drugs for the treatment of diseases in which the interaction between integrins and their natural ligands is excessive, or decreased.
13. The use of a compound as claimed in any of claims 1 to 5 as claimed in claim 12 for the treatment of diseases in which the interaction between αvβ3 integrin and its natural ligands is excessive or decreased.
14. The use of a compound as claimed in any of claims 1 to 5 as claimed in claim 13 for the treatment of atherosclerosis, rheumatoid arthritis, restenosis after vascular injury or stent implantation, angioplasty, acute kidney failure, angiogenesis-associated microangiopathies, diabetic angiopathies, blood platelet-mediated vascular occlusion, arterial thrombosis, congestive heart failure, myocardial infarct, stroke, cancer, osteoporosis, high blood pressure, psoriasis or viral, parasitic, mycotic or bacterial conditions or infections, inflammations, wound healing, hyperparathyroidism, Paget's disease, malignant hypercalcemia or metastatic osteolytic lesions.
15. A pharmaceutical preparation, comprising at least one compound as claimed in any of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group consisting of
inhibitors of blood platelet adhesion, activation or aggregation,
anticoagulants which prevent thrombin activity or formation, antagonists of blood platelet-activating compounds and selectin antagonists.
16. The us of a pharmaceutical preparation as claimed in claim 15 for the production-of a drug for treating blood platelet-mediated vascular occlusion or thrombosis.
17. A pharmaceutical preparation, comprising at least one compound as claimed in any of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group consisting of
inhibitors of blood platelet activation or aggregation,
serine protease inhibitors,
fibrinogen-lowering compounds,
selectin antagonists,
antagonists of ICAM-1 or VCAM-1
inhibitors of leukocyte adhesion
inhibitors of vascular wall transmigration,
fibrinolysis-modulating compounds,
inhibitors of complement factors,
endothelin receptor antagonists,
tyrosine kinase inhibitors,
antioxidants and
interleukin 8 antagonists.
18. The use of a pharmaceutical preparation as claimed in claim 17 for the production of a drug for treating myocardial infarct or stroke.
19. A pharmaceutical preparation comprising at least one compound as claimed in any of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group consisting of
endothelin antagonists,
ACE inhibitors,
angiotensin receptor antagonists,
endopeptidase inhibitors,
beta-blockers,
calcium channel antagonists,
phosphodiesterase inhibitors and
caspase inhibitors.
20. The use of the pharmaceutical preparation as claimed in claim 19 for the production of a drug for treating congestive heart failure.
21. A pharmaceutical preparation comprising at least one compound as claimed in any of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group consisting of
thrombin inhibitors,
inhibitors of factor Xa,
inhibitors of the coagulation pathway which leads to thrombin formation,
inhibitors of blood platelet adhesion, activation or aggregation,
endothelin receptor antagonists,
nitrogen oxide synthase inhibitors,
CD44 antagonists,
selectin antagonists,
MCP-1 antagonists,
inhibitors of signal transduction in proliferating cells,
antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF and
antioxidants.
22. The use of a pharmaceutical preparation as claimed in claim 21 for the production of a drug for treating restenosis after vascular injury or stent implantation.
23. A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group consisting of
antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF,
heparin or low-molecular weight heparins or further GAGs,
inhibitors of MMPs,
selectin antagonists,
endothelin antagonists,
ACE inhibitors,
angiotensin receptor antagonists,
glycosylation inhibitors and
AGE formation inhibitors or AGE breakers and antagonists of their receptors.
24. The use of the pharmaceutical preparation as claimed in claim 23 for the production of a drug for treating diabetic angiopathies.
25. A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group consisting of
lipid-lowering compounds,
selectin antagonists,
antagonists of ICAM-1 or VCAM-1
heparin or low-molecular weight heparins or further GAGs,
inhibitors of MMPs,
endothelin antagonists,
apolipoprotein Al antagonists,
cholesterol antagonists,
HMG CoA reductase inhibitors,
ACAT inhibitors,
ACE inhibitors,
angiotensin receptor antagonists,
tyrosine kinase inhibitors,
protein kinase C inhibitors,
calcium channel antagonists,
LDL receptor function stimulants,
antioxidants
LCAT mimetics and
free radical scavengers.
26. The use of the pharmaceutical preparation as claimed in claim 25 for the production of a drug for treating atherosclerosis.
27. A pharmaceutical preparation comprising at least one compound as claimed in any of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group consisting of
cytostatic or antineoplastic compounds,
compounds which inhibit proliferation and
heparin or low-molecular weight heparins or further GAGs.
28. The use of a pharmaceutical preparation as claimed in claim 27 for the production of a drug for treating cancer.
29. A pharmaceutical preparation comprising at least one compound as claimed in any of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group consisting of
compounds for antiresorptive therapy,
compounds for hormone replacement therapy,
recombinant human growth hormone,
bisphosphonates,
compounds for calcitonin therapy,
calcitonin stimulants,
calcium channel antagonists,
bone formation stimulants,
interleukin-6 antagonists and
Src tyrosine kinase inhibitors.
30. The use of the pharmaceutical preparation as claimed in claim 29 for the production of a drug for treating osteoporosis.
31. A pharmaceutical preparation comprising at least one compound as claimed in any of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group consisting of
TNF inhibitors,
antagonists of VLA-4 or VCAM-1,
antagonists of LFA-1, Mac-1 or ICAMs,
complement inhibitors,
immunosuppressants,
interleukin-1, -5 or -8 antagonists and
dihydrofolate reductase inhibitors.
32. The use of a pharmaceutical preparation as claimed in claim 31 for the production of a drug for treating rheumatoid arthritis.
33. A pharmaceutical preparation comprising at least one compound as claimed in any of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group consisting of
collagenase,
PDGF antagonists and
MMPs.
34. The use of the pharmaceutical preparation as claimed in claim 33 for the production of a drug for improving wound healing.
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