ZA200108035B - Integrin receptor ligands. - Google Patents

Integrin receptor ligands. Download PDF

Info

Publication number
ZA200108035B
ZA200108035B ZA200108035A ZA200108035A ZA200108035B ZA 200108035 B ZA200108035 B ZA 200108035B ZA 200108035 A ZA200108035 A ZA 200108035A ZA 200108035 A ZA200108035 A ZA 200108035A ZA 200108035 B ZA200108035 B ZA 200108035B
Authority
ZA
South Africa
Prior art keywords
radical
alkylene
optionally substituted
aryl
alkyl
Prior art date
Application number
ZA200108035A
Inventor
Johann-Christian Zechel
Andreas Kling
Herve Geneste
Udo Lange
Arnulf Lauterbach
Graef Claudia Isabella
Thomas Subkowski
Jens Sadowski
Wilfried Hornberger
Original Assignee
Basf Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Basf Ag filed Critical Basf Ag
Publication of ZA200108035B publication Critical patent/ZA200108035B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

0050/51042
Integrin receptor ligands
The invention relates to novel compounds which bind to integrin receptors, and to their preparation and use.
Integrins are cell surface glycoprotein receptors which mediate interactions between cells of the same and different types, and between cells and extracellular matrix proteins. They are involved in physiological processes such as, for example, embryogenesis, hemostasis, wound healing, immune response and formation/maintenance of tissue architecture.
Disturbances of the expression of cell adhesion molecule genes, oe 15 and disturbances of receptor function may contribute to the pathogenesis of a large number of disorders such as, for example, tumors, thromboembolic events, cardiovascular disorders, pulmonary diseases, disorders of the CNS, of the kidney, of the gastrointestinal tract or inflammations.
Integrins are heterodimers each consisting of an a and a B transmembrane subunit, which are connected non-covalently. To : date, 16 different a and 8 different PB subunits and 22 different combinations have been identified.
Integrin ayfi3, also called vitronectin receptor, mediates adhesion to a large number of ligands - plasma proteins, extracellular matrix proteins, cell surface proteins - most of which contain the amino acid sequence RGD (Cell, 1986, 44, 517-518; Science 1987, 238, 491-497), such as, for example, vitronectin, 1) fibrinogen, fibronectin, von Willebrand factor, thrombospondin, osteopontin, laminin, collagen, thrombin, tenascin, MMP-2, bone sialoprotein II, various viral, fungal, parasitic and bacterial proteins, natural integrin antagonists such as disintegrins, neurotoxins - mambin - and leech proteins - decorsin, ornatin - and some non-RGD ligands such as, for example, 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). 40 several integrin receptors show cross-reactivity with ligands containing the RGD motif. Thus, integrin ar;pf3, also called platelet fibrinogen receptor, recognizes fibronectin, vitronectin, thrombospondin, von Willebrand factor and fibrinogen.
0050/51042
Integrin ayf3 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, for example, melanomas, glioblastomas, carcinomas of the lung, breast, prostate and bladder, osteosarcomas or neuroblastomas.
Increased expression is observed under various pathological conditions, such as, for example, the prothrombotic state, in cases of vessel injury, tumor growth or metastasis or reperfusion, and on activated cells, in particular on endothelial cells, smooth muscle cells or macrophages.
Involvement of integrin ayf3 has been detected inter alia in the following pathological states: ®e 15
Cardiovascular disorders such as atherosclerosis, restenosis after vessel injury, and angioplasty (neointima formation, smooth muscle cell migration and proliferation) (J. Vasc. Surg. 1994, 19, 125-134; Circulation 1994, 90, 2203-2206), acute kidney failure (Kidney Int. 1994, 46, 1050-1058; Proc.
Natl. Acad. Sci. 1993, 90, 5700-5704; Kidney Int. 1995, 48, 1375-1385), angiogenesis-associated microangiopathies such as, for example, 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),
Py 30 arterial thrombosis, o stroke (phase II studies with ReoPro, Centocor Inc., 8th annual
European Stroke Meeting), cancers such as, for example, in tumor metastasis or tumor growth (tumor-induced angiogenesis) (Cell 1991, 64, 327-336; Nature 1989, 339, 58-61; Science 1995, 270, 1500-1502), osteoporosis (bone resorption after proliferation, chemotaxis and 40 adhesion of osteoclasts to bone matrix) (FASEB J. 1993, 7, 1475-1482; Exp. Cell Res. 1991, 195, 368-375, Cell 1991, 64, 327-336), high blood pressure (Am. J. Physiol. 1998, 275, H1449-H1454), 45 psoriasis (Am. J. Pathol. 1995, 147, 1661-1667),
AMENDED SHEET
0050/51042 hyperparathyroidism,
Paget’s disease (J. Clin. Endocrinol. Metab. 1996, 81, 1810-1820),
Ss malignant hypercalcemia (Cancer Res. 1998, 58, 1930-1935), metastatic osteolytic lesions (Am. J. Pathol. 1997, 150, 1383-1393), pathogen protein (for example HIV-1 tat)-induced processes (for example angiogenesis, Kaposi’s sarcoma) (Blood 1999, 94, 663-672) inflammation (J. Allergy Clin. Immunol. 1998, 102, 376-381), ® ‘heart failure, CHF, and for 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).
Because of its key role, pharmaceutical preparations which contain low molecular weight integrin a.P3; ligands are of great therapeutic and diagnostic value and are used inter alia for the indications mentioned.
Advantageous a,B3 integrin receptor ligands bind to the integrin ayf3 receptor with increased affinity.
Particularly advantageous ayf3 integrin receptor ligands
C additionally have increased selectivity for the integrin ayf3 and have less effect on the integrin ar;pB; by a factor of at least 10, preferably by a factor of at least 100.
An integrin af; antagonistic effect has been shown, and a beneficial in vivo effect has been demonstrated, for a large number of compounds such as anti-a,f3 monoclonal antibodies, peptides containing the RGD binding sequence, natural 40 RGD-containing proteins (for example disintegrins) and low molecular weight compounds (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).
0050/51042 AMENDED SHEET tetrahydropyrimidin-2(1H)one derivatives and piperidin-2-one derivatives, WO 99/31099 describes 1,3-substituted imidazolin-2-one derivatives, WO 98/35949 describes 2,6-substituted 2H-1,4-benzoxazin-3(4H)one derivatives,
WO 9800395 and WO 9723451 describe O-substituted tyrosine derivatives, EP 710657 and EP 741133 describe 3,5-substituted 1,3-oxazolidin-2-ones and WO 97/37655 describes isoindoles as antagonists of the ayf; integrin receptor.
A need exists to provide novel integrin receptor ligands with advantageous properties.
The present invention provides compounds of the formula I o
B-G-L I where B, G and L have the following meanings:
L is a structural element of the formula Ii : -u-T I : 25 where
T is a COOH group or a radical which can be hydrolyzed to
COOH and -U~ is = (CRLIRLZ) a= (VL) b= (CRLIRL4 ) e~ (We) a (CRLSRLS )e- (XL) £- (CRLRLS) g- ® where a, ¢, e, g are, independently of one another, 0, 1, 2 or 3, b, d, £ are, independently of one another, 0 or 1, 40 Rel, Ry2, Ri3, Rp%, RLS, Rp6, RZ, Rp 8 are, independently of one another, hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-Cg-alkyl, Cp-Cg-alkenyl,
C2-Cg-alkynyl or Ci1-Cg-alkylene-C3-C;-cycloalkyl 45 radical, a radical =(CH2)y-(Y¥y)y-Ry?, an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical or, in each case
0050/51042 independently of one another, two radicals Rp! and Rp? or Ry? and Rp4 or Ry® and Rp or Ry? and Ry 8 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocyclic or heterocyclic system 5 which may contain up to three heteroatoms from the group of O, N or S, w is 0, 1, 2, 3 or 4, y is 0 or 1 ‘
Y;, is -CO-, -CO-N(Ryl)-, -N(Ryl)-CO-, -N(Ryl!)-CO-N(Ryl*)-, -N(Ry!)-CO-0-, -0-, -S-, -S0;-, -S0,-N(Ryl)-, -S03-0-, -CO-0-, -0-CO-, -O0-CO-N(Ry!)-, oe 15 -N(Ryl)~ or -N(Ryl!)-SOz-,
Ryl/ Ryl* are, independently of one another, hydrogen, a branched or unbranched, optionally substituted
C1-Cg¢-alkyl, C;-Cg-alkoxyalkyl, C,-Cg¢-alkenyl,
C3-Cjio-alkynyl, CO-C;-Cg-alkyl, CO-0—C;-Cg-alkyl or S0,-C;-Cg¢-alkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl,
CO-0O-alkylene-aryl, CO-alkylene-aryl, CO-aryl,
SO,-aryl, hetaryl, CO-hetaryl or SO,-alkylene-aryl radical,
R;? is hydrogen, or a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted
C;-Cg¢-alkyl radical, an optionally substituted
L 1) C3-C7-cycloalkyl, aryl, heteroaryl or arylalkyl radical, an optionally C;-C4-alkyl- or aryl-substituted C,—Cg—alkynyl or C,—Cg—alkenyl radical, an optionally substituted
C¢—Ci12-bicycloalkyl, C;-Cg-alkylene-Ce¢—Cjiy—bicyclo- alkyl, C;—Cjo~tricycloalkyl or
C;-C¢-alkylene-C;—Cyo—tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical 40 or different radicals and which may contain up to three different or identical heteroatoms O, N, S, it being possible for two radicals together to be a fused, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three 45 different or identical heteroatoms 0, N, S, and it being possible for the cyclic system to be optionally substituted, or for another, optionally substituted,
0050/51042 saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, or the radical Rp? forms together with Ry! or Ryl* a saturated or unsaturated C3-C;-heterocycle which may optionally contain up to two further heteroatoms selected from the group of 0, 8 or N,
Wp is an optionally substituted 4- to 1l-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which may contain up to 6 double bonds and up to 6 heteroatoms selected from the group of N, O, S,
Vi, Xi, are, independently of one another, -CO-, -CO-NRy10-, -NR10-CO-, -S-, -SO-, -SO;~, =-SO,-NRyl0-, -NR;10-S0,-,
LL) ~CS-, -CS-NRy10-, -NR;10-CsS-, -CS-0-, -0-Cs-, -C0-0-, -0-CO-, -0-, ethynylene, -CHRyll-0-CHR12-, ~-C(=CRpl1R;12)-, -CRy,11=CR;12~, -CRp11(ORy13)-CHRy 12, ~CHRL11-CR,12(0ORp13)~, -CH(NRpl4-S0,-R;15)-, ~CH(NRL14-CO-Ry,15)~, -CH(NRy14~CO-OR16)-,
CH(NRy14-CO-NRy,14'R,15)-, -CH(CO-Rpl5)-, -CH(CO-ORy16)- or CH(CO-NRpl4Rr;15)-,
Rp10 is hydrogen, a branched or unbranched, optionally substituted C;-Cg~alkyl, C;-Cg-alkoxyalkyl, C,-Cg- alkenyl, C3-C;;-alkynyl, CO-C;-Cg-alkyl,
CO-0-C;-Cg-alkyl or SO,;-C;-Cg-alkyl radical or an optionally substituted C3-C;-cycloalkyl,
CO-0O-alkylene-aryl, CO-alkylene-aryl, arylalkyl, cO-aryl, S0,-aryl, hetaryl, CO-hetaryl, hetarylalkyl
L J) or SO;-alkylene-aryl radical, or Ryl? and a radical selected from the group of Rpl, Rp2, Rp3, Rp4, Ry5, RS,
Ry’ or Rp? together are an optionally substituted 4- to 8-membered heterocycle which may contain up to five identical or different heteroatoms O, N or §,
R11. Rp12 are, independently of one another, hydrogen, a hydroxyl group, a branched or unbranched, optionally 40 substituted C;-Cg¢-alkyl, C;-Cy-alkoxy, C,-Cg¢-alkenyl,
C2-Cg-alkynyl or alkylene—cycloalkyl radical or an optionally substituted C3-Cj-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, 45 Ry!3 is hydrogen, a branched or unbranched, optionally substituted C;-C¢-alkyl, C;-Cg¢-alkenyl, C2-Cg-alkynyl or alkylene-cycloalkyl radical or an optionally
0050/51042 substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
Rp 14, Rp 14 are, independently of one another, hydrogen, a branched or unbranched, optionally substituted
C;-C¢-alkyl, C;-Cg¢-alkoxyalkyl, C,-Cg-alkenyl,
C3-Cjy-alkynyl, CO-C;-Cg-alkyl, CO-0—C;-Cg¢-alkyl,
C;-Cg¢-alkylene-C3-Cy-cycloalkyl, or S0;-C;-Cg-alkyl radical or an optionally substituted
C3~Cy-cycloalkyl, CO-O-alkylene-aryl,
CO-alkylene-aryl, aryl, CO-aryl, SO,-aryl, hetaryl,
CO-hetaryl, hetarylalkyl, arylalkyl or
SOjz-alkylene-aryl radical, o9 15
Rpl5 is a branched or unbranched, optionally substituted
C1-Cg¢-alkyl, alkoxyalkyl, C;-Cg-alkylene-C;3-C;-cyclo- alkyl radical, Cg¢—Cj o-bicycloalkyl,
C1-C¢-alkylene-Cg-—Cjiy—bicycloalkyl,
C1—Cyo—tricycloalkyl or C;-Cg¢-alkylene-C;—Cyq— tricycloalkyl radical, a C3-Cy-cycloalkyl, aryl, arylalkyl, hetarylalkyl or 3— to 8-membered, saturated, unsaturated or aromatic heterocyclic radical which may be substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N,
S, it being possible for two radicals together to be a fused, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N,
L J) S, and it being possible for this cyclic system to be optionally substituted, or for another, optionally substituted, saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, or the radical R;l%> forms together with Rpl4 or Rplé* a saturated or unsaturated C3-C; heterocycle which may optionally contain up to two further heteroatoms selected from the group of 0, S or N, and 40 Rp 16 is a branched or unbranched, optionally substituted
C;-Cg-alkyl, alkoxyalkyl or
C;-Cg-alkylene-C;3-C7-cycloalkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, 45
G is a structural element of the formula Ig
0050/51042 xX
N ey teh, Ig
RG, where the structural element G can be incorporated in both orientations, and
Zs is oxygen, sulfur or NRg3, ®e © are, independently of one another, hydrogen, CN, NO, halogen, a branched or unbranched, optionally substituted
C1-Cg-alkyl, C,-C¢-alkenyl or C,-Cg-alkynyl radical, a branched or unbranched, optionally substituted
C1-Cq4-alkylene-ORg%, C;-Cy4-alkylene-CO-ORg4,
C1-C4-alkylene-CO-Rg?, C;-Cy-alkylene-SO,-NRGSRgS,
Ci-C4-alkylene-CO-NRgRg6, C;-Cz-alkylene-NRg5Rg6 or
C1-Cg4-alkylene-SRg? radical, an optionally substituted
C3-C;-cycloalkyl, C3-C;-heterocycloalkyl,
C3-C;-heterocycloalkenyl, C;-Cy-alkylene-C3-Cj-cycloalkyl,
C;-C4-alkylene-C3-C;-heterocycloalkyl or
Ci1-C4-alkylene-C3-C;-heterocycloalkenyl radical, an optionally substituted aryl, arylalkyl, hetaryl or hetarylalkyl radical, an -S-Rg!, -0-Rg%, -SO-Rg%, =-SO,-Rg%, ~-CO-ORg%, -0-CO-Rg!, -0O-CO-NRg5Rg6, -SO,-NRGS5Rg6,
J -CO-NRg?Rg®, -NRG7Rgé, CO-Rg? radical, or Rg! and Rg? together are an optionally substituted, saturated, unsaturated or aromatic 3- to 9-membered carbocyclic, polycarbocyclic, heterocyclic or polyheterocyclic system which may contain up to 4 heteroatoms selected from the group of O, N, S,
Rg? is hydrogen, a hydroxyl group, CN, a branched or unbranched, optionally substituted C;—Cg¢—alkyl or 40 C,-C4-alkoxy radical or an optionally substituted
C3-Cy-cycloalkyl, —0-C3-Cj-cycloalkyl radical, aryl, —O-aryl, arylalkyl or —O-alkylene—aryl radical,
Rg? is hydrogen, a branched or unbranched, optionally 45 substituted C;-Cg-alkyl, C,-C¢-alkenyl, C,-Cg-alkynyl,
C1-Cs—alkylene-C;-C4-alkoxy, mono- and bisalkylaminoalkylene or acylaminoalkylene radical or an
0050/51042 optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C;-cycloalkyl, ’
C;-Cy-alkylene-C;3-Cyj-cycloalkyl, arylalkyl,
C1-C4-alkylene-heterocycloalkyl, C;-Cs-alkylene- heterocycloalkenyl or hetarylalkyl radical,
Rg3, Rg are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl,
C2-Cg¢~-alkenyl, C;-Cg-alkynyl, Cj;-Cs—alkylene-Ci-C,- alkoxy, mono- and bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl,
C3-C;-cycloalkyl, C;-C4-alkylene-C3-C;-cycloalkyl, ® 15 arylalkyl, C;-C4-alkylene-heterocycloalkyl,
Qo C1-C4-alkylene-heterocycloalkenyl or hetarylalkyl radical, or an -S0;-Rg%, -CO-ORg%, -CO-NRg4Rg4* or -CO-Rg! radical, and
Rg?* is an Rg? radical independent of Rg4,
B is a structural element containing at least one atom which can, under physiological conditions, form hydrogen bonds as hydrogen acceptor, where the distance between at least one hydrogen acceptor atom and structural element G along the shortest possible route along the structural element framework is from 4 to 13 atomic linkages, and the physiologically tolerated salts, prodrugs and enantiomerically pure or diastereomerically pure and oo tautomeric forms.
A halogen radical means for all radicals and substituents in the present invention for example F, Cl, Br or I, unless mentioned otherwise.
Optionally substituted radicals mean the corresponding unsubstituted and substituted radicals. For all substituted radicals in the present invention if the substituents are not 40 specified in detail then, independently of one another, up to 5 substituents are suitable, for example selected from the following group: -NO,, -NH;, -OH, -CN, -COOH, -0-CH;-COOH, halogen, a branched or 45 unbranched, optionally substituted C;~C4—alkyl radical such as, for example, methyl, CF3, CFs or CHF, a branched or unbranched, optionally substituted -CO-0-C;-C4-alkyl,
0050/51042
C3-Cj-cycloalkyl, C;—Cg—alkoxy, Ci;—Cs—thioalkyl, -NH-CO-0-C;-C4-alkyl, -0-CH;-CO0-C;-C4-alkyl, -NH-CO-C;-C4-alkyl, -CO-NH-C;-C4-alkyl, -NH-SO,-C;-C4-alkyl, -SO,-NH-C;-Cg-alkyl, -N(C;-C4-alkyl),, -NH-C;-C4-alkyl, or -S0O,-C;-C4-alkyl radical, such as, for example, -S0;-CF3, an optionally substituted -NH-CO-aryl, -CO-NH-aryl, -NH-CO-O-aryl, -NH-CO-O-alkylene-aryl, -NH-SO;-aryl, -SO,-NH-Aryl, -CO-NH-benzyl, -NH-SO;-benzyl or -S0,-NH-benzyl radical, an optionally substituted -S0,-NR4R5 or -CO-NR4R5 radical, it being possible for RY and R3 radicals independently of one another to have the meaning as Rpl4 hereinafter, or the two R% and R® radicals together being a 3- to 6-membered, optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, may contain up to three other different or identical heteroatoms O, ( 15 N, S and optionally two radicals substituted on this heterocycle together are a fused, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and it being possible for the cyclic system optionally to be substituted, or for another, optionally substituted cyclic system to be fused to this cyclic system.
With all terminally bonded, substituted hetaryl and hetarylalkyl radicals in the present invention it is possible, in addition to the aforementioned list of substituents, for two substituents in the hetaryl moiety to form a fused 5- to 7-membered, unsaturated or aromatic carbocyclic system.
T in the structural element L means a COOH group or a radical which can be hydrolyzed to COOH. A radical which can be %0 hydrolyzed to COOH means a radical which is converted into a COOH group after hydrolysis.
A group which may be mentioned as an example of a radical T which can be hydrolyzed to COOH is . 0
Ag 40 in which R! has the following meaning: 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 45 barium, or an environmentally compatible organic ammonium ion such as primary, secondary, tertiary or quaternary
0050/51042
C1-C4-alkylammonium or an ammonium ion, such as, for example,
ONa, OK or OLi, b) a branched or unbranched, optionally halogen-substituted
Ci-Cg-alkoxy radical such as, for example, methoxy, ethoxy, propoxy, l-methylethoxy, butoxy, l-methylpropoxy, 2-methylpropoxy, 1,l-dimethylethoxy, in particular methoxy, ethoxy, l-methylethoxy, pentoxy, hexoxy, heptoxy, octoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, l-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2~trifluoroethoxy or pentafluoroethoxy €) a branched or unbranched, optionally halogen-substituted
Ci1-C4-alkylthio radical such as methylthio, ethylthio,
LL) propylthio, l-methylethylthio, butylthio, l-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio radical d) an optionally substituted -O-alkylene-aryl radical such as, for example, -O-benzyl e) R! also a radical -(O)pm-N(R2)(R3), in which ml is 0 or 1, and R2 and R3, which may be identical or different, have the following meaning: hydrogen, a branched or unbranched, optionally substituted
Ci1-Ce-alkyl radical, such as, for example, methyl, ethyl, \ J propyl, l-methylethyl, butyl, 1l-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, l-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, l-ethylpropyl, hexyl, l-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, l-ethylbutyl, 2-ethylbutyl or l-ethyl-2-methylpropyl or the corresponding substituted radicals, preferably methyl, ethyl, propyl, butyl or i-butyl, 40
C,-Cg¢-alkenyl radical such as, for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1l-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, l-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 45 l-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, l-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,
J AMENDED SHEET
0050/51042 12 5-hexenyl, l-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, l-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, l-ethyl-2-butenyl, l-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, l-ethyl-l-methyl-2-propenyl and l-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl and 3-methyl-2-pentenyl or the (J 15 corresponding substituted radicals,
C2-C¢-alkynyl radical such as, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-3-butynyl, 2-methyl-3-butynyl, l-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, S5-hexynyl, l-methyl-2-pentynyl, l1-methyl-2-pentynyl, l-methyl-3-pentynyl, l-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, l-ethyl-2-butynyl, l-ethyl-3-butynyl, 2-ethyl-3-butynyl and l-ethyl-l-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, l-methyl-2-propynyl or l-methyl-2-butynyl, or the corresponding substituted
C radicals,
C3-Cg-cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl or the corresponding substituted radicals, or a phenyl radical, optionally substituted one or more times, for example one to three times, by halogen, nitro, 40 cyano, C;-C4-alkyl, C1-C4-haloalkyl, C,-C4-alkoxy,
Ci1-Cq4-haloalkoxy or C,;-C4-alkylthio, such as, for example, 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 45 4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-dichlorophenyl, 2-methoxy-3-methylphenyl,
0050/51042 2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl, 2,6-difluorophenyl, or R? and R3 together form a C4-C;-alkylene chain which is closed to a ring, is optionally substituted, for example by
C1-C4-alkyl and may contain a heteroatom selected from the group of oxygen, sulfur or nitrogen, such as, for example, -(CH2)4-, -(CH2)5-, -(CHz)¢~, -(CH2)7-, =-(CH:)2-0-(CHz),-, -CH;-5-(CH;)3~, -(CH2)2-0-(CHz)3-, -NH-(CH;)3-, -CH,-NH-(CH;).-, -CH,-CH=CH-CH;-, -CH=CH-(CH;)3-, -CO-(CH;);-CO- or -CO-(CH32)3~CO-.
Preferred T radicals are -COOH, -CO-0O-C;-Cg-alkyl or -CO-O-benzyl. ® 15 The coefficients a, ¢, e and g in structural element -U- are, o independently of one another, 0, 1, 2 or 3, preferably 0, 1 or 2.
In further, preferred structural elements -U- the total of the coefficients a, c, e and g is less than 7.
In particularly preferred structural elements -U- the coefficients a, c, e and g are, independently of one another, 0 or 1.
The preferred halogen radical for Rp!, Rp?, Rp3, Rp4, RS, Ry, Ry7 or
R,8 is F.
Examples of branched or unbranched C;-Cg-alkyl radicals for Rl,
Rp?, Ri, Rp4, Rp, Rb, Ry7 or Rp® in structural element L are, independently of one another, methyl, ethyl, propyl, l-methyl- d0 ethyl, butyl, l-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, l-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, l-ethylpropyl, hexyl, l-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, l-ethylbutyl, 2-ethylbutyl or l-ethyl-2-methylpropyl, preferably branched or unbranched C;-C4-alkyl radicals such as, for example, methyl, ethyl, propyl, l-methylethyl, butyl, l-methylpropyl, 40 2-methylpropyl or 1,1-dimethylethyl, particularly preferably methyl.
A branched or unbranched C,-Cg-alkenyl radical for
Ril, Ry?, Rp3, Ryd, Ri5, Rp, RL7 or Rp? in structural element L 45 means, independently of one another, for example vinyl, 2-propenyl, 2-butenyl, 3-butenyl, l-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
’ AMENDED SHEET @ 0050/51042 l-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, l-ethyl-2- propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, l-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, l-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1l,1-dimethyl- 3-butenyl, 1,2~dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, - 10 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, l-ethyl-2-butenyl, l-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, l-ethyl-1- methyl-2-propenyl or l-ethyl-2-methyl-2-propenyl.
J 15
A branched or unbranched C;-Cg-alkynyl radical for Ry}, Rp?, Rp3,
Ret, Rp3, Rp6, Ry’ or Ry? in structural element L means, independently of one another, for example ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-3-butynyl, 2-methyl-3-butynyl, l-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, l-methyl-2-pentynyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, l-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, l,l-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl- 3-butynyl, l-ethyl-2-butynyl, l-ethyl-3-butynyl, 2-ethyl-3- butynyl and l-ethyl-l-methyl-2-propynyl, preferably ethynyl, 2-propynyl, 2-butynyl, l-methyl-2-propynyl or l-methyl-2- butynyl, particularly preferably ethynyl. ® A C3-Cy-cycloalkyl radical for Rl, Rp2, Rp3, Rp4, Ry3, Reb, R.7 or
Rp? in structural element L means, independently of one another, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Branched or unbranched C1~Ce~alkylene-C3-Cy-cycloalkyl radicals are composed, for example, of branched or unbranched
C1-Cg~alkylene radicals and the aforementioned C3-Cy-cycloalkyl 40 radicals.
Preferred optionally substituted aryl radicals for Ril, Rp2?2, Ry3,
Rp4, Rp3, Rp%, Ry’ or Ri® in structural element IL, are, independently of one another, optionally substituted phenyl, l-naphthyl or 45 2-naphthyl.
AMENDED SHEET
@ 0050/51042
Preferred optionally substituted arylalkyl radicals for Ry!, R.2,
Rp3, Ref, Rp5, Re®, Ry? or Ri8 in structural element L are, independently of one another, optionally substituted benzyl or phenethyl.
Hetaryl radicals for Rpl, Ry2, Ry3, Rpt, Ry5, R86, R.7 or R 8 in structural element L mean, independently of one another, for example radicals such as 2-pyridyl, 3-pyridyl, 4-pyridyl, : 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, S5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, S-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, S5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, ® 15 6-pyridazinyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, i thiadiazolyl, oxadiazolyl or triazinyl.
Substituted hetaryl radicals for Rpl, Rp2, Rp3, Rp4, RS, Rp%, R.? or
Rp8 in structural element L mean, as described above generally for terminal substituted hetaryl radicals, also fused derivatives of the aforementioned hetaryl radicals, such as, for example, . indazole, indole, benzothiophene, benzofuran, indoline, benzimidazole, benzothiazole, benzoxazole, quinoline, } 2,3-dihydro-~l1l-benzofuran, furo[2,3]pyridine, furo[3,2 pyridine or isoquinoline.
Hetarylalkyl radicals for Rel, Ru2, Ryd, Rpt, RS, Ru%, Ry’ or Ri® in structural element L mean radicals which are composed, for example, of C,-Cg-alkylene radicals and of the hetaryl radicals described above, such as, for example, the radicals ® -CH;-2-pyridyl, -CH;-3-pyridyl, -CH,-4-pyridyl, -CH3-2~-thienyl, -CH;-3-thienyl, -CH;~2-thiazolyl, -CH;-4-thiazolyl,
CHp-5-thiazolyl, -CH;-CH;-2-pyridyl, -CH,;-CH;~3-pyridyl, -CH;~-CH;-4-pyridyl, -CH;-CH;-2-thienyl, -CH;-CH,;-3-thienyl, -CH;-CH;-2-thiazolyl, -CH,-CH;-4-thiazolyl, or -CH;-CH;-5-thiazolyl.
It is further possible for two radicals Ry! and Rp? or R;3 and Rp 4 or Ry’ and Rf or Ry? and Rp? in each case independently of one 40 another together to be a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocyclic or heterocyclic system which may contain up to three heteroatoms from the group of O, N or S. 45 The -(CHz)u-(YrL)y-Rp% radical is composed of a Cg-Cs-alkylene radical, optionally a linking element Y; selected from the group of -CO-, -CO-N(Ryl)-, -N(Ryl)-CO-, -N(Ryl)-CO-N(Ryl*)-,
) AMENDED SHEET 0050/51042 -@ 16 -N(Ry!)-CO-0-, -0-, =-S=-, =S03-, -S0;-N(Ryl)-, -50,-0-, -CO-0-, -0-CO-, -O-CO-N(Ryl)-, -N(Ry!)- or -N(Ry!)-S0,- and the Ry? radical, where
Ry} Ryl* are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C1~Cs-alkyl, C;-Cg-alkoxyalkyl,
C2-C¢-alkenyl, C3-C;p;-alkynyl, CO-C;-Cg-alkyl, CO-0-C,-Cg-alkyl or 503-C;-Cg-alkyl radical or an optionally substituted
C3-Cy-cycloalkyl, aryl, arylalkyl, CO-0-alkylene-aryl,
CO-alkylene-aryl, CO—aryl, SO;-aryl, hetaryl, CO-hetaryl or
SO;-alkylene-aryl radical, preferably hydrogen, methyl, cyclopropyl, allyl or propargyl, particularly preferably hydrogen or methyl, and ® 15
Ry? is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-Cg-alkyl radical, an optionally substituted C3-Cy-cycloalkyl, aryl, heteroaryl or arylalkyl radical, an optionally C1—C4—alkyl- or aryl-substituted
Ca—Cg¢—alkynyl or C—Cg—alkenyl radical, an optionally substituted
Ce—Cy12—-bicycloalkyl, C1-Ce—alkylene-C¢—C)—bicycloalkyl,
C)—Cyo—~tricycloalkyl or Ci1-Cg-alkylene-C;—Cg—tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, it being possible for two radicals together to be a fused, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and it being possible for the cyclic system optionally to be substituted, or for é another, optionally substituted, saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, such as, for example, optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, S-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, S5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 40 4-imidazolyl, S-imidazolyl, 3-pyridazinyl, 4-pyridazinyl,
S-pyridazinyl, 6-pyridazinyl, 2-(1,3,4)-thiadiazolyl, 2-(1,3,4)-oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, S-isoxazolyl or triazinyl.

Claims (1)

  1. 0050/51042 We claim:
    1. A compound of the formula I
    5 . B-G-L I where B, G and L have the following meanings: L is a structural element of the formula Ij -U-T Ip where @® T is a COOH group or a radical which can be hydrolyzed to COOH and -U- is —(CRLIR12) a= (VL) b= (CRL3RL4 ) c— (Wr) a= (CRLORL® ) e= (XL) £= (CRL7R.8) o- where a, ¢, €, g are, independently of one another, 0, 1, 2 or 3, b, d, £ are, independently of one another, 0 or 1, Rp!, Rp2, Ry3, Rp4, Rp3, RpS, Ry’, Ry8 are, independently of one another, hydrogen, halogen, ® a hydroxyl group, a branched or unbranched, optionally substituted C;-Cg-alkyl, C;-Cg-alkenyl, C,-Cg¢-alkynyl or C;-Cg¢-alkylene-C3-Cy-cycloalkyl radical, a radical -(CHz)w-(YpL)y-Ry?, an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical or, in each case independently of one another, two radicals Ry! and Ry? or Ryd and Ry? or Ry5 and Rp 6 or Ry? and R;® together are a 3- to 7-membered, optionally substituted, saturated 40 or unsaturated carbocyclic or heterocyclic system which may contain up to three heteroatoms from the group of 0, N or §S, w is 0, 1, 2, 3 or 4, 45 y is 0 or 1
    0050/51042
    Y;, is -CO-, -CO-N(Ryl)-, =-N(Ryl)-cO-, -N(Ry!)-CO-N(Ryl*)-, -N(Ryl)-CO-0-, -0-, -S-, -S0,-, -S02-N(Ry!)-, -SO2-0-, ~CO-0O-, -0-CO-, -0-CO-N(Ry!)-, -N(Ry!)- or -N(Ry!)-SO;-,
    Ryl/ Ryl* are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C;-Cg-alkoxyalkyl, C,-Cg¢-alkenyl, C3-Ciy-alkynyl, CO-C,-Cg¢-alkyl, CO-0—C;-Cg-alkyl or S0;-C;-Cg¢-alkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, CO-0O-alkylene-aryl, CO-alkylene-aryl, CO—aryl, SO,-aryl, hetaryl, CO-hetaryl or SOj;-alkylene-aryl PY 15 radical, R;? is hydrogen, or a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-Cg-alkyl radical, an optionally substituted C3-Cy-cycloalkyl, aryl, heteroaryl or arylalkyl radical, an optionally C;-C4-alkyl- or aryl-substituted C,—Cg—alkynyl or C,-—Cg—alkenyl radical, an optionally substituted Cg—Cio—bicycloalkyl, C;-Cg-alkylene-Cg—Ciy—bicyclo- alkyl, C3—Cj¢o—tricycloalkyl or C;-Cg¢-alkylene- C7—Cyo—tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, it being possible ® for two radicals together to be a fused, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and it being possible for the cyclic system to be optionally substituted, or for another, optionally substituted, saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, or the radical Ry? forms together with Ry! or Ryl* a saturated or unsaturated 40 C3-Cy-heterocycle which may optionally contain up to two further heteroatoms selected from the group of O, S or N,
    0050/51042
    Wp is an optionally substituted 4- to ll-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which may contain up to 6 double bonds and up to 6 heteroatoms selected from the group of N, O, S,
    Vi, Xi, are, independently of one another, -CO-, -CO-NRy10-, -NRy10-c0-, -S-, -S0-, -S0,-, -S0,-NRp10-, -NR.10-S0,-, -CS-, -CS-NR.10-, -NR!9-CS-, -CS-0-, -0-CS-, -CO-O-,
    -0-C0O-, -0-, ethynylene, -CHR;l1-O-CHR;12-, -C(=CRy,11R 12) -, -CRy,11=CR;12-, -CRy,11(ORy13)-CHRy12-, ~CHRp11-CR;12(OR13)-, -CH(NRpl4-S0,-Rp15)-, -CH(NRp14-CO-Ry15)-, -CH(NR;!4-CO-ORy16)-, CH(NR14-CO-NRy14'R15)~, -CH(CO-Rp15)-, -CH(CO-ORyl16)-
    PY 15 or CH(CO-NR;l4R;15)-,
    Rp10 is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C;-Cg-alkoxyalkyl, C,-Cg- alkenyl, C3-C;z-alkynyl, CO-C;-Cg-alkyl,
    CO-0-C;-Cg-alkyl or S0,-C;-Cg-alkyl radical or an optionally substituted C3-C;-cycloalkyl, CO-0O-alkylene-aryl, CO-alkylene-aryl, arylalkyl, CO—-aryl, SOz-aryl, hetaryl, CO-hetaryl, hetarylalkyl or SO;-alkylene-aryl radical, or Rpl? and a radical selected from the group of Rypl, Rp?, Ry3, Rp4, Ry5, R.S, Rp? or R 8 together are an optionally substituted 4- to 8-membered heterocycle which may contain up to five identical or different heteroatoms O, N or §,
    Ry ll.
    Rp l2
    ® are, independently of one another, hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C;-Cg-alkyl, C;-Cs-alkoxy, Cy-Cg-alkenyl, C,-Cg-alkynyl or alkylene—cycloalkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
    Ry13 is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C,-Cg-alkenyl, C,-Cg-alkynyl
    40 or alkylene—cycloalkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
    Rp l4, Ryl4-
    45 are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C1-Cg¢-alkyl, C;-Cg¢-alkoxyalkyl, Cy-Cg-alkenyl,
    0050/51042
    C3-Cjyz2-~alkynyl, CO-C;-Cg-alkyl, CO-0-C;-Cg¢-alkyl, C1-Cg-alkylene-C3-C;-cycloalkyl, or S0,-C;-Cg-alkyl radical or an optionally substituted C3-C;-cycloalkyl, CO-O-alkylene-aryl,
    CO-alkylene-aryl, aryl, CO-aryl, SO;-aryl, hetaryl, CO-hetaryl, hetarylalkyl, arylalkyl or SO,-alkylene-aryl radical,
    Rpl> is a branched or unbranched, optionally substituted C1-Cg-alkyl, alkoxyalkyl, C;-Cg-alkylene-C3-C;-cyclo- alkyl radical, Ce¢—C;,-bicycloalkyl, C1-Cg-alkylene-Cg—C;r—bicycloalkyl, C7—Cjo—tricycloalkyl or C1-Cg-alkylene-C;—Cyo—tricycloalkyl radical, a C3-Cy-cycloalkyl, aryl, arylalkyl, hetarylalkyl or 3— ® to 8-membered, saturated, unsaturated or aromatic heterocyclic radical which may be substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, it being possible for two radicals together to be a fused, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and it being possible for this cyclic system to be optionally substituted, or for another, optionally substituted, saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, or the radical Rpl> forms together with Rpl4 or Rpl4* a saturated or unsaturated C3-C, heterocycle which may optionally contain up to ® two further heteroatoms selected from the group of O, S or N, and Rp 16 is a branched or unbranched, optionally substituted C1-Ce-alkyl, alkoxyalkyl or C1-Cg¢-alkylene-C3-Cj-cycloalkyl radical or an optionally substituted C3-Cy-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, 40 G is a structural element of the formula Ig Zc BSE 45 Thr, Ie RG,
    0050/51042 where the structural element G can be incorporated in both orientations, and
    Zs 1s oxygen, sulfur or NRg3, Rgl/ Rg? are, independently of one another, hydrogen, CN, NO,
    halogen, a branched or unbranched, optionally substituted C1-Cg-alkyl, C;-Cg-alkenyl or C;-Cg-alkynyl radical, a branched or unbranched, optionally substituted C;-C4-alkylene-ORg4, C;-C4-alkylene-CO-ORg?, C1-C4~alkylene-CO-Rg4, C;-Cy-alkylene-S0O,-NRg Rg,
    C;-C4~alkylene-CO-NRg5Rg®, C;-Cs-alkylene-NRgSRg6 or
    ® C;-C4-alkylene-SRg4 radical, an optionally substituted C3-C;-cycloalkyl, C;-C4-alkylene-C;3-C;-cycloalkyl, C;-C4-alkylene-C3-C;-heterocycloalkyl or C;-C4-alkylene-C3-Cy-heterocycloalkenyl radical,
    optionally substituted aryl, arylalkyl, hetaryl or hetarylalkyl radical, an -S-Rg?, -0-Rg?, -SO-Rg?, -SO0,-Rg4, -CO-0ORg4, -0-CO-Rg4, -0-CO-NRgSRg6, -S0,-NRGSRGS, -CO-NRg5Rg6, -NRg5Rg6, CO-Rg? radical, or Rg! and Rg? together are an optionally substituted, saturated,
    unsaturated or aromatic 3- to 9-membered carbocyclic, polycarbocyclic, heterocyclic or polyheterocyclic system which may contain up to 4 heteroatoms selected from the group of 0, N, S,
    Rg3 is hydrogen, a hydroxyl group, CN, a branched or
    ® unbranched, optionally substituted C;—Cg—alkyl or C1-Cs-alkoxy radical or an optionally substituted C3-Cy-cycloalkyl, -0-C3-Cy-cycloalkyl radical, aryl, —O-aryl, arylalkyl or —O-alkylene—aryl radical,
    Rg? is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, Cy-Cg¢-alkenyl, C,-Cg¢-alkynyl, C,;-Cs—alkylene-C;-C4~alkoxy, mono- and bisalkylaminoalkylene or acylaminoalkylene radical or an
    40 optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C;-cycloalkyl, C;-Cs-alkylene-C3-Cy-cycloalkyl, arylalkyl, C;-C4-alkylene-heterocycloalkyl, C;-Cs4-alkylene- heterocycloalkenyl or hetarylalkyl radical,
    0050/51042 Rg®, Reb are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C,-Cg-alkenyl, C,-Cg¢-alkynyl, C;-Cs—alkylene-C;-C4- alkoxy, mono- and bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C;-cycloalkyl, C;-Cs-alkylene-C3-C;-cycloalkyl, arylalkyl, C;-Cs-alkylene-heterocycloalkyl, C;-C4-alkylene-heterocycloalkenyl or hetarylalkyl radical, or an -SO,-Rg4, -CO-ORg%, -CO-NRg%Rg4* or -CO-Rg! radical, and Rg4* is an Rg4 radical independent of Rg4, ® B is a structural element containing at least one atom which can, under physiological conditions, form hydrogen bonds as hydrogen acceptor, where the distance between at least one hydrogen acceptor atom and structural element G along the shortest possible route along the structural element framework is from 4 to 13 atomic linkages, and the physiologically tolerated salts, prodrugs and 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 Ip A-E- Ip ® where A and E have the following meanings: A a structural element selected from the group: a 4- to 8-membered monocyclic saturated, unsaturated or aromatic hydrocarbon which may contain up to 4 heteroatoms selected from the group of 0, N or S, it being possible in each case, independently of one 40 another, for the ring nitrogen which is present where appropriate or the carbons to be substituted, with the proviso that at least one heteroatom selected from the group of O, N or S is present in the structural element A, 45 or
    0050/51042 a 9- to l4-membered polycyclic saturated, unsaturated or aromatic hydrocarbon which may contain up to 6 heteroatoms selected from the group of N, O or S, it being possible in each case, independently of one another, for the ring nitrogen which is present where appropriate or the carbons to be substituted, with the proviso that at least one heteroatom selected from the group of 0, N or S is present in the structural element A,
    a radical
    Z o of where Zal is oxygen, sulfur or optionally substituted nitrogen,
    and 2p? is optionally substituted nitrogen, oxygen or sulfur,
    or a radical
    8 ; 13 FN where ® Rpl8, Rpl9 are, independently of one another, hydrogen, a branched or unbranched, optionally substituted
    C;-Cg-alkyl, C;-Cg-alkenyl, C,-Cg-alkynyl, C;-Cs—alkylene-C;-Cs4-alkoxy, mono- and bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C;-cycloalkyl,
    40 C1-Cy-alkylene-C3~C;~-cycloalkyl, arylalkyl, C;-Cy-alkylene-heterocycloalkyl, C;-Cs-alkylene-heterocycloalkenyl or hetarylalkyl radical, or an -S0;-Rg%, -CO-ORg%, -CO-NRg4Rg%* or -CO-Rg4 radical,
    45 and
    0050/51042 E a spacer structural element which covalently connects structural element A to structural element G, where the number of atomic linkages along the shortest possible route along the structural element framework E is from 3 to 12.
    3. A compound as claimed in either of claims 1 or 2, wherein the structural element A used is a structural element selected from the group of structural elements of the formulae Ip! to Ipl9, Rp? Rp? Rp? X NN AR 1 2 3 1 Tn! Ra £1 Ta wt) Ta PN 15 N N N S oO 3 Rp 0 Rp3 PE 4 ~ He 5 A Ia Rp3 6 Sn y Noy Ia Rpé Rat Rp’ X 13 Ral3* ZEN Rp6* i a “ T » 9 A 7 ~ N Ia ( Yer II 1,8 2x N Ia J vo no 8 6 | Ra Rp Ry® Ral3* 0 Rp13 A Rpl13* Rp13* N RabX N | Rpl3 Ip10 11 N 12 I I [ Ne oP A | A P Rp® 9 R10 q Ra A r . Rpl0 da A 16 1x13 0 T,l4 J N Ip : HS TD SE Rpll R, 40 I. R, A 8 R, > Iat7 » ; 19 A = =~ Ipl8 iN Ia N N R N N H H
    AMENDED SHEET -@ 0050/51042 where m,p,q are, independently of one another, 1, 2 or 3,
    Ral, Rp? are, independently of one another, hydrogen, CN, halogen, a branched or unbranched, optionally substituted Ci-Cg-alkyl or CO-C;-Cg-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C3-Cy-cycloalkyl radical or a CO-0-Rpl4, 0-Rpl4, S-R,l4, NRalS5Ra16, CO-NRa15Rp16 or SO,;NRa15RA16 radical or the two radicals Ra! and Ra? together are a fused, optionally
    ® substituted, 5- or 6-membered, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up h to three heteroatoms selected from the group of O, N or Ss, Rpl3, Rpl13*
    are, independently of one another, hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-Cgs-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-Cy-cycloalkyl radical or a CO-O-Rpl4, O-Ral?, S-Ra14, NRLISR,!S, SO2-NRa15R,16 or
    CO-NRp15Rp16 radical, where Rpal% is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, alkylene-C,-C4q~alkoxy,
    ] C2-C¢-alkenyl, C,-Cg-alkynyl or Ci-C¢-alkylene-C3-C;-cycloalkyl radical or an optionally substituted C3-Cy-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
    Rpls, Ral6,
    are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C1-Cg-alkyl, CO-C3-Cg-alkyl, 50,-C,-Cg-alkyl,
    40 C00-Cy-Cg-alkyl, CO-NH-C;-Cg-alkyl, arylalkyl, COO-alkylene-aryl, SO,-alkylene-aryl, CO-NH-alkylene-aryl, CO-NH-alkylene-hetaryl or hetarylalkyl radical or an optionally substituted C3-C7~-cycloalkyl, aryl, CO-aryl, CO-NH-aryl,
    45 SO;-aryl, hetaryl, CO-NH-hetaryl, or CO-hetaryl radical,
    0050/51042
    Rp3r Rpt are, independently of one another, hydrogen, -(CHz)n=-(Xa)3-Ral?, or the two radicals together are a 3- to 8-membered, saturated, unsaturated or aromatic N heterocyclic system which may additionally contain two other, identical or different heteroatoms 0, N or S, it being possible for the cyclic system optionally to be substituted, or for another, optionally substituted, saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, where n is 0, 1, 2 or 3, ® 15 3 is 0 or 1, Xa is -CO-, -CO-N(Rxl)-, =-N(Ryxl)-CcO-, -N(Rx!)~CO-N(Rxl*)-, -N(Rx!)-CO-0-, -0-, -S-, -S0;-, -S0,-N(Rgl)-, -S80;-0-, -CO-0-, -0-CO-, -0-CO-N(Rgl)-, -N(Rx!)- or -N(Rx!)-SO,-, Ral? is hydrogen, a branched or unbranched, optionally substituted C;-Cg¢-alkyl radical, an optionally C1-Cy-alkyl- or aryl-substituted C;-Cg-alkynyl or C,-Cg-alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, or C3-Cy-cycloalkyl, aryl or heteroaryl radical, it ® being possible for two radicals together to be a fused, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and it being possible for the cyclic system optionally to be substituted or for another, optionally substituted, saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, or the Ral? radical forms together with Rx! or Ryxl* a saturated or 40 unsaturated C3-C;-heterocycle which may optionally contain up to two other heteroatoms selected from the group of 0, S or N, Ryl: Ryl* 45 are, independently of one another, hydrogen, a branched or unbranched, optionally substituted : C;-Cg¢-alkyl, C;-Cg-alkoxyalkyl, Cy-Cg-alkenyl,
    0050/51042
    C,-Cyy-alkynyl, CO-C;-Cg-alkyl, CO-0—C;-Cg-alkyl or S0,-C;-Cg-alkyl radical or an optionally substituted C;3-C;-cycloalkyl, aryl, arylalkyl, CO-0O-alkylene-aryl, CO-alkylene-aryl, CO-aryl, SOp-aryl, hetaryl, CO-hetaryl or SOj;-alkylene-aryl radical,
    Rp is a branched or unbranched, optionally substituted
    C1~Cg¢-alkyl, arylalkyl, C3-C7-cycloalkyl or
    C,-C4-alkylene-C3-Cy-cycloalkyl radical or an optionally substituted aryl, hetaryl, heterocycloalkyl or heterocycloalkenyl radical,
    Rab, Rp6* are hydrogen, a branched or unbranched, optionally ® substituted C;-C4-alkyl, -CO-0-C;-C4-alkyl, arylalkyl, -CO-0O-alkylene-aryl, -CO-0-allyl, -CO-C;-C4-alkyl, -CO-alkylene-aryl, C3-C;-cycloalkyl or -CO-allyl radical or the two radicals Rp® and Rpa6* in the structural element
    In’ together are an optionally substituted, saturated, unsaturated or aromatic heterocyclic system which, in addition to the ring nitrogen, may contain up to two other different or identical heteroatoms O, N, S,
    Ra’ is hydrogen, -OH, -CN, -CONH;, a branched or unbranched, optionally substituted C;-Cs-alkyl, C;-Cy-alkoxy, C3~-C7-cycloalkyl or -0-CO-C;-C4-alkyl radical or an optionally substituted arylalkyl, -O-alkylene-aryl, -0-CO-aryl, -0-CO-alkylene-aryl or -0-CO-allyl radical,
    or the two radicals Rp® and Rp’ together are an optionally
    [ substituted, unsaturated or aromatic heterocyclic system which, in addition to the ring nitrogen, may contain up to two other different or identical heteroatoms O, N, S,
    Rp8 is hydrogen, a branched or unbranched, optionally substituted C;-C4-alkyl, CO-C;-C4-alkyl, S0,-C;-Csz-alkyl or CO-0-C;-C4-alkyl radical or an optionally substituted aryl, CO-aryl, SOj-aryl, CO-O-aryl, CO-alkylene-aryl, SO,-alkylene-aryl, CO-O-alkylene-aryl or alkylene-aryl
    40 radical,
    Ra?, Ral? are, independently of one another, hydrogen, -CN, halogen, a branched or unbranched, optionally substituted
    45 C;~C¢-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-Cj-cycloalkyl radical or a CO-0-Rpl4, 0-Ral4, S-Ral4, NRalS5Rp16, S0O,-NRp15Rp16 or
    0050/51042 AMENDED SHEET -@ CO-NRpISR,a!6 radical, or the two radicals R,? and Ral? in the structural element I,l4 together are a 5- to 7-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, Rall is hydrogen, -CN, halogen, a branched or unbranched, optionally substituted C;-Cg-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-Cy-cycloalkyl radical or a CO-O-Rpl4, 0-Rpl4, S-R,l4, NRa15Rp16, SO,-NRp15Rp16 or CO-NRa15Ral6 radical, @® 15 Ral? is hydrogen or the two radicals Ra? and Rpl7 in the structural element X,16 together are a 5- to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, may contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or : different radicals, : Ral8, Ra19 are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C2-Cg-alkenyl, C-Cg~alkynyl-, Ci-Cs—alkylene- C1~C4-alkoxy, mono- and bisalkylaminoalkylene or : acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, ® 30 C3~Cy-cycloalkyl, Cj)~Csq-alkylene-C3-Cy-cycloalkyl, arylalkyl, C,-Cgq-alkylene-heterocycloalkyl, C1-C4-alkylene-heterocycloalkenyl or hetarylalkyl radical, or an -S0;-Rg%, -CO-ORg%, -CO-NRg%Rg%* or -CO-Rg4 radical, zl, 22, 23, 24 are, independently of one another, nitrogen, C-H, C-halogen or a branched or unbranched, optionally substituted C-C;-C4-alkyl or C-C;-Cs-alkoxy radical, 40 23 is NRp®, oxygen or sulfur.
    4. A compound as claimed in any one of claims 1 to 3, wherein the spacer structural element E is a structural element of the 45 formula Ig
    0050/51042
    -(NRg!); — E; — (Ug)n- Ig where Ug 1s oxygen, sulfur or NRg?, h is 0 or 1, i is 0 or 1,
    Rel, Rg? are, independently of one another, hydrogen, a branched or branched, optionally substituted C;-Cg-alkyl, C;-Cg—-alkoxyalkyl, C;-Cg-alkenyl, C,-Cip;-alkynyl, CO~Cy-Cg¢-alkyl, CO-0-—C;-Cg-alkyl, CO-NB—C;-Cg¢-alkoxyalkyl, ® CO-NH—C;-Cg-alkyl or S0,-C;-Cg-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C;-cycloalkyl, CO-O-alkylene-aryl, CO-NH-alkylene- aryl, CO-alkylene-aryl, CO—aryl, CO-NH-aryl, SO;-aryl, CO-hetaryl, SO,-alkylene-aryl, SO;-hetaryl or SO,-alkylene-hetaryl radical, E; is a structural element of the formula Ig; ~(CRg3Rg4)x1- (LE) k2- (CRESRE® ) k3~ (QE) ka- (CRE7RE®) k5- (TE) k6- (CRE®RE10) k7- Ik where k2, k4, k6 ® are 0 or 1, kl, k3, k5, k7 are 0, 1 or 2,
    Rg3, Rg4, Rg3, Rg®, Rg’, Rg8, Rg?, Rg!0 are, independently of one another, hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C;-Cg¢-alkyl, C,-Cg-alkenyl, C,-Cg¢-alkynyl or 40 alkylene—cycloalkyl radical, a -(CH;)x-(Yg)Rg!! radical, an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical or, independently of one another, in each case two radicals Rg? and Rg! or RgS and Rg® or Rg’ and Rg® or Rg? and Rgl? 45 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocyclic system
    0050/51042 which may contain up to three heteroatoms from the group of O, Nor §S, Xx is 0, 1, 2, 3 or 4,
    z is 0 or 1,
    Yg is -CO-, -CO-N(Ry2)-, -N(Ry2)-CO-, -N(Ry?)-CO-N(Ry?*)-, -N(Ry%)-C0-0-, -0-, -S-, -SOz-, -SO2-N(Ry?)-, -S02-0-,
    -C0-0-, -0-CO-, -0-CO-N(Ry2)-, -N(Ry?)- or -N(Ry?)-SOz-,
    Ry?- Ry2* are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl,
    ® 15 C,-Cg¢-alkenyl, C;-Cg-alkynyl, CO-C;-Cg¢-alkyl, CO-0—C;-Cg-alkyl or S0,-C;-Cg¢-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-Cy-cycloalkyl, CO-O-alkylene-aryl, CO-alkylene-aryl, CO-aryl, SOj;-aryl, CO-hetaryl or SO;-alkylene-aryl radical,
    Rgll is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C;-Cg¢-alkyl radical, an optionally substituted C3-C;-cycloalkyl, aryl, hetaryl or arylalkyl radical, an optionally C;—C4—alkyl- or aryl-substituted C;—Cg—alkynyl or C,—Ce—alkenyl radical, an optionally substituted Cg—Cj;,—bicycloalkyl, C;-Cg-alkylene-C¢—Ci—bicycloalkyl, C;—Cjo—tricycloalkyl or C;-Cg-alkylene-C;—Cyo—tricycloalkyl radical, or a 3- to
    8-membered, saturated or unsaturated heterocyclic system
    ] which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, it being possible for two radicals together to be a fused,
    saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and it being possible for the cyclic system optionally to be substituted or for another, optionally substituted,
    40 saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, or the Rgll radical forms together with Ry? or Ry?* a saturated or unsaturated C3-Cy-heterocyclic system which may optionally contain up to two other hetercatoms selected from the group of O, S
    45 or N,
    0050/51042 Lg, Tg are, independently of one another, CO, CO-NRgl2, NRg!2-CO, sulfur, SO, SO,, S0,-NRgl?, NRgl2-S0,, CS, CS-NRglZ2, NRgl2-Ccs, cs-0, 0O-CS, CO-0, 0O-CO, oxygen, ethynylene, CRg!3-0-CRgl4, C(=CRgl3Rgl4), CRgl3=CRgl¢, -CRg!3 (ORgl!5) -CHRg14-, -CHRg!3-CRgl4(ORgl5)-, Rel? is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C,-Cg-alkenyl, C,-Cg-alkynyl, an optionally substituted C3-C;-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a CO-Rglé, COORg!® or S0,-Rgl® radical, Rgl3, Rpl4 are, independently of one another, hydrogen, a hydroxyl 9 group, a branched or unbranched, optionally substituted C;-Ce¢-alkyl, C;-Cy-alkoxy, C;-Cg-alkenyl, Cy-Cg-alkynyl or alkylene—cycloalkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, Rgl5 is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C,-Cg-alkenyl, C,-Cg¢-alkynyl or alkylene—cycloalkyl radical or an optionally substituted C3-Cy-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, Rgl® is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C;-Cg-alkyl, C,-Cg-alkenyl, C,-Cg¢-alkynyl or C;-Cs—alkylene-C;-Cy-alkoxy radical, or ] an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-Cy-cycloalkyl-, C;-C4-alkylene-C3-C;-cycloalkyl, arylalkyl, C;-C4-alkylene-C3-Cyj-heterocycloalkyl, C;-C4-alkylene- C3-C;-heterocycloalkenyl or hetarylalkyl radical and Qg is an optionally substituted 4- to ll-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which may contain up to 6 double bonds and up to 6 identical or 40 different heteroatoms selected from the group N, O or §S, it being possible for the ring carbons or ring nitrogens optionally to be substituted.
    5. The use of the structural element of the formula Ig,
    0050/51042
    -G-L Ig for preparing compounds which bind to integrin receptors, where G and L have the following meanings: L a structural element of the formula I; -U-T I where T is a COOH group or a radical which can be hydrolyzed to COOH .and
    ® -U- is = (CRL'Rp?) a= (VL) b= (CRL3RL?) c= (WL) d= (CRLPRLS Je (XL) £= (CRL7RLE) g~ where a, ¢c, e, g are, independently of one another, 0, 1, 2 or 3, b, d, f are, independently of one another, 0 or 1,
    Ril, Rp?, Rp3, Rpé4, Rp5, Rib, Rp7, Ri8 are, independently of one another, hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C;-Cg-alkyl, C,-Cg-alkenyl, C,-Cg-alkynyl or C;-Cg-alkylene-C;3;-Cj-cycloalkyl [ radical, a radical -(CHy)w-(Yr)y-R.?, an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical or, in each case independently of one another, two radicals Ry! and Ry2 or Ry3 and Rp? or Ry® and Rpb or Rp’ and Rp® together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocyclic or heterocyclic system which may contain up to three heteroatoms from the group of O, N or S, 40 \ is 0, 1, 2, 3 or 4, yY is 0 or 1
    0050/51042
    Y;, is -CO-, -CO-N(Ryl)-, =N(Ryl)-CO-, ~N(Ry!)-CO-N(Ryl*)-, -N(Ry!)-CO-0-, -0-, -S-, -SO,-, ~S02-N(Ry!)-, -50,-0-, -CO-0-, ~0-CO-, -0-CO-N(Ryl)-, ~N(Ry!)- or -N(Ry!)-SO,-, '
    Ryl/ Ryl* are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C,-Cg-alkyl, C;-Cg-alkoxyalkyl, C,-Cg-alkenyl, C3-C;;-alkynyl, CO-C;-Cg-alkyl, CO-0—C;-Cg-alkyl or S0;-C;-Cg-alkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, CO-0O-alkylene-aryl, CO-alkylene-aryl, CO-aryl, SOz-aryl, hetaryl, CO-hetaryl or SOj;-alkylene-aryl ® 15 radical, Ry? is hydrogen, or a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C;-Cg¢-alkyl radical, an optionally substituted C;3;-C;-cycloalkyl, aryl, heteroaryl or arylalkyl radical, an optionally C;-Cy-alkyl- or aryl-substituted C;—Cg¢—alkynyl or C,—Cg¢—alkenyl radical, an optionally substituted Cg—C12-bicycloalkyl, C;-Cg-alkylene-C¢—C;,—bicyclo- alkyl, C;—Cjo—tricycloalkyl or C;-Cg-alkylene-C7—Cyo—tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, it ] being possible for two radicals together to be a fused, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms 0, N, S, and it being possible for the cyclic system to be optionally substituted, or for another, optionally substituted, saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, or the radical Rj? forms together with Ry! or Ryl* a saturated or 40 unsaturated C3;-C;-heterocycle which may optionally contain up to two further heteroatoms selected from the group of 0, S or N,
    0050/51042
    Wr, 1s an optionally substituted 4- to 1ll-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which may contain up to 6 double bonds and up to 6 hetercatoms selected from the group of N, O, §S,
    Vy, Xr, are, independently of one another, -CO-, -CO-NR!0-, -NR;10-CcO-, -S-, -S50-, -SO0;-, -S0,-NR;l0-, -NR;10-50,-, -CS-, -CS-NRp10-, -NR;!0-CS-, -CS-0-, -0-CS-, -CO-O-,
    -0-CO-, -0-, ethynylene, -CHRy!1-O-CHR;l2-, -C(=CRyl1Ry12)-, -CRp,11=CRy,12-, -CRp11(ORy13)-CHRy 12, ~-CHRp,!1-CR12(ORy13)-, -CH(NRp14-S0,-R;15)-, -CH(NRy14-CO-Ry15)-, -CH(NRy14-CO-ORy!6)-, CH(NRy14-CO-NRy14'R;15)-, -CH(CO-Ryl5)-, -CH(CO-OR;!6)-
    Pe 15 or CH(CO-NRpl4Rpl15)-,
    Ry 10 is hydrogen, a branched or unbranched, optionally substituted C;-C¢-alkyl, C;-Cg¢-alkoxyalkyl, Cy-Cg- alkenyl, C3-Cjy-alkynyl, CO-C;-Cg¢-alkyl,
    CO0-0-C;-Cg¢-alkyl or SO,-C;-Cg-alkyl radical or an optionally substituted C3-C;-cycloalkyl, CO-0O-alkylene-aryl, CO-alkylene-aryl, arylalkyl, Co-aryl, SO,-aryl, hetaryl, CO-hetaryl, hetarylalkyl or SO;-alkylene-aryl radical, or Ryl? and a radical selected from the group of Rpl, Rp?, Ri3, Rp, R.5, RS, Rn? or Rp 8 together are an optionally substituted 4- to 8-membered heterocycle which may contain up to five identical or different heteroatoms O, N or §,
    Rplls R12
    ® are, independently of one another, hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C;-Cg-alkyl, C;-Cy-alkoxy, C,-Cg-alkenyl, C,-Cg-alkynyl or alkylene—cycloalkyl radical or an optionally substituted C3-Cy-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
    Rp13 is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C,-Cg-alkenyl, C,-Cg-alkynyl
    40 or alkylene—cycloalkyl radical or an optionally substituted C3-Cj-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
    R;14, Rpl4”
    45 are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C;-C¢-alkyl, C;-Cg-alkoxyalkyl, C,-Cg-alkenyl,
    0050/51042
    C3-Cjy-alkynyl, CO-C;-Cg¢-alkyl, CO-0-Ci-Cg¢-alkyl, C;-Cg¢-alkylene-C3-Cy-cycloalkyl, or S0,~C;-Cg¢-alkyl radical or an optionally substituted C3-Cy-cycloalkyl, CO-0O-alkylene-aryl,
    CO-alkylene-aryl, aryl, CO-aryl, SOj;-aryl, hetaryl, CO-hetaryl, hetarylalkyl, arylalkyl or SOj-alkylene-aryl radical,
    Rpl15 is a branched or unbranched, optionally substituted C;-Cg-alkyl, alkoxyalkyl, C;-Cg¢-alkylene-C3-C;-cyclo- alkyl radical, Cg—C;r—bicycloalkyl, C1-Cg-alkylene-C¢—C;—bicycloalkyl, C7—Cyo—tricycloalkyl or C;-Cg¢-alkylene-Cy—Cyo—tricycloalkyl radical, a C3-Cy-cycloalkyl, aryl, arylalkyl, hetarylalkyl or 3-— ® to 8-membered, saturated, unsaturated or aromatic heterocyclic radical which may be substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms 0, N, S, it being possible for two radicals together to be a fused, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and it being possible for this cyclic system to be optionally substituted, or for another, optionally substituted, saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, or the radical Ryl> forms together with Rp l4 or Rp l4* a saturated or unsaturated C3-C7 heterocycle which may optionally contain up to ® two further heteroatoms selected from the group of O, S or N, and Rpl1® is a branched or unbranched, optionally substituted C1-Cg-alkyl, alkoxyalkyl or C;-Cg-alkylene-C3-Cy-cycloalkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, 40 G 1s a structural element of the formula Ig Zc wot 45 Te, Ic RG,
    0050/51042 where the structural element G can be incorporated in both orientations, and
    Zc is oxygen, sulfur or NRg3, Rg!’ Rg? are, independently of one another, hydrogen, CN, NO,
    halogen, a branched or unbranched, optionally substituted C;-C¢-alkyl, C;-Cg¢-alkenyl or C,-Cg-alkynyl radical, a branched or unbranched, optionally substituted C;-C4-alkylene-ORg%, C;-Cg-alkylene-CO-ORg4, C1-Cg-alkylene-CO-Rg4, Ci;-Cz-alkylene-S0;-NRgSRgE,
    C;-Cy4-alkylene-CO-NRg5Rg®, C;-Cy-alkylene-NRgRg® or
    ® C;-Cy-alkylene-SRg? radical, an optionally substituted C3-Cy-cycloalkyl, C;-Cy-alkylene-C3-C;-cycloalkyl, Ci1-C4-alkylene-C3-Cy;-heterocycloalkyl or C1-C4-alkylene-C;3-Cy-heterocycloalkenyl radical, an optionally substituted aryl, arylalkyl, hetaryl or hetarylalkyl radical, an -S-Rg4, -0-Rg?, -SO-Rgi, -S50,-Rg!, -CO-ORg4, -0-CO-Rg4, -0-CO-NRgGS5Rg6, -SO0,-NRGSRgS, -CO-NRG5Rg6, -NRGSRg6, CO-Rg? radical, or Rgl and Rg2 together are an optionally substituted, saturated,
    unsaturated or aromatic 3- to 9-membered carbocyclic, polycarbocyclic, heterocyclic or polyheterocyclic system which may contain up to 4 heteroatoms selected from the group of 0, N, S,
    Rg is hydrogen, a hydroxyl group, CN, a branched or
    ® unbranched, optionally substituted C;—Cg—alkyl or C;-C4-alkoxy radical or an optionally substituted C3-Cy~cycloalkyl, —0—C3-Cy-cycloalkyl radical, aryl, —O-aryl, arylalkyl or —O-alkylene—aryl radical,
    Rg! is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C,-C¢-alkenyl, C,-Cg¢-alkynyl, Ci1-Cs—alkylene-C;-C4-alkoxy, mono- and bisalkylaminoalkylene or acylaminoalkylene radical or an
    40 optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C;-cycloalkyl, Ci-C4-alkylene-C;3-Cy-cycloalkyl, arylalkyl, C1-Cs-alkylene-heterocycloalkyl, C;-Cy-alkylene- heterocycloalkenyl or hetarylalkyl radical,
    0050/51042 AMENDED SHEET ® 290 Rg3, Rg" are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C;~Cg-alkyl, C;-C¢-alkenyl, C;-Cg-alkynyl, C)-Cs—alkylene-C;~Cy4~ alkoxy, mono- and bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-Cy-cycloalkyl, C1-C4-alkylene-C3-Cy-cycloalkyl, arylalkyl, C1-C4-alkylene-heterocycloalkyl, C1-C4-alkylene-heterocycloalkenyl or hetarylalkyl radical, or an -SO;-Rg4, -CO-ORg%, -CO-NRg!Rg%* or ~CO-Rg4 radical, and Rgi* is an R.* radical independent of R.*. ® 15
    6. A drug comprising the structural element of the formula Ic -G-L Ic where G and L have the following meanings: L is a structural element of the formula Ig : -U-T I; where : T is a COOH group or a radical which can be hydrolyzed to COOH and @ 30 -U- is =(CRLIRL2) a= (VL) b= (CRLIRL?) e- (WL) a= (CRLSRLS ) e- (X1) £= (CRLTRL 8) o- where a, Cc, e, g are, independently of one another, 0, 1, 2 or 3, b, d, £ are, independently of one another, 0 or 1, 40 Rpl, RpZ, Rp 3, Rp4, Ry’, Rp5, Ry 7, Ry 8 are, independently of one another, hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C,;-Cg-alkyl, Cz2-Cg-alkenyl, 45 C2-Cs-alkynyl or C;-Cg¢-alkylene-C3-C;-cycloalkyl radical, a radical -(CH2)w=(YL)y-Ry%, an optionally substituted C3;-C;-cycloalkyl, aryl, arylalkyl,
    0050/51042 hetaryl or hetarylalkyl radical or, in each case independently of one another, two radicals Rp! and Rp? or Ri? and Rp? or Rp3 and Rif or Ry? and R.® together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocyclic or heterocyclic system which may contain up to three heteroatoms from the group of O, N or S, Ww is 0, 1, 2, 3 or 4,
    y is 0 or 1 Y, is -CO-, -CO-N(Ryl)-, -N(Ry!)-CO-, -N(Ry!)-CO-N(Ryl*)-, -N(Ry!)-CO-0-, -O-, -S-, -SO,-, -S0,-N(Ry!)-, -S0,-0-, -CO-0-, -0-CO-, -0O-CO-N(Ryl)-, ® -N(Ryl!)- or -N(Ryl)-S0,-, Ryl: Ryl* are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C1-C¢-alkyl, C;-Cg-alkoxyalkyl, C,-Cg-alkenyl, C3-Cjy-alkynyl, CO-C;-Cg-alkyl, CO-0—C;-Cg-alkyl or S0;-C;-Cg¢-alkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl,
    CO-0O-alkylene-aryl, CO-alkylene-aryl, CO-aryl, SO;~-aryl, hetaryl, CO-hetaryl or SO;-alkylene-aryl radical,
    Ry? is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted
    ® C1-Ce¢-alkyl radical, an optionally substituted C3-Cy-cycloalkyl, aryl, heteroaryl or arylalkyl radical, an optionally C;-Cs-alkyl- or aryl-substituted C;—Cg¢—alkynyl or C,—Cg—alkenyl radical, an optionally substituted Ce—Ci1-bicycloalkyl, C;-Cg-alkylene-Cg—C;r—bicyclo- alkyl, C;—Cyo—tricycloalkyl or C;-Cg¢-alkylene-C7—Cyp—tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocyclic
    40 system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms 0, N, S, it being possible for two radicals together to be a fused, saturated, unsaturated or aromatic carbocyclic
    45 or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and it being possible for the cyclic system to be optionally
    0050/51042 substituted, or for another, optionally substituted, saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, or the radical Rp? forms together with Ry! or Ryl* a saturated or unsaturated C3;-Cy-heterocycle which may optionally contain up to two further heteroatoms selected from the group of 0, S or N,
    Wy, is an optionally substituted 4- to ll-membered mono-
    or polycyclic aliphatic or aromatic hydrocarbon which may contain up to 6 double bonds and up to 6 heteroatoms selected from the group of N, O, S,
    Vi, Xr, are, independently of one another, -CO-, -CO-NRpl0-, ® ~-NR;10-CO-, -S-, -SO-, -S0,-, -SO,-NR;10-, -NR;l10-50,-, -CS-, -CS~NRy10-, -NRy10-CcS-, -CS-0-, -0-CS-, -CO-0O-, -0-CO-, -0-, ethynylene, -CHRp!!-0-CHRp!2-, -C(=CRp!1R;12)-, -CRp11=CR; 12, -CRp11(OR;,13)-CHR;12~,
    -CHR;11-CR}2(ORy13)-, -CH(NRy14-S0,-Ry15)-, -CH(NR14-CO-Ry,15)-, -CH(NRp14-CO-ORy16)-, CH(NRp14-CO-NR14'Ry15)~, -CH(CO-Ryl5)~, -CH(CO-ORyl6)- or CH(CO-NRpl4R;l5)-,
    Rp? is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C;-Cg-alkoxyalkyl, Co-Cg- alkenyl, C3-C;,-alkynyl, CO-C;-Cg-alkyl, CO0-0—C;-Cg-alkyl or S0O;-C;-Cg¢-alkyl radical or an optionally substituted C3-C;-cycloalkyl,
    CO-0O-alkylene-aryl, CO-alkylene-aryl, arylalkyl-,
    ® CO-aryl, SO;-aryl, hetaryl, CO-hetaryl, hetarylalkyl or SO;-alkylene-aryl radical, or Rpl!? and a radical selected from the group of Rpl, R;2, Ry3, Rp4, Ry>, Ry6, Rp’? or Ry® together are an optionally substituted 4-
    to 8-membered heterocycle which may contain up to five identical or different heteroatoms O, N or S,
    Rplls Rpl2 are, independently of one another, hydrogen, a
    40 hydroxyl group, a branched or unbranched, optionally substituted C;-Cg¢-alkyl, C;-Cy-alkoxy, C,-Cg¢-alkenyl, C,-Cg-alkynyl or alkylene—cycloalkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
    0050/51042
    Rp!3 is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C,-Cg¢-alkenyl, C,-Cg-alkynyl or alkylene—cycloalkyl radical or an optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, Rp14, Rp14’ are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C1~Cg-alkyl, C;-Cg-alkoxyalkyl, Cp-Cg-alkenyl, C3~Cqp-alkynyl, CO-C;-Cg-alkyl, CO-0-C;-Cg-alkyl, C;~-Cg-alkylene-C3-C;-cycloalkyl, or SO,-C;-Cg-alkyl radical or an optionally substituted C3~Cy-cycloalkyl, CO-O-alkylene-aryl, ® 15 CO-alkylene-aryl, aryl, CO-aryl, SO,-aryl, hetaryl, CO-hetaryl, hetarylalkyl, arylalkyl or SO;-alkylene-aryl radical, Ry15 is a branched or unbranched, optionally substituted C;~-Cg-alkyl, alkoxyalkyl, C;-Cg-alkylene-C3-C;-cyclo- alkyl radical, Cg¢—Ciz-bicycloalkyl, C;~Cg¢-alkylene-C¢—Cjiy—bicycloalkyl, C7—Cyp—tricycloalkyl or C;~Cg-alkylene-C;—Cjo—tricycloalkyl radical, a C3-C;-cycloalkyl, aryl, arylalkyl, hetarylalkyl or 3— to 8-membered, saturated, unsaturated or aromatic heterocyclic radical which may be substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, it being possible for two ® radicals together to be a fused, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and it being possible for this cyclic system to be optionally substituted, or for another, optionally substituted, saturated, unsaturated or aromatic cyclic system to be fused to this cyclic system, or the radical Ryl5 forms together with Rpl4 or Rpl4* a saturated or unsaturated 40 C3~-C,7 heterocycle which may optionally contain up to two further heteroatoms selected from the group of O, S or N, and R16 is a branched or unbranched, optionally substituted 45 C;-Cg¢-alkyl, alkoxyalkyl or C;-Cg¢-alkylene-C3-Cj-cycloalkyl radical or an
    0050/51042 optionally substituted C3-C;-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, G is a structural element of the formula Ig
    Za a teh, Ig RG, where the structural element G can be incorporated in both PY 15 orientations, and Ze is oxygen, sulfur or NRg3, Rg! Rg?
    are, independently of one another, hydrogen, CN, NO, halogen, a branched or unbranched, optionally substituted C;~-Cg-alkyl, C,;-Cg-alkenyl or Cy-Cg-alkynyl radical, a branched or unbranched, optionally substituted C;~Cy-alkylene-ORg4, C1-Cs-alkylene-CO-ORg4,
    C;-Cy4-alkylene-CO-Rg%, C;-Cy-alkylene-SO,-NRgRgb, C;-C4-alkylene-CO-NRg°Rgb, C;-Cs-alkylene-NRg5Rgé or C;-Cgq-alkylene-SRg* radical, an optionally substituted C3-Cq7-cycloalkyl, C;-Cs4-alkylene-C3-C,;-cycloalkyl, C;-C4-alkylene-C3-Cy-heterocycloalkyl or
    C;-C4-alkylene-C3-Cy;-heterocycloalkenyl radical, an
    ® optionally substituted aryl, arylalkyl, hetaryl or hetarylalkyl radical, an -S-Rg?, -0-Rg?, -SO-Rg%, -S0,-Rg4, -CO-ORg?, -0-CO-Rg?, -0-CO-NRGSRgf, -SO,-NRgSRg6, ~CO-NRgSRg6, -NRg°Rg6, CO-Rg? radical, or Rg! and Rg?
    together are an optionally substituted, saturated, unsaturated or aromatic 3- to 9-membered carbocyclic, polycarbocyclic, heterocyclic or polyheterocyclic system which may contain up to 4 heteroatoms selected from the group of O, N, S,
    40
    Rg3 is hydrogen, a hydroxyl group, CN, a branched or unbranched, optionally substituted C;—Cg—alkyl or C1-C4-alkoxy radical or an optionally substituted C;3;-C;-cycloalkyl, —0-C3-C;-cycloalkyl radical, aryl—,
    45 —O-aryl, arylalkyl or —O-alkylene—aryl radical,
    AMENDED SHEET 0050/51042 -@ 295 Rg? is hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, C,-Cg-alkenyl, C2-Cg-alkynyl, C1-Cs—alkylene-C;-Cz-alkoxy-, mono- and bisalkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-Cy~-cycloalkyl, C1-C4-alkylene-C3~Cy~-cycloalkyl, arylalkyl, Ci1~C4-alkylene-heterocycloalkyl, C;-Cs-alkylene- heterocycloalkenyl or hetarylalkyl radical, Re%, RgS are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C;-Cg-alkyl, ® C2-Cg-alkenyl, C-Cg-alkynyl, C)-Cs—alkylene-C;~-C4~ 1s alkoxy, mono- and bisalkylaminoalkylene ox acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C;-cycloalkyl, C,-C4-alkylene-C3-C;~-cycloalkyl, arylalkyl, C1~Cs~-alkylene-heterocycloalkyl, C1-C4-alkylene-heterocycloalkenyl or hetarylalkyl radical, or an -S02-Rg?, -CO-ORg?, -CO-NRg%Rgi* or ~CO-Rg4 radical, and Rg4* is an R.* radical independent of Rg‘.
    7. A ‘pharmaceutical preparation comprising at least one compound as claimed in any one of claims 1 to 4 in addition to conventional pharmaceutical excipients. @ 30 8. The use of the compounds as claimed in any one of claims 1 to 4 for producing drugs for the treatment of diseases.
    9. The use of the compounds as claimed in any one of claims 1 to 4 as integrin receptor ligands.
    10. The use as claimed in claim 9 of the compounds as claimed in any of claims 1 to 4 as ligands of the ayf3 integrin receptor.
    11. The use as claimed in claim 8 of the compounds as claimed in 40 any one of claims 1 to 4 for producing drugs for the treatment of diseases in which the interaction between integrins and their natural ligands is increased or decreased.
    AMENDED SHEET 0050/51042 -@ 296
    12. The use as claimed in claim 11 of compounds as claimed in any one of claims 1 to 4 for the treatment of diseases in which the interaction between ayfi3 integrin and its natural ligand is increased or decreased.
    13. The use as claimed in claim 12 of compounds as claimed in any one of claims 1 to 4 for the treatment of atherosclerosis, rheumatoid arthritis, restenosis after vessel injury or stent implantation, angioplasty, acute kidney failure, : angiogenesis-associated microangiopathies, diabetic angiopathies, vascular occlusion mediated by blood platelets, arterial thrombosis, congestive heart failure, myocardial infarct, stroke, cancer, osteoporosis, high blood pressure, ® psoriasis or viral, parasitic or bacterial diseases, inflammations, wound healing, hyperparathyroidism, Paget's disease, malignant hypercalcemia or metastatic osteolytic lesions.
    14. A pharmaceutical preparation comprising at least one compound as claimed in any one of claims 1 to 4, where appropriate pharmaceutical excipients and at least one other compound selected from the group of inhibitors of blood platelet adhesion, activation or aggregation, anticoagulants which impede thrombin activity or formation, antagonists of blood platelet-activating compounds, or selectin antagonists.
    15. The use of the pharmaceutical preparation as claimed in @® 30 claim 14 for producing a drug for the treatment of vascular occlusion mediated by blood platelets or thrombosis.
    16. A pharmaceutical preparation comprising at least one compound as claimed in any one of claims 1 to 4, where appropriate pharmaceutical excipients and at least one other compound selected from the group of inhibitors of blood platelet activation or aggregation, serine protease inhibitors, fibrinogen-reducing compounds, 40 selectin antagonists, antagonists of ICAM-1 or VCAM-1 inhibitors of leukocyte adhesion inhibitors of vessel wall transmigration, fibrinolysis-modulating compounds, 45 inhibitors of complement factors, endothelin receptor antagonists, tyrosine kinase inhibitors,
    AMENDED SHEET 0050/51042 : -@ 297 antioxidants or interleukin 8 antagonists.
    17. The use of the pharmaceutical preparation as claimed in claim 16 for producing a drug for the treatment of myocardial infarct or stroke.
    18. A pharmaceutical preparation comprising at least one compound as claimed in any one of claims 1 to 4, where appropriate pharmaceutical excipients and at least one other compound selected from the group of endothelin antagonists, ACE inhibitors, ® angiotensin receptor antagonists, endopeptidase inhibitors, beta blockers, calcium channel blockers, phosphodiesterase inhibitors or caspase inhibitors.
    19. The use of the pharmaceutical preparation as claimed in claim 18 for producing a drug for the treatment of congestive heart failure.
    20. A pharmaceutical preparation comprising at least one compound as claimed in any one of claims 1 to 4, where appropriate pharmaceutical excipients and at least one other compound selected from the group of thrombin inhibitors, C 30 inhibitors of factor Xa, inhibitors of the coagulation pathway leading to thrombin formation, inhibitors of blood platelet adhesion, activation or aggregation, endothelin receptor antagonists, nitric oxide synthase inhibitors, CD44 antagonists, selectin antagonists, MCP-1 antagonists, 40 inhibitors of signal transduction in proliferating cells, antagonists of the cellular response mediated by EGF, PDGF, VEGF or bFGF or antioxidants. .
    AMENDED SHEET 0050/51042 “¢@ 298
    21. The use of the Pharmaceutical preparation as claimed in claim 20 for producing a drug for the treatment of restenosis after vessel injury or stent implantation.
    22. A pharmaceutical Preparation comprising at least one compound as claimed in any one of claims 1 to 4, where appropriate Pharmaceutical excipients and at least one other compound selected from the group of antagonists of the cellular response mediated by EGF, PDGF, VEGF or bFGF, heparin or low molecular weight heparins or other GaGs, inhibitors of MMPs, selectin antagonists, endothelin antagonists, ® 15 ACE inhibitors, angiotensin receptor antagonists, glycosylation inhibitors or AGE formation inhibitors or AGE breakers and antagonists of their receptors.
    23. The use of the pharmaceutical preparation as claimed in claim 22 for producing a drug for the treatment of diabetic angiopathies.
    24. A pharmaceutical preparation comprising at least one compound as claimed in any one of claims 1 to 4, where appropriate pharmaceutical excipients and at least one other compound selected from the group of lipid-lowering compounds, ® 30 selectin antagonists, antagonists of ICAM-1 or VCAM-1 heparin or low molecular weight heparins or other GAGs, inhibitors of MMPs, endothelin antagonists, apolipoprotein Al antagonists, cholesterol antagonists, HMG-CoA reductase inhibitors, ACAT inhibitors, ACE inhibitors, 40 angiotensin receptor antagonists, tyrosine kinase inhibitors, protein kinase C inhibitors, calcium channel blockers, LDL receptor function stimulants, 45 antioxidants
    AMENDED SHEET 0050/51042 -@ 299 LCAT mimetics or free radical scavengers.
    25. The use of the pharmaceutical preparation as claimed in claim 24 for producing a drug for the treatment of atherosclerosis.
    26. A pharmaceutical preparation comprising at least one compound as claimed in any one of claims 1 to 4, where appropriate Pharmaceutical excipients and at least one other compound selected from the group of cytostatic or antineoplastic compounds, compounds which inhibit proliferation or ’ ® heparin or low molecular weight heparins or other GAGs.
    27. The use of the pharmaceutical preparation as claimed in ’ claim 26 for producing a drug for the treatment of cancer.
    28. A pharmaceutical preparation comprising at least one compound as claimed in any one of claims 1 to 4, where appropriate pharmaceutical excipients and at least one other compound selected from the group of compounds for antiresorptive therapy, compounds for hormone replacement therapy, recombinant human growth hormone, bisphosphonates, compounds for calcitonin therapy, calcitonin stimulants, calcium channel blockers, [ 30 bone formation stimulants, ~ interleukin-6 antagonists or Src tyrosine kinase inhibitors.
    29. The use of the pharmaceutical preparation as claimed in claim 28 for producing a drug for the treatment of osteoporosis.
    30. A pharmaceutical preparation comprising at least one compound as claimed in any one of claims 1 to 4, where appropriate 40 pharmaceutical excipients and at least one other compound selected from the group of TNF antagonists, antagonists of VLA-4 or VCAM-1, antagonists of LFA-1, Mac-1 or ICAMs, 45 complement inhibitors, immunosuppressants, interleukin-1, -5 or -8 antagonists or
    AMENDED SHEET 0050/51042 ® 300 dihydrofolate reductase inhibitors.
    31. The use of the pharmaceutical preparation as claimed in claim 30 for producing a drug for the treatment of rheumatoid arthritis.
    32. a pharmaceutical preparation comprising at least one compound as claimed in any one of claims 1 to 4, where appropriate pharmaceutical excipients and at least one other compound selected from the group of : collagenase, PDGF antagonists or MMPs.
    33. The use of the pharmaceutical preparation as claimed in claim 32 for producing a drug for improving wound healing.
    34. A compound of the formula I as claimed in any one of claims 1 to 4, substantially as hereinbefore described and exemplified.
    35. A compound of the formula I including any new and inventive integer or combination of integers, substantially as herein described.
    35. The use of the structural element of the formula IGL as claimed in claim 5, substantially as hereinbefore described and exemplified.
    37. The use of the structural element of the formula IGL ® 30 including any new and inventive integer or combination of integers, substantially as herein described.
    38. A drug as claimed in claim 6, substantially as hereinbefore described and exemplified.
    39. A drug including any new and inventive integer or combination of integers, substantially as herein described.
    40. A pharmaceutical preparation as claimed in any one of claims 40 7, 14, 16, 18, 20, 22, 24, 26, 28 and 30, substantially as hereinbefore described and exemplified.
    41. A pharmaceutical preparation including any new and inventive integer or combination of integers, substantially as herein 45 described.
    al 0050/51042 AMENDED SHEET '‘@ 301
    42. The use of the compound of the formula I as claimed in any one of claims 9 to 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33, substantially as hereinbefore described and exemplified.
    43. The use of the compound of the formula I including any new and inventive integer or combination of integers, substantially as herein described.
    44. A compound of the formula I or pharmaceutical preparation comprising thereof as claimed in any one of claims 1 to 4, 7, 14, 16, 18, 20, 22, 24, 26, 28, 30, 34, 35, 41 and 42 whenever supplied with instructions for the use thereof in treating diseases.
    45. A compound of the formula I or pharmaceutical preparation comprising thereof as claimed in claim 44 when the instructions are in printed or written form.
    46. A compound of the formula I or pharmaceutical preparation comprising thereof as claimed in claim 45 supplied in a package or container having the said instructions provided therein or thereon.
ZA200108035A 1999-04-13 2001-10-01 Integrin receptor ligands. ZA200108035B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19916719A DE19916719A1 (en) 1999-04-13 1999-04-13 New ECE inhibitors, their production and use

Publications (1)

Publication Number Publication Date
ZA200108035B true ZA200108035B (en) 2002-10-21

Family

ID=7904453

Family Applications (1)

Application Number Title Priority Date Filing Date
ZA200108035A ZA200108035B (en) 1999-04-13 2001-10-01 Integrin receptor ligands.

Country Status (7)

Country Link
EP (1) EP1165554A1 (en)
JP (1) JP2002541256A (en)
CN (1) CN1350533A (en)
DE (1) DE19916719A1 (en)
HK (1) HK1045688A1 (en)
WO (1) WO2000061579A1 (en)
ZA (1) ZA200108035B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103804312B (en) * 2014-02-17 2016-04-20 四川百利药业有限责任公司 Aza cyclic cpds and its production and use

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2086544C1 (en) * 1991-06-13 1997-08-10 Хоффманн-Ля Рош АГ Benzenesulfonamide derivatives of pyrimidine or their salts, pharmaceutical composition for treatment of diseases associated with endothelin activity
US5658902A (en) * 1994-12-22 1997-08-19 Warner-Lambert Company Quinazolines as inhibitors of endothelin converting enzyme
US5891892A (en) * 1996-10-29 1999-04-06 Warner-Lambert Company Small molecule biaryl compounds as inhibitors of endothelin converting enzyme

Also Published As

Publication number Publication date
JP2002541256A (en) 2002-12-03
CN1350533A (en) 2002-05-22
WO2000061579A1 (en) 2000-10-19
DE19916719A1 (en) 2000-10-19
HK1045688A1 (en) 2002-12-06
EP1165554A1 (en) 2002-01-02

Similar Documents

Publication Publication Date Title
JP5221147B2 (en) Compounds used for inflammation and immunity related applications
JP2020122015A (en) Combination therapy
CN109475537A (en) The method for treating liver fibrosis
ES2393188T3 (en) Heterocyclic compounds that bind to chemokine receptors and have improved efficacy
TW200838560A (en) Cyclodextrin-based polymers for therapeutics delivery
US20100048536A1 (en) Novel Substituted Diaryl Azepine Derivatives as Integrin Ligands
CN101365435A (en) Combination of organic compounds
CA2368049A1 (en) Integrin receptor ligands
CN110267660A (en) The inhibitor of domain protein containing Bu Luomo 4 (BRD4)
US20090048292A1 (en) Synergistic combination
JP5681227B2 (en) Therapeutic agents and pharmaceutical compositions containing methylphenidate derivatives
JP2013237709A (en) Drug for treatment of allergic rhinitis comprising pgd2 antagonist and histamine antagonist
EP1202988A2 (en) Novel integrin receptor antagonists
ZA200108035B (en) Integrin receptor ligands.
WO2002068410A1 (en) Substituted pyrimidinone derivatives as ligands of integrin receptors
WO2002051810A2 (en) Integrin receptor ligands
WO2000066618A1 (en) Integrin receptor antagonists
WO2003066624A1 (en) Pyrimidinonesulfamoylureas as integrin ligands
EP1286673A2 (en) Ligands of integrin receptors
ZA200108555B (en) Integrin receptor antagonists.
JP2004506637A (en) Novel substituted diarylazepine derivatives as integrin ligands
RU2021117507A (en) PHARMACEUTICAL COMPOSITIONS OF ACOTHIAMIDE AND PROTON PUMP INHIBITOR
DE19962998A1 (en) New integrin receptor ligands, especially integrin-alphavbeta3 ligands, useful for treating e.g. atherosclerosis, rheumatoid arthritis, restenosis, angioplasty and acute kidney failure
DE19948269A1 (en) New compounds as integrin antagonists useful for treating e.g. cardiovascular disorders, rheumatoid arthritis, kidney failure, stroke, cancer, osteoporosis, psoriasis or infection