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WO1997033887A1 - Inhibiteurs de l'integrine spirocycle - Google Patents

Inhibiteurs de l'integrine spirocycle Download PDF

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Publication number
WO1997033887A1
WO1997033887A1 PCT/US1997/004567 US9704567W WO9733887A1 WO 1997033887 A1 WO1997033887 A1 WO 1997033887A1 US 9704567 W US9704567 W US 9704567W WO 9733887 A1 WO9733887 A1 WO 9733887A1
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WIPO (PCT)
Prior art keywords
alkyl
aryl
oxa
carbonylamino
propionic acid
Prior art date
Application number
PCT/US1997/004567
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English (en)
Inventor
Prabhakar Kondaji Jadhav
Joanne Marie Smallheer
Original Assignee
Du Pont Pharmaceuticals Company
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
Priority claimed from US08/816,580 external-priority patent/US5760029A/en
Application filed by Du Pont Pharmaceuticals Company filed Critical Du Pont Pharmaceuticals Company
Priority to EP97919892A priority Critical patent/EP0888344A1/fr
Priority to JP53292497A priority patent/JP2001527513A/ja
Priority to AU24217/97A priority patent/AU2421797A/en
Publication of WO1997033887A1 publication Critical patent/WO1997033887A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to novel heterocycles which are useful as antagonists of the ⁇ v ⁇ 3 integrin and related cell surface adhesive protein receptors, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of cell adhesion, the treatment of angiogenic disorders,
  • inflammation bone degradation, cancer metastasis, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
  • Angiogenesis or neovascularization is critical for normal physiological processes such as embryonic development and wound repair (Folkman and Shing, J.
  • angiogenesis also occurs pathologically, for example, in ocular neovascularization (leading to diabetic).
  • retinopathy retinopathy, neovascular glaucoma, retinal vein
  • Tumor dissemination, or metastasis involves several distinct and complementary components, including the penetration and transversion of tumor cells through basement membranes and the establishment of self- sustaining tumor foci in diverse organ systems. To this end, the development and proliferation of new blood vessels, or angiogenesis, is critical to tumor survival. Without neovascularization, tumor cells lack the
  • Integrin ⁇ v ⁇ 3 is preferentially expressed on angiogenic blood vessels in chick and man (Brooks et al., Science, 1994, 264:569-571; Enenstein and Kramer, J. Invest. Derrnatol., 1994, 103:381-386). Integrin ⁇ v ⁇ 3 is the most promiscuous member of the integrin family, allowing endothelial cells to interact with a wide variety of extracellular matrix components (Hynes, Cell, 1992, 69:11-25). These adhesive interactions are considered to be critical for angiogenesis since vascular cells must ultimately be capable of invading virtually all tissues.
  • integrin ⁇ v ⁇ 3 promotes adhesive events important for angiogenesis
  • this receptor also transmits signals from the extracellular environment to the intracellular compartment (Leavesley et al., J. Cell Biol., 1993, 121:163-170, 1993) .
  • the interaction between the ⁇ v ⁇ 3 integrin and extracellular matrix components promotes a calcium signal required for cell motility.
  • integrins include but not limited to von Willebrand factor, fibronectin, and fibrin. Additionally, several members of the integrin family of adhesion receptors are expressed on the surface of endothelial, smooth muscle and on other circulating cells. Among these integrins is ⁇ v ⁇ 3 , the endothelial cell, fibroblast, and smooth muscle cell receptor for adhesive proteins including von Willebrand factor, fibrinogen (fibrin), vitronectin, thrombospondin, and osteopontin. These integrins initiate a calcium-dependent signaling pathway that can lead to endothelial cell, smooth muscle cell migration and, therefore, may play a fundamental role in vascular cell biology.
  • ⁇ v ⁇ 3 integrin antagonists have been shown to inhibit angiogenesis and are recognized as being useful as therapeutic agents for the treatment of human diseases such as cancer,
  • Integrin subfamilies contain a common ⁇ -subunit combined with different ⁇ -subunits to form adhesion receptors with unique specificity.
  • the genes for eight distinct ⁇ -subunits have been cloned and sequenced to date.
  • the ⁇ v ⁇ 3 heterodimer is a member of the ⁇ 3 integrin subfamily and has been described on platelets,
  • the vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialo protein II and thrombosponden in a manner mediated by the RGD sequence.
  • a key event in bone resorption is the adhesion of osteoclasts to the matrix of bone.
  • Studies with monoclonal antibodies have implicated the ⁇ v ⁇ 3 receptor in this process and suggest that a selective ⁇ v ⁇ 3 antagonist would have utility in blocking bone resorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247; Helfrich et al., J. Bone Miner. Res., 1992, 7:335-343).
  • WO95/32710 published December 7, 1995 discloses compounds for inhibition of osteoclast-mediated bone resorption of general formula shown below:
  • Aryl is a 6-membered aromatic ring system.
  • the present invention provides novel nonpeptide compounds which bind to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes.
  • the compounds of the present invention are useful for the inhibition of cell adhesion and the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastases, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
  • One aspect of this invention provides novel
  • the present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of angiogenesis, and/or for the treatment of disorders mediated by angiogenesis.
  • Another aspect of the present invention comprises agents that inhibit the binding of vitronectin to the ⁇ v ⁇ 3 receptor for the treatment (including prevention) of thrombosis which do not significantly alter hemostatic balance and do not significantly inhibit platelet aggregation and do not significantly inhibit
  • invention can be used for the treatment or prevention of restenosis.
  • the present invention also provides novel
  • rheumatoid arthritis including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis,
  • osteoporosis osteoarthritis, atherosclerosis,
  • metastasis metastasis, wound healing, diabetic retinopathy, ocular vasculopathies, thrombosis, inflammatory bowel disease and other autoimmune diseases.
  • kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula I, for the therapeutic inhibition of cell adhesion, the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
  • the present invention provides novel nonpeptide compounds of Formula I (described below) which bind to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes.
  • the compounds of the present invention are useful for the inhibition of cell adhesion and the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastases, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis, in a mammal .
  • One aspect of this invention provides novel compounds of Formula I which are useful as antagonists of the ⁇ v ⁇ 3 or vitronectin receptor.
  • the compounds of the present invention inhibit the binding of vitronectin and other RGD-containing ligands to ⁇ v ⁇ 3 and inhibit cell adhesion.
  • the present invention also includes
  • the present invention comprises spirocyclic
  • A is selected from -N(R 10 )-, -C(R 11 )- or -O-;
  • a 1 is selected from -O- or -N(R 10 )-;
  • Z is a spiro-fused 4-7 membered ring system (including the sprio atom) containing 0-2 heteroatoms selected from O, S, or N, said ring system optionally being substituted on carbon with keto, or being
  • R 1 is selected from:
  • B 1 is independently selected from -CH 2 - or -N(R 3 )-;
  • J, K, L and M are independently selected from -C(R 4 )-,
  • R 2 is selected from: H, C 1 -C 6 alkyl, (C 1 -C 6
  • cycloalkyl C 4 -C 11 cycloalkylalkyl, aryl,
  • heteroarylcarbonyl aryl C 1 -C 6 alkyl, (C 1 -C 6 alkyl) carbonyl, arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl (C 1 -C 6 alkyl) sulfonyl,
  • heteroarylsulfonyl heteroaryl (C 1 -C 6
  • alkyl alkyl sulfonyl, aryloxycarbonyl, aryl(C 1 -C 6
  • alkoxy carbonyl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
  • R 3 isselected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 - C 11 cycloalkylalkyl, aryl, aryl (C 1 -C 6 alkyl)-, or heteroaryl (C 1 -C 6 alkyl)-;
  • R 4 and R 5 are independently selected from: H, C 1 -C 4
  • cycloalkylalkyl aryl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) carbonyl, (C 1 -C 6 alkoxy) carbonyl,
  • R 4 and R 5 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups independently selected from: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 , or NO 2 ; R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, C 1 -C 6
  • alkyl C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl (C 0 -C 6 alkyl)-;
  • U is selected from:
  • V is selected from:
  • R 9 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 4 alkoxy) carbonyl, (C 1 -C 4 alkyl) carbonyl, C 1 -C 4 alkylsulfonyl, or C 1 -C 4 alkylaminosulfonyl;
  • cycloalkylalkyl substituted with 0-1 R 15 aryl substituted with 0-1 R 15 or 0-2 R 11 , or aryl (C 1 -C 6 alkyl)- substituted with 0-1 Ris or 0-2 R 11 ;
  • R 11 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 4 alkoxy) carbonyl, (C 1 -C 4 alkyl) carbonyl, C 1 -C 4 alkylsulfonyl, or C 1 -C 4 alkylaminosulfonyl;
  • W is selected from:
  • X is -(C(R 12 ) 2 ) q C(R 12 ) (R 14 )-C(R 12 ) (R 15 )-; alternatively, W and X can be taken together to be
  • R 12 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 4 -C 10 cycloalkylalkyl, (C 1 -C 4 alkyl) carbonyl, aryl, or aryl (C 1 -C 6 alkyl)-;
  • R 13 is selected from H, C 1 -C 6 alkyl, C 3 -C 7
  • R 14 is selected from:
  • R 15 is selected from:
  • Y is selected from:
  • R 16 is selected from:
  • R 17 is selected from:
  • heteroarylaryl C 1 -C 6 alkyl
  • arylheteroaryl C 1 -C 6 alkyl
  • heteroarylheteroaryl C 1 -C 6 alkyl
  • heteroaryl or aryl, wherein said aryl or
  • heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, halo, cyano, amino, CF 3 , and NO 2 ;
  • R 18 is selected from:
  • R 19 is selected from:
  • R 11 (R 12 )N-(C 1 -C 10 alkoxy)-;
  • R 20 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl (C 1 -C 6 alkyl)-, or heteroaryl (C 1 -C 6 alkyl)-;
  • m is 1-2
  • n 0-2
  • r is 0-2 provided that:
  • n, q, and r are chosen such that the number of in-chain atoms between R 1 and Y is in the range of 8-18.
  • R 1 is selected from:
  • J, K, L and M are independently selected from -C(R 4 )-,
  • R 2 is selected from: H, C 1 -C 6 alkyl, (C 1 -C 6
  • cycloalkyl C 4 -C 11 cycloalkylalkyl, aryl,
  • heteroarylcarbonyl aryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) carbonyl, arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl (C 1 -C 6 alkyl) sulfonyl,
  • heteroarylsulfonyl heteroaryl (C 1 -C 6
  • alkyl alkyl
  • aryloxycarbonyl aryl (C 1 -C 6 alkoxy) carbonyl
  • aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
  • R 3 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl (C 1 -C 6 alkyl)-, or heteroaryl (C 1 -C 6 alkyl)-;
  • R 4 and R 5 are independently selected from: H, C 1 -C 4
  • cycloalkylalkyl aryl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) carbonyl, (C 1 -C 6 alkoxy) carbonyl,
  • R 4 and R 5 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups independently selected from: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 , or NO 2 ; R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, C 1 -C 6
  • V is selected from:
  • R 9 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 4 alkoxy) carbonyl, (C 1 -C 4 alkyl) carbonyl, C 1 -C 4 alkylsulfonyl, or C 1 -C 4 alkylaminosulfonyl;
  • cycloalkylalkyl substituted with 0-1 R 15 aryl substituted with 0-1 R 15 or 0-2 R 1i , or aryl (C 1 -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 ;
  • R 11 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 4 alkoxy) carbonyl, (C 1 -C 4 alkyl) carbonyl, C 1 -C 4 alkylsulfonyl, or C 1 -C 4 alkylaminosulfonyl;
  • W is selected from:
  • X is -(C(R 12 ) 2 ) q C(R 12 ) (R 14 )-C(R 12 ) (R 15 -)-; alternatively, W and X can be taken together to be
  • R 12 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl,
  • R 13 is selected from H, C 1 -C 6 alkyl, C 3 -C 7
  • R 14 is selected from:
  • R 15 is selected from:
  • Y is selected from:
  • R 16 is selected from:
  • R 17 is selected from:
  • C 1 -C 10 alkyl C 3 -C 11 cycloalkyl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) aryl, heteroaryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) heteroaryl, arylaryl (C 1 -C 6 alkyl)-,
  • heteroarylaryl C 1 -C 6 alkyl
  • arylheteroaryl C 1 -C 6 alkyl
  • heteroarylheteroaryl C 1 -C 6 alkyl
  • heteroaryl or aryl, wherein said aryl or
  • heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, halo, cyano, amino, CF 3 , and NO 2 ;
  • R 18 is selected from:
  • R 19 is selected from:
  • R 11 (R 12 )N-(C 1 -C 10 alkoxy)-;
  • R 20 selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 - C 11 cycloalkylalkyl, aryl, aryl (C 1 -C 6 alkyl)-, or heteroaryl (C 1 -C 6 alkyl)-;
  • m is 1-2
  • n 0-2
  • r is 0-2 provided that:
  • n, q, and r are chosen such that the number of in- chain atoms between R 1 and Y is in the range of 8- 18.
  • R 2 is selected from: H, C 1 -C 4 alkyl or benzyl; U is -NH(CH 2 ) n -; V is -(CH 2 ) n -;
  • cycloalkylalkyl substituted with 0-1 R 15 aryl substituted with 0-1 R 15 or 0-2 R 11 , or aryl (C 1 -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 ;
  • cycloalkylalkyl substituted with 0-1 R 15 aryl substituted with 0-1 R 15 or 0-2 R 11 , or aryl (C 1 -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 ;
  • R 11 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 4 alkoxy) carbonyl, (C 1 -C 4 alkyl) carbonyl, C 1 -C 4 alkylsulfonyl, or C 1 -C 4 alkylaminosulfonyl;
  • X is -CH(R 14 )-CH(R 15 )-;
  • R 13 is H or CH 3 ;
  • R 14 is selected from:
  • R 15 is H or R 16 ;
  • R 16 is selected from:
  • R 17 is selected from:
  • C 1 -C 10 alkyl C 3 -C 11 cycloalkyl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) aryl, heteroaryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) heteroaryl, arylaryl (C 1 -C 6 alkyl)-,
  • heteroarylaryl C 1 -C 6 alkyl
  • arylheteroaryl C 1 -C 6 alkyl
  • heteroarylheteroaryl C 1 -C 6 alkyl
  • heteroaryl or aryl, wherein said aryl or
  • heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, halo, cyano, amino, CF 3 , and NO 2 ;
  • R 19 is selected from:
  • R 20 is H or CH 3 ; and n is 0-1,
  • Q is selected from:
  • R 1 is selected from:
  • R 2 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • U is -NH(CH 2 ) n -;
  • V is -(CH 2 ) n -;
  • cycloalkylalkyl substituted with 0-1 R 15 aryl substituted with 0-1 R 15 or 0-2 R 11 , or aryl (C 1 -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 ;
  • cycloalkylalkyl substituted with 0-1 R 15 aryl substituted with 0-1 R 15 or 0-2 R 11 , or aryl (C 1 -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 ;
  • R 11 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl (C 1 -C6 alkyl)-, (C 1 -C 4 alkoxy) carbonyl , (C 1 -C 4 alkyl) carbonyl, C 1 -C 4 alkylsulfonyl, or C 1 -C 4 alkylaminosulfonyl;
  • X is -CH(R 14 )-CH(R 15 )-;
  • R 13 is H or CH 3 ;
  • R 14 is selected from:
  • R 15 is H or R 16 ;
  • R 17 is selected from:
  • heteroarylaryl C 1 -C 6 alkyl
  • arylheteroaryl C 1 -C 6 alkyl
  • heteroarylheteroaryl C 1 -C 6 alkyl
  • heteroaryl or aryl, wherein said aryl or
  • heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, halo, cyano, amino, CF 3 , and NO 2 ;
  • R 19 is selected from:
  • R 20 is H or CH 3 ; and n is 0-1.
  • Specifically preferred compounds of the above invention are compounds including enantiomeric or diasteriomeric forms thereof, or mixtures of
  • the compounds of Formula I above are useful as inhibitors of cell-matrix and cell-cell adhesion processes.
  • the present invention includes novel compounds of Formula I and methods for using such compounds for the prevention or treatment of diseases resulting from abnormal cell adhesion to the
  • extracellular matrix which comprises administering to a host in need of such treatment a therapeutically
  • the compounds of Formula I above are useful as inhibitors of ⁇ v ⁇ 3 .
  • the compounds of the present invention inhibit the binding of vitronectin to ⁇ v ⁇ 3 and inhibit cell adhesion.
  • the present invention also provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.
  • the compounds of Formula I of the present invention are useful for the treatment (including prevention) of angiogenic disorders.
  • angiogenic disorders as used herein includes
  • abnormal neovascularization such as tumor metastasis and ocular neovascularization, including, for example, diabetic retinopathy,
  • neovascular glaucoma neovascular glaucoma, age-related macular degeneration, and retinal vein occlusion, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above.
  • the compounds of Formula I of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes,
  • the compounds of Formula I of the present invention may also be useful for wound healing.
  • thromboembolic disorders includes conditions involving platelet activation and aggregation, such as arterial or venous
  • cardiovascular or cerebrovascular thromboembolic disorders including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above.
  • the compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.
  • the compounds of the present invention can also be administered in combination with one or more additional therapeutic agents selected from: anti-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as
  • plasminogen activators anistreplase, urokinase, or streptokinase.
  • the compounds of Formula I of the present invention can be administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect.
  • the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component.
  • a lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each
  • combination therapies may be employed to achieve synergistic or additive therapeutic effects for the treatment of thromboembolic disorders.
  • terapéuticaally effective amount it is meant an amount of a compound of Formula I that when
  • administered in combination it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated.
  • each component may be administered at the same time or sequentially in any order at different points in time.
  • each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
  • anti-coagulant agents denotes agents that inhibit blood coagulation.
  • agents include warfarin (available as COUMADIN ® ) and heparin.
  • anti-platelet agents denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets.
  • agents include the various known non-steroidal anti- inflammatory drugs such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,
  • diclofenac sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof.
  • suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof.
  • Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use.
  • Still other suitable platelet inhibitory agents include thromboxane-A2-receptor antagonists and
  • thrombin inhibitors or anti-thrombin
  • agents denotes inhibitors of the serine protease thrombin.
  • thrombin By inhibiting thrombin, various thrombin-mediated processes, such as
  • thrombin-mediated platelet activation that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin
  • fibrin formation are disrupted.
  • inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban, including
  • Boroarginine derivatives and boropeptides include
  • N-acetyl and peptide derivatives of boronic acid such as C-terminal ⁇ -aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof.
  • hirudin includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.
  • Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S.
  • thrombolytics or fibrinolytic agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi).
  • agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof.
  • Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, California.
  • anistreplase refers to anisoylated plasminogen streptokinase
  • urokinase is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
  • Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each.
  • a lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
  • the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the binding of vitronectin or fibrinogen to ⁇ v ⁇ 3 .
  • Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving ⁇ v ⁇ 3 .
  • the compounds of the present invention may also be used in diagnostic assays involving ⁇ v ⁇ 3 .
  • any variable for example but not limited to, R 2 , R 4 , R 6 , R 7 , R 8 , R 12 ,and R 14 , n, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • said group may optionally be substituted with up to two R 4 and R 4 at each occurrence is selected independently from the defined list of possible R 4 .
  • each of the two R 5a substituents on N is independently selected from the defined list of possible R 5a .
  • each of the two R 7 substituents on C is independently selected from the. defined list of possible R 7 .
  • substituent may be bonded to any atom on the ring.
  • a bond joining a substituent to another group is not specifically shown or the atom in such other group to which the bond joins is not specifically shown, then such substituent may form a bond with any atom on such other group.
  • piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formula I via any atom in such piperazinyl, piperidinyl, tetrazolyl group.
  • stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • substituted means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge
  • cycloalkyl is intended to include saturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl,
  • bicyclohexyl cycloheptyl, cyclooctyl, and adamantyl
  • "biycloalkyl” is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane,
  • alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
  • alkylene alkenylene, phenylene, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I.
  • alkylene alkenylene, phenylene, and the like, may alternatively and equivalently be denoted herein as “-(alkyl)-", “-(alkyenyl)-” and “-(phenyl)-”, and the like.
  • Halo or “halogen” as used herein refers to fluoro, chloro, bromo and iodo; and " counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
  • aryl or “aromatic residue” is intended to mean phenyl or naphthyl; the term
  • arylalkyl represents an aryl group attached through an alkyl bridge.
  • carbocycle or “carbocyclic residue” is intended to mean any stable 3- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocyles include, but are not limited to, cyclopropyl,
  • cyclopentyl cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • heterocyclic is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms
  • N independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may
  • heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,
  • octahydroisoquinolinyl azocinyl, triazinyl, 6H-1,2,5- thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,
  • fused ring and spiro compounds containing, for example, the above
  • heteroaryl refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocyclic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.
  • prodrugs refer to any covalently bonded carriers which release the active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula I are prepared by modifying
  • Prodrugs include compounds of Formula I wherein
  • hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I, and the like.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound of Formula I is modified by making acid or base salts of the compound of Formula I.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the compounds of Formula I include the conventional non- toxic salts or the quaternary ammonium salts of the compounds of Formula I formed, for example, from non- toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
  • salicylic sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with
  • the pharmaceutically acceptable salts of the acids of Formula I with an appropriate amount of a base such as an alkali or alkaline earth metal hydroxide e.g.
  • an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e
  • dibenzylethylenediamine trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
  • pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
  • Compounds of Formula I wherein Q includes an isoxazoline ring as one ring of the spirocycle can be conveniently prepared by dipolar cycloaddition of nitrile oxides with appropriate dipolarophiles (for reviews of 1,3-dipolar cycloaddition chemistry, see 1,3- Dipolar Cycloaddition Chemistry (Padwa, ed.), Wiley, New York, 1984; Kanemasa and Tsuge, Heterocvcles 1990, 30, 19).
  • the requisite nitrile oxides are in turn prepared from commercially available precursors or appropriately substituted aldehydes via the intermediate oximes.
  • Scheme 1 illustrates one synthetic sequence which will provide compounds of Formula I of this invention.
  • a methylenecycloalkylmethanol with ethyl chlorooximidoacetate in a suitable solvent, such as tetrahydrofuran or dichloromethane in the presence of a mild base, such as sodium bicarbonate or triethylamine, provides a spirocycle intermediate, 1(a).
  • a suitable solvent such as tetrahydrofuran or dichloromethane
  • a mild base such as sodium bicarbonate or triethylamine
  • the cycloaddition can be carried out by thermal decomposition of diethyl nitromalonate in refluxing mesitylene by the method of Shimizu et al.
  • the coupling is carried out using any of the many methods for the formation of amide bonds known to one skilled in the art of organic synthesis. These methods include but are not limited to conversion of the acid to the corresponding acid chloride or fluoride, or use of standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide,
  • carbodiimide can be enhanced by the addition of 1- hydroxybenzotriazole.
  • Deprotection of compound 1(f) is carried out using standard methods of removal of carboxy and amino protecting groups to provide target compounds of formula 1(g). Additional compounds of formula I can be prepared as shown in Scheme 2. Cycloaddition product, 1(a) can be converted to the corresponding amino compound by
  • racemic ⁇ -amino acids may be purchased commercially or, as is shown in Scheme 4, Method 1, prepared from the appropriate aldehyde, malonic acid and ammonium acetate according to the procedure of Johnson and Livak (J. Am. Chem. Soc. 1936, 58, 299) .
  • Racemic ⁇ -substituted- ⁇ -amino esters may be prepared through the reaction of dialkylcuprates or alkyllithiums with 4-benzoyloxy-2-azetidinone followed by treatment with anhydrous ethanol (Scheme 4, Method 2) or by reductive amination of ⁇ -keto esters as is
  • Enantiomerically pure ⁇ - substituted- ⁇ -amino acids can be obtained through the optical resolution of the racemic mixture or can be prepared using numerous methods, including: Arndt- Eistert homologation of the corresponding ⁇ -amino acids as shown in Scheme 4, Method 3 (see Meier, and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within); and through an enantioselective hydrogenation of a
  • N 2 -substituted diaminopropionic acid derivatives can be carried out via Hoffman rearrangement of a wide variety of asparagine
  • a further class of spirocycles useful in the present invention is prepared as outlined in Scheme 7. Reduction of N-Cbz 4-hydroxyproline with borane-dimethyl sulfide complex in tetrahydrofuran provides diol 7(a). The primary hydroxyl is then selectively protected as its t-butyldimethylsilyl ether, 7(b). Oxidation of the remaining secondary alcohol using methods described above provides ketone 7(c) which can be converted to alkene 7(d) by olefination. Compound 7(d) then
  • suitable amine provides an imine 8(b) which can undergo 1,3-dipolarcycloaddition with a nitrile oxide to provide spirocycle 8(c). Further elaboration as described above would provide additional compounds of the present invention of Formula 8(b).
  • ethyl diazoacetate E. Keller et al., Tetrahedron, 1993, 49, 8899
  • the nitrogen of the resulting pyrazole ring may be
  • Fully saturated spirocycles are obtained by 1,3- dipolarcycloadditon of ⁇ -methoxycarbonylnitrones to an appropriately substituted alkene as illustrated in
  • N-Cbz-4-hydroxy-L-prolinol A solution of N- Cbz-4-hydroxy-L-proline (50 gm, 0.188 mol) in tetrahydrofuran (400 ml) was cooled to 0 °C in an ice bath under nitrogen and a solution of borane
  • Part B 1-benzyloxycarbonyl-2-(S)-t- butyl dimethyl silyloxymethyl-4-hydroxypyrrolidine: A mixture of the compound of Part A above (46.77 g, 0.186 mol), triethylamine (51.8 g, 0.372 mol), and t- butyldimethyIsilylchloride (30.86 g, 0.205 mol) in methylene chloride (375 ml) was stirred under nitrogen overnight at room temperature. An additional aliquot of silyl chloride (5 g, 0.033 mol) was added and stirring continued for 4-5 h.
  • Methyltriphenylphosphonium bromide (68,98 g, 0.193 mol) is added to a suspension of potassium t-butoxide (20.27 g, 0.181 mol) in anhydrous ether (700 ml) with stirring at 0°C under nitrogen. The resulting bright yellow solution is stirred for an additional 15 min. To this is added a solution of the compound of part D above
  • Part E 7-benzyloxycarbonyl-8-t-butyldimethylsilyloxy- methyl-3-ethoxycarbonyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-ene: The compound of part D above (13.04 g, 0.036 mol) was dissolved in methylene chloride (50 ml), treated with ethyl chlorooximidoacetate (8.18 g., 0.054 mol), and the mixture was cooled to 0°C followed by dropwise addition of triethylamine (7.53 ml, 0.054 mol). The reaction was allowed to come to room temperature over several hours then stirred overnight. An
  • Part F 7-benzyloxycarbonyl-8-t-butyldimethylsilyloxy- methyl-3-carboxy-1-oxa-2,7-diazaspiro-[4,4]-non-2-ene: The compound of Part E above (18.7 g, 0.038 mol) was dissolved in methanol (200 ml) and treated at room temperature with a solution of lithium hydroxide monohydrate (2.4 g, 0.057 mol) in water (50 ml). The whole was stirred for 5 h and then solvent removed in vacuo. Water was added and the pH of the solution was adjusted to 4.4 with 10% aq. citric acid solution.
  • Part G t-Butyl (S)-2-[(2,4,6-trimethylphenyl)suifonyl]- amino-3-[[7-benzyloxycarbonyl-8-(t-butyldimethylsilyl- oxy)methyl-1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid: A mixture of the compound of Part F above (10 g, 0.022 mol), t-butyl 3- amino-2- (2,4, 6-trimethylphenylsulfonylamino)propionate (7.6 g, 0.022 mol), N-methylmorpholine (5.4 ml, (0.049 mol) and Castro's reagent (14.8 g, 0.033 mol) in N,N- dimethylformamide (100 ml) was stirred under nitrogen at room temperature overnight.
  • the DMF was removed in vacuo and the residue diluted with 500 ml water and extracted 3X with ethyl acetate. The combined extracts were washed with water (2X), 10% citric acid (1X), saturated sodium bicarbonate (1X) and brine (1X) then dried over anhydrous sodium sulfate, filtered and evaporated.
  • the coupling product was purified by filtration through a pad of silica gel eluted with hexane/ethyl acetate (4:1) to provide the product as a white foam (15 gm, 88%). MS(esi) m/z 773.4 (M+H) + 795.4 (M+Na) + .
  • Part H t-Butyl (S)-2-[(2,4,6-trimethylphenyl)sulfonyl]- amino-3-[[7-benzyloxycarbonyl-8-hydroxymethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3-yl]carbonylamino] pronionic acid: The compound of Part G above (2.8 g, 3.62 mmol) was dissolved in tetrahydrofuran (12 ml) and treated with tetra-n-butylammonium floride (5.8 ml of a 1.0 M solution in THF, 5.8 mmol). The resulting solution was stirred overnight at room temperature.
  • Part J t-Butyl (S)-2-[(2,4,6-trimethylphenyl)sulfonyl]- amino-3-[[7-benzyloxycarbonyl-8-(imidazol-2- ylamino)methyl-1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylaminol propionic acid: To a solution of the compound of Part I above (0.73 g, 1.11 mmol) in benzene was added anhydrous magnesium sulfate (0.588 g, 4.88 mmol) and 2-amino-1-tritylimidazole (0.398 g, 1.22 mmol) and the whole was refluxed for 4 hrs under nitrogen. The mixture was cooled to room temperature, filtered under nitrogen and benzene removed in vacuo. The residue was taken up in 1,2-dichloroethane, treated under nitrogen at room temperature with sodium
  • Example 3055, Part J The compound of Example 3055, Part J, (0.1 g, 0.1 mmol) was taken up in neat trifluoroacetic acid (3 ml) and the mixture refluxed for 1.5 h. Reaction was cooled to room temperature and TFA removed in vacuo. The residue was purified by prep HPLC using the system described under Ex. 3055, Part K above to provide the title compound (0.043 g, 80%) . MS m/z 534.4 (M+H) + . Using the methods described above and modifications thereof known to one skilled in the art of organic synthesis, additional compounds of the present invention can be prepared, including, but not limited to the representative compounds listed in the Tables below.
  • the compounds of Formula I of the present invention possess activity as antagonists of integrins such as, for example, the ⁇ v ⁇ 3 or vitronectin receptor, ⁇ v ⁇ s or c.5 ⁇ l, and as such have utility in the treatment and diagnosis of cell adhesion, angiogenic disorders, inflammation, bone degradation, cancer metastases, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
  • integrins such as, for example, the ⁇ v ⁇ 3 or vitronectin receptor, ⁇ v ⁇ s or c.5 ⁇ l
  • integrin antagonist activity of the compounds of the present invention is demonstrated using assays which measure the binding of a specific integrin to a native ligand, for example, using the ELISA assay described below for the binding of vitronectin to the ⁇ v ⁇ 3
  • the compounds of the present invention possess selectivity for the ⁇ v ⁇ 3 receptor relative to the
  • GPIIb/IIIa receptor as demonstrated by their lack of activity in standard assays of platelet aggregation, such as the platelet aggregation assay described below.
  • a cell based assay is more representative of the in vivo situation than an ELISA since the receptor is maintained in membranes in the native state.
  • the compounds of the present invention have activity in cell-based assays of adhesion, for example as demonstrated in using the cell adhesion assays described below.
  • the compounds of Formula I of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes,
  • osteoporosis including, but not limited to, osteoporosis, rheumatoid arthritis, autoimmune disorders, bone degradation, rheumatoid arthritis, asthma, allergies, adult
  • respiratory distress syndrome graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoarthritis,
  • the compounds of Formula I have the ability to suppress/inhibit angiogenesis in vivo, for example, as demonstrated using animal models of ocular
  • the compounds provided by this invention are also useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit
  • integrin-ligand binding may be provided in a commercial kit comprising a compound of this invention.
  • ⁇ g denotes microgram
  • mg denotes milligram
  • g denotes gram
  • ⁇ L denotes microliter
  • mL denotes milliliter
  • L denotes liter
  • M nM denotes nanomolar
  • ⁇ M denotes micromolar
  • mM denotes micromolar
  • a compound of the present invention is considered to be active if it has an IC 50 or Ki value of less than about 10 ⁇ M for the inhibition of ⁇ v ⁇ 3 -Vitronectin Binding Assay, with compounds preferably having Ki values of less than about 0.1 ⁇ M.
  • Tested compounds of the present invention are active in the ⁇ v ⁇ 3 -Vitronectin Binding Assay as well as in cell-based assays of integrin adhesion mediated by the ⁇ v ⁇ 3 -receptor.
  • Purified ⁇ v ⁇ 3 (human placenta) - Vitronectin ELISA The ⁇ v ⁇ 3 receptor was isolated from human placental extracts prepared using octylglucoside. The extracts were passed over an affinity column composed of anti- ⁇ v ⁇ 3 monoclonal antibody (LM609) to Affigel. The column was subsequently washed extensively at pH 7 and pH 4.5 followed by elution at pH 3. The resulting sample was concentrated by wheat germ agglutinin chromatography to provide gave two bands on SDS gel which were confirmed as ⁇ v ⁇ 3 by western blotting.
  • LM609 anti- ⁇ v ⁇ 3 monoclonal antibody
  • Affinity purified protein was diluted at different levels and plated to 96 well plates.
  • ELISA was performed using fixed concentration of biotinylated vitronectin (approximately 80 nM/well).
  • This receptor preparation contains the ⁇ v ⁇ 3 with no detectable levels of ⁇ v ⁇ 3 according to the gel ( ⁇ v ⁇ 3 ) and according to effects of blocking antibodies for the ⁇ v ⁇ 3 or ⁇ v ⁇ 3 in the ELISA.
  • vitronectin was selected based on cone, response curve with fixed receptor cone, and variable concentrations of biotinylated vitronectin. ⁇ -Vitronectin Binding Assay
  • the purified receptor is diluted with coating buffer (20 mM Tris HCl, 150 mM NaCl, 2.0 mM CaCl 2 , 1.0 mM MgCl 2 ⁇ 6H 2 O, 1.0 mM MnCl 2 ⁇ 4H 2 O) and coated (100 ⁇ L/well) on Costar (3590) high capacity binding plates overnight at 4°C.
  • the coating solution is discarded and the plates washed once with blocking/binding buffer (B/B buffer, 50 mM Tris HCl, 100 mM NaCl, 2.0 mM CaCl 2 ,1.0 mM MgCl 2 ⁇ 6H 2 O,1.0 mM MnCl 2 ⁇ 4H 2 O).
  • Receptor is then blocked (200 ⁇ L/well) with 3.5% BSA in B/B buffer for 2 hours at room temperature. After washing once with 1.0% BSA in B/B buffer, biotinylated vitronectin (100 ⁇ L) and either inhibitor (11 ⁇ L) or B/B buffer w/1.0% BSA (11 ⁇ L)is added to each well. The plates are incubated 2 hours at room temperature. The plates are washed twice with B/B buffer and incubated 1 hour at room temperature with anti-biotin alkaline phosphatase (100 ⁇ L/well) in B/B buffer containing 1.0% BSA. The plates are washed twice with B/B buffer and alkaline phosphatase substrate (100 ⁇ L) is added. Color is developed at room temperature. Color development is stopped by addition of 2N NaOH (25 ⁇ L/well) and absorbance is read at 405 nm. The IC 50 is the concentration of test substance needed to block 50% of the vitronectin binding to the receptor
  • a 96 well plate was coated with the ligand (i.e., fibrinogen) and incubated
  • test compounds were tested for their ability to block cell adhesion using assays specific for ⁇ v ⁇ 3 , ⁇ v ⁇ 5 and ⁇ 5 ⁇ 1 integrin interactions.
  • Venous blood was obtained from anesthetized mongrel dogs or from healthy human donors who were drug- and aspirin-free for at least two weeks prior to blood collection. Blood was collected into citrated Vacutainer tubes. The blood was centrifuged for 15 minutes at 150 x g (850 RPM in a Sorvall RT6000 Tabletop Centrifuge with H-1000 B rotor) at room temperature, and platelet- rich plasma (PRP) was removed. The remaining blood was centrifuged for 15 minutes at 1500 x g (26,780 RPM) at room temperature, and platelet-poor plasma (PPP) was removed. Samples were assayed on a PAP-4 Platelet Aggregation Profiler, using PPP as the blank (100% transmittance).
  • PPP platelet-poor plasma
  • the compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action, the ⁇ v ⁇ 3 integrin, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents, such as a antiplatelet agent such as aspirin, piroxicam, or ticlopidine which are agonist-specific, or an
  • anti-coagulant such as warfarin or heparin
  • a thrombin inhibitor such as a boropeptide, hirudin or argatroban, or a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof.
  • tissue plasminogen activator anistreplase, urokinase or streptokinase, or combinations thereof.
  • a daily dosage of active ingredient can be expected to be about 0.001 to 10 milligrams per kilogram of body weight.
  • compositions suitable for injection compositions suitable for injection.
  • compositions contain from about 0.1 milligram to about 100 milligrams of active ingredient per unit.
  • active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • saline aqueous dextrose (glucose)
  • glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • suitable stabilizing agents such as sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite
  • bisulfite, sodium sulfite, or ascorbic acid are suitable stabilizing agents.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 10 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • a mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive
  • the dosage unit was 10 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.
  • Appropriate coatings may be applied to increase the dosage unit.
  • combination products of this invention such as the novel ⁇ v ⁇ 3 antagonist compounds of this invention in combination with an anti-coagulant agent such as
  • warfarin or heparin or an anti-platelet agent such as aspirin, piroxicam or ticlopidine, or a thrombin
  • inhibitor such as a boropeptide, hirudin or argatroban, or a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof, can be in any dosage form, such as those described above, and can also be administered in various ways, as described above.
  • the combination products of the invention are formulated together, in a single dosage form (that is, combined together in one capsule, tablet, powder, or liquid, etc.).
  • a single dosage form that is, combined together in one capsule, tablet, powder, or liquid, etc.
  • the ⁇ v ⁇ 3 antagonist compounds of this invention and the anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent may be administered at the same time (that is, together), or in any order, for example the compounds of this invention are
  • thrombolytic agent administered first, followed by administration of the anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent.
  • administration of the compound of this invention and any anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent occurs less than about one hour apart, more preferably less than about 30 minutes apart, even more preferably less than about 15 minutes apart, and most preferably less than about 5 minutes apart.
  • administration of the combination products of the invention is oral.
  • oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered.
  • the ⁇ 3 antagonist compounds of this invention and the anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent are both
  • component of the combination product may be administered orally, and another component may be administered intravenously) .
  • the dosage of the combination products of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of
  • the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when
  • the preferred dosage forms of the combination products of this invention are formulated such that although the active ingredients are combined in a single dosage form, the physical contact between the active ingredients is minimized (that is, reduced).
  • one embodiment of this invention where the product is orally administered provides for a combination product wherein one active ingredient is enteric coated.
  • enteric coating one of the active ingredients it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the
  • Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active
  • sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
  • Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of
  • HPMC hydroxypropyl methylcellulose
  • Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer.
  • one or more placebo layers may be present such that the placebo layer is between the layers of active
  • dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non- perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.
  • kits useful in, for example, the inhibition of thrombus formation, the prevention of blood clots, and/or the treatment of thromboembolic disorders which comprise a therapeutically effective amount of a compound according to the method of the present invention along with a therapeutically effective amount of an anti-coagulant agent such as warfarin or heparin, or an antiplatelet agent such as aspirin, piroxicam or ticlopidine, or a thrombin inhibitor such as a boropeptide, hirudin or argatroban, or a
  • thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or
  • the sterile containers of materials may comprise separate containers, or one or more multi-part containers, as exemplified by the
  • kits may further include, if desired, one or more of various conventional
  • pharmaceutical kit components such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art.
  • guidelines for administration, and/or guidelines for mixing the components may also be included in the kit.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Heart & Thoracic Surgery (AREA)
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  • Urology & Nephrology (AREA)
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Cette invention concerne de nouveaux hétérocycles, comprenant l'acide (S)-2-phénylsulfonylamino-3[8-(2-pirydinilaminométhyl)-]-1-oxa-2-azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]propionique, qui sont utiles en tant qu'antagonistes de l'intégrine αvβ3 et les récepteurs apparentés de protéines adhérant à la surface de cellules, l'invention concernant également des compositions pharmaceutiques contenant ces composés, des procédés de préparation de ces composés, ainsi que des méthodes d'utilisation de ces composés, seuls ou combinés à d'autres agents thérapeutiques pour empêcher l'adhésion cellulaire, le traitement de troubles angiogéniques, l'inflammation, la dégradation osseuse, les métastases de cancer, la rétinopathie diabétique, la thrombose, la resténose, la dégénération maculaire et d'autres états pathologiques induits par l'adhésion cellulaire et/ou la migration cellulaire et/ou l'angiogenèse.
PCT/US1997/004567 1996-03-15 1997-03-17 Inhibiteurs de l'integrine spirocycle WO1997033887A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97919892A EP0888344A1 (fr) 1996-03-15 1997-03-17 Inhibiteurs de l'integrine spirocycle
JP53292497A JP2001527513A (ja) 1996-03-15 1997-03-17 スピロ環インテグリン阻害剤
AU24217/97A AU2421797A (en) 1996-03-15 1997-03-17 Spirocycle integrin inhibitors

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US1353996P 1996-03-15 1996-03-15
US60/013,539 1996-03-15
US64689696A 1996-05-08 1996-05-08
US08/646,896 1996-05-08
US08/816,580 1997-03-14
US08/816,580 US5760029A (en) 1996-03-15 1997-03-14 Spirocycle integrin inhibitors

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Cited By (23)

* Cited by examiner, † Cited by third party
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WO1998043962A1 (fr) * 1997-03-28 1998-10-08 Du Pont Pharmaceuticals Company Promedicaments heterocycliques inhibiteurs d'integrine
WO1999052872A1 (fr) 1998-04-09 1999-10-21 Meiji Seika Kaisha, Ltd. DERIVES D'AMINOPIPERIDINE COMME ANTAGONISTES D'INTEGRINE αvβ¿3?
WO1999058139A3 (fr) * 1998-05-08 2000-02-10 Univ California Procedes de detection et d'inhibition de l'angiogenese
WO2000066593A3 (fr) * 1999-05-03 2001-05-31 Schering Ag Nouveaux composes spirocycliques, procede permettant de les preparer et leur utilisation pour traiter des affections hyperproliferatives
US6429214B1 (en) 1999-07-21 2002-08-06 Wyeth Bicyclic antagonists selective for the αvβ3 integrin
US6586187B1 (en) 1999-04-14 2003-07-01 Wyeth Methods for solid phase combinatorial synthesis of integrin inhibitors
US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
JP2004536095A (ja) * 2001-06-25 2004-12-02 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 苦痛治療用医薬としての置換された１−オキサ−２，８−ジアザ−スピロ［４．５］デセ−２−エン−誘導体
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6852318B1 (en) 1998-05-08 2005-02-08 The Regents Of The University Of California Methods for detecting and inhibiting angiogenesis
WO2005118528A3 (fr) * 2004-06-04 2006-01-26 Univ Aberdeen Aryle-alkyle sulfonamides utilises en tant qu'agents therapeutiques pour le traitement de pathologies osseuses
DE102005044814A1 (de) * 2005-05-19 2006-11-23 Grünenthal GmbH Substituierte Sprio-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln
DE102005023784A1 (de) * 2005-05-19 2006-11-30 Grünenthal GmbH Substituierte Spiro-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln
EP1739078A1 (fr) 2005-05-30 2007-01-03 Jerini AG Antagonistes du recepteur C5a
US7276589B2 (en) 2002-11-26 2007-10-02 Pdl Biopharma, Inc. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
DE102005044813A1 (de) * 2005-05-19 2007-10-04 Grünenthal GmbH Substituierte Spiro-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln
US7662384B2 (en) 2004-03-24 2010-02-16 Facet Biotech Corporation Use of anti-α5β1 antibodies to inhibit cancer cell proliferation
US8017116B2 (en) 2002-11-26 2011-09-13 Abbott Biotherapeutics Corp. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US8207167B2 (en) 2008-09-19 2012-06-26 Pimco 2664 Limited Aryl-phenyl-sulfonamide-phenylene compounds and their use
US8435968B2 (en) 2008-09-19 2013-05-07 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US8524778B2 (en) 2007-03-21 2013-09-03 Pimco 2664 Limited Biphenyl-4-yl-sulfonic acid arylamides and their use as therapeutic agents
US9624167B2 (en) 2013-06-26 2017-04-18 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10005733B2 (en) 2014-12-17 2018-06-26 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use

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JP6480653B2 (ja) * 2013-09-26 2019-03-13 株式会社トーキン 導電性高分子溶液

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EP0529858A1 (fr) * 1991-08-23 1993-03-03 Takeda Chemical Industries, Ltd. Composés de 2-pipérazinone, leur production et leur usage
WO1995014682A1 (fr) * 1993-11-24 1995-06-01 The Du Pont Merck Pharmaceutical Company Composes d'isoxazoline utiles en tant qu'antagonistes du recepteur fibrinogene
WO1995014683A1 (fr) * 1993-11-24 1995-06-01 The Du Pont Merck Pharmaceutical Company Nouveaux antagonistes de recepteur de fibrinogene, a base d'isoxazoline et d'isoxazole
WO1996037492A1 (fr) * 1995-05-25 1996-11-28 The Du Pont Merck Pharmaceutical Company Derives d'isoxazoline et d'isoxadole utilises comme antagonistes des recepteurs de l'integrine

Cited By (46)

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Publication number Priority date Publication date Assignee Title
US6214834B1 (en) 1997-03-28 2001-04-10 Dupont Pharmaceuticals Company Integrin inhibitor prodrugs
WO1998043962A1 (fr) * 1997-03-28 1998-10-08 Du Pont Pharmaceuticals Company Promedicaments heterocycliques inhibiteurs d'integrine
WO1999052872A1 (fr) 1998-04-09 1999-10-21 Meiji Seika Kaisha, Ltd. DERIVES D'AMINOPIPERIDINE COMME ANTAGONISTES D'INTEGRINE αvβ¿3?
US8454958B2 (en) 1998-05-08 2013-06-04 The Regents Of The University Of California Methods for detecting and inhibiting angiogenesis
WO1999058139A3 (fr) * 1998-05-08 2000-02-10 Univ California Procedes de detection et d'inhibition de l'angiogenese
AU746662B2 (en) * 1998-05-08 2002-05-02 Regents Of The University Of California, The Methods for detecting and inhibiting angiogenesis
EP2044955A3 (fr) * 1998-05-08 2009-04-29 The Regents of the University of California Procédé de détection et d'inhibition de l'angiogénèse
US6852318B1 (en) 1998-05-08 2005-02-08 The Regents Of The University Of California Methods for detecting and inhibiting angiogenesis
US7056506B2 (en) 1998-05-08 2006-06-06 The Regents Of The University Of California Methods for detecting and inhibiting angiogenesis
EP2327451A3 (fr) * 1998-05-08 2012-05-09 The Regents of the University of California Procédés de détection et d'inhibition de l'angiogénèse
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6586187B1 (en) 1999-04-14 2003-07-01 Wyeth Methods for solid phase combinatorial synthesis of integrin inhibitors
WO2000066593A3 (fr) * 1999-05-03 2001-05-31 Schering Ag Nouveaux composes spirocycliques, procede permettant de les preparer et leur utilisation pour traiter des affections hyperproliferatives
US6429214B1 (en) 1999-07-21 2002-08-06 Wyeth Bicyclic antagonists selective for the αvβ3 integrin
US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
US8557796B2 (en) 2001-06-25 2013-10-15 Gruenenthal Gmbh Substituted 1-oxa-2,8-diaza-spiro [4,5] dec-2-ene derivatives and related treatment methods
US8048890B2 (en) * 2001-06-25 2011-11-01 Gruenenthal Gmbh Substituted 1-oxa-2,8-diaza-spiro[4,5]dec-2-ene derivatives and related treatment methods
JP2004536095A (ja) * 2001-06-25 2004-12-02 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 苦痛治療用医薬としての置換された１−オキサ−２，８−ジアザ−スピロ［４．５］デセ−２−エン−誘導体
US8309084B2 (en) 2002-11-26 2012-11-13 Abbott Biotherapeutics Corp. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US8017116B2 (en) 2002-11-26 2011-09-13 Abbott Biotherapeutics Corp. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US7276589B2 (en) 2002-11-26 2007-10-02 Pdl Biopharma, Inc. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US7897148B2 (en) 2002-11-26 2011-03-01 Abbott Biotherapeutics Corp. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US7776585B2 (en) 2002-11-26 2010-08-17 Facet Biotech Corporation Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US7879987B2 (en) 2002-11-26 2011-02-01 Facet Biotech Corporation Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US7662384B2 (en) 2004-03-24 2010-02-16 Facet Biotech Corporation Use of anti-α5β1 antibodies to inhibit cancer cell proliferation
WO2005118528A3 (fr) * 2004-06-04 2006-01-26 Univ Aberdeen Aryle-alkyle sulfonamides utilises en tant qu'agents therapeutiques pour le traitement de pathologies osseuses
US7964643B2 (en) 2004-06-04 2011-06-21 The University Court Of The University Of Aberdeen Aryl alkyl sulfonamides as therapeutic agents for the treatment of bone conditions
EP2292625A1 (fr) * 2005-05-19 2011-03-09 Grünenthal GmbH Composés spiro substitués, et leur utilisation pour produire des médicaments contre la douleur
DE102005044814A1 (de) * 2005-05-19 2006-11-23 Grünenthal GmbH Substituierte Sprio-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln
WO2006122769A3 (fr) * 2005-05-19 2007-03-15 Gruenenthal Gmbh Composes spiro substitues, et leur utilisation pour produire des medicaments
US8772307B2 (en) 2005-05-19 2014-07-08 Gruenenthal Gmbh Substituted spiro compounds and their use for producing pain-relief medicaments
DE102005044813A1 (de) * 2005-05-19 2007-10-04 Grünenthal GmbH Substituierte Spiro-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln
DE102005023784A1 (de) * 2005-05-19 2006-11-30 Grünenthal GmbH Substituierte Spiro-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln
EP1739078A1 (fr) 2005-05-30 2007-01-03 Jerini AG Antagonistes du recepteur C5a
US8524778B2 (en) 2007-03-21 2013-09-03 Pimco 2664 Limited Biphenyl-4-yl-sulfonic acid arylamides and their use as therapeutic agents
US8435968B2 (en) 2008-09-19 2013-05-07 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US8207167B2 (en) 2008-09-19 2012-06-26 Pimco 2664 Limited Aryl-phenyl-sulfonamide-phenylene compounds and their use
US8822507B2 (en) 2008-09-19 2014-09-02 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US9050329B1 (en) 2008-09-19 2015-06-09 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US9302984B2 (en) 2008-09-19 2016-04-05 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US9616037B2 (en) 2008-09-19 2017-04-11 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US9624167B2 (en) 2013-06-26 2017-04-18 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US9796670B2 (en) 2013-06-26 2017-10-24 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10029979B2 (en) 2013-06-26 2018-07-24 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10233147B2 (en) 2013-06-26 2019-03-19 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10005733B2 (en) 2014-12-17 2018-06-26 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use

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AU2421797A (en) 1997-10-01
JP2001527513A (ja) 2001-12-25
CA2249733A1 (fr) 1997-09-18

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