WO1996037492A1 - Derives d'isoxazoline et d'isoxadole utilises comme antagonistes des recepteurs de l'integrine - Google Patents

Derives d'isoxazoline et d'isoxadole utilises comme antagonistes des recepteurs de l'integrine Download PDF

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Publication number
WO1996037492A1
WO1996037492A1 PCT/US1996/007646 US9607646W WO9637492A1 WO 1996037492 A1 WO1996037492 A1 WO 1996037492A1 US 9607646 W US9607646 W US 9607646W WO 9637492 A1 WO9637492 A1 WO 9637492A1
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Prior art keywords
propionic acid
isoxazolin
ylamino
ylcarbonylamino
alkyl
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PCT/US1996/007646
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English (en)
Inventor
Matthew Ernst Voss
Prabhakar Kondaji Jadhav
Joanne Marie Smallheer
Douglas Guy Batt
William John Pitts
John Wityak
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The Du Pont Merck Pharmaceutical Company
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Priority claimed from US08/647,132 external-priority patent/US5710159A/en
Application filed by The Du Pont Merck Pharmaceutical Company filed Critical The Du Pont Merck Pharmaceutical Company
Priority to JP8535899A priority Critical patent/JPH11506436A/ja
Priority to AU58762/96A priority patent/AU5876296A/en
Priority to MX9708840A priority patent/MX9708840A/es
Priority to EP96920476A priority patent/EP0828737A1/fr
Publication of WO1996037492A1 publication Critical patent/WO1996037492A1/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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • 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
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to novel heterocycles which are useful as antagonists of the ⁇ v ⁇ 3 and related
  • integrin 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 and the treatment of angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell
  • Angiogenesis or neovascularization is critical for normal physiological processes such as embryonic
  • angiogenesis 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. Dermatol., 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. Based on this property, therapeutic utility of such agents is expected in human diseases such as cancer, rheumatoid arthritis and ocular vasculopathies (Folkman and Shing, J. Biol. Chem., 1992, 267 : 10931-10934).
  • 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.
  • Antibodies to ⁇ 4 prevent adhesion of lymphocytes to synovial endothelial cells in vitro, a process which may be of importance in rheumatoid arthritis (VanDinther- Janssen et al., J. Immunol., 1991, 147:4207).
  • ⁇ 4/ ⁇ 1 may additionally have a role in allergy, asthma, and autoimmune disorders (Walsh et al., J. Immunol., 1991, 146:3419; Bochner et al., J. Exp. Med., 1991 173:1553; Yednock et al., Nature, 1992, 356:63).
  • Anti- ⁇ 4 antibodies also block the migration of leukocytes to the site of inflammation (Issedutz et al., J. Immunol., 1991, 147:4178).
  • 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).
  • 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 treatment of angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell aggregation-related conditions in a mammal.
  • One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the ⁇ v / ⁇ 3 or vitronectin receptor.
  • the compounds of the present invention inhibit the binding of vironectin to ⁇ v / ⁇ 3 and inhibit cell adhesion.
  • 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 angiogenic disorders.
  • the present invention also provides novel
  • osteoarthritis atherosclerosis, metastasis, wound healing, diabetic retinopathy, ocular vasculopathies, thrombosis, inflammatory bowel disease and other
  • kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula I, for the treatment of cell adhesion related disorders, including, but not limited to, angiogenic disorders.
  • 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 treatment of angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell
  • One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the ⁇ v / ⁇ 3 or vitronectin receptor.
  • the compounds of the present invention inhibit the binding of vitronectin to ⁇ v / ⁇ 3 and inhibit cell adhesion.
  • 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 angiogenic disorders.
  • the present invention comprises compounds of the Formula I: including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein: b, the bond between carbon atoms numbered 4 and 5, is a carbon-carbon single or double bond; R 1 is selected from:
  • a and B are independently -CH 2 -, -O-, -N(R 12 )-, or
  • a 1 and B 1 are independently -CH 2 - or -N(R 10 )-;
  • J, K, L and M are independently selected from -C(R 2 )- or -N-, provided that at least one of J, K, L and M is -C(R 2 )-;
  • R 2 and R 3 are independently selected from: H, C 1 -C 4
  • NR 11 R 12 NR 12 , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 6 -C 10 carbonyl or C 7 -C 11 arylcarbonyl; alternatively, R 2 and R 3 , when substituents on adjacent atoms, 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 nonaromatic ring system said carbocyclic or heterocyclic ring being optionally substituted with 0-2 R 7 ;
  • R 2a is absent or R 12 ;
  • U is selected from:
  • V is selected from:
  • Q is selected from:
  • W is selected from:
  • X is selected from:
  • Y is selected from:
  • Z is selected from -CH(R 9 )-, or -N(R 16 )-;
  • R 4 is selected from H, C 1 -C 10 alkyl, C 1 -C 10
  • R 5 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 7 -C 14 bicycloalkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, nitro, C 1 -C 6 alkylcarbonyl, C 6 -C 10 aryl, -N(R 11 -)R 12 , halo, CF 3, CN, C 1 -C 6 alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl; R 6 is selected from:
  • R 6 is a substituent on aryl, or a 5-10 membered heterocyclic ring containing 1-3 N, 0, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7 ;
  • R 7 is selected from:
  • R 8 is selected from:
  • heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7 ;
  • R 9 is selected from H, hydroxy, C 1 -C 10 alkoxy, nitro,
  • R 10 is selected from H, C 1 -C 8 alkyl, C 3 -C 6 alkenyl,
  • R 11 is selected from hydrogen, hydroxy, C 1 to C 8 alkyl, C 3 -C 6 alkenyl, C 3 to C 11 cycloalkyl, C 4 to C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 to C 10 aryl, heteroaryl, heteroarylalkyl, C 7 to C 11 arylalkyl, adamantylmethyl, or C 1 -C 10 alkyl
  • R 10 and R 11 when both are substituents on the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
  • cycloalkylcarbonyl C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
  • R 12 is selected from:
  • alkoxycarbonyl C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkylsulfonyl, aryl(C 1 -C 10 alkyl)sulfonyl,
  • arylsulfonyl aryl(C 2 -C 10 alkenyl) sulfonyl
  • heteroarylsulfonyl aryl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 7 -C 11
  • aryl(C 1 -C 10 alkoxy) carbonyl wherein said aryl groups are optionally substituted with 0-3
  • R 13 is selected from: H, hydroxy, C 1 -C 10 alkoxy, nitro, N(R 10 )R 11 , -N(R 16 )R 17 , C 1 -C 10 alkyl substituted with 0-3 R 7 , aryl substituted with 0-3 R 7 , heteroaryl substituted with 0-3 R 7 , or C 1 -C 10 alkylcarbonyl;
  • R 15 is selected from:
  • heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7 ;
  • R 16 is selected from:
  • R 17 is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 - C 11 cycloalkyl, C 4 -C 15 cycloalkylalkyl, aryl, aryl (C 1 -C 10 alkyl)-;
  • R 18 a is selected from:
  • aryl(C 1 -C 6 alkyl)- substituted with 0-4 R 19 a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R 19 ,
  • heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R 19 ;
  • R 18b is selected from R 18a or H
  • R 19 is selected from H, halogen, CF 3 , CO 2 H, CN, NO 2 ,
  • NR 11 R 12 C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl,
  • aryl(C 1 -C 6 alkyl)- C 1 -C 6 alkoxy, OCF 3 , or C 1 -C 4 alkoxycarbonyl, aryl, -O-aryl, -SO 2 -aryl,
  • heteroaryl or -SO 2 -heteroaryl, wherein said aryl and heteroaryl groups may be substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
  • R 20 is selected from hydroxy, C 1 to C 10 alkyloxy, C 3 to C 11 cycloalkyloxy, C 6 to C 10 aryloxy, C 7 to C 11 arylalkyloxy, C 3 to C 10 alkylcarbonyloxyalkyloxy, C 3 to C 10 alkoxycarbonyloxyalkyloxy, C 2 to C 10
  • alkoxycarbonylalkyloxy C 5 to C 10
  • R 21 is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 5 ;
  • R 22 is selected from:
  • n 0-4;
  • P is 0-2;
  • s 0-1; with the following provisos:
  • n, m and q are chosen such that the number of atoms connecting R 1 and Y is in the range of 8 - 14;
  • Preferred compounds of the present invention are compounds of Formula I:
  • stereoisomeric forms thereof or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein: b, the bond between carbon atoms numbered 4 and 5, is a carbon-carbon single or double bond; A is selected from -CH 2 -, or -N(R 12 )-;
  • a 1 and B are independently -CH 2 - or -N(R 10 )-;
  • D is -N(R 12 )-, or -S-;
  • J is either -C(R 2 )- or -N-, and K, L and M are
  • R 2 and R 3 are independently selected from: H, C 1 -C 4
  • R 2 and R 3 when substituents on adjacent atoms, can be taken together when substituents on adjacent atoms, with the carbon atoms to which they are attached, to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic with the carbon atoms to which they are attached, aromatic or nonaromatic ring system, said
  • carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 or NO 2 ;
  • R 2a is absent or R 12 ;
  • U is selected from:
  • V is selected from:
  • W is selected from:
  • X is selected from:
  • X is either absent or -CH 2 - Y is selected from:
  • Z is selected from -CH(R 9 )-, or -N(R 16 )-;
  • R 4 is selected from H, C 1 -C 10 alkyl, C 1 -C 10
  • R 6 is selected from:
  • R 7 is selected from selected from H, C 1 - C 4 alkyl , hydroxy, C 1 - C 4 alkoxy, C 6 - C 10 aryl , C 7 - C 11
  • arylalkyl (C 1 - C 4 alkyl) carbonyl , CO 2 R 18a , SO 2 R 11 , SO 2 NR 10 R 11 , OR 10 , or N (R 11 ) R 12 ;
  • R 8 is selected from:
  • heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7 ;
  • R 9 is selected from H, hydroxy, C 1 -C 10 alkoxy, nitro,
  • R 10 is selected from H, C 1 -C 8 alkyl, C 3 -C 6 alkenyl,
  • R 11 is selected from hydrogen, hydroxy, C 1 to C 8 alkyl, C 3 -C 6 alkenyl, C 3 to C 11 cycloalkyl, C 4 to C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 to C 10 aryl, heteroaryl, heteroarylalkyl, C 7 to C 11 arylalkyl, adamantylmethyl, or C 1 -C 10 alkyl
  • R 10 and R 11 when both are substituents on the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
  • cycloalkylcarbonyl C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl,C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
  • R 12 is selected from:
  • cycloalkyl C 4 -C 11 cycloalkylalkyl, aryl,
  • heteroarylcarbonyl aryl C 1 -C 6 alkyl, (C 1 -C 6 alkyl)carbonyl, or arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6
  • alkyl alkylsulfonyl, heteroarylsulfonyl,
  • R 13 is selected from: H, hydroxy, C 1 -C 10 alkoxy, nitro, N(R 10 )R 11 , -N(R 16 )R 17 , C 1 -C 10 alkyl substituted with 0-3 R 7 , aryl substituted with 0-3 R 7 , heteroaryl substituted with 0-3 R 7 , or C 1 -C 10 alkylcarbonyl;
  • cycloalkylalkyl substituted with 0-1 R 9 aryl substituted with 0-1 R 9 or 0-2 R 7 , or aryl(C 1 -C 6 alkyl)- substituted with 0-1 R 9 or 0-2 R 7 ;
  • R 16 is selected from:
  • R 17 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl,
  • R 18 a is selected from: C 1 -C 8 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, biaryl(C 1 -C 6 alkyl), heteroaryl, or aryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19 ;
  • R 18b is selected from R 18a or H;
  • R 19 is selected from H, halogen, CF 3 , CO 2 H, CN, NO 2 ,
  • NR 11 R 12 C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl,
  • R 20 is selected from hydroxy, C 1 to C 10 alkyloxy, C 3 to C 11 cycloalkyloxy, C 6 to C 10 aryloxy, C 7 to C 11 aralkyloxy, C 3 to C 10 alkylcarbonyloxyalkyloxy, C 3 to C 10 alkoxycarbonyloxyalkyloxy, C 2 to C i0
  • alkoxycarbonylalkyloxy C 5 to C 10
  • R 21 is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 7 ;
  • R 22 is selected from:
  • n 0-4;
  • P is 0-2;
  • r 0-2;
  • s 0-1; with the following provisos:
  • n, m and q are chosen such that the number of atoms connecting R 1 and Y is in the range of 8-14;
  • R 2 and R 3 are independently selected from: H, C 1 -C 4
  • R 2 and R 3 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 nonaromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 R 7 ;
  • U is selected from:
  • V is selected from:
  • Q is selected from:
  • W is selected from:
  • X is - ( CH 2 ) q - CH (R 8 ) - CH (R 9 ) - ;
  • Y is - COR 20 ;
  • R 6 is selected from:
  • a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,
  • R 7 is selected from:
  • R 8 is selected from:
  • aryl substituted with 0-1 R 6 or, a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl,
  • R 9 is selected from: H or -N(R 16 )R 17 ;
  • R 10 is selected from H or C 1 -C 10 alkyl, or C 7 -C 10
  • R 11 is selected from hydrogen, hydroxy, Ci to Cs alkyl, C 3 -C 6 alkenyl, C 3 to C 11 cycloalkyl, C 4 to C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, Cg to C 10 aryl, heteroaryl, heteroarylalkyl, C 7 to C 11 arylalkyl, adamantylmethyl, or C 1 -C 10 alkyl
  • R 10 and R 11 when both are substituents on the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
  • cycloalkylcarbonyl C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl,C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
  • R 12 is selected from:
  • alkoxycarbonyl C 1 -C 6 alkylcarbonyl, C 1 -C 6
  • alkylsulfonyl aryl (C 1 -C 4 alkyl) sulfonyl,
  • heteroarylalkylcarbonyl wherein said aryl groups are substituted with 0-3 substituents selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and NO 2 ;
  • R 13 is selected from: H, hydroxy, C 1 -C 10 alkoxy,
  • R 16 is selected from:
  • R 17 is selected from H or C 1 -C 4 alkyl
  • R 18 a is selected from:C 1 -C 6 alkyl, C 3 -C 11 cycloalkyl, aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) aryl,
  • R 18 b is selected from R 18a or H;
  • R 19 is selected from H, halogen, CF 3 , CO 2 H, CN, NO 2 ,
  • NR 11 R 12 C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl,
  • heteroaryl or -SO 2 -heteroaryl, wherein said aryl and heteroaryl groups may be substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
  • R 20 is selected from:
  • R 21 is selected from C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 4 ; m is 0-2;
  • n 0-4;
  • P is 0-2;
  • r 0-2; with the following provisos:
  • n, m and q are chosen such that the number of atoms connecting R 1 and Y is in the range of 8-14;
  • R 1 -U taken together are selected from:
  • R 2 and R 3 are independently selected from: H, C 1 -C 4
  • V is selected from:
  • Q is selected from: - ( CH 2 ) n- ,
  • R 7 is selected from:
  • R 8 is selected from:
  • R 18a C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 8 cycloalkyl, pyridinyl, or aryl, wherein said aryl or pyridinyl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, halo, cyano, CF 3 , and NO 2 .
  • R 9 is selected from: H or -NHR 16 ;
  • R 10 is selected from H or C 1 -C 10 alkyl
  • R 11 is selected from hydrogen, hydroxy, C 1 to C 8 alkyl, C 3 -C 6 alkenyl, C 3 to C 11 cycloalkyl, C 4 to C 11 cycloalkylmethyl,C 1 -C 6 alkoxy, benzyloxy, C 6 to C 10 aryl, heteroaryl, heteroarylalkyl, C 7 to C 11 arylalkyl, or adamantylmethyl;
  • R 13 is selected from: H, hydroxy, C 1 -C 10 alkoxy,
  • R 16 is selected from:
  • R 18 a is selected from: C 1 -C 8 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, biaryl(C 1 -C 6 alkyl), heteroaryl, or aryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-2 R 19 ;
  • R 19 is selected from: H, Br, F, CI, CF 3 , CN, NO 2 , NHR 11 , C 1 -C 4 alkyl, aryl, aryl(C 1 -C 4 alkyl)-, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, or -O-aryl, wherein said aryl groups are optionally substituted with 0-3
  • substituents selected from a group consisting of halogen, CF 3 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
  • R 20 is selected from:
  • n is C-4;
  • q is 0-1; with the proviso that n, and q are chosen such that the number of atoms connecting R 1 and COR 20 is in the range of 8-14;
  • enantiomeric or diasteriomeric forms thereof or mixtures of enantiomeric or diasteriomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof selected from the group consisting 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 effective amount of such compound of Formula I.
  • 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 includes conditions involving abnormal neovascularization, such as tumor metastasis and ocular neovascularization, including, for example, diabetic retinopathy, 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
  • 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 thrombophlebitis
  • arterial embolism coronary and cerebral arterial thrombosis
  • myocardial infarction cerebral embolism
  • kidney embolisms pulmonary embolisms
  • 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 or “combination therapy” it is meant that the compound of Formula I and one or more additional therapeutic agents are
  • anti-coagulant agents or coagulation inhibitory agents
  • agents that inhibit blood coagulation include warfarin (available as COUMADIN TM ) and heparin.
  • anti-platelet agents or platelet
  • inhibitory agents denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of
  • Such agents include the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • ASA acetylsalicyclic acid
  • Piroxicam is commercially available from Pfizer Inc.
  • Suitable anti- platelet agents include ticlopidine, including
  • 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 denotes inhibitors of the serine protease thrombin.
  • anti-thrombin agents 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,
  • Tissue plasminogen activator tPA
  • anistreplase refers to anisoylated plasminogen streptokinase
  • EMINASE TM European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by reference herein, in their entirety.
  • Anistreplase is commercially available as EMINASE TM .
  • the term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
  • 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 .
  • the compounds herein described may have asymmetric centers.
  • substituted carbon atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically
  • 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.
  • 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.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, “C 1 -C 10 " denotes alkyl having 1 to 10 carbon atoms); “haloalkyl” is intended to include both branched and straight-chain saturated aliphatic
  • 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
  • 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 tt 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
  • 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 monocylic 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!
  • 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.
  • “Prodrugs” are considered to be 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.
  • Examples of representative carboxyl and amino prodrugs are included under the definition of R 2 , R 3 , and Y.
  • 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. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g.,
  • dibenzylethylenediamine trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum 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
  • 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.
  • heterocycle is a 3, 5-disubstituted isoxazoline ring 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, Heterocycles 1990, 30, 719).
  • the requisite nitrile oxides are in turn prepared from the corresponding aldehydes via the intermediate oximes.
  • Scheme I illustrates one synthetic sequence which will provide the 3 , 5-isoxazolines of this invention.
  • hydroxylamine is treated with NCS in DMF according to the method of Liu, et al. (J. Org. Chem. 1980, 45, 3916).
  • the resulting hydroximinoyl chloride is then dehydrohalogenated in situ using TEA to give a nitrile oxide, which undergoes a 1,3-dipolar cycloaddition to a suitably substituted alkene to afford the isoxazoline.
  • the oxime may be oxidatively chlorinated, dehydrochlorinated and the resulting nitrile oxide trapped by a suitable alkene under phase transfer conditions according to the method of Lee (Synthesis 1982, 508).
  • Additional isoxazolinyl acetates useful as starting materials for the preparation of compounds of Formula I, wherein V is -(phenyl)-Q- and Q is other than a single bond can be prepared by cycloaddition of a suitably substituted chloro or bromooxime with an ester of vinyl acetic acid as shown in Scheme lb using literature methods or modifications thereof.
  • Y is an oxyalkoxy group, e.g.
  • alkoxycarbonyloxyalkoxy may be prepared by reacting a suitably protected carboxylic acid of Formula I with an e.g. an alkoxycarbonyloxyalkyl chloride in the presence of an iodide source, such as tetrabutylammonium iodide or potassium iodide, and an acid scavenger, such as triethylamine or potassium carbonate, using procedures known to those skilled in the art.
  • an iodide source such as tetrabutylammonium iodide or potassium iodide
  • an acid scavenger such as triethylamine or potassium carbonate
  • racemic ⁇ -amino acids may be purchased commercially or, as is shown in Scheme II, 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 I, 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
  • N 2 - substituted diaminopropionic acid derivatives can be carried out via Hoffman
  • the dipolarophiles used to prepare the compounds of this invention may be prepared by numerous methods.
  • the ⁇ -alkenoic ester class of dipolarophile may be purchased commercially or prepared by oxidation of the
  • reverse isoxazolines may be prepared by reaction of an appropriate nitro ester with an appropriately
  • dehydrating agent such as phenylisocyanate or phosphorus oxychloride in the presence of an organic amine base, such as triethylamine or diisopropylethylamine.
  • N-protected aminoalkenes useful in the synthesis of compounds of this invention can be prepared from the commercially available alcohols as shown in Scheme IVb, via reaction with a suitable activating agent such as p- toluenesulfonyl chloride in the presence of a base such as pyridine, followed by displacement with sodium azide in a suitable solvent such as DMF. Reduction of the azide by the action of triphenylphosphine in the presence of water (for example see, Scriven, E. F.V., Turnbull, K., Chemical Rev. 1988, 88, 297-360, and the references therein ) provides an amine which is suitably protected, for example, Fmoc, Boc or phthalimide group according to literature procedures. (Protecting Groups in Organic Synthesis 2nd Ed. Green, T. W., Wits, P. G. M. pp 309-406. 1991 John Wiley & Sons, Inc. NY)
  • nitroesters are available from commercial sources or can be synthesized according to literature methods (Seebach, D.et al., Chem. Ber. 1982, 115, 1705-1720; Chaser. D.W., Syn. Comm. 1982, 841-842).
  • Oxidation of theresuiting alcohol the corresponding aldehyde can be achieved by numerous methods described in the literature (for example see Comprehensive Organic Transformations by Larock, R.C., p 604, 605, 607-613. VCH publishers, New York, New York, 1989). Reductive amination of the intermediate aldehyde (for suitable methods see, Abdel-Magid, A. F., Maryanoff, C. A., and Carson, K.G., Tetrahedron Lett., 1990, 31, 5595-5598, and references contained therein ) with a variety of heteroaryl amines, which may
  • the reductive amination can be carried out in a two step procedure, wherein initial formation of an imine is carried out by treatment of the aldehyde with the desired amine in the presence of a dehydrating agent such as magnesium sulfate, sodium sulfate, or molecular sieves, in a suitable solvent such as carbon
  • the imine is then subsequently reduced with a variety of reducing agents such as sodium borohydride, sodium cyanoborohydride, or sodium
  • Coupling of the resulting acids to an appropriately substituted ⁇ - or ⁇ -amino ester is accomplished using standard coupling reagents, as described above.
  • Bases suitable for this reaction include alkaline hydrogen carbonates, alkaline carbonates, cesium carbonate, alkaline hydrides, and alkaline alcoholates such as sodium ethoxide and potassium t- butoxide.
  • the reaction can be run in a number of different solvents including lower alkyl and branched alcohols, ethereal solvents, or halocarbons, but it proceeds most readily in polar aprotic solvents such as DMF and DMSO. Saponification of the ester using standard conditions known to one skilled in the art provides an acid intermediate which can be converted using the methods described above into compounds of Formula I.
  • Heterocyclic alkenes and aldehydes useful as intermediates for the preparation of compounds of formula I in the methods depicted in Schemes I -VII can be prepared as illustrated in Scheme Villa and Vlllb.
  • the carboxylic acids prepared in scheme III can be converted to an acid halide, by a variety of methods, such as treatment with oxalyl chloride or thionyl chloride either neat or in the presence of a suitable solvent such as methylene chloride or toluene, as outlined in the literature (for example, see
  • the ⁇ - haloketone can be treated with N-acetylguanidine in a suitable solvent such as acetonitrile from room
  • the lithio intermediate can be trapped with a variety of electrophiles such as formaldehyde, ethylene oxide or 3-
  • the reductive amination can be carried out on appropriate esterified ⁇ -hydroxy aldehydes, as outlined in method B.
  • the resulting amines can be converted to additional compound of formula I by treatment with a wide variety of reagents, for example, acyl halides, chloroformates, isocyanates, sulfonylchlorides, chlorosulfonamides, and sulfonylisocyanates, etc. using standard methods.
  • reagents for example, acyl halides, chloroformates, isocyanates, sulfonylchlorides, chlorosulfonamides, and sulfonylisocyanates, etc. using standard methods.
  • N-(4-Oxobutyl)phthalimide Oxalyl Chloride (4.01ml; 46mmol) in 90ml dichloromethane was cooled at -78°C in a dry ice-acetone bath. Dimethylsulfoxide (4.26ml;
  • Triethylamine (23g; 230mmol) in 23ml dichloromethane was then added and the stirred for an additional 30 minutes. The mixture was worked up by washing with water. The organic layer was separated, dried (MgSO 4 ), filtered, concentrated and the residue purified by flash
  • part G (199mg; 0.5mmol), methyl 3 -amino-2-phenylsulfonylaminopropionate (147mg; 0.5mmol), and triethylamine (100mg; lmmol) in 3ml dimethylformamide was treated with 265mg (0.6mmol) of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP Reagent) and the mixture stirred at room temperature for 18 hours. TLC indicated no starting material; the mixture was pumped to remove most of the dimethylformamide.
  • BOP Reagent benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
  • 5-Hexene-1-ol (5.0g, 0.05M) was dissolved in 30 mL of tetrahydrofuran, an aqueous solution of NaHCO 3 (29.4g,

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Abstract

Cette invention se rapporte à de nouveaux composés hétérocycliques comprenant notamment, mais pas exclusivement, l'acide 3-[3-[3-(imidazoline-2-yl- amino)propyloxy]isoxasol-5-ylcarbonylamino]-2-(benzyloxycarbonylamino)-propionique et qui sont utilisés comme antagonistes des récepteurs αvβb3 et de l'intégrine apparentée. L'invention se rapporte également aux compositions pharmaceutiques contenant ces composés, aux procédés de préparation et d'utilisation de ces composés, seuls ou associés à d'autres agents thérapeutiques et destinés à être utilisés dans des procédés d'inhibition de l'adhésion cellulaire et de traitement de troubles angiogéniques, des inflammations, de la déperdition osseuse, des tumeurs, des métastases, de la thrombose et d'autres états apparentés à l'agrégation cellulaire.
PCT/US1996/007646 1995-05-25 1996-05-24 Derives d'isoxazoline et d'isoxadole utilises comme antagonistes des recepteurs de l'integrine WO1996037492A1 (fr)

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JP8535899A JPH11506436A (ja) 1995-05-25 1996-05-24 インテグリン受容体拮抗剤としてのイソオキサゾリンおよびイソオキサゾール誘導体
AU58762/96A AU5876296A (en) 1995-05-25 1996-05-24 Isoxazoline and isoxazole derivatives as integrin receptor antagonists
MX9708840A MX9708840A (es) 1995-05-25 1996-05-24 Derivados de isoxazolina e isoxazol como antagonistas del receptor integrina.
EP96920476A EP0828737A1 (fr) 1995-05-25 1996-05-24 Derives d'isoxazoline et d'isoxadole utilises comme antagonistes des recepteurs de l'integrine

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WO1997033887A1 (fr) * 1996-03-15 1997-09-18 Du Pont Pharmaceuticals Company Inhibiteurs de l'integrine spirocycle
WO1997036860A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. Derives de l'acide cinnamique et leur utilisation comme antagonistes de l'integrine
WO1997048395A1 (fr) * 1996-06-19 1997-12-24 Du Pont Pharmaceuticals Company Administration iontophoretique d'inhibiteurs de l'integrine
US5760029A (en) * 1996-03-15 1998-06-02 The Dupont Merck Pharmaceutical Company Spirocycle integrin inhibitors
US5760028A (en) * 1995-12-22 1998-06-02 The Dupont Merck Pharmaceutical Company Integrin receptor antagonists
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?
WO2000075129A1 (fr) * 1999-06-07 2000-12-14 Shire Biochem Inc. Inhibiteurs d'integrine thiophene
WO2001051487A1 (fr) * 1999-12-28 2001-07-19 Pfizer Products Inc. Inhibiteurs non peptidyle de liaison cellulaire dependant de vla-4 utiles pour le traitement de maladies inflammatoires, auto-immunes et respiratoires
US6429214B1 (en) 1999-07-21 2002-08-06 Wyeth Bicyclic antagonists selective for the αvβ3 integrin
US6566381B1 (en) * 1999-03-03 2003-05-20 The Procter & Gamble Company Hetero-substituted metalloprotease inhibitors
US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
WO2005118528A2 (fr) * 2004-06-04 2005-12-15 The University Court Of The University Of Aberdeen Aryle-alkyle sulfonamides utilises en tant qu'agents therapeutiques pour le traitement de pathologies osseuses
WO2006090234A1 (fr) * 2005-02-22 2006-08-31 Ranbaxy Laboratories Limited Derives heterocycliques utilises en tant qu'inhibiteurs d'adherence cellulaire
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US9505728B2 (en) 2012-03-09 2016-11-29 Inception 2, Inc. Triazolone compounds and uses thereof
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US9676754B2 (en) 2012-12-20 2017-06-13 Inception 2, Inc. Triazolone compounds and uses thereof
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US11603365B2 (en) 2015-12-22 2023-03-14 Board Of Regents, The University Of Texas System Salt forms and polymorphs of (r)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-n-methyl-1H-1,2,3-triazole-4-carboxamide
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KR100594544B1 (ko) * 2003-08-27 2006-06-30 주식회사 엘지생명과학 이소옥사졸린 구조를 갖는 캐스파제 저해제
DK3538528T3 (da) * 2016-11-08 2021-02-15 Bristol Myers Squibb Co Pyrrolamider som alpha v-integrinhæmmere

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WO1997033887A1 (fr) * 1996-03-15 1997-09-18 Du Pont Pharmaceuticals Company Inhibiteurs de l'integrine spirocycle
WO1997036860A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. Derives de l'acide cinnamique et leur utilisation comme antagonistes de l'integrine
US6185453B1 (en) 1996-06-19 2001-02-06 Dupont Pharmaceuticals Company Iontophoretic delivery of integrin inhibitors
WO1997048395A1 (fr) * 1996-06-19 1997-12-24 Du Pont Pharmaceuticals Company Administration iontophoretique d'inhibiteurs de l'integrine
US6214834B1 (en) 1997-03-28 2001-04-10 Dupont Pharmaceuticals Company Integrin inhibitor prodrugs
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WO1999052872A1 (fr) 1998-04-09 1999-10-21 Meiji Seika Kaisha, Ltd. DERIVES D'AMINOPIPERIDINE COMME ANTAGONISTES D'INTEGRINE αvβ¿3?
US6566381B1 (en) * 1999-03-03 2003-05-20 The Procter & Gamble Company Hetero-substituted metalloprotease inhibitors
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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
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US8524778B2 (en) 2007-03-21 2013-09-03 Pimco 2664 Limited Biphenyl-4-yl-sulfonic acid arylamides and their use as therapeutic agents
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MX9708840A (es) 1998-03-31
EP0828737A1 (fr) 1998-03-18
JPH11506436A (ja) 1999-06-08
AU5876296A (en) 1996-12-11
CA2221980A1 (fr) 1996-11-28

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