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  • 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
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  • A61P19/00—Drugs for skeletal disorders
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  • 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
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  • 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. Biol. Chem. 1992, 267:10931-10934: D'Amore and Thompson, Ann. Rev. Physiol. 1987, !_:453-464) .
• angiogenesis also occurs pathologically, for example, in ocular neovascularization (leading to diabetic retinopathy, neovascular glaucoma, retinal vein occlusion and blindness) , in rheumatoid arthritis and in solid tumors (Folkman and Shing, J. Biol. Chem., 1992, 2£2:10931-10934; Blood and Zetter, Biochim. Biophys. Acta., 1990, ⁇ __2:118-128).
• 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 nourishment to divide and will not be able to leave the primary tumor site (Folkman and Shing, J. Biol. Chem., 1992, 267:10931-10934) .
• 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, 102:381-386). 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, ⁇ 9_: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 ⁇ y ⁇ 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.
• the basement membrane zones of blood vessels express several adhesive proteins, including 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 ctv ⁇ 3 , the endothelial cell, fibroblast, and smooth muscle cell receptor for adhesive proteins including von Willebrand factor, fibrinogen (fibrin) , vitronectin, thro bospondin, 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, restenosis, thromoembolic disorders, rheumatoid arthritis and ocular vasculopathies (Folkman and Shing, J. Biol. Chem., 1992, 2 l-10931-10934) .
• integrins a gene superfamily
• 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 o- v ⁇ 3 heterodimer is a member of the ⁇ 3 integrin subfamily and has been described on platelets, endothelial cells, melanoma, smooth muscle cells, and osteoclasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies et al. , J. Cell. Biol. 1989, 1___:1817- 1826; Horton, Int. J. Exp. Pathol. , 1990, 21:741-759).
• 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 01 ⁇ 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) .
• 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 compounds of Formula I (described below) which are useful as antagonists of the 0: ⁇ 3 integrin, which is also referred to as the vitronectin receptor.
• the compounds of the present invention inhibit the binding of vitronectin or other RGD-containing ligands to ⁇ 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 disorders mediated by angiogenesis.
• Another aspect of the present invention comprises agents that inhibit the binding of vitronectin to the ot 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 coagulation. Also the compounds of the current invention can be used for the treatment or prevention of restenosis.
• the present invention also provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment or prevention of other diseases which involve cell adhesion processes, 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, wound healing, diabetic retinopathy, ocular vasculopathies, thrombosis, inflammatory bowel disease and other autoimmune diseases.
• diseases which involve cell adhesion processes, 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, wound healing, diabet
• 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 ⁇ 3 or vitronectin receptor.
• the compounds of the present invention inhibit the binding of vitronectin and other RGD-containing ligands to ctv ⁇ 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 spirocyclic compounds of Formula I:
• A is selected from -N(R 10 )-, -C(R 11 )- or -0-;
• a 1 is selected from -0- or -N(R 10 )-;
• Z is a spiro-fused 4-7 membered ring system (including the sprio atom) containing 0-2 heteroatoms selected from 0, S, or N, said ring system optionally being substituted on carbon with keto, or being substituted on carbon or nitrogen independently with 0-2 R 9 or R 10 or R 10a ;
• 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 ⁇ -C 6 alkyl, (C ⁇ -C 6 alkyl) carbonyl, (Ci-C ⁇ alkoxy) carbonyl; (C ⁇ -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl (C1-C6 alkyl) carbonyl, heteroarylcarbonyl, aryl Ci-C ⁇ alkyl, (Ci-C ⁇ alkyl) carbonyl, arylcarbonyl, Ci-C ⁇ alkylsulfonyl, arylsulfonyl, aryl (Ci-C ⁇ alkyl)sulfonyl, heteroarylsulfonyl, heteroarylsulfonyl, heteroaryl, heteroary
• R 3 isselected from: H, Ci-C ⁇ alkyl, C 3 -C 7 cycloalkyl, C 4 - C1 1 cycloalkylalkyl, aryl, aryl(C ⁇ -C6 alkyl)-, or heteroaryl (C1-C6 alkyl) - ;
• R 4 and R 5 are independently selected from: H, C 1 -C 4 alkoxy, NR 2 R 3 , halogen, NO2, CN, CF 3 , Ci-C ⁇ alkyl, C 3 -Ce alkenyl, C 3 -C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl (C ⁇ -C 6 alkyl)-, (C ⁇ -C 6 alkyl) carbonyl, (C ⁇ -C 6 alkoxy) carbonyl, arylcarbonyl;
• R 4 and R 5 when substituents on adjacent atoms, 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, a ino, CF3, or N0 2 ; R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
• R 7 and R 8 are independently selected from: H, Ci-C ⁇ alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C ⁇ -C6 alkyl)-, or heteroaryl (C0-C 6 alkyl) - .
• U is selected from: -N(R 6 ) (CH 2 ) n -»
• V is selected from:
• R 9 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C ⁇ -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;
• R 11 - is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C ⁇ -C ⁇ 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 -(C(R 12 ) 2 )qC(R 12 ) (R 14 )-C(R 12 ) (R 15 )-;
• W and X can be taken together to be
• R 12 is selected from H, C ⁇ -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 aryKCi-Ce alkyl)-;
• R 13 is selected from H, C ⁇ -C 6 alkyl, C 3 -C7 cycloalkylmethyl, or aryl(C ⁇ -C 6 alkyl)-
• R 15 is selected from:
• Y is selected from:
• R 16 is selected from:
• R 17 is selected from:
• R 18 is selected from: H,
• R 19 is selected from: hydroxy, C 1 -C 10 alkyloxy, C3 -C11 cycloalkyloxy , aryloxy, aryl (C ⁇ -C6 alkoxy)-,
• R 20 is selected from: H, Ci-Ce alkyl, C 3 -C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryKCi-C ⁇ alkyl)-, or heteroaryl (Ci-C ⁇ alkyl)--
• 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 f rom:
• J, K, L and M are independently selected from -C(R 4 )-,
• R 2 is selected from: H, C ⁇ -C 6 alkyl, (C -C ⁇ alkyl)carbonyl, (C -C ⁇ alkoxy) carbonyl; (Ci-C ⁇ alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl (Ci-Ce alkyl) carbonyl, heteroarylcarbonyl, aryl (C ⁇ -C 6 alkyl)-, (C ⁇ -C 6 alkyl) carbonyl, arylcarbonyl, C ⁇ -C 6 alkylsulfonyl, arylsulfonyl, aryKCi-C ⁇ alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl (Ci-C ⁇ alkyl)sulfonyl, aryloxycarbonyl, or aryl (C
• R 3 is selected from: H, Ci-C ⁇ alkyl, C 3 -C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryKCi-C ⁇ alkyl)-, or heteroaryl (Ci-C ⁇ alkyl) - ;
• R 4 and R 5 are independently selected from: H, C 1 -C 4 alkoxy, NR 2 R 3 , halogen, N0 , CN, CF 3 , C ⁇ -C 6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl (Ci-C ⁇ alkyl)-, (Ci-C ⁇ alkyl) carbonyl, (Ci-C ⁇ alkoxy)carbonyl, arylcarbonyl, or
• R 4 and R 5 when substituents on adjacent atoms, 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 N0 2 ;
• R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
• R 7 and R 8 are independently selected from: H, Ci-C ⁇ alkyl, C3-C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C ⁇ -C 6 alkyl)-, or heteroaryl ⁇ o ⁇ alkyl)-.
• V is selected from:
• R 9 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryKC -Ce alkyl)-, (C 1 -C4 alkoxy) carbonyl, (C 1 -C 4 alkyl)carbonyl, C 1 -C 4 alkylsulfonyl, or C 1 -C 4 alkylaminosulfonyl;
• R 11 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C ⁇ -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: C 1 -C 4 alkylene
• X is -(C(R l ) 2 )qC(R 12 ) (R 14 )-C(R 12 ) (R 15 -)-;
• W and X can be taken together to be
• R 12 is selected from H, Ci-C ⁇ alkyl, C 2 -C 6 alkenyl, C 2 -C6 alkynyl, C 3 -C7 cycloalkyl,
• R 13 is selected from H, Ci-C ⁇ alkyl, C 3 -C7 cycloalkylmethyl, or aryl(C ⁇ -C 6 alkyl)-;
• R 15 is selected from:
• Y is selected from:
• R 16 is selected from:
• R 17 is selected from:
• R 18 is selected from:
• R 19 is selected from: hydroxy, C1-C10 alkyloxy,
• R 20 selected from: H, Ci-C ⁇ alkyl, C 3 -C 7 cycloalkyl, C 4 - C 11 cycloalkylalkyl, aryl, aryl (C 1 -C 6 alkyl) -, or heteroaryl (C ⁇ -C6 alkyl)--
• 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:
• heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH 2 , halogen, N0 2 , CN, CF 3 , C 1 -C 4 alkoxy, Ci-C ⁇ alkyl, and C3-C7 cycloalkyl;
• R 2 is selected from: H, C1-C4 alkyl or benzyl
• U is -NH ( CH 2 ) n -;
• V is -(CH 2 ) n -;
• R 11 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C ⁇ -C6 alkyl)-, (C 1 -C4 alkoxy) carbonyl, (C 1 -C 4 alkyl)carbonyl, C 1 -C 4 alkylsulfonyl, or C 1 -C 4 alkylaminosulfonyl;
• X is -CH (R 1 ) -CH (R 15 ) - ;
• R 13 is H or CH 3 ;
• R 14 is selected from:
• Ci-Cio alkyl, aryl, or heteroaryl 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, C1-C4 alkoxy, aryl, halo, cyano, a ino, CF 3 , and N0 2 ;
• R 15 is H or R 16 ;
• R 16 is selected from:
• R 17 is selected from: C 1 -C 10 alkyl, C3-C11 cycloalkyl, aryl (C ⁇ -C 6 alkyl)-, (Ci-Ce alkyl)aryl, heteroaryl (C ⁇ -C 6 alkyl)-, (C ⁇ -C 6 alkyl)heteroaryl, arylaryl (Ci-C ⁇ alkyl)-, heteroarylaryKCi-C ⁇ alkyl)-, arylheteroaryl (Ci-C ⁇ alkyl)-, heteroarylheteroaryl (Ci-C ⁇ 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, a ino, CF 3 , and N0 ; R 19 is selected from: hydroxy
• Ci-Cio alkoxy methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy- ,
• R 20 is H or CH 3;
• n 0-1
• Still further preferred compounds of the above invention as described above are compounds of the Formula I including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
• 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 -;
• R 11 - is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C ⁇ -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 )-CH(R 15 )-;
• R 13 is H or CH 3 ;
• R 14 is selected from:
• C 1 -C 10 alkyl, aryl, or heteroaryl 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 N0 2 ;
• R 15 is H or R 16 ;
• R 17 is selected from:
• R 19 is selected from: hydroxy
• R 20 is H or CH 3 ;
• n 0-1.
• Specifically preferred compounds of the above invention are compounds including enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diastereomeric 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 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, including, but not limited to, inflammation, bone degradation, thromboembolic disorders, restenosis, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation rejection, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, inflammatory bowel disease and other autoimmune diseases.
• 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 ische ic 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.
• 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
• thrombolytic or fibrinolytic agents such as plasminogen activators, anistreplase, urokinase,
• 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 component when used as a single agent.
• Such 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 alone or in combination with an additional therapeutic agent to a cell or mammal is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.
• 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. Such agents include warfarin (available as COUMADIN ® ) and heparin.
• anti-platelet agents or platelet inhibitory agents, as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets.
• Such 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.
• thrombin inhibitors include thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
• thrombin inhibitors or anti-thrombin agents
• 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) and/or fibrin formation are disrupted.
• Such inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof.
• 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. Patent No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference.
• boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471 651 A2, the disclosures of which are hereby incorporated herein by reference, in their entirety.
• thrombolytics or fibrinolytic agents
• fibrinolytics or fibrinolytics 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 activator complex, as described, for example, in European Patent Application No.
• 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 o 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 5 substituents on N is independently selected from the defined list of possible R 5 .
• each of the two R 7 substituents on C is independently selected from the. defined list of possible R 7 .
• substituents When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formula I, then such substituent may be bonded via any atom in such substituent.
• substituent when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise, said 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.
• Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• 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.
• alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, "Co-Cio” denotes alkyl having 0 to 10 carbon atoms; thus, Co denotes a direct bond between the groups linked by the Co group) ;
• 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, cyclohexyl, cyclo
• 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.
• Such "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) .
• heterocycle or “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 independently selected from the group consisting of N, 0 and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the 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, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, isoxazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl
• heteroaryl refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocyclic groups or 8-10 membered fused bicyclic groups.
• 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 functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
• Prodrugs include compounds of Formula I wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
• Examples of 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.
• 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, hydroxymaleic, phenylacetic, glutamic, benzoic, 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 stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
• 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., dibenzylethylenediamine, trimethyla ine, 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 appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences , 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
• 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. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
• 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. ( Bull Chem. Soc . Jpn . , 1985, ⁇ jl, 2519-2522).
• the hydroxyl group in 1(a) can be subsequently oxidized to the corresponding aldehyde by any of a number of known methods for carrying out this transformation, i.e., (See Manacuso & Swern, Synthesis, 1981, 165; Tidwell, Synthesis, 1990, 857; D.B. Dess & J.C. Martin, J. Org. Chem. , 1983, 4 4155; op cit. J. Amer. Chem. Soc , 199J., 22., 77; R.E. Ireland & L. Liu, J " . Org. Chem, 1993, 5_8_, 2899) .
• Reductive a ination of the resulting aldehyde with an appropriate aminoheterocycle, such as 2-aminopyridine can be achieved using sodium triacetoxyborohydride (Abdel-Magid, A. F.; Maryanoff, C. A. Synlet t , 1990, __., 537) to provide a secondary amine.
• Optional protection of the nitrogen as its BOC derivative yields 1(c).
• Subsequent hydrolysis of the ethyl ester using conventional methods known to one skilled in the art of organic synthesis gives the corresponding acid 1(d).
• Coupling of compound 1(d) to an appropriately substituted a- or /J-amino ester, 1(e) affords compounds of formula 1(f).
• 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, diisopropylcarbodiimide, or water-soluble carbodiimides) method, active ester (p-nitrophenyl ester, N- hydroxysuccinic imido ester) method, carbonyldiimidazole method, or coupling with phosphorus reagents such as BOP-C1.
• 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, carbodiimi
• the amine function can be introduced prior to cycloaddition by conversion of the starting methylenecycloalkylmethanol to the corresponding tosylate, displacement of the tosyl group with sodium azide, reduction to the amine and treatment with di-t- butyldicarbonate. Subsequent 1,3 dipolarcycloaddition provides 2(a) .
• Ester hydrolysis and amide coupling as described above provides compounds of formula 2(d).
• Hydrolysis of the ester, removal of the BOC protecting group and treatment of the free amine with an appropriate heterocyclic isothiouronium salt, such as those listed in the scheme, provides compounds of Formula 2(f) .
• 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. So , 1936, 5_&, 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 described in WO9316038.
• 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, An ⁇ ew. Chem. Int. Ed. En ⁇ l. 1975, 11, 32; Rodriguez, et al. Tetrahedron Lett. 1990, _ L, 5153; Greenlee, J- Med. Chem.
• N 2 -substituted diaminopropionic acid derivatives can be carried out via Hoffman rearrangement of a wide variety of asparagine derivatives as described in Synthesis, 266-267, (1981] or by manipulation of the commercially available 3- amino-2-benzyloxycarbonylaminoprop ⁇ onic acid.
• 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 undergoes 1,3-dipolarcycloaddition to provide spirocycle 7(e).
• the nitrogen of the resulting pyrazole ring may be optionally functionalized using standard methodology prior to carrying out the remaining steps leading to compounds of formula 9(g).
• N-Chz-4-hvdroxv-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 dimethylsulfide complex (2.0M in THF, 122 ml, 0.244 mol) was added dropwise over lh. The resulting mixture is then allowed to stir overnight at room temperature, the reaction mixture was recooled to 0 °C and a second portion of borane-dimethylsulfide complex was added as described above.
• Reaction mixture was transferred to a separatory funnel and washed with water (4X) and brine (IX) then dried over anhydrous sodium sulfate, filtered and solvent removed in vacuo .
• the residue was chromatographed on silica gel (hexane - hexane/ethyl acetate 8:2 - hexane/ethyl acetate 7:3) to provide the silyl ether (47.11 g, 69%) Part C.
• the resulting mixture was stirred 15 min, followed by dropwise addition of a solution of the compound of part B above in methylene chloride (130 ml) over 45 min at T ⁇ -65°C.
• the reaction was stirred for 30 min followed by dropwise addition of triethylamine (119.2 ml, 0.855 mol) over 30 min again at T ⁇ -65°C.
• the cooling bath was removed and the reaction temperature was allowed to rise to 5-10°C, and then quenched by addition of 645 ml of 10% aqueous potassium hydrogen sulfate solution.
• the mixture was then transferred to a separatory funnel and layers separated.
• 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-henzvloxvcarbonvl-8-t-butvldimethvlsilv1oxy- methvl-3-ethoxvcarbonvl-l-oxa-2.7-diazaspiro-r4.41-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.
• Part F 7-henzvloxvcarbonvl-8-t-bntvldimethvlsilvloxv- rnethyl-3-ca bnxv-l-oxa-2.7-diazaspiro- f4.41-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-Butvl (S)-2- f (2. . -trimethvlphenvl )sirifonvl 1- amino-3- f r7-benzvloxvcarbonvl-8- (t-butvldimethvlsi1vl- oxv)methv1-1-oxa-2.7-diazaspiro- T4.
• 1-non-2-en-3- yllcarbonylamino1 ropionic 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.
• Part H t-Butvl (S) -2- ( .4.6-trimethvlphenvl)sulfonvl - aminn-3- I r7-henzyloxvcarbonvl-8-hvdroxvmethvl-l-oxa- .7- diazaspjro- T .41-non-2-en-3-v!1carbonvlaminoloronionic 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) .
• Part J t-Butyl (S) -2- r (2.4,6-trimethylphenyl)sulfonyll- amino- -f f7-benzvloxvcarbonvl-8- (imidazol-2- vlamino)me hvl-l-oxa-2.7-diazaspiro- T .41-non-2-en-3- yllcarbonvlaminol ropionic 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-l-tritylimidazole (0.398 g, 1.22 mmol) and the whole was refluxed for 4 hrs under nitrogen.
• anhydrous magnesium sulfate 0.588 g, 4.88 mmol
• 2-amino-l-tritylimidazole 0.398 g, 1.22
• 1-non-2-en-3-vl1carbonvlamino1- propionic acid The compound of part J above (0.3 g, 0.31 mmol) was dissolved in 20% acetic acid in methanol (10 ml) and refluxed for 24 h under nitrogen. The reaction was cooled to room temperature, methanol removed by evaporation and residue diluted with ethyl acetate. This solution was washed with saturated sodium bicarbonate (2X) , water and brine then dried over anhydrous magnesium sulfate, filtered and evaporated. Filtration through silica gel (eluted with (i)methylene chloride/methanol 95:5; (2) methylene chloride/methanol/conc.
• Example 3063 (fi) -2- ⁇ ( 2.4.6-trimethvlphenvl) sulf nvl 1 - amino-3-r ffi- (imidazol-2-v1 mino ⁇ r ⁇ ethvl-l-oxa-2.7- diazaspiro- f , 41 -non-2-en-3-vll carbonylamino1 -nrn ⁇ inni c acid
• 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) + .
• the compounds of Formula I of the present invention possess activity as antagonists of integrins such as, for example, the o-vp3 or vitronectin receptor, ⁇ ⁇ 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 o-vp3 or vitronectin receptor, ⁇ ⁇ s or c.5 ⁇ l
• the 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 ⁇ 3 receptor.
• 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.
• One of the major roles of integrins in vivo is to mediate cellular interactions with adjacent cells.
• Cell based adhesion assays can be used to mimic these interactions in vitro.
• 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, 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, atherosclerosis, metastasis, wound healing, inflammatory bowel disease and other angiogenic disorders.
• the compounds of Formula I have the ability to suppress/inhibit angiogenesis in vi vo, for example, as demonstrated using animal models of ocular neovascularization.
• 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. These 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 illiliter
• L denotes liter
• M nM denotes nanomolar
• ⁇ M denotes micromolar
• mM denotes millimolar
• M denotes molar
• nm denotes nanometer.
• Sigma stands for the Sigma-Aldrich Corp. of St. Louis, MO.
• the utility of the compounds of the present invention may be assessed by testing in one or more of the following assays as described in detail below: Purified ctv ⁇ 3 (human placenta) - Vitronectin ELISA, «v ⁇ 3 -Vitronectin Binding Assay, Human Aortic Smooth Muscle Cell Migration Assay, In Vivo Angiogenesis Model, Pig Restenosis Model, Mouse Retinopathy Model.
• 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 ctv ⁇ 3 -receptor.
• the ocv ⁇ 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. 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 ctv ⁇ 3 with no detectable levels of ⁇ v ⁇ s according to the gel ( ⁇ v ⁇ 3) and according to effects of blocking antibodies for the a ⁇ 3 or ay ⁇ s in the ELISA.
• LM609 anti-
• a submaximal concentration of biotinylated vitronectin was selected based on cone, response curve with fixed receptor cone, and variable concentrations of biotinylated vitronectin.
• the purified receptor is diluted with coating buffer (20 mM Tris HCl, 150 mM NaCl, 2.0 mM CaCl2, 1.0 mM MgCl 2 -6H 2 ⁇ , 1.0 mM MnCl 2 ' H 2 ⁇ ) 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 ⁇ ,1.0 mM MnCl 2 -4H 0).
• 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 ⁇ D 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 overnight at 4° C. The following day, the cells were harvested, washed and loaded with a fluorescent dye. Compounds and cells were added together and then were immediately added to the coated plate. After incubation, loose cells are removed from the plate, and the plate (with adherent cells) is counted on a fluorometer. The ability of test compounds to inhibit cell adhesion by 50% is given by the IC50 value and represents a measure of potency of inhibition of integrin mediated binding. Compounds were tested for their ability to block cell adhesion using assays specific for ⁇ v ⁇ 3 , ⁇ v ⁇ s and ⁇ s ⁇ i 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, 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.
• the compounds of the invention, or compounds of the invention in combination with other therapeutic agents can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
• the dosage of the novel cyclic compounds of this invention administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired.
• a daily dosage of active ingredient can be expected to be about 0.001 to 10 milligrams per kilogram of body weight.
• Dosage forms contain from about 0.1 milligram to about 100 milligrams of active ingredient per unit.
• the 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 atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. 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.
• Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
• Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
• citric acid and its salts and sodium EDTA are also used.
• 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.
• Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
• 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 displacement pump into gelatin to form soft gelatin capsules containing 10 milligrams of the active ingredient.
• the capsules are washed and dried.
• a large number of tablets are prepared by conventional procedures so that 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 palatability or delay absorption.
• the 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.
• an anti-coagulant agent such as warfarin or heparin
• an anti-platelet agent such as aspirin, piroxicam or ticlopidine
• a thrombin inhibitor such as a boropeptide, hirudin or argatroban
• a thrombolytic agent such as tissue plasminogen activator, anistreplase
• 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.).
• the combination products are not formulated together in a single dosage form, 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 administered first, followed by administration of the anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent.
• the 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 administered in the same fashion (that is, for example, both orally) , if desired, they may each be administered in different fashions (that is, for example, one 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 administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.
• 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 administered alone, in view of the additive or synergistic effect which would be obtained as a result of addition of further agents in accordance with the present invention.
• the potential exists for a chemical interaction between the combined active ingredients for example, a novel compound of this invention and an anti-coagulant such as warfarin or heparin, or a novel compound of this invention and an anti-platelet agent such as aspirin, piroxica or ticlopidine, or a novel compound of this invention and a thrombin inhibitor such as a boropeptide, hirudin or argatroban, or a novel compound of this invention and a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof) .
• an anti-coagulant such as warfarin or heparin
• an anti-platelet agent such as aspirin, piroxica or ticlopidine
• a novel compound of this invention and a thrombin inhibitor such as a boropeptide, hirudin or argatroban, or a novel compound of this invention and a thrombolytic agent
• 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 gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
• Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
• the 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 hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
• HPMC hydroxypropyl methylcellulose
• the polymer coating serves to form an additional barrier to interaction with the other component.
• 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 ingredients.
• 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.
• 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 combinations thereof, in one or more sterile containers, are also within the ambit of the present invention.
• an anti-coagulant agent such as warfarin or heparin
• an antiplatelet agent such as aspirin, piroxicam or ticlopidine
• a thrombin inhibitor such as a boropeptid
• 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. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

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• 1997
  • 1997-03-17 WO PCT/US1997/004567 patent/WO1997033887A1/en not_active Application Discontinuation
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