WO1997033887A1 - Spirocycle integrin inhibitors - Google Patents

Spirocycle integrin inhibitors Download PDF

Info

Publication number
WO1997033887A1
WO1997033887A1 PCT/US1997/004567 US9704567W WO9733887A1 WO 1997033887 A1 WO1997033887 A1 WO 1997033887A1 US 9704567 W US9704567 W US 9704567W WO 9733887 A1 WO9733887 A1 WO 9733887A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
oxa
carbonylamino
propionic acid
Prior art date
Application number
PCT/US1997/004567
Other languages
French (fr)
Inventor
Prabhakar Kondaji Jadhav
Joanne Marie Smallheer
Original Assignee
Du Pont Pharmaceuticals Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/816,580 external-priority patent/US5760029A/en
Application filed by Du Pont Pharmaceuticals Company filed Critical Du Pont Pharmaceuticals Company
Priority to EP97919892A priority Critical patent/EP0888344A1/en
Priority to JP53292497A priority patent/JP2001527513A/en
Priority to AU24217/97A priority patent/AU2421797A/en
Publication of WO1997033887A1 publication Critical patent/WO1997033887A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention relates to novel heterocycles, including (S)-2-phenylsulfonylamino-3-[[[8-(2-pyridinylaminomethyl)-]-1-oxa-2-azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]propionic acid, which are useful as antagonists of the αvβ3 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.

Description

TITLE
Spirocycle Integrin Inhibitors
FIELD OF THE INVENTION This invention relates to novel heterocycles which are useful as antagonists of the αvβ3 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.
BACKGROUND OF THE INVENTION 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, 49:453-464). However,
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, 267: 10931-10934; Blood and Zetter, Biochim. Biophys.
Acta., 1990, 1032:118-128).
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).
Inhibition of angiogenesis in animal models of cancer has been shown to result in tumor growth
suppression and prevention of metastatic growth (Herblin et al., Exp. Opin. Ther. Patents, 1994, 1-14). Many angiogenic inhibitors have been directed toward blocking initial cytokine-dependent induction of new vessel growth, e.g. antibodies to endothelial cell growth factors. However, these approaches are problematic because tumor and inflammatory cells can secrete
multiple activators of angiogenesis (Brooks et al., Cell, 1994, 79: 1157-1164). Therefore, a more general approach that would allow inhibition of angiogenesis due to a variety of stimuli would be of benefit.
The integrin αvβ3 is preferentially expressed on angiogenic blood vessels in chick and man (Brooks et al., Science, 1994, 264:569-571; Enenstein and Kramer, J. Invest. Derrnatol., 1994, 103:381-386). Integrin αvβ3 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.
While integrin αvβ3 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) . For example, the interaction between the αvβ3 integrin and extracellular matrix components promotes a calcium signal required for cell motility.
During endothelium injury, 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 αvβ3, 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.
Recently, an antibody to the αvβ3 integrin has been developed that inhibits the interaction of this integrin with agonists such as vitronectin (Brooks et al.,
Science, 1994, 264:569-571) . Application of this antibody has been shown to disrupt ongoing angiogenesis on the chick chorioallantoic membrane (CAM), leading to rapid regression of histologically distinct human tumor transplanted onto the CAM (Brooks et al., Cell, 1994, 79:1157-1164) . In this model, antagonists of the αvβ3 integrin induced apoptosis of the proliferating angiogenic vascular cells, leaving pre-existing
quiescent blood vessels unaffected. Thus, αvβ3 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, 267:10931-10934).
Increasing numbers of other cell surface receptors have been identified which bind to extracellular matrix ligands or other cell adhesion ligands thereby mediating cell-cell and cell-matrix adhesion processes. These receptors belong to a gene superfamily called integrins and are composed of heterodimeric transmembrane
glycoproteins containing α- and β-subunits. Integrin subfamilies contain a common β-subunit combined with different α-subunits to form adhesion receptors with unique specificity. The genes for eight distinct β-subunits have been cloned and sequenced to date.
The αvβ3 heterodimer is a member of the β3 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, 109:1817- 1826; Horton, Int. J. Exp. Pathol., 1990, 71:741-759). Like GPIIb/IIIa, 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 αvβ3 receptor in this process and suggest that a selective αvβ3 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).
PCT Patent Application Publication Number
W095/14683, published June 1, 1995 discloses isoxazoline and isoxazole fibrinogen receptor antagonists of general formula shown below:
Figure imgf000007_0001
Copending, commonly assigned U.S. Patent
Application Serial Number 08/455,768 filed 5/31/95 discloses integrin inhibitors of the general formula shown below:
Figure imgf000007_0002
PCT Patent Application Publication Number
WO95/32710, published December 7, 1995 discloses compounds for inhibition of osteoclast-mediated bone resorption of general formula shown below:
X-Y-Z-Aryl-A-B wherein Aryl is a 6-membered aromatic ring system.
None of the above references discloses or suggests the spirocyclic compounds of the present invention which are described in detail below. SUMMARY OF THE INVENTION
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 αvβ3 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 αvβ3 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 αvβ3 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.
Also included in the present invention are
pharmaceutical 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.
DETAILED DESCRIPTION OF THE INVENTION
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 αvβ3 or vitronectin receptor. The compounds of the present invention inhibit the binding of vitronectin and other RGD-containing ligands to αvβ3 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. [1] The present invention comprises spirocyclic
compounds of Formula I : R1-Q-W-X-Y
(I) including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein: Q is selected from
Figure imgf000010_0001
A is selected from -N(R10)-, -C(R11)- or -O-; A1 is selected from -O- or -N(R10)-;
Z is a spiro-fused 4-7 membered ring system (including the sprio atom) containing 0-2 heteroatoms selected from O, S, or N, said ring system optionally being substituted on carbon with keto, or being
substituted on carbon or nitrogen independently with 0-2 R9 or R10 or R10a; R1 is selected from:
Figure imgf000011_0001
B is independently selected from -CH2-, -O-, -N(R2)-, or -C(=O)-; B1 is independently selected from -CH2- or -N(R3)-;
D is -N(R2)-, -O-, -S-, -C(=O)- or -SO2-;
E-F is -C(R4)=C(R5)-, -N=C(R4)-, -C(R4)=N-, or
-C(R4)2C(R5)2-;
J, K, L and M are independently selected from -C(R4)-,
-C(R5)- or -N-, provided that at least one of J, K, L and M is not -N-; R2 is selected from: H, C1-C6 alkyl, (C1-C6
alkyl) carbonyl, (C1-C6 alkoxy) carbonyl; (C1-C6 alkyl) aminocarbonyl, C3-C6 alkenyl, C3-C7
cycloalkyl, C4-C11 cycloalkylalkyl, aryl,
heteroaryl (C1-C6 alkyl) carbonyl,
heteroarylcarbonyl, aryl C1-C6 alkyl, (C1-C6 alkyl) carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl (C1-C6 alkyl) sulfonyl,
heteroarylsulfonyl, heteroaryl (C1-C6
alkyl) sulfonyl, aryloxycarbonyl, aryl(C1-C6
alkoxy) carbonyl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R3 isselected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4- C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C1-C6 alkyl)-; R4 and R5 are independently selected from: H, C1-C4
alkoxy, NR2R3, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C4-C11
cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, (C1-C6 alkyl) carbonyl, (C1-C6 alkoxy) carbonyl,
arylcarbonyl; alternatively, when substituents on adjacent atoms, R4 and R5 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: C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3, or NO2; R6 is selected from: H, C1-C4 alkyl, or benzyl;
R7 and R8 are independently selected from: H, C1-C6
alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, or heteroaryl (C0-C6 alkyl)-;
U is selected from:
-N(R6) (CH2)n-,
-N(R6) (CH2)mO-,
-N(R6) (CH2)mN(R7)-
-N(R6) (CH2) nS(O )p-
-N(R6)C(=O) (CH2)n-;
-N(R6) (CH2)mC(=O)-;
V is selected from:
-(CH2)n- ,
-(CH2)mO-(CH2) n-.
-(CH2)mN(R7) (CH2)n-,
-(CH2)nS(O ) p(CH2) n-,
-(CH2)mN(R7)C(=O) (CH2)n-,
-(CH2)nC(=O)N(R7) (CH2)n-,
-(CH2)nC(=O) (CH2)n-;
R9 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl (C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
R10 is selected from: H, CO2R17, C(=O)R17, C(=O)NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0-
1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11; R10a is selected from: CO2R17, C(=O)R17, C(=O)NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 Ris or 0-2 R11;
R11 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl (C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
W is selected from:
C1-C4 alkylene,
-(C(R12)2)qO(C(R12)2)q-,
-(C(R12)2)qC(=0) (C(R12)2)q-,
-(C(R12)2)qC(=O)N(R13)-7
-C(=O)-N(R13)-(C(R12)2)q-;
X is -(C(R12)2)qC(R12) (R14)-C(R12) (R15)-; alternatively, W and X can be taken together to be
Figure imgf000014_0001
R12 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C10 cycloalkylalkyl, (C1-C4 alkyl) carbonyl, aryl, or aryl (C1-C6 alkyl)-; R13 is selected from H, C1-C6 alkyl, C3-C7
cycloalkylmethyl, or aryl (C1-C6 alkyl)-
R14 is selected from:
H, C1-C6 alkylthio (C1-C6 alkyl)-, aryl (C1-C10 alkylthioalkyl)-, aryl (C1-C10 alkoxyalkyl)-, C1-C10 alkyl, C1-C10 alkoxyalkyl, C1-C6 hydroxyalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl (C1-C6 alkyl)-,
heteroaryl (C1-C6 alkyl)-, aryl, heteroaryl, CO2R17, C(=O)R17, or CONR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0- 1 R16 or 0-2 R11;
R15 is selected from:
H, R16, C1-C10 alkyl, C1-C10 alkoxyalkyl,
C1-C10 alkylaminoalkyl, C1-C10 dialkylaminoalkyl, (C1-C10 alkyl) carbonyl, aryl (C0-C6 alkyl) carbonyl, C1-C10 alkenyl, C1-C10 alkynyl , C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl (C1-C6 alkyl)-,
heteroaryl (C1-C6 alkyl)-, aryl, heteroaryl, CO2R17, C(=O)R17, CONR17R20, SO2R17, or SO2NR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0-2 R11;
Y is selected from:
-COR19, -SO3H, -PO3H, tetrazolyl, -CONHNHSO2CF3, -CONHSO2R17, -CONHSO2NHR17, -NHCOCF3, -NHCONHSO2R17, -NHSO2R17, -OPO3H2, -OSO3H, -PO3H2, -SO3H,
-SO2NHCOR17, -SO2NHCO2R17,
Figure imgf000016_0001
R16 is selected from:
-N(R20)-C(=O)-O-R17,
-N(R20)-C(=O)-R17,
-N(R20)-C(=O)-NH-R17,
-N(R20)SO2-R17, or
-N(R20)SO2-NR20R17; R17 is selected from:
C1-C1 0 alkyl, C3-C11 cycloalkyl, aryl (C1-C6 alkyl)-, (C1-C6 alkyl) aryl, heteroaryl (C1-C6 alkyl)-, (C1-C6 alkyl) heteroaryl, arylaryl (C1-C6 alkyl)-,
heteroarylaryl (C1-C6 alkyl)-, arylheteroaryl (C1-C6 alkyl)-, heteroarylheteroaryl (C1-C6 alkyl)-, heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;
R18 is selected from:
H,
-C(=O)-O-R17,
-C(=O)-R17,
-C(=O)-NH-R17,
-SO2-R17, or
-SO2-NR20R17; R19 is selected from:
hydroxy,
C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy,
aryl (C1-C6 alkoxy)-,
C3-C10 alkylcarbonyloxyalkyloxy,
C3-C10 alkoxycarbonyloxyalkyloxy,
C2-C10 alkoxycarbonylalkyloxy,
C5-C10 cycloalkylcarbonyloxyalkyloxy,
C5-C10 cycloalkoxycarbonyloxyalkyloxy,
C5-C10 cycloalkoxycarbonylalkyloxy,
C7-C11 aryloxycarbonylalkyloxy,
C8-C12 aryloxycarbonyloxyalkyloxy,
C8-C12 arylcarbonyloxyalkyloxy,
C5-C10 alkoxyalkylcarbonyloxyalkyloxy,
C5-C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one- yl)methyloxy,
C10-C14 (5-aryl-1,3-dioxa-cyclopenten-2-one- yl) methyloxy, or
(R11) (R12)N-(C1-C10 alkoxy)-; R20 is selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C1-C6 alkyl)-; m is 1-2
n is 0-2
p is 0-2
q is 0-2 and
r is 0-2 provided that:
n, q, and r are chosen such that the number of in-chain atoms between R1 and Y is in the range of 8-18. [2] Preferred compounds of the invention as described above are spirocyclic compounds of Formula I:
R1-Q-W-X-Y
(I) including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
Q is selected from
Figure imgf000019_0001
R1 is selected from:
Figure imgf000020_0001
D is -N(R2)-, -O-, -S-, -C(=O)- or -SO2-;
E-F is -C(R4)=C(R5)-, -N=C(R4)-, -C(R4)=N-, or
-C(R4)2C(R5)2-;
J, K, L and M are independently selected from -C(R4)-,
-C(R5)- or -N-, provided that at least one of J, K, L and M is not -N-; R2 is selected from: H, C1-C6 alkyl, (C1-C6
alkyl) carbonyl, (C1-C6 alkoxy) carbonyl; (C1-C6 alkyl) aminocarbonyl, C3-C6 alkenyl, C3-C7
cycloalkyl, C4-C11 cycloalkylalkyl, aryl,
heteroaryl (C1-C6 alkyl) carbonyl,
heteroarylcarbonyl, aryl (C1-C6 alkyl)-, (C1-C6 alkyl) carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl (C1-C6 alkyl) sulfonyl,
heteroarylsulfonyl, heteroaryl (C1-C6
alkyl) sulfonyl, aryloxycarbonyl, or aryl (C1-C6 alkoxy) carbonyl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R3 is selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C1-C6 alkyl)-;
R4 and R5 are independently selected from: H, C1-C4
alkoxy, NR2R3, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C4-C11
cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, (C1-C6 alkyl) carbonyl, (C1-C6 alkoxy) carbonyl,
arylcarbonyl, or alternatively, when substituents on adjacent atoms, R4 and R5 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: C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3, or NO2; R6 is selected from: H, C1-C4 alkyl, or benzyl;
R7 and R8 are independently selected from: H, C1-C6
alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C0-C6 alkyl)-. U is selected from:
-N(R6) (CH2)n- ,
-N(R6) (CH2)m0-,
-N(R6) (CH2)mN(R7)- -N(R6) (CH2)nS(O ) p- -N(R6)C(=O) (CH2)n-;
V is selected from:
-(CH2)n- ,
-(CH2)mp-(CH2) n-,
-(CH2)mN(R7) (CH2) n-,
-(CH2) nS(O ) p(CH2) n-,
-(CH2)mN(R7)C(=O) (CH2)n-,
-(CH2)nC(=O)N(R7) (CH2)n-,
-(CH2)nC(=O) (CH2)n-;
R9 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl (C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
R10 is selected from: H, CO2R17, C(=O)R17, C(=O)NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11; R10a is selected from: CO2R17, C(=O)R17, C (=O)NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R1i, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11;
R11 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl (C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
W is selected from:
C1-C4 alkylene,
-(C(R12)2)qO(C(R12)2)q-,
-(C(R12)2)qC(=O) (C(R12)2)q-,
-(C(R12)2)qC(=O)N(R13)-,
-C(=O)-N(R13)-(C(R12)2)q-;
X is -(C(R12)2)qC(R12) (R14)-C(R12) (R15-)-; alternatively, W and X can be taken together to be
Figure imgf000023_0001
R12 is selected from H, C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C3-C7 cycloalkyl,
C4-C10 cycloalkylalkyl, (C1-C4 alkyl) carbonyl, aryl, or aryl (C1-C6 alkyl)-;
R13 is selected from H, C1-C6 alkyl, C3-C7
cycloalkylmethyl, or aryl (C1-C6 alkyl)-;
R14 is selected from:
H, C1-C6 alkylthio (C1-C6 alkyl)-, aryl (C1-C10 alkylthioalkyl)-, aryl (C1-C10 alkoxyalkyl)-, C1-C10 alkyl, C1-C10 alkoxyalkyl, C1-C6 hydroxyalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C1-C6 alkyl)-,
heteroaryl (C1-C6 alkyl)-, aryl, heteroaryl, CO2R17, C(=O)R17, or CONR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0- 1 R16 or 0-2 R11;
R15 is selected from:
H, R16, C1-C10 alkyl, C1-C10 alkoxyalkyl,
C1-C10 alkylaminoalkyl, C1-C10 dialkylaminoalkyl, (C1-C10 alkyl) carbonyl, aryl (C0-C6 alkyl) carbonyl, C1-C10 alkenyl, C1-C10 alkynyl , C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C1-C6 alkyl)-,
heteroaryl (C1-C6 alkyl)-, aryl, heteroaryl, CO2R17, C(=O)R17, CONR17R20, SO2R17, or SO2NR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0-2 R11;
Y is selected from:
-COR19, -SO3H, -PO3H, tetrazolyl, -CONHNHSO2CF3 , -CONHSO2R17, -CONHSO2NHR17, -NHCOCF3, -NHCONHSO2R17, -NHSO2R17, -OPO3H2, -OSO3H, -P03H2, -SO3H,
-SO2NHCOR17, -SO2NHCO2R17,
Figure imgf000024_0001
R16 is selected from:
-N(R20)-C(=O)-O-R17,
-N(R20)-C(=O)-R17,
-N(R20)-C(=O)-NH-R17,
-N(R20)SO2-R17, or -N(R20)SO2-NR20R17;
R17 is selected from:
C1-C10 alkyl, C3-C11 cycloalkyl, aryl (C1-C6 alkyl)-, (C1-C6 alkyl) aryl, heteroaryl (C1-C6 alkyl)-, (C1-C6 alkyl) heteroaryl, arylaryl (C1-C6 alkyl)-,
heteroarylaryl (C1-C6 alkyl)-, arylheteroaryl (C1-C6 alkyl)-, heteroarylheteroaryl (C1-C6 alkyl)-, heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2; R18 is selected from:
H,
-C(=O) -O-R17,
-C(=O)-R17,
-C(=O)-NH-R17,
-SO2-R17, or
-SO2-NR20R17;
R19 is selected from:
hydroxy,
C1-C10 alkyloxy,
C3-C11 cycloalkyloxy,
aryloxy,
aryl (C1-C6 alkoxy)-,
C3-C10 alkylcarbonyloxyalkyloxy,
C3-C10 alkoxycarbonyloxyalkyloxy,
C2-C10 alkoxycarbonylalkyloxy,
C5-C10 cycloalkylcarbonyloxyalkyloxy,
C5-C10 cycloalkoxycarbonyloxyalkyloxy,
C5-C10 cycloalkoxycarbonylalkyloxy,
C7-C11 aryloxycarbonylalkyloxy, C8-C12 aryloxycarbonyloxyalkyloxy,
C8-C12 arylcarbonyloxyalkyloxy,
C5-C10 alkoxyalkylcarbonyloxyalkyloxy,
C5-C10 (5-alkyl-l, 3-dioxa-cyclopenten-2-one- yl)methyloxy,
C10-C14 (5-aryl-1,3-dioxa-cyclopenten-2-one- yl) methyloxy, or
(R11) (R12)N-(C1-C10 alkoxy)-; R20 selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4- C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C1-C6 alkyl)-; m is 1-2
n is 0-2
p is 0-2
q is 0-2 and
r is 0-2 provided that:
n, q, and r are chosen such that the number of in- chain atoms between R1 and Y is in the range of 8- 18.
[3] Further preferred compounds of the 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:
Figure imgf000027_0001
Figure imgf000028_0001
wherein the above heterocycles are optionally
substituted with 0-2 substituents selected from the group consisting of: NH2, halogen, NO2, CN, CF3, C1-C4 alkoxy, C1-C6 alkyl, and C3-C7 cycloalkyl;
R2 is selected from: H, C1-C4 alkyl or benzyl; U is -NH(CH2)n-; V is -(CH2)n-;
R10 is selected from: H, CO2R17, C(=O)R17, C0NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11;
R10a is selected from: CO2R17, C(=O)R17, CONR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11;
R11 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl (C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
W is -C(=O)-N(R13)-; X is -CH(R14)-CH(R15)-;
R13 is H or CH3; R14 is selected from:
H, C1-C10 alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally
substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;
R15 is H or R16; Y is -C(=O)R19;
R16 is selected from:
-N(R20)-C(=O)-O-R17,
-N(R20)-C(=O)-R17,
-N(R20)-C(=O)-NH-R17,
-N(R20)SO2-R17, or
-N(R20)SO2-N(R20)R17;
R17 is selected from:
C1-C10 alkyl, C3-C11 cycloalkyl, aryl (C1-C6 alkyl)-, (C1-C6 alkyl) aryl, heteroaryl (C1-C6 alkyl)-, (C1-C6 alkyl) heteroaryl, arylaryl (C1-C6 alkyl)-,
heteroarylaryl (C1-C6 alkyl)-, arylheteroaryl (C1-C6 alkyl)-, heteroarylheteroaryl (C1-C6 alkyl)-, heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2; R19 is selected from:
hydroxy,
C1-C10 alkoxy,
methylcarbonyloxymethoxy-,
ethylcarbonyloxymethoxy-,
t-butylcarbonyloxymethoxy-,
cyclohexylcarbonyloxymethoxy-,
1-(methylcarbonyloxy)ethoxy-,
1-(ethylcarbonyloxy)ethoxy-,
1-(t-butylcarbonyloxy)ethoxy-,
1-(cyclohexylcarbonyloxy)ethoxy-,
i-propyloxycarbonyloxymethoxy-,
t-butyloxycarbonyloxymethoxy-,
1-(i-propyloxycarbonyloxy)ethoxy-,
1-(cyclohexyloxycarbonyloxy)ethoxy-,
1-(t-butyloxycarbonyloxy)ethoxy-,
dimethylaminoethoxy-,
diethylaminoethoxy-,
(5-methyl-1,3-dioxacyclopenten-2-on-4-y1)methoxy-, (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4- yl)methoxy-,
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-, or
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R20 is H or CH3; and n is 0-1,
[4] 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:
Figure imgf000032_0001
R1 is selected from:
Figure imgf000033_0001
R2 is selected from: H, C1-C4 alkyl, or benzyl;
U is -NH(CH2)n-;
V is -(CH2)n-; R10 is selected from: H, CO2R17, C(=O)R17, C (=O)NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11;
R10a is selected from: CO2R17, C(=O)R17, CONR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0-
1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11;
R11 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl (C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl , (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
W is -C(=O)-N(R13)-;
X is -CH(R14)-CH(R15)-;
R13 is H or CH3;
R14 is selected from:
H, C1-C10 alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally
substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;
R15 is H or R16;
Y is -C(=O)R19; R16 is selected from: -N(R20)-C(=O)-O-R17,
-N(R20)-C(=O)-R17,
-N(R20)SO2-R17, R17 is selected from:
C1-C1 0 alkyl, C3-C11 cycloalkyl, aryl (C1-C6 alkyl)-, (C1-C6 alkyl) aryl, heteroaryl (C1-C6 alkyl)-, (C1-C6 alkyl) heteroaryl, arylaryl (C1-C6 alkyl)-,
heteroarylaryl (C1-C6 alkyl)-, arylheteroaryl (C1-C6 alkyl)-, heteroarylheteroaryl (C1-C6 alkyl)-, heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;
R19 is selected from:
hydroxy,
C1-C10 alkoxy,
methylcarbonyloxymethoxy-,
ethylcarbonyloxymethoxy-,
t-butylcarbonyloxymethoxy-,
cyclohexylcarbonyloxymethoxy-,
1-(methylcarbonyloxy)ethoxy-,
1-(ethylcarbonyloxy)ethoxy-,
1-(t-butylcarbonyloxy)ethoxy-,
1-(cyclohexylcarbonyloxy)ethoxy-,
i-propyloxycarbonyloxymethoxy-,
t-butyloxycarbonyloxymethoxy-,
1-(i-propyloxycarbonyloxy)ethoxy-,
1-(cyclohexyloxycarbonyloxy)ethoxy-,
1-(t-butyloxycarbonyloxy)ethoxy-,
dimethylaminoethoxy-,
diethylaminoethoxy-,
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-, (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4- yl)methoxy-,
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-, or
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R20 is H or CH3; and n is 0-1.
[5] 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:
(S)-2-phenylsulfonylamino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl)carbonylamino]propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3-
[[[8-(2-pyridinylaminomethyl)-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(3,5-dimethylisoxazol4-yl)sulfonyl] amino-3-
[[[8-(2-pyridinylaminomethyl)-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid, (S)-2-phenylsulfonylamino-3-[[[8-[(6-aminopyridin- 2-yl)methyl]-]-1-oxa-2,8-diazaspiro-[4,5]-dec- 2-en-3-yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[[8-[(6-aminopyridin- 2-yl)methyl]]-1-oxa-2,8-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[[8-[2-(4,5- dihydroimidazol-2-yl)aminomethyl]-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]- propionic acid,
(S)-2-[(2-methylphenyl)sulfonyl] amino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2-chloro-4-methylphenyl)sulfonyl] amino-3- [[[8-(2-pyridinylaminomethyl)-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(4-biphenyl)sulfonyl] amino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2-bromophenyl)sulfonyl] amino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl] amino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid, (S)-2-[(1-naphthyl)sulfonyl] amino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid.
(S)-2-phenylsulfonylamino-3-[[[8-(2- imidazolylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[[8-(2- imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3- [[[8-(2-imidazolylaminomethyl)-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl] amino-3-[[ [8- (2-imidazolylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[[8- (2-imidazolylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino- 3-[[[8-(2-imidazolylaminomethyl)-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl] amino-3-[[[8-(2- imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl] amino-3-[[[8-(2- imidazolylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[7-benzyloxycarbonyl- 8-(2-imidazolylaminomethyl)-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl] carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino- 3-[[7-benzyloxycarbonyl-8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid, (S)-2-phenylsulfonylamino-3-[[8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3-[[8- (2-imidazolylaminomethyl)-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl] amino-3-[[8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl] amino- 3-[[8-(2-imidazolylaminomethyl)-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl] amino-3-[[8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[7-benzyloxycarbonyl- 8-(2-pyridinylaminomethyl)-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino- 3-[[7-benzyloxycarbonyl-8-(2- pyridinylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[7-benzyloxycarbonyl- 8-(4,5-dihydroimidazol-2-yl)aminomethyl-1-oxa- 2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid, (S)-2-benzyloxycarbonylamino-3-[[7- benzyloxycarbonyl-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-[[7- benzyloxycarbonyl-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino- 3-[[7-benzyloxycarbonyl-8-(4,5- dihydroimidazol-2-yl) aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl] carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[7- benzyloxycarbonyl-8-(4,5-dihydroimidazol-2- yl) aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[7- benzyloxycarbonyl-8-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-en-3-yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[8-(4,5- dihydroimidazol-2-yl) aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[8-(4,5- dihydroimidazol-2-yl) aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-[[8- (4,5-dihydroimidazol-2-yl) aminomethyl-1-oxa- 2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl] amino-3-[[8- (4,5-dihydroimidazol-2-yl)aminomethyl-1-oxa- 2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[8- (4,5-dihydroimidazol-2-yl) aminomethyl-1-oxa- 2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino- 3-[[8-(4,5-dihydroimidazol-2-yl) aminomethyl-1- oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl] amino-3-[[8-(4,5- dihydroimidazol-2-yl)aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl] amino-3-[[8-(4,5- dihydroimidazol-2-yl) aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid, and (S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3-[[8- (2-benzimidazolyl)aminomethyl-1-oxa-2,7- diazaspiro- [4,4] -non-2-en-3- yl]carbonylamino] propionic acid.
In the present invention it has been discovered that 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.
In the present invention it has also been discovered that the compounds of Formula I above are useful as inhibitors of αvβ3. The compounds of the present invention inhibit the binding of vitronectin to αvβ3 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. The term
"angiogenic disorders" as used herein 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.
The term "thromboembolic disorders" as used herein includes conditions involving platelet activation and aggregation, such as arterial or venous
cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above.
The compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.
The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents selected from: anti-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as
plasminogen activators, anistreplase, urokinase, or streptokinase.
The compounds of Formula I of the present invention can be administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect. Thus, 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.
By "therapeutically 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.
By "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. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
The term anti-coagulant agents (or coagulation inhibitory agents), as used herein, denotes agents that inhibit blood coagulation. Such agents include warfarin (available as COUMADIN®) and heparin.
The term 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. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include thromboxane-A2-receptor antagonists and
thromboxane-A2-synthetase inhibitors, as well as
pharmaceutically acceptable salts or prodrugs thereof. The phrase thrombin inhibitors (or anti-thrombin
agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as
thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) 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 α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, 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. Other suitable 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.
The phrase thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such 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. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase
activator complex, as described, for example, in
European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by reference herein, in their entirety. 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.
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 αvβ3. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving αvβ3. The compounds of the present invention may also be used in diagnostic assays involving αvβ3.
The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically 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 indicated.
When any variable (for example but not limited to, R2, R4, R6, R7, R8, R12,and R14, n, etc.) occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R4, then said group may optionally be substituted with up to two R4 and R4 at each occurrence is selected independently from the defined list of possible R4.
Also, by way of example, for the group -N(R5a)2, each of the two R5a substituents on N is independently selected from the defined list of possible R5a. Similarly, by way of example, for the group -C(R7)2-, each of the two R7 substituents on C is independently selected from the. defined list of possible R7.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such
substituent may be bonded to any atom on the ring. When 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.
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. For example, 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. By 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.
The term "substituted", as used herein, 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. When a substitent is keto (i.e., =O), then 2 hydrogens on the atom are replaced.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, "C0-C10" denotes alkyl having 0 to 10 carbon atoms; thus, C0 denotes a direct bond between the groups linked by the C0 group); "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CvFw where v = 1 to 3 and w = 1 to (2v+1));
"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, cycloheptyl, cyclooctyl, and adamantyl; and "biycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2] bicyclooctane, and so forth. "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.
The terms "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.
As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or naphthyl; the term
"arylalkyl" represents an aryl group attached through an alkyl bridge.
As used herein, "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. Examples of such carbocyles include, but are not limited to, cyclopropyl,
cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term "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, O 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, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl or
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5- thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,
phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolinyl, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,
pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or
oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above
heterocycles.
As used herein, the term "heteroaryl" refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocyclic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.
As used herein, "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.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound of Formula I is modified by making acid or base salts of the compound of Formula I.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
The pharmaceutically acceptable salts of the compounds of Formula I include the conventional non- toxic salts or the quaternary ammonium salts of the compounds of Formula I formed, for example, from non- toxic inorganic or organic acids. For example, 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.
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 tetramethylammonium hydroxide and the like.
As discussed above, 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 disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.
Synthesis
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.
Compounds of Formula I wherein Q includes an isoxazoline ring as one ring of the spirocycle can be conveniently prepared by dipolar cycloaddition of nitrile oxides with appropriate dipolarophiles (for reviews of 1,3-dipolar cycloaddition chemistry, see 1,3- Dipolar Cycloaddition Chemistry (Padwa, ed.), Wiley, New York, 1984; Kanemasa and Tsuge, Heterocvcles 1990, 30, 19). The requisite nitrile oxides are in turn prepared from commercially available precursors or appropriately substituted aldehydes via the intermediate oximes.
Scheme 1 illustrates one synthetic sequence which will provide compounds of Formula I of this invention. Scheme 1
Figure imgf000057_0001
Treatment of 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). Alternately, 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, 58, 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, 48, 4155; op cit. J. Amer. Chem. Soc., 199J., 72, 77; R.E. Ireland & L. Liu, J. Org. Chem, 1993, 58, 2899). Reductive amination 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. Synlett, 1990, 9, 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 α- or β-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-Cl. Some of these methods (especially the
carbodiimide) can be enhanced by the addition of 1- hydroxybenzotriazole. Deprotection of compound 1(f) is carried out using standard methods of removal of carboxy and amino protecting groups to provide target compounds of formula 1(g). Additional compounds of formula I can be prepared as shown in Scheme 2. Cycloaddition product, 1(a) can be converted to the corresponding amino compound by
conversion to azide 2(a) using diphenylphosphoryl azide under Mitsunobu conditions (Mitsunobu, O. Synthesis 1981, 1) and reduction of the resulting azide with triphenylphosphine (Staudinger, H.; Meyer, J. Helv.
Chim. Acta. 1919, 2, 635) Protection of the resulting amino group as its BOC derivative provides intermediate 2(b). Alternately, 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). Scheme 2
Figure imgf000060_0001
XX
Compounds of Formula I, wherein R1 is a 7- azabenzimidazol-2-yl, group can also be prepared from cycloaddition product 1(a) as depicted in Scheme 3. Jones oxidation of the primary hydroxyl group provides acid 3(a) which is condensed with 2,3-diaminopyridine to provide the 7-azabenzimidazole derivative, 3(b). This intermediate is converted to compounds of the invention by the steps of ester hydrolysis, coupling to compounds of formula 1(e) and deprotection described in detail above.
Scheme 3
Figure imgf000061_0001
Figure imgf000061_0002
The appropriately substituted racemic β-amino acids may be purchased commercially or, as is shown in Scheme 4, Method 1, prepared from the appropriate aldehyde, malonic acid and ammonium acetate according to the procedure of Johnson and Livak (J. Am. Chem. Soc. 1936, 58, 299) . Racemic β-substituted-β-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 β-keto esters as is
described in WO9316038. (Also see Rico et al., J. Org. Chem. 1993, 58, 7948-51.) Enantiomerically pure β- substituted-β-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 α-amino acids as shown in Scheme 4, Method 3 (see Meier, and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within); and through an enantioselective hydrogenation of a
dehydroamino acid as is shown in Scheme 4, Method 4 (see Asymmetric Synthesis, Vol. 5, (Morrison, ed.) Academic Press, New York, 1985) . A comprehensive treatise on the preparation of β-amino acid derivatives may be found in patent application WO 93/07867, the disclosure of which is hereby incorporated by reference.
Scheme 4
Figure imgf000063_0001
The synthesis of N2-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-benzyloxycarbonylaminopropιonic acid.
Additional dipolarophiles useful for the
preparation of the compounds of this invention are either commercially available or may be prepared by numerous methods. Synthesis of representative examples and their conversion into compounds of Formula I are illustrated in the following schemes.
Heating a neat mixture of 8-aza-1,4- dioxaspiro(4, 5)decane and 2,6-dibromopyridine provides bromopyridine intermediate 5(a) as shown in Scheme 5. Hydrolysis of the acetal protecting group gives the ketone, 5(b) which can then undergo olefination to compound 5(c). The olefination can be carried out by a number of methods known to one skilled in the art. (For suitable olefination methods, see S. H. Pine et al., Synthesis 1991, 165; Bull. Chem Soc. Jpn., 1980, 53, 1698; or J. Org. Chem. 1968, 33, 780.) The alkene is then subjected to the 1,3-dipolar cycloaddition
conditions described above to provide the spirocyclic system, 5(d). Amination with potassium amide in liquid ammonia followed by protection of the resulting amine as its BOC derivative gives compound 5(e). This
intermediate is then carried on to compounds of Formula 5(g) using the steps previously described.
Figure imgf000065_0001
Preparation of the analogous (4,4) spiro system is outlined in Scheme 6. Hydrogenation of commercially available 1-benzyl-3-hydroxypyrolidine and selective reprotection of the amine as the t-butylcarbamate provides 6(a). Oxidation of the hydroxyl to the ketone 6(b) by Swern oxidation or other standard methods followed by olefination as described above provides alkene 6(c). This alkene is then subjected to 1,3- dipolar cycloaddition as previously described to provide the spirocycle 6(d). Ester hydrolysis and coupling to a suitable β-amino ester gives 6(e). Removal of the BOC protecting group and treament with 2-bromo-6-t- butoxycarbonylaminopyridine (Aust. J. Chem. 1982, 35, 202-5) gives intermediate 6(f). Finally, deprotection provides compounds of this invention of Formula 6(g).
V
Figure imgf000067_0001
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). Deprotection of the silyl ether by treatment with fluoride ion followed by Swern oxidation of the
resulting alcohol provides aldehyde 7(f). Reductive amination with 2-aminopyridine followed by Boc
protection of the resulting secondary amine yields 7(g). Ester hydrolysis, coupling to the desired 2,3- diaminopropionate derivative and deprotection gives 7 (h). Alternately prior to deprotection the Cbz group can be selectively removed and alternate R10 groups introduced using standard methods known to one skilled in the art to provide compounds 7(i).
Figure imgf000069_0001
Compounds of Formula I wherein Q includes a 1,2,4- oxadiazoline as one ring of the spriocycle are prepared as shown in Scheme- 8. Protection of 4- methylenecyclohexylmethanol as its t-butyldimethylsilyl ether followed by ozonolysis of the double bond provides ketone 8(a). Treatment of compound 8(a) with a
suitable amine provides an imine 8(b) which can undergo 1,3-dipolarcycloaddition with a nitrile oxide to provide spirocycle 8(c). Further elaboration as described above would provide additional compounds of the present invention of Formula 8(b).
Figure imgf000071_0001
Additional spirocyclic compounds useful in the present invention can be prepared as outlined in Scheme 9 wherein 1,3-dipolarcycloaddition is carried using ethyl diazoacetate (E. Keller et al., Tetrahedron, 1993, 49, 8899) to provide spirocycle 9(b) (R10 = H). 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).
Figure imgf000073_0001
Fully saturated spirocycles are obtained by 1,3- dipolarcycloadditon of α-methoxycarbonylnitrones to an appropriately substituted alkene as illustrated in
Scheme 10. (Y. Inouye et al., Bull Chem. Soc. Jpn, 1979, 52, 3763; J. Hara et al., ibid., 1981, 54, 3871) .
Figure imgf000075_0001
The detailed processes for preparing the compounds of Formula I are illustrated by the following Examples. It is, however, understood that this invention is not limited to the specific details of these examples.
Melting points (mp) are uncorrected. Proton nuclear magnetic resonance spectra (NMR) were measured in chloroform-d (CDCl3) unless otherwise specified and the peaks are reported in parts per million (ppm) downfield from tetramethylsilane (TMS) . The coupling patterns are reported as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet; bm, broad multiplet. Infrared spectra are reported in reciprocal centimeters (cm- ). All final compounds gave satisfactory nmr and HRMS data and were analyzed to be >98% pure by reverse phase analytical HPLC.
Examples Example 1081
(S)-2-benzyloxycarbonylamino-3- [[8-(2- pyridinylamino)methyl-1-oxa-2-azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino]propionic acid
Ethyl [(8-hydroxymethyl)-1-oxa-2-azaspiro-[4,5]-dec-2- en-3-yl]carboxylate: 1(a)
Method A: 4-Methylenecyclohexylmethanol (2.52g, 20mmol, Wiley Organics, 63% purity) and sodium bicarbonate
(8.4g, 100mmol) in 45ml of 2:1 THF:H2O was cooled in an ice bath. Ethyl chlorooximidoacetate (5.00g, 33mmol) in 30ml 2:1 THF:H2O was then added, and the mixture stirred at room temperature for 18 hours. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was extracted with one more portion of ethyl acetate. The organic layers were combined, dried (MgSO4), filtered, concentrated and the residue purified by flash chromatography (silica gel column/1:1
EtOAc:Hexane) to afford 1(a) as a colorless oil (57.6% yield). HRMS calcd. for C12H19NO4 ([M+H]+): 242.139233; found: 242.140376.
Method B: A mixture of 4-Methylenecyclohexylmethanol
(10g, mol, Wiley Organics, 63% purity, 0.051 mol) and diethylnitromalonate (14 ml, 0.08 mol) in 100 ml
mesitylene was refluxed for 4-5 hrs under a nitrogen atmosphere with stirring. The resulting yellow solution was evaporated on a rotary evaporator in vacuo and the residue purified by flash chromatography (silica
gel/70: 30 Hexane/ethyl acetate) to provide 6.4 g of 1(a)
(52%) as 3/2 mixture of diastereomers by nmr.
Ethyl [(B-formyl)-1-oxa-2-azaspiro-[4,5]-dec-2-en-3- yl] carboxylate: 1(b) : Oxalyl chloride (0.70ml, 8mmol) in 5ml CH2CI2 was cooled to -78°C in dry ice-acetone bath and treated with dimethylsulfoxide (0.74ml, 10.4mmol) in 10ml CH2CI2 and stirred at -78°C for 15 minutes.
Intermediate 1(a) (992mg, 4mmol) in 10ml CH2CI2 was then added, and the mixture stirred at -78°C for 1 hour.
Triethylamine (2.0g, 20mmol) in 5 ml CH2CI2 was then added, and the mixture stirred at -78°C for 15 minutes. The bath was removed and the mixture allowed to warm up over a 30 minute period, diluted with CH2CI2 (50ml) and washed with water followed by brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 0.68g of 1(b) as a clear oil. HRMS calcd. for C12H17NO4 ([M+H]+):
240.123583; found: 240.123665. Ethyl [8-[(N-t-butoxycarbonyl)-(N-2- pyridinyl)aminomethyl]-1-oxa-2-azaspiro-[4,5]-dec-2-en- 3-yl]carboxylate 1(c): The intermediate 1(b) (1.068g, 4 mmol crude) and acetic acid (240mg, 4mmol) in 15ml 1,2- dichloroethane were treated with sodium
triacetoxyborohydride (1.19g, 5.6mmol), and the mixture stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with sat.
sodium bicarbonate and then brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 1.32g of amine as an oil. HRMS calcd. for C17H23N3O3 ([M+H]+) : 318.181767; found: 318.183254.
The crude amine and triethylamine (1.0g, 10mmol) in 20ml dichloromethane were treated with di-t-butyldicarbonate (2.18g, lOmmol), and stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, concentrated and the residue purified by flash chromatography (silica gel/1: 3 EtOAc:Hexane) to afford 845mg of 1(c) as a colorless oil (50.6% yield from
1(a)). HRMS calcd. for C22H31N3O5 ([M+H]+): 418.234197; found: 418.233666. [8-[(N-t-Bυtoxycarbonyl)-(N-2-pyridinyl)aminomethyl]-1- oxa-2-azaspiro-[4,5]-dec-2-en-3-yl]carboxylic acid 1(d):
The intermediate 1(c) (209mg, 0.5mmol) in 4.5ml of 2:1 THF:H2θ was treated with lithium hydroxide monohydrate (25mg, 0.6mmol) and the mixture stirred at room
temperature for 18 hours. The mixture was quenched with 0.6ml of 1 N HCl and extracted with ethyl acetate
(2x25ml) . The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 199mg of 1(d) as a colorless foam. HRMS calcd. for C20H27N3O5 ([M+H]+) : 390.202896; found: 390.202306.
Methyl (S)-2-henzyloxycarbonylamino-3-[[8-[N-(t- butoxycarbonyl)-N-(2-pyridinyl)amino]methyl-1-oxa-2- azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]propionate 1(f) (R15 = NHCbz, R = Me) : The intermediate 1(d) (199mg, 0.5mmol crude), 1(e) (R15 = NHCbz, R = Me, 144mg, 0.5mmol) and BOP Reagent (265 mg, 0.6 mmol) in 3ml DMF were treated with 4-N-methylmorpholine (152 mg, 1.5 mmol) in 2ml DMF and the mixture stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with sat. sodium bicarbonate, water and then brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, concentrated and the residue purified by flash
chromatography (silica gel column/1:1 EtOAc:Hexane followed by 10:1:10 EtOAc:EtOH:Hexane) to afford 213mg of 1(f) (R15 = NHCbz, R = Me) as a white solid (68.3% yield from 1(c)) . HRMS calcd. for C32H41N5O8 ([M+H]+): 624.303339; found: 624.303031.
(S)-2-benzyloxycarbonylamino-3-[[8-(2- pyridinylamino)methyl-1-oxa-2-azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid 1(g) (R15 = NHCbz) : The intermediate 1(f) (205mg, 0.33mmol crude) in 4ml of 1:1 MeOH:H2θ was treated with lithium hydroxide monohydrate (21mg, 0.5mmol) and the mixture stirred at room
temperature for 18 hours. The mixture was neutralised with 0.5ml of 1 N HCl and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 205mg of the free acid as a white solid. HRMS calcd. for C31H39N5O8 ([M+H]+) : 610.287689; found: 610.290115. Crude acid was treated with 3ml of 4M HCl in dioxane and stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and the residue purified by preparative HPLC (C18/80% CH3CN:20% H2O:0.05% TFA) to afford 132mg of a white solid. The compound was lyophilyzed from 2ml of 1:1 CH3CN:H2O to afford 107mg of 1(g) (R15 = NHCbz) as a white solid (52.0% yield from 1(f)) . 1H NMR (DMSO-D6; Mixture of diastereoisomers) d 7.8 (m, 2H), 7.35 (bs, 5H), 6.8 (m, 2H), 5.11 (s, 2H),
4.44 (s, 1H), 3.4 (bm, 2H), 3.2 (m, 2H), 2.8 (s, 2H) ,2.0 - 1.2 (bm, 8H) ; HRMS calcd. for C26H31N5O6 ([M+H]+) :
510.235259; found: 510.236039.
Similarly prepared from 1(d) were the following:
Example 1111
(S)-2-phenylsulfonylamino-3-[[8- (2- pyridinylamino)methyl-1-oxa-2-azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino]propionic acid
1H NMR (DMSO-D6) d 8.8 (bs,1H), 8.23 (t, 1H, J = 6), 8.18 (d, 1H, J = 9), 7.85-7.40 (m, 5H), 7.03 (d, 1H, J = 9), 6.8 (t, 1H, J = 7), 3.93 (dd, 1H, J = 13, 7), 3.38 (m, 1H), 3.19 (bm, 3H), 2.8 (s, 2H), 1.85-1.2 (bm, 8H); MS calcd. for C24H29N5O6S ([M+H]+) : 516.2; found: 516.1.
Example 1121
(S)-2-[(2,5-dimethylisoxazol-2-yl)sulfonyl]amino-3-[[8- (2-pyridinylamino)methyl-1-oxa-2-azaspiro-[4,5]-dec-2- en-3-yl]carbonylamino]propionic acid
1H NMR (DMSO-D6) d 8.8 (bs,1H), 8.54 (d, 1H, J = 9), 8.27 (t, 1H, J = 6), 7.86 (m, 1H), 7.03 (d, 1H, J = 9), 3.94 (m, 1H), 3.44 (m, 1H), 3.19 (bm, 3H), 2.8 (s, 2H),
2.45 (s, 3H), 2.5 (s, 3H), 2.9 - 1.2 (bm, 8H); MS calcd. for C23H30N6O7S ([M+H]+) : 535.2; found: 535.1.
Example 3055
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl]amino-3-[[7- benzy1oxycarbonyl-8-(2-imidazolylamino)methyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3-yl]carbonylamino] propionic acid
Part A: N-Cbz-4-hydroxy-L-prolinol: A solution of N- Cbz-4-hydroxy-L-proline (50 gm, 0.188 mol) in tetrahydrofuran (400 ml) was cooled to 0 °C in an ice bath under nitrogen and a solution of borane
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 was again stirred at room temperature overnight, then cooled to 0 °C and quenched by addition of approximately 200ml of 1:1
methanol /water. Solvents were removed on rotary
evaporator and residue diluted with water and extracted 4X with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution (2X) and brine (IX) then dried over anhydrous magnesium sulfate, filtered and evaporated to a clear oil (46.77 g, 99%) which was used without purification in part B below.
Part B. 1-benzyloxycarbonyl-2-(S)-t- butyl dimethyl silyloxymethyl-4-hydroxypyrrolidine: A mixture of the compound of Part A above (46.77 g, 0.186 mol), triethylamine (51.8 g, 0.372 mol), and t- butyldimethyIsilylchloride (30.86 g, 0.205 mol) in methylene chloride (375 ml) was stirred under nitrogen overnight at room temperature. An additional aliquot of silyl chloride (5 g, 0.033 mol) was added and stirring continued for 4-5 h. 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. 1-benzyloxycarbonyl-2(S)-t- butyldimethylsilyl oxymethyl-4-pyrrolidinone: To a solution of oxalyl chloride (12.4 ml, 0.142 mol) in methylene chloride (330 ml) precooled to -70 °C in an acetone/dry ice bath was added a solution of anhydrous dimethylsulfoxide (20.60ml, 0.29 mol) in methylene chloride (66 ml) dropwise under nitrogen over 30 min at T < -65°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. The aqueous was extracted with methylene chloride and the combined organic layers are washed with 10% citric acid solution (3X) and brine (IX) then dried over anhydrous sodium sulfate, filtered and concentrated to a clear oil (46.8 g, 100%) which was used without
purification in part D below.
Part D. 1-benzyloxycarbonyl-2(S)-t- butyldimethylsilyloxymethyl-4-methylenepyrrolidine:
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
(46.8 g, 0.129 mol) in ether (100 ml) . The mixture is allowed to assume room temperature and stirred
overnight. The resulting mixture was cooled in an ice bath and quenched by addition 700 ml of a saturated solution of ammonium chloride. The phases were separated and aqueous reextracted 2X with ether. The combined organics were washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash
chromatography (silica gel, hexane-ether 9:1) to provide the olefin (42.6 g, 91%) as a pale yellow oil.
Part E: 7-benzyloxycarbonyl-8-t-butyldimethylsilyloxy- methyl-3-ethoxycarbonyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-ene: The compound of part D above (13.04 g, 0.036 mol) was dissolved in methylene chloride (50 ml), treated with ethyl chlorooximidoacetate (8.18 g., 0.054 mol), and the mixture was cooled to 0°C followed by dropwise addition of triethylamine (7.53 ml, 0.054 mol). The reaction was allowed to come to room temperature over several hours then stirred overnight. An
additional 1.5 eq. of the chlorooxime was then added, and the mixture was cooled to 0°C and treated with triethylamine (1.5 eq) as described above. Resulting mixture was stirred at room temperature for 48 h, then diluted with additional methylene chloride and washed with 10% aqueous citric acid (3X), and brine (IX) then dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude was charged to silica gel and eluted first with Hexane/ether (80:20) to provide unreacted starting material (6.64 g, 51%) and then with hexane/ethyl acetate (75:25) to provide the two
diastereomers of the product (S,S isomer, 5.54 g, 32%; S,R isomer, 1.34 g, 8%). Anal. Calcd. for C24H36N2O6Si: C, 60.48; H, 7.61; N, 5.89. Found: C, 60.46; H, 7.33; N, 5.96.
Part F: 7-benzyloxycarbonyl-8-t-butyldimethylsilyloxy- methyl-3-carboxy-1-oxa-2,7-diazaspiro-[4,4]-non-2-ene: The compound of Part E above (18.7 g, 0.038 mol) was dissolved in methanol (200 ml) and treated at room temperature with a solution of lithium hydroxide monohydrate (2.4 g, 0.057 mol) in water (50 ml). The whole was stirred for 5 h and then solvent removed in vacuo. Water was added and the pH of the solution was adjusted to 4.4 with 10% aq. citric acid solution. The resulting mixture was extracted 3X with ethyl acetate with adjustment of pH back to 4.4 between extractions. The combined extracts were washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dried under vacuum to provide the acid (16.2 g, 95%) as a foam which was used without
purification in Part G below. MS(esi) m/z 449.4 (M+H)+, 335.2 (M+H-TBMDS)+
Part G: t-Butyl (S)-2-[(2,4,6-trimethylphenyl)suifonyl]- amino-3-[[7-benzyloxycarbonyl-8-(t-butyldimethylsilyl- oxy)methyl-1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid: A mixture of the compound of Part F above (10 g, 0.022 mol), t-butyl 3- amino-2- (2,4, 6-trimethylphenylsulfonylamino)propionate (7.6 g, 0.022 mol), N-methylmorpholine (5.4 ml, (0.049 mol) and Castro's reagent (14.8 g, 0.033 mol) in N,N- dimethylformamide (100 ml) was stirred under nitrogen at room temperature overnight. The DMF was removed in vacuo and the residue diluted with 500 ml water and extracted 3X with ethyl acetate. The combined extracts were washed with water (2X), 10% citric acid (1X), saturated sodium bicarbonate (1X) and brine (1X) then dried over anhydrous sodium sulfate, filtered and evaporated. The coupling product was purified by filtration through a pad of silica gel eluted with hexane/ethyl acetate (4:1) to provide the product as a white foam (15 gm, 88%). MS(esi) m/z 773.4 (M+H)+ 795.4 (M+Na)+.
Part H: t-Butyl (S)-2-[(2,4,6-trimethylphenyl)sulfonyl]- amino-3-[[7-benzyloxycarbonyl-8-hydroxymethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3-yl]carbonylamino] pronionic acid: The compound of Part G above (2.8 g, 3.62 mmol) was dissolved in tetrahydrofuran (12 ml) and treated with tetra-n-butylammonium floride (5.8 ml of a 1.0 M solution in THF, 5.8 mmol). The resulting solution was stirred overnight at room temperature. Reaction was quenched by addition of water and THF removed on rotary evaporator. The remaining aqueous was extracted 3X with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. Chromatography on silica gel (hexane/ethyl acetate 1:1 followed by methylene
chloride/methanol 95:5) provided the alcohol (2.02 g., 85%) ms m/z 659.3 (M+H)+.
Part T: t-Butyl (S)-2-[(2,4,6-trimethylphenyl)sulfonyl]- amino-3-[[7-benzyloxycarbonyl-8-formyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3-yl]carbonylamino] propionic acid: A solution of the compound of Part H above (0.8 g, 1.21 mmol) in anhydrous methylene chloride (1 ml) was added dropwise to a a solution of Dess-Martin
periodinane (0.59g, 1.30 mmol) in approximately 4 ml of dry methylene chloride at room temperature under nitrogen. The resulting mixture was stirred for 1 hr, the diluted with ethyl acetate and poured into a solution of saturated sodium bicarbonate (20 ml) containing 5 g sodium thiosulfate. This was stirred for 10 min. The phases were separated, aqueous reextracted with ethyl acetate, and combined organics washed with saturated sodium bicarbonate, water and brine, then dried over anhydrous magnesium sulfate, filtered and evaporated to give the aldehyde as a clear oil (0.74 g, 93%).
Part J: t-Butyl (S)-2-[(2,4,6-trimethylphenyl)sulfonyl]- amino-3-[[7-benzyloxycarbonyl-8-(imidazol-2- ylamino)methyl-1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylaminol propionic acid: To a solution of the compound of Part I above (0.73 g, 1.11 mmol) in benzene was added anhydrous magnesium sulfate (0.588 g, 4.88 mmol) and 2-amino-1-tritylimidazole (0.398 g, 1.22 mmol) and the whole was refluxed for 4 hrs under nitrogen. The mixture was cooled to room temperature, filtered under nitrogen and benzene removed in vacuo. The residue was taken up in 1,2-dichloroethane, treated under nitrogen at room temperature with sodium
triacetoxyborohydride (0.588 g, 2.78 mmol), and the whole was stirred overnight. The reaction was quenched by addition of water and then diluted with ethyl
acetate. Aqueous was reextracted with ethyl acetate, and combined organic layers were washed with saturated sodium bicarbonate, water and brine, then dried over anhydrous magnesium sulfate, filtered and evaporated. Filtration through silica gel provided the desired product (0.682 g, 63%) as an off-white foam which was used without further purification in part K below.
Part K; (S)-2-[(2,4,6-trimethylphenyl)sulfonyl]-amino-3- [[7-benzyloxycarbonyl-8-(imidazol-2-ylamino)methyl-1- oxa-2,7-diazaspiro-[4,4]-non-2-en-3-yl]carbonylamino]- 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. ammonium hydroxide 95:5:0/5; (3) 90/10/1) provided the intermediate detritylated t-butyl ester 0.139 mg, 62%). This was taken up in methylene chloride (8 ml) and trifluoroacetic acid (2 ml) was added. The solution was stirred for 72 h, then
evaporated and triturated with ether. The resulting solid was purified by prep HPLC (C18, gradient from 100% A to 100% B: A=90/10/0.05 H2O/CH3CN/TFA; B=90/10/0.05 CH3CN/H2O/TFA) to provide the title compound (0.078g, 50%) . MS m/z 690.4 (M+Na)+ 668.4 (M+H)+.
Example 3063: (S)-2-[(2,4,6-trimethylphenyl)sulfonyl]- amino-3-[[8-(imidazol-2-ylamino)methyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3-yl]carbonylamino]-propionic 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)+. Using the methods described above and modifications thereof known to one skilled in the art of organic synthesis, additional compounds of the present invention can be prepared, including, but not limited to the representative compounds listed in the Tables below.
Utility
The compounds of Formula I of the present invention possess activity as antagonists of integrins such as, for example, the αvβ3 or vitronectin receptor, αvβs or c.5βl, 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. 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 αvβ3
receptor.
The compounds of the present invention possess selectivity for the αvβ3 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 vivo, 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.
As used herein "μg" denotes microgram, "mg" denotes milligram, "g" denotes gram, "μL" denotes microliter, "mL" denotes milliliter, "L" denotes liter, MnM" denotes nanomolar, "μM" denotes micromolar, "mM" denotes
millimolar, "M" denotes molar and "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 αvβ3 (human placenta) - Vitronectin ELISA, «vβ3-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 IC50 or Ki value of less than about 10 μM for the inhibition of αvβ3-Vitronectin Binding Assay, with compounds preferably having Ki values of less than about 0.1 μM. Tested compounds of the present invention are active in the αvβ3-Vitronectin Binding Assay as well as in cell-based assays of integrin adhesion mediated by the αvβ3-receptor. Purified αvβ3 (human placenta) - Vitronectin ELISA The αvβ3 receptor was isolated from human placental extracts prepared using octylglucoside. The extracts were passed over an affinity column composed of anti-αvβ3 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 αvβ3 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 αvβ3 with no detectable levels of αvβ3 according to the gel (αvβ3) and according to effects of blocking antibodies for the αvβ3 or αvβ3 in the ELISA.
A submaximal concentration of biotinylated
vitronectin was selected based on cone, response curve with fixed receptor cone, and variable concentrations of biotinylated vitronectin. α^-Vitronectin Binding Assay
The purified receptor is diluted with coating buffer (20 mM Tris HCl, 150 mM NaCl, 2.0 mM CaCl2, 1.0 mM MgCl2·6H2O, 1.0 mM MnCl2·4H2O) and coated (100 μL/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 CaCl2,1.0 mM MgCl2·6H2O,1.0 mM MnCl2·4H2O). Receptor is then blocked (200 μL/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 μL) and either inhibitor (11 μL) or B/B buffer w/1.0% BSA (11 μL)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 μL/well) in B/B buffer containing 1.0% BSA. The plates are washed twice with B/B buffer and alkaline phosphatase substrate (100 μL) is added. Color is developed at room temperature. Color development is stopped by addition of 2N NaOH (25 μL/well) and absorbance is read at 405 nm. The IC50 is the concentration of test substance needed to block 50% of the vitronectin binding to the receptor.
Integrin Cell-Based Adhesion Assays
In the adhesion assays, 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 αvβ3, αvβ5 and α5β1 integrin interactions.
Platelet Aggregation Assay
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). 200 μL of PRP (5x108 platelets/mL) were added to each micro test tube, and transmittance was set to 0%. 20 μL of ADP (10 μM) was added to each tube, and the aggregation profiles were plotted (% transmittance versus time). Test agent (20 μL) was added at different concentrations prior to the addition of the platelet agonist. Results are expressed as % inhibition of agonist-induced platelet aggregation. Human Aortic Smooth Muscle Cell Migration Assay
A method for assessing αvβ3-mediated smooth muscle cell migration and agents which inhibit αvβ3-mediated smooth muscle cell migration is described in Liaw et al., J. Clin. Invest. (1995) 95: 713-724).
In Vivo Angiogenesis Model
A quantitative method for assessing angiogenesis and antiangiogenic agents is described in Passaniti et al., Laboratory Investigation (1992) 67: 519-528
Pig Restenosis Model
A method for assessing restenosis and agents which inhibit restenosis is described in Schwartz et al., J. Am. College of Cardiology (1992) 19: 267-274.
Mouse Retinopathy Model
A method for assessing retinopathy and agents which inhibit retinopathy is described in Smith et al.,
Invest. Ophthal. & Visual Science (1994) 35: 101-111. Dosage and Formulation
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 αvβ3 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 (compositions suitable for
administration) contain from about 0.1 milligram to about 100 milligrams of active ingredient per unit. In these pharmaceutical compositions 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.
In general, 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.
Also used are citric acid and its salts and sodium EDTA. In addition, 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: Capsules
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.
Soft Gelatin Capsules
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. Tablets
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 αvβ3 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.
In a preferred embodiment, 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.). When the combination products are not formulated together in a single dosage form, the αvβ3 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. When not
administered at the same time, preferably 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. Preferably, administration of the combination products of the invention is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that the αγβ3 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.
As discussed above, where two or more of the foregoing therapeutic agents are combined or
co-administered with the compounds of this invention, generally 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.
Particularly when provided as a single dosage form, 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, piroxicam 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). For this reason, 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).
In order to minimize contact, one embodiment of this invention where the product is orally administered provides for a combination product wherein one active ingredient is enteric coated. By 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. Furthermore, 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. 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.
Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active
ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non- perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
Pharmaceutical 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.
Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. The sterile containers of materials may comprise separate containers, or one or more multi-part containers, as exemplified by the
UNIVIAL™ two-part container (available from Abbott Labs, Chicago, Illinois), as desired. The compounds according to the method of the invention and the anti-coagulant agent, anti-platelet agent, thrombin inhibitor,
thrombolytic agent, and/or combinations thereof, may be separate, or combined into a single dosage form as described above. Such 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.
Representative compounds of the present invention are listed in the Tables below.
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
- -y am nome y
Figure imgf000256_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula I:
R1-Q-W-X-Y
(I) and pharmaceutically acceptable salt forms thereof, wherein:
Q is selected from
Figure imgf000269_0001
A is selected from -N(R10)-, -C(R11)- or -O-; A1 is selected from -O- or -N(R10)-;
Z is a spiro-fused 4-7 membered ring system (including the sprio atom) containing 0-2 heteroatoms selected from O, S, or N, said ring system optionally being substituted on carbon with keto, or being
substituted on carbon or nitrogen independently with 0-2 R9 or R10 or R10a;
R1 is selected from:
Figure imgf000270_0001
B is independently selected from -CH2-, -O-, -N(R2)-, or -C(=O)-;
B1 is independently selected from -CH2- or -N(R3)-; D is -N(R2)-, -O-, -S-, -C(=O)- or -SO2-;
E-F is -C(R4)=C(R5)-, -N=C(R4)-, -C(R4)=N-, or
-C(R4)2C(R5)2-; J, K, L and M are independently selected from -C(R4)-,
-C(R5)- or -N-, provided that at least one of J, K, L and M is not -N-;
R2 is selected from: H, C1-C6 alkyl, (C1-C6
alkyl) carbonyl, (C1-C6 alkoxy) carbonyl; (C1-C6 alkyl) aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl,
heteroaryl (C1-C6 alkyl) carbonyl,
heteroarylcarbonyl, aryl C1-C6 alkyl, (C1-C6 alkyl) carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl (C1-C6 alkyl) sulfonyl,
heteroarylsulfonyl, heteroaryl (C1-C6
alkyl) sulfonyl, aryloxycarbonyl, aryl(C1-C6 alkoxy) carbonyl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R3 isselected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4- C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C1-C6 alkyl)-;
R4 and R5 are independently selected from: H, C1-C4
alkoxy, NR2R3, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C4-C11
cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, (C1-C6 alkyl) carbonyl, (C1-C6 alkoxy) carbonyl,
arylcarbonyl; alternatively, when substituents on adjacent atoms, R4 and R5 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: C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3, or NO2;
R6 is selected from: H, C1-C4 alkyl, or benzyl; R7 and R8 are independently selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C0-C6 alkyl)-;
U is selected from:
-N(R6) (CH2)n-,
-N(R6) (CH2)mO-,
-N(R6) (CH2)mN(R7)- -N(R6) (CH2)nS(O)p- -N(R6)C(=O) (CH2)n-;
-N(R6) (CH2)mC(=O)-;
V is selected from:
-(CH2)n-,
-(CH2)mO-(CH2)n-,
-(CH2)mN(R7) (CH2)n-,
-(CH2)nS(O)p(CH2)n-,
-(CH2)mN(R7)C(=O) (CH2)n-»
-(CH2)nC(=O)N(R7) (CH2)n-,
-(CH2)nC(=O) (CH2)n-;
R9 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl (C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
R10 is selected from: H, CO2R17, C(=O)R17, C(=O)NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11; R10a is selected from: CO2R17, C(=O)R17, C (=O)NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11;
R11 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
W is selected from:
C1-C4 alkylene,
-(C(R12)2)qO(C(R12)2)q-,
-(C(R12)2)qC(=O) (C(R12)2)q-,
-(C(R12)2)qC(=O)N(R13)-,
-C(=O)-N(R13)-(C(R12)2)q-;
X is -(C(R12)2)qC(R12) (R14)-C(R12) (R15)-; alternatively, W and X can be taken together to be
Figure imgf000273_0001
R12 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C10 cycloalkylalkyl, (C1-C4 alkyl) carbonyl, aryl, or aryl (C1-C6 alkyl)-; R13 is selected from H, C1-C6 alkyl, C3-C7
cycloalkylmethyl, or aryl (C1-C6 alkyl)-
R14 is selected from: H, C1-C6 alkylthio(C1-C6 alkyl)-, aryl(C1-C10 alkylthioalkyl)-, aryl (C1-C.o alkoxyalkyl)-, C1-C10 alkyl, C1-C10 alkoxyalkyl, C1-C6 hydroxyalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl (C1-C6 alkyl)-,
heteroaryl (C1-C6 alkyl)-, aryl, heteroaryl, CO2R17, C(=O)R17, or CONR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0- 1 R16 or 0-2 R11;
R15 is selected from:
H, R16, C1-C10 alkyl, C1-C10 alkoxyalkyl,
C1-C10 alkylaminoalkyl, C1-C10 dialkylaminoalkyl, (C1-C10 alkyl) carbonyl, aryl (Co-C6 alkyl) carbonyl, C1-C10 alkenyl, C1-C10 alkynyl , C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C1-C6 alkyl)-,
heteroaryl (C1-C6 alkyl)-, aryl, heteroaryl, CO2R17, C(=O)R17, CONR17R20, SO2R17, or SO2NR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0-2 R11,-
Y is selected from:
-COR19, -SO3H, -PO3H, tetrazolyl, -CONHNHSO2CF3 ,
-CONHSO2R17, -CONHSO2NHR17, -NHCOCF3, -NHCONHSO2R17, -NHSO2R17, -OPO3H2, -OSO3H, -PO3H2, -SO3H,
-SO2NHCOR17, -SO2NHCO2R17,
Figure imgf000274_0001
R16 is selected from:
-N(R20)-C(=O)-O-R17, -N(R20)-C(=O)-R17,
-N(R20)-C(=O)-NH-R17,
-N(R20)SO2-R17, or
-N(R20)SO2-NR20R17;
R17 is selected from:
C1-C1 0 alkyl, C3-C11 cycloalkyl, aryl (C1-C6 alkyl)-, (C1-C6 alkyl) aryl, heteroaryl (C1-C6 alkyl)-, (C1-C6 alkyl) heteroaryl, arylaryl (C1-C6 alkyl)-,
heteroarylaryl (C1-C6 alkyl)-, arylheteroaryl (C1-C6 alkyl)-, heteroarylheteroaryl (C1-C6 alkyl)-, heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;
R18 is selected from:
H,
-C(=O)-O-R17,
-C(=O)-R17,
-C(=O)-NH-R17,
-SO2-R17, or
-SO2-NR20R17;
R19 is selected from:
hydroxy,
C1-C10 alkyloxy,
C3-C11 cycloalkyloxy,
aryloxy,
aryl(C1-C6 alkoxy)-,
C3-C10 alkylcarbonyloxyalkyloxy,
C3-C10 alkoxycarbonyloxyalkyloxy,
C2-C10 alkoxycarbonylalkyloxy,
C5-C10 cycloalkylcarbonyloxyalkyloxy,
C5-C10 cycloalkoxycarbonyloxyalkyloxy, C5-C10 cycloalkoxycarbonylalkyloxy,
C7-C11 aryloxycarbonylalkyloxy,
C8-C12 aryloxycarbonyloxyalkyloxy,
C8-C12 arylcarbonyloxyalkyloxy,
C5-C10 alkoxyalkylcarbonyloxyalkyloxy,
C5-C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one- yUmethyloxy,
C10-C14 (5-aryl-1,3-dioxa-cyclopenten-2-one- yl)methyloxy, or
(R11) (R12)N-(C1-C10 alkoxy)-;
R20 is selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C1-C6 alkyl)-,. m is 1-2 ;
n is 0-2;
P is 0-2;
q is 0-2 ; and
r is 0-2 ; provided that:
n, q, and r are chosen such that the number of in-chain atoms between R1 and Y is in the range of 8-18.
2. A compound of Claim 1 of the Formula I : R1-Q-W-X-Y
(I) and pharmaceutically acceptable salt forms thereof wherein: Q is selected from:
Figure imgf000277_0001
R1 is selected from:
Figure imgf000278_0001
D is -N(R2)-, -O-, -S-, -C(=O)- or -SO2-;
E-F is -C(R4)=C(R5)-, -N=C(R4)-, -C(R4)=N-, or
-C(R4)2C(R5)2-; J, K, L and M are independently selected from -C(R4)-,
-C(R5)- or -N-, provided that at least one of J, K, L and M is not -N-;
R2 is selected from: H, C1-C6 alkyl, (C1-C6
alkyl) carbonyl, (C1-C6 alkoxy) carbonyl; (C1-C6 alkyl) aminocarbonyl, C3-C6 alkenyl, C3-C7
cycloalkyl, C4-C11 cycloalkylalkyl, aryl,
heteroaryl (C1-C6 alkyl) carbonyl,
heteroarylcarbonyl, aryl(C1-C6 alkyl)-, (C1-C6 alkyl) carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl (C1-C6 alkyl) sulfonyl, heteroarylsulfonyl, heteroaryl (C1-C6
alkyl) sulfonyl, aryloxycarbonyl, or aryl (C1-C6 alkoxy) carbonyl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R3 is selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl,
C4-C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C1-C6 alkyl)-;
R4 and R5 are independently selected from: H, C1-C4
alkoxy, NR2R3, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C4-C11
cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, (C1-C6 alkyl) carbonyl, (C1-C6 alkoxy) carbonyl,
arylcarbonyl, or alternatively, when substituents on adjacent atoms, R4 and R5 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: C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3, or NO2;
R6 is selected from: H, C1-C4 alkyl, or benzyl;
R7 and R8 are independently selected from: H, C1-C6
alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C0-C6 alkyl)-;
U is selected from: -N(R6) (CH2)n-,
-N(R6) (CH2)mO-,
-N(R6) (CH2)mN(R7)- -N(R6) (CH2)nS(O)p- -N(R6)C(=O) (CH2)n-;
V is selected from:
-(CH2)n-,
-(CH2)mO-(CH2)n-,
-(CH2)mN(R7) (CH2)n-,
-(CH2)nS(O)p(CH2)n-,
-(CH2)mN(R7)C(=O) (CH2)n-,
-(CH2)nC(=O)N(R7) (CH2)n-,
-(CH2)nC(=O) (CH2)n-;
R9 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl (C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
R10 is selected from: H, CO2R17, C(=O)R17, C(=O)NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0-
1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11;
R10a is selected from: CO2R17, C(=O)R17, C(=O)NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11; R11 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl (C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
W is selected from:
C1-C4 alkylene,
-(C(R12)2)qO(C(R12)2)q-,
-(C(R12)2)qC(=O) (C(R12)2)q-,
-(C(R12)2)qC(=O)N(R13)-,
-C(=O)-N(R13)-(C(R12)2)q-;
X is -(C(R12)2)qC(R12) (R14)-C(R12) (R15)-; alternatively, W and X can be taken together to be
Figure imgf000281_0001
R12 is selected from H, C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C3-C7 cycloalkyl,
C4-C10 cycloalkylalkyl, (C1-C4 alkyl) carbonyl, aryl, or aryl (C1-C6 alkyl)-;
R13 is selected from H, C1-C6 alkyl, C3-C7
cycloalkylmethyl, or aryl(C1-C6 alkyl)-;
R14 is selected from:
H, C1-C6 alkylthio (C1-C6 alkyl)-, aryl (C1-C10 alkylthioalkyl)-, aryl (C1-C10 alkoxyalkyl)-, C1-C10 alkyl, C1-C10 alkoxyalkyl, C1-C6 hydroxyalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl (C1-C6 alkyl)-,
heteroaryl (C1-C6 alkyl)-, aryl, heteroaryl, CO2R17, C(=O)R17, or CONR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0- 1 R16 or 0-2 R11; R15 is selected from:
H, R16, C1-C10 alkyl, C1-C10 alkoxyalkyl,
C1-C10 alkylaminoalkyl, C1-C10 dialkylaminoalkyl, (C1-C10 alkyl) carbonyl, aryl (C0-C6 alkyl) carbonyl, C1-C10 alkenyl, C1-C10 alkynyl , C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C1-C6 alkyl)-,
heteroaryl (C1-C6 alkyl)-, aryl, heteroaryl, CO2R17, C(=O)R17, CONR17R20, SO2R17, or SO2NR17R20, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0-2 R11;
Y is selected from:
-COR19, -SO3H, -PO3H, tetrazolyl, -CONHNHSO2CF3 , -CONHSO2R17, -CONHSO2NHR17, -NHCOCF3, -NHCONHSO2R17, -NHSO2R17, -OPO3H2, -OSO3H, -PO3H2, -SO3H,
-SO2NHCOR17, -SO2NHCO2R17,
Figure imgf000282_0001
R16 is selected from:
-N(R20)-C(=O)-O-R17,
-N(R20)-C(=O)-R17,
-N(R20)-C(=O)-NH-R17,
-N(R20)SO2-R17, or
-N(R20)SO2-NR20R17;
R17 is selected from: C1-C10 alkyl, C3-C11 cycloalkyl, aryl(C1-C6 alkyl)-, (C1-C6 alkyl) aryl, heteroaryl (C1-C6 alkyl)-, (C1-C6 alkyl) heteroaryl, arylaryl (C1-C6 alkyl)-,
heteroarylaryl (C1-C6 alkyl)-, arylheteroaryl (C1-C6 alkyl)-, heteroarylheteroaryl (C1-C6 alkyl)-, heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;
R18 is selected from:
H,
-C(=O)-O-R17,
-C(=O)-R17,
-C(=O)-NH-R17,
-SO2-R17, or
-SO2-NR20R17; R19 is selected from:
hydroxy,
C1-C10 alkyloxy,
C3-C11 cycloalkyloxy,
aryloxy,
aryl (C1-C6 alkoxy)-,
C3-C10 alkylcarbonyloxyalkyloxy,
C3-C10 alkoxycarbonyloxyalkyloxy,
C2-C10 alkoxycarbonylalkyloxy,
C5-C10 cycloalkylcarbonyloxyalkyloxy,
C5-C10 cycloalkoxycarbonyloxyalkyloxy,
C5-C10 cycloalkoxycarbonylalkyloxy,
C7-C11 aryloxycarbonylalkyloxy,
C8-C12 aryloxycarbonyloxyalkyloxy,
C8-C12 arylcarbonyloxyalkyloxy,
C5-C10 alkoxyalkylcarbonyloxyalkyloxy, C5-C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one- yl) methyloxy,
C10-C14 (5-aryl-1,3-dioxa-cyclopenten-2-one- yl)methyloxy, or
(R11) (R12)N-(C1-C10 alkoxy)-;
R20 selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4- C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, or heteroaryl (C1-C6 alkyl)-; m is 1-2
n is 0-2
P is 0-2
q is 0-2 and
r is 0-2 provided that:
n, q, and r are chosen such that the number of in- chain atoms between R1 and Y is in the range of 8-
18.
3. A compound of Claim 1 of the Formula I and pharmaceutically acceptable salt forms thereof wherein:
Q is selected from:
Figure imgf000285_0001
Figure imgf000286_0001
wherein the above heterocycles are optionally
substituted with 0-2 substituents selected from the group consisting of: NH2, halogen, NO2, CN, CF3, C1-C4 alkoxy, C1-C6 alkyl, and C3-C7 cycloalkyl;
R2 is selected from: H, C1-C4 alkyl or benzyl; U is -NH(CH2)n-;
V is -(CH2)n-;
R10 is selected from: H, CO2R17, C(=O)R17, CONR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11; R10a is selected from: CO2R17, C(=O)R17, CONR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11;
R11 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
W is -C(=O)-N(R13)-;
X is -CH(R14)-CH(R15)-; R13 is H or CH3 ;
R14 is selected from:
H, C1-C10 alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally
substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;
R15 is H or R16;
Y is -C(=O)R19;
R16 is selected from:
-N(R20)-C(=O)-O-R17,
-N(R20)-C(=O)-R17,
-N(R20)-C(=O)-NH-R17,
-N(R20)SO2-R17, or
-N(R20)SO2-N(R20)R17;
R17 is selected from:
C1-C10 alkyl, C3-C11 cycloalkyl, aryl (C1-C6 alkyl)-, (C1-C5 alkyl) aryl, heteroaryl (C1-C6 alkyl)-, (C1-C6 alkyl) heteroaryl, arylaryl (C1-C6 alkyl)-,
heteroarylaryl (C1-C6 alkyl)-, arylheteroaryl (C1-C6 alkyl)-, heteroarylheteroaryl (C1-C6 alkyl)-, heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2; R19 is selected from:
hydroxy, C1-C10 alkoxy,
methylcarbonyloxymethoxy-,
ethylcarbonyloxymethoxy-,
t-butylcarbonyloxymethoxy-,
cyclohexylcarbonyloxymethoxy-,
1-(methylcarbonyloxy)ethoxy-,
1-(ethylcarbonyloxy)ethoxy-,
1-(t-butylcarbonyloxy)ethoxy-,
1-(cyclohexylcarbonyloxy)ethoxy-,
i-propyloxycarbonyloxymethoxy-,
t-butyloxycarbonyloxymethoxy-,
1-(i-propyloxycarbonyloxy)ethoxy-,
1-(cyclohexyloxycarbonyloxy)ethoxy-,
1-(c-butyloxycarbonyloxy)ethoxy-,
dimethylaminoethoxy-,
diethylaminoethoxy-,
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4- yl)methoxy-,
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-, or
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R20 is H or CH3; and n is 0-1.
4. A compound of Claim 1 of the Formula I and pharmaceutically acceptable salt forms thereof wherein:
Q is selected from:
Figure imgf000290_0001
Figure imgf000291_0001
R2 is selected from: H, C1-C4 alkyl, or benzyl;
U is -NH(CH2)n-;
V is -(CH2)n-; R10 is selected from: H, CO2R17, C(=O)R17, C(=O)NR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl(C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11; R10a is selected from: CO2R17, C(=O)R17, CONR17R20,
-SO2R17, -SO2NR17R20, C1-C6 alkyl substituted with 0- 1 R15, C3-C6 alkenyl substituted with 0-1 R15, C3-C7 cycloalkyl substituted with 0-1 R15, C4-C11
cycloalkylalkyl substituted with 0-1 R15, aryl substituted with 0-1 R15 or 0-2 R11, or aryl (C1-C6 alkyl)- substituted with 0-1 R15 or 0-2 R11;
R11 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C6 alkyl)-, (C1-C4 alkoxy) carbonyl, (C1-C4 alkyl) carbonyl, C1-C4 alkylsulfonyl, or C1-C4 alkylaminosulfonyl;
W is -C(=O)-N(R13)-;
X is -CH(R14)-CH(R15)-;
R13 is H or CH3;
R14 is selected from:
H, C1-C10 alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally
substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;
R15 is H or R16;
Y is -C(=O)R19; R16 is selected from:
-N(R20)-C(=O)-O-R17, -N (R20 ) -C ( =O) -R17 ,
-N (R20 ) SO2-R17 ,
R17 is selected from:
C1-C10 alkyl , C3-C11 cycloalkyl , aryl (C1-C6 alkyl ) - ,
(C1-C6 alkyl) aryl, heteroaryl (C1-C6 alkyl)-, (C1-C6 alkyl) heteroaryl, arylaryl (C1-C6 alkyl)-,
heteroarylaryl (C1-C6 alkyl)-, arylheteroaryl (C1-C6 alkyl)-, heteroarylheteroaryl(C1-C6 alkyl)-, heteroaryl, or aryl, wherein said aryl or
heteroaryl groups are optionally substituted with
0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and NO2;
R19 is selected from:
hydroxy,
C1-C10 alkoxy,
methylcarbonyloxymethoxy-,
ethylcarbonyloxymethoxy-,
t-butylcarbonyloxymethoxy-,
eyelohexylcarbonyloxymethoxy-,
1-(methylcarbonyloxy)ethoxy-,
1-(ethylcarbonyloxy)ethoxy-,
1-(t-butylcarbonyloxy)ethoxy-,
1-(cyclohexylcarbonyloxy)ethoxy-,
i-propyloxycarbonyloxymethoxy-,
c-butyloxycarbonyloxymethoxy-,
1-(i-propyloxycarbonyloxy)ethoxy-,
1-(cyclohexyloxycarbonyloxy)ethoxy-,
1-(t-butyloxycarbonyloxy)ethoxy-,
dimethylaminoethoxy-,
diethylaminoethoxy-,
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-, (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4- yl)methoxy-, (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-, or
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; R20 is H or CH3; and n is 0-1.
5. A compound of Claim 1 and enantiomeric or diasteriomeric forms thereof, or mixtures of
enantiomeric or diastereomeric forms thereof, and pharmaceutically acceptable salt forms thereof, selected from the group consisting of:
(S)-2-phenylsulfonylamino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3- [[[8-(2-pyridinylaminomethyl)-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(3,5-dimethylisoxazol4-yl)sulfonyl] amino-3- [[[8-(2-pyridinylaminomethyl)-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[[8-[(6-aminopyridin- 2-yl)methyl]-]-1-oxa-2,8-diazaspiro-[4,5]-dec- 2-en-3-yl]carbonylamino] propionic acid, (S)-2-phenylsulfonylamino-3-[[[8-[(6-aminopyridin- 2-yl)methyl]]-1-oxa-2,8-diazaspiro- [4,4]-non- 2-en-3-yl]carbonylamino] propionic acid, (S)-2-phenylsulfonylamino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro-
[4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[[8-[2-(4,5- dihydroimidazol-2-yl)aminomethyl]-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]- propionic acid,
(S)-2-[(2-methylphenyl)sulfonyl]amino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2-chloro-4-methylphenyl)sulfonyl] amino-3- [[[8-(2-pyridinylaminomethyl)-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(4-biphenyl)sulfonyl]amino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2-bromophenyl)sulfonyl]amino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(1-naphthyl)sulfonyl]amino-3-[[[8-(2- pyridinylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid. (S)-2-phenylsulfonylamino-3-[[[8-(2- imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[[8-(2- imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3- [[[8-(2-imidazolylaminomethyl)-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl] amino-3-[[[8-
(2-imidazolylaminomethyl)-]-1-oxa-2-azaspiro- [4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[[8-
(2-imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino-
3-[[[8-(2-imidazolylaminomethyl)-]-1-oxa-2- azaspiro-[4,5]-dec-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl] amino-3-[[[8-(2- imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[[8-(2- imidazolylaminomethyl)-]-1-oxa-2-azaspiro-
[4,5]-dec-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[7-benzyloxycarbonyl-
8-(2-imidazolylaminomethyl)-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid, (S)-2-benzyloxycarbonylamino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl] carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)-
1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl) phenylsulfonyl] amino- 3-[[7-benzyloxycarbonyl-8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[7- benzyloxycarbonyl-8-(2-imidazolylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3-[[8- (2-imidazolylaminomethyl)-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl]amino-3-[[8- (2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl] amino- 3-[[8-(2-imidazolylaminomethyl)-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl] amino-3-[[8-(2- imidazolylaminomethyl)-1-oxa-2,7-diazaspiro-
[4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[8-(2- imidazolylaminomethyl )-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[7-benzyloxycarbonyl- 8-(2-pyridinylaminomethyl)-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl]amino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl) phenylsulfonyl]amino- 3-[[7-benzyloxycarbonyl-8-(2- pyridinylaminomethyl)-1-oxa-2,7-diazaspiro- [4,4]-non-2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl]amino-3-[[7- benzyloxycarbonyl-8-(2-pyridinylaminomethyl)- 1-oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid, (S)-2-phenylsulfonylamino-3-[[7-benzyloxycarbonyl- 8-(4,5-dihydroimidazol-2-yl) aminomethyl-1-oxa- 2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[7- benzyloxycarbonyl-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-en-3-yl] carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino] propionic acid, (S)-2-[(2,6-dimethylphenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino- 3-[[7-benzyloxycarbonyl-8-(4,5- dihydroimidazol-2-yl)aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl] amino-3-[[7- benzyloxycarbonyl-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non- 2-en-3-yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl] amino-3-[[7- benzyloxycarbonyl-8-8-(4,5-dihydroimidazol-2- yl)aminomethyl-1-oxa-2,7-diazaspiro-[4,4]-non-
2-en-3-yl]carbonylamino] propionic acid,
(S)-2-phenylsulfonylamino-3-[[8-(4,5- dihydroimidazol-2-yl) aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl] carbonylamino] propionic acid,
(S)-2-benzyloxycarbonylamino-3-[[8-(4,5- dihydroimidazol-2-yl) aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3-[[8- (4,5-dihydroimidazol-2-yl)aminomethyl-1-oxa- 2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethylphenyl)sulfonyl]amino-3-[[8- (4,5-dihydroimidazol-2-yl)aminomethyl-1-oxa- 2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dichlorophenyl)sulfonyl] amino-3-[[8- (4,5-dihydroimidazol-2-yl) aminomethyl-1-oxa- 2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2,6-dimethyl-4-phenyl)phenylsulfonyl]amino- 3-[[8-(4,5-dihydroimidazol-2-yl)aminomethyl-1- oxa-2,7-diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[(2-naphthyl)sulfonyl]amino-3-[[8-(4,5- dihydroimidazol-2-yl) aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid,
(S)-2-[biphenylsulfonyl] amino-3-[[8-(4,5- dihydroimidazol-2-yl) aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid, and (S)-2-[(2,4,6-trimethylphenyl)sulfonyl] amino-3-[[8- (2-benzimidazolyl)aminomethyl-1-oxa-2,7- diazaspiro-[4,4]-non-2-en-3- yl]carbonylamino] propionic acid.
6. A method for the treatment of cancer
metastasis, diabetic retinopathy, neovascular glaucoma, thrombosis, restenosis, osteoporosis, or macular degeneration which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1-5.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 1-5.
PCT/US1997/004567 1996-03-15 1997-03-17 Spirocycle integrin inhibitors WO1997033887A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97919892A EP0888344A1 (en) 1996-03-15 1997-03-17 Spirocycle integrin inhibitors
JP53292497A JP2001527513A (en) 1996-03-15 1997-03-17 Spirocyclic integrin inhibitors
AU24217/97A AU2421797A (en) 1996-03-15 1997-03-17 Spirocycle integrin inhibitors

Applications Claiming Priority (6)

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

Publications (1)

Publication Number Publication Date
WO1997033887A1 true WO1997033887A1 (en) 1997-09-18

Family

ID=27359885

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/004567 WO1997033887A1 (en) 1996-03-15 1997-03-17 Spirocycle integrin inhibitors

Country Status (5)

Country Link
EP (1) EP0888344A1 (en)
JP (1) JP2001527513A (en)
AU (1) AU2421797A (en)
CA (1) CA2249733A1 (en)
WO (1) WO1997033887A1 (en)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043962A1 (en) * 1997-03-28 1998-10-08 Du Pont Pharmaceuticals Company Heterocyclic integrin inhibitor prodrugs
WO1999052872A1 (en) 1998-04-09 1999-10-21 Meiji Seika Kaisha, Ltd. AMINOPIPERIDINE DERIVATIVES AS INTEGRIN αvβ3 ANTAGONISTS
WO1999058139A2 (en) * 1998-05-08 1999-11-18 The Regents Of The University Of California Methods for detecting and inhibiting angiogenesis
WO2000066593A2 (en) * 1999-05-03 2000-11-09 Schering Aktiengesellschaft Novel spirocyclic compounds, method for the production thereof and their use for treating hyperproliferative diseases
US6429214B1 (en) 1999-07-21 2002-08-06 Wyeth Bicyclic antagonists selective for the αvβ3 integrin
US6586187B1 (en) 1999-04-14 2003-07-01 Wyeth Methods for solid phase combinatorial synthesis of integrin inhibitors
US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
JP2004536095A (en) * 2001-06-25 2004-12-02 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Substituted 1-oxa-2,8-diaza-spiro [4.5] dec-2-ene-derivatives as a medicament for the treatment of pain
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6852318B1 (en) 1998-05-08 2005-02-08 The Regents Of The University Of California Methods for detecting and inhibiting angiogenesis
WO2005118528A2 (en) * 2004-06-04 2005-12-15 The University Court Of The University Of Aberdeen Aryl alkyl sulfonamides as therapeutic agents for the treatment of bone conditions
DE102005044814A1 (en) * 2005-05-19 2006-11-23 Grünenthal GmbH New spiro-isoxazole-cycloalkane compounds, useful as vanilloid receptor 1 ligands for treating e.g. pain, depression and neurodegeneration
DE102005023784A1 (en) * 2005-05-19 2006-11-30 Grünenthal GmbH Substituted spiro compounds and their use for the preparation of medicaments
EP1739078A1 (en) 2005-05-30 2007-01-03 Jerini AG Antagonists of C5a-receptor
US7276589B2 (en) 2002-11-26 2007-10-02 Pdl Biopharma, Inc. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
DE102005044813A1 (en) * 2005-05-19 2007-10-04 Grünenthal GmbH Substituted spiro compounds and their use for the preparation of medicaments
US7662384B2 (en) 2004-03-24 2010-02-16 Facet Biotech Corporation Use of anti-α5β1 antibodies to inhibit cancer cell proliferation
US8017116B2 (en) 2002-11-26 2011-09-13 Abbott Biotherapeutics Corp. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US8207167B2 (en) 2008-09-19 2012-06-26 Pimco 2664 Limited Aryl-phenyl-sulfonamide-phenylene compounds and their use
US8435968B2 (en) 2008-09-19 2013-05-07 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US8524778B2 (en) 2007-03-21 2013-09-03 Pimco 2664 Limited Biphenyl-4-yl-sulfonic acid arylamides and their use as therapeutic agents
US9624167B2 (en) 2013-06-26 2017-04-18 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10005733B2 (en) 2014-12-17 2018-06-26 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6480653B2 (en) * 2013-09-26 2019-03-13 株式会社トーキン Conductive polymer solution

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0529858A1 (en) * 1991-08-23 1993-03-03 Takeda Chemical Industries, Ltd. 2-Piperazinone compounds, their production and use
WO1995014683A1 (en) * 1993-11-24 1995-06-01 The Du Pont Merck Pharmaceutical Company Novel isoxazoline and isoxazole fibrinogen receptor antagonists
WO1995014682A1 (en) * 1993-11-24 1995-06-01 The Du Pont Merck Pharmaceutical Company Isoxazoline compounds useful as fibrinogen receptor antagonists
WO1996037492A1 (en) * 1995-05-25 1996-11-28 The Du Pont Merck Pharmaceutical Company Isoxazoline and isoxazole derivatives as integrin receptor antagonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0529858A1 (en) * 1991-08-23 1993-03-03 Takeda Chemical Industries, Ltd. 2-Piperazinone compounds, their production and use
WO1995014683A1 (en) * 1993-11-24 1995-06-01 The Du Pont Merck Pharmaceutical Company Novel isoxazoline and isoxazole fibrinogen receptor antagonists
WO1995014682A1 (en) * 1993-11-24 1995-06-01 The Du Pont Merck Pharmaceutical Company Isoxazoline compounds useful as fibrinogen receptor antagonists
WO1996037492A1 (en) * 1995-05-25 1996-11-28 The Du Pont Merck Pharmaceutical Company Isoxazoline and isoxazole derivatives as integrin receptor antagonists

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043962A1 (en) * 1997-03-28 1998-10-08 Du Pont Pharmaceuticals Company Heterocyclic integrin inhibitor prodrugs
US6214834B1 (en) 1997-03-28 2001-04-10 Dupont Pharmaceuticals Company Integrin inhibitor prodrugs
WO1999052872A1 (en) 1998-04-09 1999-10-21 Meiji Seika Kaisha, Ltd. AMINOPIPERIDINE DERIVATIVES AS INTEGRIN αvβ3 ANTAGONISTS
WO1999058139A2 (en) * 1998-05-08 1999-11-18 The Regents Of The University Of California Methods for detecting and inhibiting angiogenesis
WO1999058139A3 (en) * 1998-05-08 2000-02-10 Univ California Methods for detecting and inhibiting angiogenesis
US8454958B2 (en) 1998-05-08 2013-06-04 The Regents Of The University Of California Methods for detecting and inhibiting angiogenesis
EP2327451A3 (en) * 1998-05-08 2012-05-09 The Regents of the University of California Method for detecting and inhibiting angiogenesis
AU746662B2 (en) * 1998-05-08 2002-05-02 Regents Of The University Of California, The Methods for detecting and inhibiting angiogenesis
EP2044955A3 (en) * 1998-05-08 2009-04-29 The Regents of the University of California Methods for detecting and inhibiting angiogenesis
US7056506B2 (en) 1998-05-08 2006-06-06 The Regents Of The University Of California Methods for detecting and inhibiting angiogenesis
US6852318B1 (en) 1998-05-08 2005-02-08 The Regents Of The University Of California Methods for detecting and inhibiting angiogenesis
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6586187B1 (en) 1999-04-14 2003-07-01 Wyeth Methods for solid phase combinatorial synthesis of integrin inhibitors
WO2000066593A2 (en) * 1999-05-03 2000-11-09 Schering Aktiengesellschaft Novel spirocyclic compounds, method for the production thereof and their use for treating hyperproliferative diseases
WO2000066593A3 (en) * 1999-05-03 2001-05-31 Schering Ag Novel spirocyclic compounds, method for the production thereof and their use for treating hyperproliferative diseases
US6429214B1 (en) 1999-07-21 2002-08-06 Wyeth Bicyclic antagonists selective for the αvβ3 integrin
US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
US8557796B2 (en) 2001-06-25 2013-10-15 Gruenenthal Gmbh Substituted 1-oxa-2,8-diaza-spiro [4,5] dec-2-ene derivatives and related treatment methods
US8048890B2 (en) * 2001-06-25 2011-11-01 Gruenenthal Gmbh Substituted 1-oxa-2,8-diaza-spiro[4,5]dec-2-ene derivatives and related treatment methods
JP2004536095A (en) * 2001-06-25 2004-12-02 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Substituted 1-oxa-2,8-diaza-spiro [4.5] dec-2-ene-derivatives as a medicament for the treatment of pain
US8017116B2 (en) 2002-11-26 2011-09-13 Abbott Biotherapeutics Corp. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US7897148B2 (en) 2002-11-26 2011-03-01 Abbott Biotherapeutics Corp. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US7276589B2 (en) 2002-11-26 2007-10-02 Pdl Biopharma, Inc. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US8309084B2 (en) 2002-11-26 2012-11-13 Abbott Biotherapeutics Corp. Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US7776585B2 (en) 2002-11-26 2010-08-17 Facet Biotech Corporation Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US7879987B2 (en) 2002-11-26 2011-02-01 Facet Biotech Corporation Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis
US7662384B2 (en) 2004-03-24 2010-02-16 Facet Biotech Corporation Use of anti-α5β1 antibodies to inhibit cancer cell proliferation
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
WO2005118528A2 (en) * 2004-06-04 2005-12-15 The University Court Of The University Of Aberdeen Aryl alkyl sulfonamides as therapeutic agents for the treatment of bone conditions
WO2005118528A3 (en) * 2004-06-04 2006-01-26 Univ Aberdeen Aryl alkyl sulfonamides as therapeutic agents for the treatment of bone conditions
EP2292625A1 (en) * 2005-05-19 2011-03-09 Grünenthal GmbH Substituted spiro compounds and their use for producing pain-relief medicaments
DE102005023784A1 (en) * 2005-05-19 2006-11-30 Grünenthal GmbH Substituted spiro compounds and their use for the preparation of medicaments
DE102005044814A1 (en) * 2005-05-19 2006-11-23 Grünenthal GmbH New spiro-isoxazole-cycloalkane compounds, useful as vanilloid receptor 1 ligands for treating e.g. pain, depression and neurodegeneration
US8772307B2 (en) 2005-05-19 2014-07-08 Gruenenthal Gmbh Substituted spiro compounds and their use for producing pain-relief medicaments
WO2006122769A3 (en) * 2005-05-19 2007-03-15 Gruenenthal Gmbh Substituted spiro compounds and their use for producing pain-relief drugs
DE102005044813A1 (en) * 2005-05-19 2007-10-04 Grünenthal GmbH Substituted spiro compounds and their use for the preparation of medicaments
EP1739078A1 (en) 2005-05-30 2007-01-03 Jerini AG Antagonists of C5a-receptor
US8524778B2 (en) 2007-03-21 2013-09-03 Pimco 2664 Limited Biphenyl-4-yl-sulfonic acid arylamides and their use as therapeutic agents
US8435968B2 (en) 2008-09-19 2013-05-07 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US8207167B2 (en) 2008-09-19 2012-06-26 Pimco 2664 Limited Aryl-phenyl-sulfonamide-phenylene compounds and their use
US8822507B2 (en) 2008-09-19 2014-09-02 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US9050329B1 (en) 2008-09-19 2015-06-09 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US9302984B2 (en) 2008-09-19 2016-04-05 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US9616037B2 (en) 2008-09-19 2017-04-11 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US9624167B2 (en) 2013-06-26 2017-04-18 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US9796670B2 (en) 2013-06-26 2017-10-24 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10029979B2 (en) 2013-06-26 2018-07-24 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10233147B2 (en) 2013-06-26 2019-03-19 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10005733B2 (en) 2014-12-17 2018-06-26 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use

Also Published As

Publication number Publication date
EP0888344A1 (en) 1999-01-07
AU2421797A (en) 1997-10-01
JP2001527513A (en) 2001-12-25
CA2249733A1 (en) 1997-09-18

Similar Documents

Publication Publication Date Title
US5760029A (en) Spirocycle integrin inhibitors
US6153628A (en) 1,3,4-thiadiazoles and 1,3,4-Oxadiazoles as αv β3 antagonists
US6358976B1 (en) Integrin receptor antagonists
WO1997033887A1 (en) Spirocycle integrin inhibitors
EP0730590B1 (en) isoxazoline and isoxazole fibrinogen receptor antagonists
TW454007B (en) Novel isoxazoline and isozazole fibrinogen receptor antagonists
AU5876296A (en) Isoxazoline and isoxazole derivatives as integrin receptor antagonists
US5710159A (en) Integrin receptor antagonists
WO1997023480A1 (en) Novel integrin receptor antagonists
US6455560B1 (en) Isoxazoline fibrinogen receptor antagonists
HRP960234A2 (en) Novel integrin receptor antagonists
MXPA99004891A (en) Novel integrin receptor antagonists
MXPA00005155A (en) 1,3,4-THIADIAZOLES AND 1,3,4-OXADIAZOLES AS&amp;agr;v

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AU AZ BR BY CA CN CZ EE HU IL JP KG KR KZ LT LV MD MX NO NZ PL RO RU SG SI SK TJ TM UA VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1997919892

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2249733

Country of ref document: CA

Ref country code: CA

Ref document number: 2249733

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1997919892

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1997919892

Country of ref document: EP