EP1047425A1 - Integrinrezeptor antagonisten - Google Patents
Integrinrezeptor antagonistenInfo
- Publication number
- EP1047425A1 EP1047425A1 EP98962096A EP98962096A EP1047425A1 EP 1047425 A1 EP1047425 A1 EP 1047425A1 EP 98962096 A EP98962096 A EP 98962096A EP 98962096 A EP98962096 A EP 98962096A EP 1047425 A1 EP1047425 A1 EP 1047425A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- aryl
- oxo
- tetrahydro
- propyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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]
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- A—HUMAN NECESSITIES
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to compounds and derivatives thereof, their synthesis, and their use as integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors ⁇ v ⁇ 3, ⁇ v ⁇ 5, and/or ⁇ v ⁇ 6 and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, wound healing, viral disease, tumor growth, and metastasis.
- Integrin receptors are heterodimeric transmembrane receptors through which cells attach and communicate with extracellular matrices and other cells (See S.B. Rodan and G.A. Rodan, "Integrin Function In Osteoclasts", Journal of Endocrinology , Vol. 154, S47- S56 (1997), which is incorporated by reference herein in its entirety).
- the compounds herein are useful for inhibiting bone resorption.
- Bone resorption is mediated by the action of cells known as osteoclasts.
- Osteoclasts are large multinucleated cells of up to about 400 mm in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates.
- Osteoclasts are actively motile cells that migrate along the surface of bone, and can bind to bone, secrete necessary acids and proteases, thereby causing the actual resorption of mineralized tissue from the bone. More specifically, osteoclasts are believed to exist in at least two physiological states, namely, the secretory state and the migratory or motile state.
- osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone.
- the adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption.
- the osteoclasts migrate across bone matrix and do not take part in resorption until they again attach to bone.
- Integrins are involved in osteoclast attachment, activation and migration.
- the most abundant integrin in osteoclasts e.g., in rat, chicken, mouse mid human osteoclasts, is an integrin receptor known as ⁇ v ⁇ 3, which is thought to interact in bone with matrix proteins that contain the RGD sequence.
- Antibodies to ⁇ v ⁇ 3 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process.
- ⁇ v ⁇ 3 ligands can be used effectively to inhibit osteoclast mediated bone resorption in vivo in mammals.
- osteoporosis hypercalcemia of malignancy
- osteopenia due to bone metastases
- periodontal disease hyperparathyroidism
- hyperparathyroidism hyperparathyroidism
- periarticular erosions in rheumatoid arthritis Paget's disease
- immobilization- induced osteopenia and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average.
- the rate of bone turnover differs from site to site; for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones.
- the potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
- ⁇ v ⁇ 3 ligands have been found to be useful in treating and/or inhibiting restenosis, i.e. recurrence of stenosis after corrective surgery on the heart valve, atherosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis, i.e. formation of new blood vessels.
- restenosis i.e. recurrence of stenosis after corrective surgery on the heart valve
- atherosclerosis CAD
- diabetic retinopathy macular degeneration
- angiogenesis i.e. formation of new blood vessels.
- angiogenesis i.e. formation of new blood vessels.
- ⁇ v ⁇ 3 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See e.g., Brooks et al., Cell, 79:1157- 1164 (1994), which is incorporated by reference herein in its entirety).
- compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor, ⁇ v ⁇ .
- a monoclonal antibody for v ⁇ has been shown to inhibit VEGF- induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model (See M.C. Friedlander, et al., Science 270, 1500-1502, (1995), which is incorporated by reference herein in its entirety).
- compounds that antagonize ⁇ v ⁇ are useful for treating and preventing macular degeneration, diabetic retinopathy, tumor growth, and metastasis.
- compounds of the instant invention can inhibit angiogenesis and inflammation by acting as antagonists of the integrin receptor, ⁇ v ⁇ 6, which is expressed during the later stages of wound healing and remains expressed until the wound is closed (See Christofidou-Solomidou, et al., "Expression and Function of Endothelial Cell ⁇ v Integrin Receptors in Wound-Induced Human Angiogenesis in Human Skin/SCID Mice. Chimeras. American Journal of Pathology. Vol. 151, No. 4, pp. 975-983 (October 1997), which is incorporated by reference herein in its entirety). It is postulated that ⁇ v ⁇ 6 plays a role in the remodeling of the vasculature during the later stages of angiogenesis.
- ⁇ v ⁇ 6 participates in the modulation of epithelial inflammation and is induced in response to local injury or inflammation (See Xiao-Zhu Huang, et al., "Inactivation of the Integrin ⁇ 6 Subunit Gene Reveals a Role of Epithelial Integrins in Regulating Inflammation in the Lungs and Skin," Journal of Cell Biology. Vol. 133, No.4, pp. 921-928 (May 1996), which is incorporated by reference herein in its entirety). Accordingly, compounds that antagonize ⁇ v ⁇ 6 are useful in treating or preventing cancer by inhibiting tumor growth and metastasis.
- certain compounds of this invention antagonize both the ⁇ v ⁇ 3 and ⁇ v ⁇ receptors.
- These compounds referred to as “dual ⁇ v ⁇ 3/ ⁇ v ⁇ antagonists,” are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, tumor growth, and metastasis.
- certain compounds of this invention are useful as mixed ⁇ v ⁇ 3, ⁇ v ⁇ , and ⁇ v ⁇ 6 receptor antagonists.
- the present invention relates to compounds of the formula
- W is selected from the group consisting of
- a ⁇ - or 6-membered monocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S wherein the ring nitrogen atoms are ⁇ unsubstituted or substituted with one R ⁇ substituent and the ring carbon atoms are unsubstituted or substituted with one or two Rl substituents, and
- a 9- to 14-membered polycyclic ring system wherein one or more 10 of the rings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S, and wherein the ring nitrogen atoms are unsubstituted or substituted with one Rl substituent and the ring carbon atoms are unsubstituted or substituted with one or two R ⁇ l ⁇ substituents;
- X is selected from the group consisting of
- any methylene (CH2) carbon atom is either 20 unsubstituted or substituted with one or two R ⁇ substitutents; and a ⁇ - or 6-membered monocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one Rl substituent and the ring carbon ⁇ atoms are unsubstituted or substituted with one or two Rl substituents;
- Y is selected from the group consisting of
- l ⁇ Z is a ⁇ membered aromatic or nonaromatic mono- or bicyclic ring system having 0 to 3 heteroatoms selected from the group consisting of N, 0, and S, and wherein the ring system is either unsubstituted or substituted with 0, 1, 2, or 3 oxo or thio substituents, and either unsubstituted or substituted with one or more substituents
- R ⁇ -O independently selected from the group consisting of R ⁇ -O, R ⁇ , and R*2 ;
- R ⁇ and R ⁇ are each independently selected from the group consisting of hydrogen, halogen, C ⁇ -10 alkyl, C3-8 cycloalkyl, ⁇ C3-8 cycloheteroalkyl, C3-8 cycloalkyl Ci-6 alkyl,
- each R3 is independently selected from the group consisting of hydrogen, 10 aryl,
- C ⁇ -6 alkylsulfonyl 20 C ⁇ _6 alkylsulfonyl C ⁇ -6 alkyl, arylsulfonyl C ⁇ -6 alkyl, aryl C ⁇ _6 alkylsulfonyl, aryl C ⁇ _6 alkylsulfonyl C ⁇ -6 alkyl,
- each R4 is independently selected from the group consisting of hydrogen, l ⁇ aryl, aminocarbonyl,
- R5 and R6 are each independently selected from the group consisting of hydrogen", C ⁇ . ⁇ o alkyl, aryl, aryl-(CH 2 )r-0-(CH 2 ) s -, aryl-(CH 2 ) r S(0)p-(CH 2 ) s -, aryl-(CH )r-C(0)-(CH 2 ) s -, aryl-(CH 2 ) r -C(0)-N(R4)-(CH 2 ) s -, aryl-(CH 2 ) r -N(R4)-C(0)-(CH 2 ) s -, aryl-(CH 2 )r-N(R4)-C(0)-(CH 2 ) s -, aryl-(CH 2 )r-N(R4)-(CH 2 ) s -, halogen, hydroxyl,
- CH 2 CH-(CH 2 ) t -
- X0 C ⁇ _6 alkyl-CH CH-(CH 2 )t-
- aryl C ⁇ -8 alkyDpaminocarbonyl, and (aryl C ⁇ _8 alkyDpaminocarbonyl C ⁇ -6 alkyl; or R5 and R6 are taken together with the carbon atom to which they are attached to form a carbonyl group, wherein any of the alkyl groups of ⁇ or R ⁇ are either unsubstituted or substituted with one to three Rl substituents, and provided that each R ⁇ and R ⁇ are selected such that in the resultant compound the carbon atom to which R ⁇ and R ⁇ are attached is itself attached to no more than one heteroatom;
- R7 and R8 are each independently selected from the group consisting of hydrogen
- CH CH-(CH 2 ) t -
- C ⁇ _6 alkyl-CH CH-(CH ) t -
- C3-7 cycloalkyl-CH CH-(CH 2 ) t -
- aryl-CH CH-(CH 2 ) t -
- l ⁇ C ⁇ -6 alkylaryl-CH CH-(CH 2 )t-
- R9 is selected from the group consisting of hydrogen
- R O , RU, and Rl2 are each independently selected from the group consisting of hydrogen,
- C ⁇ _8 alkyl 0 . aryl, halogen, hydroxyl, oxo, aminocarbonyl, C3-8 cycloalkyl, amino C ⁇ -6 alkyl, (aryl)paminocarbonyl, hy dr oxycarb onyl , ⁇ (aryl C ⁇ -5 alkyDpaminocarbonyl, hydroxycarbonyl C ⁇ -6 alkyl, aryl C ⁇ -6 alkyl, (C ⁇ -6 alkyDpamino C ⁇ .6 alkyl, (aryl C ⁇ -6 alkyDpamino C -6 alkyl, 10 C ⁇ -8 alkylsulfonyl,
- aryl C ⁇ -6 alkyDpamino ⁇ (aryl C ⁇ -6 alkyDpamino C ⁇ -6 alkyl, aryl carbonyl oxy, aryl C ⁇ -6 alkylcarbonyloxy, (C ⁇ -6 alkyl )paminocarbonyloxy, C ⁇ -8 alkylsulfonylamino, 0 arylsulfonylamino,
- the present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
- the present invention also relates to methods for making ⁇ the pharmaceutical compositions of the present invention.
- the present invention also relates to methods for eliciting an integrin receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
- the present invention also relates to methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, wound healing, tumor growth, and metastasis by administering the compounds and pharmaceutical compositions of the present invention.
- the present invention also relates to methods for treating osteoporosis by administering the compounds and pharmaceutical compositions of the present invention.
- the present invention relates to compounds useful as integrin receptor antagonists.
- Representative compounds of the present invention are described by the following chemical formula:
- W is selected from the group consisting of
- a ⁇ - or 6-membered monocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S wherein the ring nitrogen atoms are l ⁇ unsubstituted or substituted with one Rl substituent and the ring carbon atoms are unsubstituted or substituted with one or two l substituents, and
- a 9- to 14-membered polycyclic ring system wherein one or more 0 of the rings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S, and wherein the ring nitrogen atoms are unsubstituted or substituted with one Rl substituent and the ring carbon atoms are unsubstituted or substituted with one or two R ⁇ substituents;
- X is selected from the group consisting of
- any methylene (CH 2 ) carbon atom is either unsubstituted or substituted with one or two Rl substitutents; and a ⁇ - or 6-membered monocyclic aromatic or nonaromatic ring system having 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one Rl substituent and the ring carbon atoms are unsubstituted or substituted with one or two Rl substituents;
- Y is selected from the group consisting of
- any methylene (CH 2 ) carbon atom in Y, other than in R4, can 0 be substituted by one or two R ⁇ substituents;
- Z is a ⁇ membered aromatic or nonaromatic mono- or bicyclic ring system having 0 to 3 heteroatoms selected from the group consisting of N, O, and S, and wherein the ring system is either unsubstituted or substituted with 0, 1, 2, or 3 oxo or thio substituents, and either unsubstituted or substituted with one or more substituents independently selected from the group consisting of RlO, RU, and 2 ;
- Rland R ⁇ are each independently selected from the group consisting of hydrogen, halogen, C ⁇ . ⁇ o alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C ⁇ -6 alkyl, C3-8 cycloheteroalkyl C ⁇ -6 alkyl, aryl, aryl C ⁇ -8 alkyl, amino, X0 amino C ⁇ -8 alkyl, C ⁇ -3 acylamino, C ⁇ _3 acylamino C ⁇ -8 alkyl,
- C ⁇ -6 alkyl nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C ⁇ -8 alkyl-S(0)p, (C ⁇ -8 alkyDpaminocarbonyl, C ⁇ -8 alkyloxycarbonylamino, (C ⁇ -8 alkyl )paminocarbonyloxy, (aryl C ⁇ -8 alkyDpamino, (aryl)pamino, aryl C ⁇ -8 20 alkylsulfonylamino, and C ⁇ -8 alkylsulfonylamino; or two Rl substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group;
- each R3 is independently selected from the group consisting of hydrogen, aryl,
- each R4 is independently selected from the group consisting of hydrogen, 0 aryl, aminocarbonyl, C3-8 cycloalkyl, amino C ⁇ -6 alkyl, (aryl)paminocarbonyl, (aryl C ⁇ -5 alkyDpaminocarbonyl, hydroxycarbonyl C ⁇ -6 alkyl, C ⁇ -8 alkyl, aryl C ⁇ -6 alkyl, ⁇ (C ⁇ -6 alkyDpamino C 2 _6 alkyl,
- R6 are each independently selected from the group consisting of hydrogen, C ⁇ . ⁇ o alkyl, 0 aryl, aryl-(CH 2 ) r -0-(CH 2 ) s -, aryl-(CH2)rS(0)p-(CH 2 ) s -, aryl-(CH 2 )r-C(0)-(CH 2 ) s -, aryl-(CH 2 ) r -C(0)-N(R4)-(CH 2 ) s -, aryl-(CH 2 )r-N(R4)-C(0)-(CH 2 ) s -, aryl-(CH 2 )r-N(R4)-(CH 2 ) s -, halogen, hydroxyl, 5 C ⁇ -8 alkylcarbonylamino, aryl C ⁇ - ⁇ alkoxy, C ⁇ -5 alkoxycarbonyl, (C ⁇ -8 alkyDpaminocarbonyl, C ⁇ -6 alkylcarbonyloxy,
- aryl C ⁇ -8 alkyDpaminocarbonyl, and 20 aryl C ⁇ -8 alkyDpaminocarbonyl C ⁇ -6 alkyl, or R5 and R6 are taken together with the carbon atom to which they are attached to form a carbonyl group, wherein any of the alkyl groups of R ⁇ or R ⁇ are either unsubstituted or substituted with one to three Rl substituents, and provided that each R ⁇ 5 and R > are selected such that in the resultant compound the carbon atom to which R ⁇ and R ⁇ are attached is itself attached to no more than one heteroatom;
- R7 and R ⁇ are each independently selected from the group consisting of 0 , hydrogen,
- C ⁇ -6 alkylcarbonyl 10 C ⁇ -6 alkylcarbonyl C ⁇ -6 alkyl, arylcarbonyl C ⁇ -6 alkyl, aryl C ⁇ -6 alkylcarbonyl, aryl C ⁇ -6 alkylcarbonyl C ⁇ -6 alkyl,
- R9 is selected from the group consisting of hydrogen, C ⁇ -8 alkyl, aryl, aryl C ⁇ _8 alkyl, C ⁇ -8 alkylcarbonyloxy C ⁇ .4 alkyl, aryl C ⁇ -8 alkylcarbonyloxy C ⁇ -4 alkyl,
- RlO , RU, and Rl2 are each independently selected from the group consisting of hydrogen,
- arylpaminosulfonyl (aryl C ⁇ -8 alkyDpaminosulfonyl, C ⁇ -6 alkylsulfonyl, aryl sulfonyl, aryl C ⁇ -6 alkylsulfonyl, ⁇ aryl C ⁇ -6 alkylcarbonyl,
- C ⁇ -6 alkylaryl-CH CH-(CH 2 ) t -, ⁇ C ⁇ . 6 alkyl-S0 2 -(CH 2 )t-,
- C ⁇ -6 alkylcarbonyloxy (C ⁇ -6 alkyDpamino, aminocarbonyl C ⁇ -6 alkyl, C ⁇ -6 alkoxy, aryl C ⁇ -6 alkoxy, (aryl)pamino, (aryl)pamino C ⁇ -6 alkyl, (aryl C ⁇ -6 alkyDpamino, ⁇ (aryl C ⁇ -6 alkyDpamino C ⁇ -6 alkyl, arylcarbonyloxy, aryl C ⁇ -6 alkylcarbonyloxy, (C ⁇ -6 alkyl )paminocarbonyloxy, C ⁇ -8 alkylsulfonylamino,
- W is preferably a 6-membered monocyclic aromatic or nonaromatic ring system having 1 or 2 nitrogen atoms wherein each carbon atom is either unsubstituted or substituted with one Rl substituent, or
- polycyclic ring system wherein one or more of the rings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S
- W is selected from the group consisting of
- X is preferably 0 -(CH 2 )v- , wherein any methylene (CH 2 ) carbon atom is either unsubstituted or substituted with one or two Rl substituents. More preferably X is a direct bond, that is, v is 0.
- Y is preferably selected from the group consisting of
- Y is selected from the group consisting of
- any methylene (CH ) carbon atom in Y, other than in R4, can be substituted by one or two R ⁇ substituents.
- Z is preferably ⁇ selected from the group consisting of
- Z is selected from the group consisting of
- Rl and R are preferably selected from the group consisting of hydrogen, halogen, O ⁇ . X0 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, hydroxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy.
- Rl and R2 are selected from the group consisting of hydrogen, halogen, C ⁇ . ⁇ o alkyl, C3-8 cycloalkyl, trifluoromethyl, and trifluoromethoxy.
- R ⁇ is preferably 10 selected from the group consisting of hydrogen, fluoro, trifluoromethyl, aryl, l ⁇ C ⁇ -8 alkyl, arylC ⁇ -6 alkyl hydroxyl, oxo, arylaminocarbonyl, 20 aryl C ⁇ -5 alkylaminocarbonyl, aminocarbonyl, and aminocarbonyl C ⁇ -6 alkyl.
- R ⁇ is selected from the group consisting of ⁇ fluoro, aryl,
- R4 is preferably selected from the group consisting of hydrogen, aryl,
- R is selected from the group consisting of hydrogen
- R ⁇ and R ⁇ are ⁇ each independently selected from the group consisting of hydrogen, aryl,
- CH 2 CH-(CH 2 )t-, and HC ⁇ C-(CH 2 ) t -.
- ⁇ is hydrogen and R ⁇ is selected from the group consisting of ⁇ hydrogen, aryl,
- R ⁇ , R?, and R8 are each hydrogen and R ⁇ is selected from the group consisting of 0 hydrogen, aryl,
- R' and R& are each independently selected from the group consisting of 0 hydrogen, aryl, C ⁇ -8 alkylcarbonylamino, arylcarbonylamino, C ⁇ -8 alkylsulfonylamino, ⁇ arylsulfonylamino,
- R ⁇ is hydrogen and R ⁇ is selected from the group consisting of consisting of hydrogen, ⁇ aryl,
- R ⁇ , R6. and R8 are each hydrogen and R is selected from the group consisting of hydrogen
- R is preferably ⁇ selected from the group consisting of hydrogen, methyl, and ethyl. More preferably, R is hydrogen.
- R O, RU, and Rl are preferably each independently selected from the group consisting of hydrogen and C ⁇ -8 alkyl. More preferably RlO, RU, and 0 Rl are hydrogen.
- m is preferably an integer from 0 to 4, more preferably from 0 to 3.
- n is preferably an integer from 0 to 4, more preferably from 0 to 3.
- r is preferably an integer from 1 to 2.
- s is preferably an integer from 0 to 2.
- t is preferably an integer from 0 to 2, more preferably from 0 to 1.
- v is preferably 0.
- the compounds have the formula with the following designated 10 stereochemistry:
- Illustrative but nonlimiting examples of compounds of the present invention that are useful as integrin receptor antagonists are the following:
- salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.”
- Other salts may, however, be useful in the preparation of the compounds 0 according to the invention or of their pharmaceutically acceptable salts.
- Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
- Representative salts include the following: acetate, ⁇ benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, ⁇ isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxa
- suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable l ⁇ organic ligands, e.g., quaternary ammonium salts.
- the compounds of the present invention can have chiral centers and occur as racemates, racemic mixtures, diastereomeric mixtures, and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. Therefore,
- the term "administering" 0 shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, ⁇ for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 198 ⁇ , which is incorporated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
- terapéuticaally effective amount shall mean ⁇ that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
- integrated receptor antagonist refers to a compound which binds to and antagonizes either the ⁇ v ⁇ 3 10 receptor, the ⁇ v ⁇ receptor, or the ⁇ v ⁇ 6 receptor, or a compound which binds to and antagonizes combinations of these receptors (for example, a dual ⁇ v ⁇ 3/ ⁇ v ⁇ receptor antagonist).
- alkyl shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
- alkenyl shall mean straight or branched chain 20 alkenes of two to ten total carbon atoms, or any number within this range.
- alkynyl shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range.
- cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
- cycloheteroalkyl shall mean a 3- to 8-membered fully saturated heterocyclic ring containing one or two 0 heteroatoms chosen from N, O or S.
- Examples of cycloheteroalkyl groups include, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl.
- alkoxy refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., C ⁇ -5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).
- aryl refers to a monocyclic or polycyclic system comprising at least one aromatic ring, wherein the 5 monocylic or polycyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, 0, or S, and wherein the monocylic or polycylic system is either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, C ⁇ . ⁇ o alkyl, C3-8 cycloalkyl, aryl, aryl C ⁇ -8 alkyl, amino, amino C ⁇ -8 alkyl, C ⁇ .3
- aryl examples include, but are not limited to, phenyl, naphthyl, pyridyl, pyrryl, pyrazolyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, thienyl, furyl, dihydrobenzofuryl, benzo(l,3) dioxolane, oxazolyl, isoxazolyl and thiazolyl, which are either unsubstituted or substituted with one or more
- 20 groups independently selected from hydrogen, halogen, C ⁇ . ⁇ o alkyl, C3-8 cycloalkyl, aryl, aryl C ⁇ -8 alkyl, amino, amino C ⁇ -8 alkyl, C ⁇ -3 acylamino, C ⁇ -3 acylamino C ⁇ -8 alkyl, C ⁇ -6 alkylamino, C ⁇ _6 alkylamino-C ⁇ -8 alkyl, C ⁇ -6 dialkylamino, C ⁇ -6 dialkylamino C ⁇ -8 alkyl, C ⁇ -4 alkoxy, C ⁇ -4 alkoxy C ⁇ -6 alkyl, hydroxycarbonyl, hydroxycarbonyl ⁇ C ⁇ -6 alkyl, C ⁇ .5 alkoxycarbonyl, C ⁇ -3 alkoxycarbonyl C ⁇ -6 alkyl, hydroxycarbonyl C ⁇ -6 alkyloxy, hydroxy, hydroxy C ⁇ -6 alkyl, cyano, trifluoromethyl, oxo or C ⁇ -5 alkylcarbonyloxy.
- the aryl group is unsubstituted, mono-, di-, tri- or tetra-substituted with one to four of the above-named substituents; more preferably, the aryl group is 0 unsubstituted, mono-, di- or tri-substituted with one to three of the above- named substituents; most preferably, the aryl group is unsubstituted, mono- or di-substituted with one to two of the above-named substituents.
- alkyl or "aryl” or either of their prefix roots appear in a name of a substituent (e.g., aryl C ⁇ -8 alkyl) it shall be
- Designated numbers of carbon atoms shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl ⁇ appears as its prefix root.
- arylalkyl and “alkylaryl” include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
- arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, X0 phenylpropyl, fluorophenyl ethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl.
- alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.
- two Rl l ⁇ substituents when on the same carbon atom, can be taken together with the carbon to which they are attached to form a carbonyl group.
- two R ⁇ substituents when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a carbonyl group.
- the limitation, that in the resultant compound the carbon atom or atoms to which B ⁇ is attached is itself attached to no more than one heteroatom, does not apply.
- two R3 substituents when on the same carbon atom, can be taken together with the carbon atom to which they are ⁇ attached to form a cyclopropyl group.
- R5 and R ⁇ can be taken together with the carbon atom to which they are attached to form a carbonyl group.
- halogen shall include iodine, bromine, chlorine, and fluorine.
- oxy means an oxygen (0) atom.
- thio means a sulfur (S) atom.
- ⁇ carbonyl
- substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or ⁇ claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
- Representative compounds of the present invention typically 0 display submicromolar affinity for the integrin receptors, particularly the ⁇ v ⁇ 3, ⁇ v ⁇ , and/or ⁇ v ⁇ 6 receptors.
- Compounds of this invention are therefore useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy.
- Pharmacologically effective amounts of the compounds, ⁇ including pharamaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts.
- the compounds of the present invention are administered in dosages effective to antagonize the ⁇ v ⁇ 3 receptor where such treatment is needed, as, for example, in the prevention or treatment of 0 osteoporosis.
- ⁇ v ⁇ 3 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, or metastasis.
- ⁇ the ⁇ v ⁇ 3 antagonizing effect is the inhibition of bone resorption.
- an example of the invention is the method wherein the integrin receptor antagonizing effect is an ⁇ v ⁇ antagonizing effect. More specifically, the ⁇ v ⁇ antagonizing effect is selected from inhibition of: restenosis, angiogenesis, diabetic retinopathy, macular
- Illustrating the invention is the method wherein the integrin receptor antagonizing effect is a dual ⁇ v ⁇ 3/ ⁇ v ⁇ antagonizing effect. More particularly, the dual ⁇ v ⁇ 3/ ⁇ v ⁇ antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, l ⁇ diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, or metastasis.
- Illustrating the invention is the method wherein the integrin receptor antagonizing effect is an ⁇ v ⁇ 6 antagonizing effect. More particularly, the ⁇ v ⁇ 6 antagonizing effect is selected from
- the ⁇ v ⁇ 3 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of ⁇ atherosclerosis, inflammation, viral disease, or inhibition of tumor growth or metastasis.
- the ⁇ v ⁇ 3 antagonizing effect is the inhibition of bone resorption.
- More particularly illustrating the invention is a pharmaceutical composition comprising any of the compounds 0 . described above and a pharmaceutically acceptable carrier.
- Another example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
- Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
- the invention is a method of treating and/or preventing a condition mediated by antagonism of an integrin ⁇ receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds described above.
- the condition is selected from bone resorption, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, viral
- the condition is selected from osteoporosis and cancer. Most preferably, the condition is osteoporosis.
- the invention is a method of eliciting an integrin antagonizing effect in a mammal in need thereof, l ⁇ comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.
- the integrin antagonizing effect is an ⁇ v ⁇ 3 antagonizing effect; more specifically, the ⁇ v ⁇ 3 antagonizing effect is selected from inhibition of bone resorption, 0 inhibition of restenosis, inhibition of atherosclerosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of inflammation, inhibition of viral disease, or inhibition of tumor growth or metastasis.
- the ⁇ v ⁇ 3 antagonizing effect is inhibition of bone resorption.
- the ⁇ integrin antagonizing effect is an ⁇ v ⁇ antagonizing effect, an ⁇ v ⁇ 6 antagonizing effect, or a mixed ⁇ v ⁇ 3, ⁇ v ⁇ , and ⁇ v ⁇ 6 antagonizing effect.
- ⁇ v ⁇ antagonizing effects are inhibition of restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, or tumor growth.
- Examples 0 of dual ⁇ v ⁇ 6 antagonizing effects are inhibition of angiogenesis, inflammatory response and wound healing.
- Additional examples of the invention are methods of inhibiting bone resorption and of treating and/or preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.
- Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone ⁇ metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization- induced osteopenia, and glucocorticoid treatment in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical 10 compositions described above.
- More particularly exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for -the treatment and/or prevention of osteoporosis in a mammal in need thereof. Still further exemplifying the invention is the l ⁇ use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of bone resorption, tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and/or angiogenesis.
- compositions further comprising an active ingredient selected from the group consisting of a.) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b.) an estrogen receptor modulator, ⁇ c.) a cytotoxic/antiproliferative agent, d.) a matrix metalloproteinase inhibitor, e.) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factors, f.) an inhibitor of VEGF, 0 g.) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, h.) a cathepsin K inhibitor, and i.) a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; ⁇ and mixtures thereof.
- an active ingredient selected from the group consisting of a.) an organic
- the active ingredient is selected from the group consisting of: a.) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b.) an estrogen receptor modulator, and 10 c.) a cathepsin K inhibitor; and mixtures thereof.
- Nonlimiting examples of such bisphosphonates include alendronate, etidronate, pamidronate, risedronate, ibandronate, and pharmaceutically acceptable salts and esters thereof.
- a particularly preferred bisphosphonate is alendronate, especially alendronate l ⁇ mono sodium trihydrate.
- Nonlimiting examples of estrogen receptor modulators include estrogen, progesterin, estradiol, droloxifene, raloxifene, and tamoxifene.
- Nonlimiting examples of cytotoxic/antiproliferative agents 20 are taxol, vincristine, vinblastine, and doxorubicin.
- Cathepsin K formerly known as cathepsin 02, is a cysteine protease and is described in PCT International Application Publication No. WO 96/13 ⁇ 23, published May 9, 1996; U.S. Patent No. 5,501,969, issued March 3, 1996; and U.S. Patent No. 5,736,3 ⁇ 7, issued April 7, 1998, ⁇ all of which are incorporated by reference herein in their entirety. Cysteine proteases, specifically cathepsins, are linked to a number of disease conditions, such as tumor metastasis, inflammation, arthritis, and bone remodeling. At acidic pH's, cathepsins can degrade type-I collagen.
- Cathepsin protease inhibitors can inhibit osteoclastic bone 0 resorption by inhibiting the degradation of collagen fibers and are thus useful in the treatment of bone resorption diseases, such as osteoporosis.
- the present invention is also directed to combinations of the compounds of the present invention with one or more agents useful in the prevention or treatment of osteoporosis.
- the ⁇ compounds of the instant invention may be effectively administered in combination with effective amounts of other agents such as an organic bisphosphonate, an estrogen receptor modulator, or a cathepsin K inhibitor.
- Additional illustrations of the invention are methods of ⁇ treating tumor growth in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound described above and one or more agents known to be cytotoxic/antiproliferative. Also, the compounds of the present invention can be administered in combination with radiation therapy for treating
- the integrin ⁇ v ⁇ 3 antagonist compounds of the present invention may be effectively administered in combination with a growth hormone secretagogue in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and l ⁇ associated diseases.
- diseases include conditions which can benefit from a reduction in bone resorption.
- a reduction in bone resorption should improve the balance between resorption and formation, reduce bone loss or result in bone augmentation.
- a reduction in bone resorption can alleviate the pain associated with osteolytic
- osteoporosis including estrogen deficiency, immobilization, glucocorticoid induced and senile
- osteodystrophy Paget's disease
- myositis ossificans Bechterew's disease
- malignant hypercalcemia metastatic bone disease
- periodontal disease ⁇ cholelithiasis
- nephrolithiasis urolithiasis
- urinary calculus hardening of the arteries (sclerosis), arthritis, bursitis, neuritis and tetany.
- ⁇ v ⁇ 3 receptor antagonist of the present invention and a growth hormone secretagogue, optionally including a third component comprising an organic bisphosphonate, preferably ⁇ alendronate monosodium trihydrate.
- a third component comprising an organic bisphosphonate, preferably ⁇ alendronate monosodium trihydrate.
- the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or l ⁇ indirectly, from combination of the specified ingredients in the specified amounts.
- the compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills,
- powders, granules, elixirs, tinctures, suspensions, syrups and emulsions may also be administered in intravenous (bolus or infusion), intraperitoneal, topical (e.g., ocular eyedrop), subcutaneous, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical ⁇ arts.
- An effective but non-toxic amount of the compound desired can be employed as an ⁇ v ⁇ 3 antagonist.
- the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the 0 severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
- An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the ⁇ condition.
- Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to ⁇ .O mg/kg/day.
- compositions are preferably provided in the form of tablets containing 0.01, O.O ⁇ , 0.1, O. ⁇ , 1.0, 2. ⁇ , ⁇ .O, 10.0, l ⁇ .0, 2 ⁇ .O, ⁇ .0, 100 and ⁇ OO milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- a medicament typically contains from about 0.01 mg to about ⁇ OO mg of the active
- compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be l ⁇ administered in divided doses of two, three or four times daily.
- preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
- the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
- the compounds herein described in detail can form the active ingredient, and are ⁇ typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
- the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;
- an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like
- the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
- Suitable ⁇ binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
- the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small l ⁇ unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
- Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the 0 compound molecules are coupled.
- the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include poly ⁇ inylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy- ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted ⁇ with palmitoyl residues.
- the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, 0 polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
- a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, 0 polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
- CBZ(Cbz) Carbobenzyloxy or benzyloxycarbonyl.
- CDI Carbonyldiimidazole.
- CH 2 C1 2 Methylene chloride.
- CH3CN Acetonitrile
- CHCI3 Chloroform
- DIAD Diisopropyl azodicarboxylate.
- DIBAH or DIBAL-H Diisobutylaluminum hydride.
- DIPEA Diisopropylethylamine.
- DMAP 4-Dimethylaminopyridine.
- l ⁇ DME 1,2-Dimethoxyethane.
- DMF Dimethylformamide.
- DMSO Dimethylsulfoxide.
- DPFN 3, ⁇ -Dimethyl-l-pyrazolylformamidine nitrate.
- EDC l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide # HC1
- PCA'HCl Pyrazole carboxamidine hydrochloride.
- Pd/C Palladium on activated carbon catalyst.
- Ph Phenyl.
- pTSA p-Toluenesulfonic acid.
- ⁇ TEA Triethylamine.
- TFA Trifluoroacetic acid.
- THF Tetrahydrofuran
- TMEDA N,N,N',N'-Tetramethylethylenediamine.
- TMS Trimethylsilyl.
- novel compounds of the present invention can be prepared according to the procedure of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples.
- the compounds illustrated in the following schemes and examples can be prepared according to the procedure of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples.
- N-Benzyl-(R)- ⁇ -methylbenzyl-3(S)-fluorophenyl- ⁇ -alanine ethyl ester (1-3) l ⁇
- N-benzyl-(R)- ⁇ -methylbenzylamine (33.4 g, l ⁇ 8 mmol) in THF (4 ⁇ 0 mL) at 0°C
- n-butyllithium (1.6M in hexanes; 99 mL, l ⁇ 8 mmol).
- the dark violet solution was stirred at 0°C for 30 minutes, cooled to -78°C, and the ester 1 ⁇ (29.2 g, l ⁇ O mmol) in THF (100 mL) was added over ⁇ minutes.
- Acid 5S ( ⁇ .O g, l ⁇ mmol) was suspended in water (3.5 L), then treated with IN NaOH (15 mL) to afford a clear solution.
- Penicillin 0 amidase (Sigma, EC 3.5.1.11, 10,000 U) in 0.1 M phosphate buffer was added.
- the pH of the mixture was adjusted to 7.8 with IN NaOH and the solution was stirred at room temperature for 4 days.
- the reaction was monitored periodically by HPLC and the reaction stopped once the ⁇ 0% conversion was reached.
- N-BOC-(L)-aspartic acid-alpha benzyl ester (1.5 g, 4.6 mmol) in THF (20 mL) at 0°C was added N-methylmorpholine (0.61 mL, 5. ⁇ mmol) followed by isobutyl chloroformate (0.66 mL, 5.1 mmol). After 0 30 minutes, a solution of the above crude oxime in DMF (5 mL) was added. The solution was allowed to warm to 2 ⁇ °C and stir for 1 h, then toluene (20 mL) was added and the mixture heated to 110°C, allowing the THF to evaporate. The resulting mixture was heated at reflux for 6 h.
- 1,4-Cyclohexadiene (2 mL. 21.1 mmol) was then gradually added. The reaction mixture was stirred for 3 hr and filtered through a celite pad.
- Ethyl 3-(6-methoxypyridin-3-yl)acrylate (19-3) A solution of the ⁇ -bromo-2-methoxypyridine 18-2 (74.3 g, 0.4 mol), ethyl acrylate (150 mL, 1.4 mol), triethylamine (150 mL, 1.08 mol), palladium acetate (10 g, 0.045 mol) and tri-o-tolylphosphine (20 g, 0.066 mol) in 100 mL acetonitrile was degassed with argon for 10 minutes. The mixture was heated at 90°C for 12 hr then the volatiles were removed in vacuo.
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Applications Claiming Priority (11)
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US6991097P | 1997-12-17 | 1997-12-17 | |
US69910P | 1997-12-17 | ||
US8325198P | 1998-04-27 | 1998-04-27 | |
US83251P | 1998-04-27 | ||
GBGB9810182.7A GB9810182D0 (en) | 1998-05-13 | 1998-05-13 | Vitronectin receptor antagonists |
GB9810182 | 1998-05-13 | ||
GB9811283 | 1998-05-26 | ||
GBGB9811283.2A GB9811283D0 (en) | 1998-05-26 | 1998-05-26 | Vironectin receptor antagonists |
US9258898P | 1998-07-13 | 1998-07-13 | |
US92588P | 1998-07-13 | ||
PCT/US1998/026539 WO1999030709A1 (en) | 1997-12-17 | 1998-12-14 | Integrin receptor antagonists |
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EP1047425A1 true EP1047425A1 (de) | 2000-11-02 |
EP1047425A4 EP1047425A4 (de) | 2009-04-22 |
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EP98962096A Withdrawn EP1047425A4 (de) | 1997-12-17 | 1998-12-14 | Integrinrezeptor antagonisten |
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EP (1) | EP1047425A4 (de) |
JP (1) | JP2002508323A (de) |
AU (1) | AU736026B2 (de) |
CA (1) | CA2315370A1 (de) |
WO (1) | WO1999030709A1 (de) |
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DE1946638A1 (de) * | 1968-09-13 | 1970-09-03 | Ici Ltd | Heterocyclische Verbindungen |
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JPS5295661A (en) * | 1976-02-04 | 1977-08-11 | Yoshitomi Pharmaceut Ind Ltd | 5-alkoxy-4-oxazolealkanoic acid derivatives |
US4480106A (en) * | 1981-10-28 | 1984-10-30 | Ciba-Geigy Corporation | Process for the preparation of asymmetrically substituted maleic anhydrides, and asymmetrically substituted maleic anhydrides |
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JPH09165370A (ja) * | 1995-10-13 | 1997-06-24 | Fuji Yakuhin Kogyo Kk | ラクタム誘導体およびその塩 |
TR199801255T2 (xx) * | 1995-12-29 | 1998-10-21 | Smithkline Beecham Corporation | Vitronektin resept�r antagonistleri. |
TR199801253T2 (xx) * | 1995-12-29 | 1998-12-21 | Smithkline Beecham Corporation | Vitronektin resept�r� antagonistleri. |
CN1209063A (zh) * | 1995-12-29 | 1999-02-24 | 史密丝克莱恩比彻姆公司 | 玻连蛋白受体拮抗剂 |
ATE212990T1 (de) * | 1996-03-20 | 2002-02-15 | Hoechst Ag | Inhibitoren der knochenresorption und vitronectinrezeptor-antagonisten |
JP4289688B2 (ja) * | 1996-04-03 | 2009-07-01 | 武田薬品工業株式会社 | オキサゾール誘導体、その製造法および剤 |
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JP2001505585A (ja) * | 1996-12-16 | 2001-04-24 | 藤沢薬品工業株式会社 | 新規アミド化合物およびそれらの一酸化窒素シンターゼ阻害剤としての用途 |
DK1040111T3 (da) * | 1997-12-17 | 2005-10-10 | Merck & Co Inc | Integrinreceptorantagonister |
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1998
- 1998-12-14 JP JP2000538692A patent/JP2002508323A/ja active Pending
- 1998-12-14 EP EP98962096A patent/EP1047425A4/de not_active Withdrawn
- 1998-12-14 AU AU17257/99A patent/AU736026B2/en not_active Ceased
- 1998-12-14 CA CA002315370A patent/CA2315370A1/en not_active Abandoned
- 1998-12-14 WO PCT/US1998/026539 patent/WO1999030709A1/en active IP Right Grant
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GB1025439A (en) * | 1963-10-09 | 1966-04-06 | Abbott Lab | Nitrofuryl substituted oxadiazoles |
DE1620057A1 (de) * | 1965-12-13 | 1970-03-19 | Miles Lab | Verfahren zur Herstellung von omega-(5-substituierten-2-Tetrazolyl)-alkansaeuren |
DE1946638A1 (de) * | 1968-09-13 | 1970-09-03 | Ici Ltd | Heterocyclische Verbindungen |
WO1995006038A1 (en) * | 1993-08-24 | 1995-03-02 | G.D. Searle & Co. | Platelet aggregation inhibitors |
WO1995017397A1 (en) * | 1993-12-20 | 1995-06-29 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
WO1995032710A1 (en) * | 1994-05-27 | 1995-12-07 | Merck & Co., Inc. | Compounds for inhibiting osteoclast-mediated bone resorption |
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Title |
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See also references of WO9930709A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU736026B2 (en) | 2001-07-26 |
CA2315370A1 (en) | 1999-06-24 |
JP2002508323A (ja) | 2002-03-19 |
WO1999030709A1 (en) | 1999-06-24 |
AU1725799A (en) | 1999-07-05 |
EP1047425A4 (de) | 2009-04-22 |
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