WO1998008840A1 - Antagonistes de l'integrine - Google Patents

Antagonistes de l'integrine Download PDF

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Publication number
WO1998008840A1
WO1998008840A1 PCT/US1997/014912 US9714912W WO9808840A1 WO 1998008840 A1 WO1998008840 A1 WO 1998008840A1 US 9714912 W US9714912 W US 9714912W WO 9808840 A1 WO9808840 A1 WO 9808840A1
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Prior art keywords
alkyl
aryl
oxo
tetrahydro
naphthyridin
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PCT/US1997/014912
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English (en)
Inventor
Mark E. Duggan
George D. Hartman
William F. Hoffman
Robert S. Meissner
James J. Perkins
Ben C. Askew
Paul J. Coleman
John H. Hutchinson
Adel M. Naylor-Olsen
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Merck & Co., Inc.
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Priority claimed from GBGB9703015.9A external-priority patent/GB9703015D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to US09/242,885 priority Critical patent/US6211184B1/en
Priority to EP97938568A priority patent/EP0934305A4/fr
Priority to JP51178398A priority patent/JP2002511052A/ja
Priority to AU40865/97A priority patent/AU724191B2/en
Priority to CA002263999A priority patent/CA2263999A1/fr
Publication of WO1998008840A1 publication Critical patent/WO1998008840A1/fr

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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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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
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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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • 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
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • A—HUMAN NECESSITIES
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Definitions

  • the present invention provides novel compounds and derivatives thereof, their synthesis, and their use as vitronectin receptor ligands. More particularly, the compounds of the present invention are ⁇ v ⁇ 3 antagonists, v ⁇ 5 antagonists or dual ⁇ v ⁇ 3/ ⁇ v ⁇ 5 antagonists useful for inhibiting bone reso ⁇ tion, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation and tumor growth.
  • This invention relates to compounds for inhibiting bone resorption that is mediated by the action of a class of cells known as osteoclasts.
  • Osteoclasts are multinucleated cells of up to 400 ⁇ m in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. They are actively motile cells that migrate along the surface of bone. They can bind to bone, secrete necessary acids and proteases and thereby cause the actual reso ⁇ tion of mineralized tissue from the bone.
  • osteoclasts are believed to exist in at least two physiological states.
  • the secretory 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 reso ⁇ tion.
  • the osteoclasts migrate across bone matrix and do not take part in reso ⁇ tion until they attach again to bone.
  • Integrins are transmembrane, heterodimeric, glycoproteins which interact with extracellular matrix and are involved in osteoclast attachment, activation and migration.
  • the most abundant integrin in osteoclasts (rat, chicken, mouse and human) is the vitronectin receptor, or txv ⁇ 3, thought to interact in bone with matrix proteins that contain the RGD sequence.
  • Antibodies to ⁇ v ⁇ 3 block bone reso ⁇ tion in vitro indicating that this integrin plays a key role in the reso ⁇ tive process.
  • v ⁇ 3 ligands can be used effectively to inhibit osteoclast mediated bone resoption in vivo in mammals.
  • osteoporosis hypercalcemia of malignancy
  • osteopenia due to bone metastases
  • periodontal disease hype ⁇ arathyroidism
  • periarticular erosions in rheumatoid arthritis Paget's disease
  • immobilization-induced osteopenia and glucocorticoid treatment.
  • All these conditions are characterized by bone loss, resulting from an imbalance between bone reso ⁇ tion (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 (recurrence of stenosis after corrective surgery on the heart valve), atherosclerosis, diabetic retinopathy, macular degeneration and angiogenesis (formation of new blood vessels).
  • restenosis recurrence of stenosis after corrective surgery on the heart valve
  • atherosclerosis recurrence of stenosis after corrective surgery on the heart valve
  • diabetic retinopathy diabetic retinopathy
  • macular degeneration macular degeneration
  • angiogenesis formation of new blood vessels.
  • ⁇ v ⁇ 3 antagonists which inhibit angiogenesis, are therefore useful in the treatment of cancer for inhibiting tumor growth. (See e.g., Brooks et al., CV7, 79:1157-1164 (1994)).
  • compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor ⁇ v ⁇ 5.
  • a monoclonal antibody for ⁇ v ⁇ 5 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model; M.C. Friedlander, et.al., Science 270, 1500-1502, 1995.
  • compounds that antagonize ⁇ v ⁇ 5 are useful for treating and preventing macular degeneration, diabetic retinopathy, and tumor growth.
  • certain compounds of this invention antagonize both the v ⁇ 3 and ⁇ v ⁇ 5 receptors.
  • These compounds referred to as “dual ⁇ v ⁇ 3/ v ⁇ 5 antagonists,” are useful for inhibiting bone reso ⁇ tion, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation and tumor growth.
  • the compounds of the present invention are useful for inhibiting bone reso ⁇ tion in mammals.
  • the compounds of the present invention are useful for preventing or reducing the incidence of osteoporosis.
  • the ⁇ v ⁇ 3 ligands of the present invention are also useful for treating and/or inhibiting restenosis, diabetic retinopathy, macular degeneration, atherosclerosis and/or angiogenesis in mammals.
  • the present invention provides a method of eliciting a vitronectin receptor antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of the formula
  • a 9- to 10-membered polycyclic ring system wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1 , 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups chosen from Rl , R ⁇ , Rl5 or R ⁇ 6;
  • Y is selected from
  • Z is a 5-1 1 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R4, R5 ? R6 and R7 ; provided that Z is not a 6-membered monocyclic aromatic ring system, an isoxazoline ring or an isoxazole ring; Rl , R2, R4, R5 ? R 13, R 14 ?
  • R 15 and Rl6 are each independently selected from hydrogen, halogen, Cl -io alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl Cl-6 alkyl, C3-8 cycloheteroalkyl Cl-6 alkyl, aryl, aryl Cl -8 alkyl, amino, amino Cl -8 alkyl, Cl-3 acylamino, Cl-3 acylamino Cl -8 alkyl, (Cl-6 alky qamino, (Cl -6 alkyl)qamino Cl-8 alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl -6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl-3 alkoxy carbonyl, Cl-3 alkoxycarbonyl Cl -6 alkyl, hydroxy carbonyl -
  • Cl-6 alkyloxy hydroxy, hydroxy Cl -6 alkyl, Cl-6 alkyloxy- Cl -6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, Cl -8 alkyl-S(0)q, (Cl -8 alkyOqaminocarbonyl, Cl -8 alkyloxycarbonylamino, (Cl -8 alkyl)qaminocarbonyloxy, oxo, (aryl Cl -8 alkyl)qamino, (aryl)qamino, aryl Cl-8 alkylsulfonylamino or Cl -8 alkylsulfonylamino;
  • R3 is selected from hydrogen, aryl, aryl-(CH2)p-, hydroxyl,
  • R6> R7, R8 ? R9 ? R IO and Rl 1 are each independently selected from hydrogen, aryl, aryl-(CH2)p-, aryl-(CH2)n-0-(CH2)m-, aryl-(CH2)n-S(0) q -(CH2)m-, aryl-(CH2)n-C(0)-(CH 2 )m-, aryl-(CH2)n-C(0)-N(R3)-(CH 2 )m-, aryl-(CH2)n-N(R3)-C(0)-(CH2)m-, aryl-(CH2)n-N(R3)-(CH2)m-, halogen, hydroxyl,
  • aryl Cl-8 alkyOqaminocarbonyl or (aryl Cl-8 alkyOqaminocarbonyl Cl-6 alkyl, wherein any of the alkyl groups may be unsubstituted or substituted with R l3 and Rl4; and provided that the carbon atom to which R& and R ⁇ are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which RlO and R* 1 are attached is itself attached to no more than one heteroatom;
  • Rl2 i s selected from hydrogen, Cl-8 alkyl, aryl, aryl Cl-8 alkyl,
  • n is an integer from 1 to 3
  • p is an integer from 1 to 4
  • q is an integer from 0 to 2
  • r is an integer from 0 to 6; and the pharmaceutically acceptable salts thereof.
  • X is a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1 , 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with R and R ⁇ ; and
  • Z is selected from
  • Y is selected from -(CH2)r or -(CH2)m-NR 3 -(CH2)t-;
  • R is selected from hydrogen, aryl-(CH2)p-,
  • R4 is selected from hydrogen, Cl-6 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl Cl-6 alkyl, C3-8 cycloheteroalkyl Cl-6 alkyl, aryl or aryl Cl -8 alkyl
  • R ⁇ is selected from hydrogen, aryl, aryl-(CH2)p-,
  • r is an integer from 0 to 3; and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
  • R ⁇ is selected from hydrogen
  • Cl-6 alkylaryl-CH CH-(CH2)s-, Ci- 6 alkyl-S ⁇ 2-(CH2)s-,
  • R l2 i selected from hydrogen or Cl -8 alkyl; s is an integer from 0 to 3; and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
  • the compound is selected from:
  • Exemplifying the invention is the method wherein the vitronectin receptor antagonizing effect is an ⁇ v ⁇ 3 antagonizing effect.
  • An illustration of the invention is the method wherein the v ⁇ 3 antagonizing effect is selected from inhibition of: bone reso ⁇ tion, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
  • the cxv ⁇ 3 antagonizing effect is the inhibition of bone reso ⁇ tion.
  • An example of the invention is the method wherein the vitronectin receptor antagonizing effect is an ⁇ v ⁇ 5 antagonizing effect.
  • the txv ⁇ 5 antagonizing effect is selected from inhibition of: restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
  • Illustrating the invention is the method wherein the vitronectin receptor antagonizing effect is a dual ⁇ v ⁇ 3/ ⁇ v ⁇ 5 antagonizing effect.
  • the dual ⁇ v ⁇ 3/ ⁇ v ⁇ 5 antagonizing effect is selected from inhibition of: bone reso ⁇ tion, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
  • a second embodiment of the present invention is a method of eliciting an ⁇ v ⁇ 3 antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of the formula
  • Y is selected from
  • Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4 , R5, R6 nd R ⁇ ; provided that Z is not a 6-membered monocyclic aromatic ring system; preferably, Z is selected from
  • R 1 , R 2 , R3, R4 5 R5, R13 and R* 4 are each independently selected from hydrogen, halogen, C] -10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl -8 alkyl, amino, amino Cl-8 alkyl, Cl -3 acylamino, Cl -3 acylamino Cl -8 alkyl, Cl -6 alkylamino, Cl -6 alkylamino- Cl -8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino Cl-8 alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl -3 alkoxycarbonyl, Cl -3 alkoxycarbonyl Cl-6 alkyl, hydroxycarbonyl- Cl -6 alkyloxy, hydroxy or hydroxy Cl -6 alkyl;
  • R6, R , R8, R9, R IO and R 1 ! are each independently selected from hydrogen, aryl,
  • Cl -8 alkyl either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, Cl-5 alkylcarbonylamino, aryl Cl-5 alkoxy, Cl-5 alkoxycarbonyl, aminocarbonyl, Cl-5 alkylaminocarbonyl, Cl-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, Cl -3 alkylamino, amino Cl-3 alkyl, arylamino- carbonyl, aryl Cl-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Cl -4 alkyl, hydroxycarbonyl, or hydroxycarbonyl Cl-5 alkyl,
  • any of the alkyl groups may be unsubstituted or substituted with R l and R ⁇ 4 ; and provided that the carbon atom to which R& and R9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which RlO and R ⁇ are attached is itself attached to no more than one heteroatom;
  • R 2 is selected from hydrogen
  • n is an integer from 1 to 3
  • p is an integer from 1 to 4
  • q is an integer from 0 to 2
  • r is an integer from 0 to 6
  • s is an integer from 0 to 3
  • t is an integer from 0 to 3;
  • a third embodiment of the invention is a method of eliciting an ctv ⁇ 3 antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of the formula
  • polycyclic ring system a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or
  • Y is selected from - (CH 2 )- ,
  • Z is a 5-1 1 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4 , R5, R6 and R7; provided that Z is not a 6-membered monocyclic aromatic ring system; preferably Z is selected from
  • Rl, R 2 , R 4 , R5, Rl3 a nd Rl 4 are each independently selected from hydrogen, halogen, Ci-io alkyl, C3- cycloalkyl, aryl, aryl Cl -8 alkyl, amino, amino Cl- alkyl, Cl -3 acylamino, Cl-3 acylamino Cl-8 alkyl, Cl-6 alkylamino, Cl -6 alkylamino- Cl -8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino Cl-8 alkyl, Ci-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl-3 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl-6 alkyl, hydroxycarbonyl- Ci-6 alkyloxy, hydroxy, hydroxy Cl -6 alkyl, Cl-6 alkyloxy- Cl -6 alkyl, nitro, cyano, trifluoromethyl, trifluo
  • R6, R7, R8 ? R9 ? RIO anc j R1 1 a re each independently selected from hydrogen, aryl,
  • Cl-8 alkyl either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl,
  • Cl-8 alkylsulfonylamino Cl-8 alkylsulfonylamino, Cl-8 alkylsulfonylamino C l -6 alkyl, arylsulfonylamino Cl-6 alkyl, aryl Cl-6 alkylsulfonylamino, aryl Cl-6 alkylsulfonylamino Cl-6 alkyl,
  • any of the alkyl groups may be unsubstituted or substituted with Rl3 and R ⁇ 4 ; and provided that the carbon atom to which R& and R ⁇ are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which R ⁇ O and R 1 1 are attached is itself attached to no more than one heteroatom;
  • R 2 is selected from hydrogen
  • Cl-8 dialkylaminocarbonylmethyleneoxy m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 1 to 4; q is an integer from 0 to 2; r is an integer from 0 to 6; and s is an integer from 0 to 3;
  • the ⁇ v ⁇ 3 antagonizing effect is selected from inhibition of bone reso ⁇ tion, inhibition of restenosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of atherosclerosis, inflammation or inhibition of tumor growth.
  • the ocv ⁇ 3 antagonizing effect is the inhibition of bone reso ⁇ tion.
  • X is a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups chosen from Rl , R 2 , R ! 5 or Rl6;
  • Y is selected from R ⁇ O
  • Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4 , R5, R6 and R7; provided that Z is not a 6-membered monocyclic aromatic ring system, an isoxazoline ring or an isoxazole ring;
  • R 1 , R 2 , R 4 , R5, Rl3, R14 ? R15 and R!6 are each independently selected from hydrogen, halogen, Ci -10 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl Cl -6 alkyl,
  • R6, R7, R R9 ? RIO a nd R 1 1 are each independently selected from hydrogen, aryl, aryl-(CH2)p-, aryl-(CH2)n-0-(CH2)m-, aryl-(CH2)n-S(0) q -(CH2)m-, aryl-(CH2)n-C(0)-(CH2)m-, aryl-(CH2)n-C(0)-N(R3)-(CH2)m-, aryl-(CH2)n-N(R3)-C(0)-(CH2)m-, aryl-(CH2)n-N(R3)-(CH2)m-, halogen, hydroxyl,
  • Cl-8 alkyl either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, Cl-5 alkylcarbonylamino, aryl Cl-5 alkoxy,
  • Cl-6 alkylsulfonyl Cl-6 alkylsulfonyl, Cl-6 alkylsulfonyl Cl-6 alkyl, arylsulfonyl Cl-6 alkyl, aryl Cl-6 alkylsulfonyl, aryl Cl-6 alkylsulfonyl Cl-6 alkyl,
  • aryl Cl-8 alkyOqaminocarbonyl Cl-6 alkyl wherein any of the alkyl groups may be unsubstituted or substituted with Rl and R ⁇ 4 ; and provided that the carbon atom to which R ⁇ and R9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which RlO and R ⁇ are attached is itself attached to no more than one heteroatom;
  • R1 is selected from hydrogen
  • n is an integer from 1 to 3
  • p is an integer from 1 to 4
  • q is an integer from 0 to 2
  • r is an integer from 0 to 6; and the pharmaceutically acceptable salts thereof.
  • Z is a 5-1 1 membered nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4 , R ⁇ , R6 and R7; and all other variables are as defined above.
  • Exemplifying the invention is the compound wherein
  • Z is selected from
  • An example of the invention is the compound of the formula
  • Y is selected from -(CH2)r- or -(CH2) m -NR 3 -(CH2)t-;
  • R is selected from hydrogen, aryl-(CH2)p-, Cl- alkoxycarbonyl,
  • R 4 is selected from hydrogen, Cl-6 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl,
  • r is an integer from 0 to 3; wherein all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
  • R8 is selected from hydrogen
  • Ci-6 alkyl-CH CH-(CH2)s-
  • Rl2 is selected from hydrogen or Cl-8 alkyl; and s is an integer from 0 to 3; and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
  • the compound is selected from:
  • An additional example of the invention is a compound of the formula
  • X is a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1 , 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with R ⁇ and R2;
  • Y is selected from R 3 R 3 ° O
  • Z is a 5-1 1 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4 , R5, R6 and R7; provided that Z is not a 6-membered monocyclic aromatic ring system; preferably, Z is selected from
  • R 1 , R 2 , R3, R 4 , R5, R 13 and R14 ar e each independently selected from hydrogen, halogen, Cl-lO alkyl, C3-8 cycloalkyl, aryl, aryl Cl -8 alkyl, amino, amino Cl-8 alkyl, Cl-3 acylamino, Cl -3 acylamino Cl-8 alkyl, Cl-6 alkylamino, Cl-6 alkylamino- C ⁇ _8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino Cl- alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl _3 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl-6 alkyl, hydroxycarbonyl- Cl-6 alkyloxy, hydroxy or hydroxy Cl -6 alkyl;
  • Cl-8 alkyl either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, Cl-5 alkylcarbonylamino, aryl Cl -5 alkoxy,
  • Cl-6 alkylsulfonyl Cl-6 alkylsulfonyl, Cl-6 alkylsulfonyl Cl-6 alkyl, arylsulfonyl Cl-6 alkyl, aryl Cl-6 alkylsulfonyl, aryl C 1 -6 alkylsulfonyl C 1 -6 alkyl,
  • Cl-6 alkylcarbonyl Cl-6 alkylcarbonyl, Cl-6 alkylcarbonyl Cl-6 alkyl, arylcarbonyl Cl-6 alkyl, aryl Cl-6 alkylcarbonyl, aryl Cl-6 alkylcarbonyl Cl-6 alkyl,
  • any of the alkyl groups may be unsubstituted or substituted with R l and R ⁇ 4 ; and provided that the carbon atom to which R$ and R9 are attached is itself attached to no more than one heteroatom; and provided further that the carbon atom to which RlO and R 1 1 are attached is itself attached to no more than one heteroatom;
  • Rl ⁇ is selected from hydrogen, Cl-8 alkyl, aryl, aryl Cl-8 alkyl, hydroxy, Cl-8 alkoxy, aryloxy, aryl Cl -6 alkoxy,
  • n is an integer from 1 to 3
  • p is an integer from 1 to 4
  • q is an integer from 0 to 2
  • r is an integer from 0 to 6
  • s is an integer from 0 to 3; and the pharmaceutically acceptable salts thereof.
  • An additional illustration of the invention is a compound of the formula wherein X is a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1 , 2, 3 or 4 heteroatoms selected from N, O or
  • Y is selected from
  • Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4 , R5, R6 and R ; provided that Z is not a 6-membered monocyclic aromatic ring system; preferably, Z is selected from 63 -
  • Rl , R 2 , R 4 , R5, R13 and R ⁇ 4 are each independently selected from hydrogen, halogen, Cl -10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, Cl -3 acylamino,
  • Cl-6 alkyloxy hydroxy, hydroxy Cl-6 alkyl, Cl-6 alkyloxy- Cl -6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, Cl-8 alkyl-S(0)q, Cl-8 aminocarbonyl, Cl -8 dialkylaminocarbonyl, Cl-8 alkyloxycarbonylammo, Cl-8 alkylaminocarbonyloxy or Cl -8 alkylsulfonylamino;
  • R3 is selected from hydrogen, aryl, -(CH )p-aryl, hydroxyl, Cl-5 alkoxycarbonyl, aminocarbonyl,
  • Cl-8 alkyl either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl,
  • Cl-8 alkylsulfonylamino Cl-8 alkylsulfonylamino, Cl-8 alkylsulfonylamino Cl -6 alkyl, arylsulfonylamino Cl-6 alkyl, aryl Cl-6 alkylsulfonylamino, aryl Cl-6 alkylsulfonylamino Cl-6 alkyl,
  • R! is selected from hydrogen, Cl-8 alkyl, aryl, aryl Cl-8 alkyl, hydroxy,
  • n is an integer from 1 to 3
  • p is an integer from 1 to 4
  • q is an integer from 0 to 2
  • r is an integer from 0 to 6
  • s is an integer from 0 to 3; and the pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier is another illustration of the invention.
  • 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 condition is selected from bone reso ⁇ tion, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, cancer and tumor growth. More preferably, the condition is selected from osteoporosis and cancer. Most preferably, the condition is osteoporosis.
  • the vitronectin antagonizing effect is an ⁇ v ⁇ 3 antagonizing effect; more specifically the ⁇ v ⁇ 3 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of atherosclerosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of inflammation or inhibition of tumor growth.
  • the ⁇ v ⁇ 3 antagonizing effect is inhibition of bone resorption.
  • the vitronectin antagonizing effect is an ⁇ v ⁇ 5 antagonizing effect or a dual ⁇ v ⁇ 3/ocv ⁇ 5 antagonizing effect.
  • ⁇ v ⁇ 5 antagonizing effects are inhibition of: restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
  • dual ⁇ v ⁇ 3/ ⁇ v ⁇ 5 antagonizing effects are inhibition of: bone resorption, restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
  • 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 decribed above.
  • compositions described above further comprising a therapeutically effective amount of a second bone reso ⁇ tion inhibitor; preferably, the second bone reso ⁇ tion inhibitor is alendronate.
  • More particularly illustrating the invention is any of the methods of treating and/or preventing osteoporosis and/or of inhibiting bone resoption described above, wherein the compound is administered in combination with a second bone reso ⁇ tion inhibitor; preferably, the second bone reso ⁇ tion inhibitor is alendronate.
  • Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hype ⁇ arathyroidism, 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 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 use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of: bone reso ⁇ tion, tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammation and/or angiogenesis.
  • 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 cy to toxic or antiproliferative, e.g., taxol and doxorubicin.
  • Representative compounds of the present invention are integrin antagonists which display submicromolar affinity for the human v ⁇ 3 receptor. Compounds of this invention are therefore useful for treating mammals suffering from a bone condition caused or mediated by increased bone reso ⁇ tion, 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 osteoporosis.
  • 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 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:
  • 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 organic ligands, e.g., quaternary ammonium salts.
  • the compounds of the present invention may 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, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymo ⁇ hs and hydrates of the compounds of the instant invention.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • the term “administering” 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, 1985. 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.
  • vitronectin receptor antagonist refers to a compound which binds to and antagonizes either the ⁇ v ⁇ 3 receptor or the v ⁇ 5 receptor, or a compound which binds to and antagonizes both the ocv ⁇ 3 and ⁇ v ⁇ 5 receptors (i.e., a dual ⁇ v ⁇ 3/ ⁇ v ⁇ 5 receptor antagonist).
  • bone reso ⁇ tion refers to the process by which osteoclasts degrade bone.
  • 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 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 heteroatoms chosen from N, O or S.
  • cycloheteroalkyl groups include, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl, mo ⁇ holinyl, piperazinyl.
  • alkoxy refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., Cl-5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).
  • aryl refers to a monocyclic or polycyclic system composed of 5- and 6-membered fully unsaturated or partially unsaturated rings, such that the system comprises at least one fully unsaturated ring, wherein the rings contain 0, 1 , 2, 3 or 4 heteroatoms chosen from N, O or S, and either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Cl-10 alkyl, C3- cycloalkyl, aryl, aryl Cl -8 alkyl, amino, amino Cl -8 alkyl, Cl-3 acylamino, Cl -3 acylamino Cl -8 alkyl, Cl -6 alkylamino, C] -6 alkylamino Cl -8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino-Ci-8 alkyl, Cl-4 alkoxy, Cl -4 alkoxy Cl -6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl
  • aryl examples include, but are not limited to, phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, indolyl, thienyl, furyl, dihydrobenzofuryl, benzo(l,3) dioxolane, oxazolyl, isoxazolyl and thiazolyl, which are either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Cl -10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl -8 alkyl, amino, amino Cl-8 alkyl, Cl-3 acylamino, Cl -3 acylamino Cl-8 alkyl, Cl-6 alkylamino, Cl-6 alkylamino-Cl-8 alkyl, Cl -6 dialkylamino, Cl-6 dialkylamino Cl-8 alkyl, Cl-4 alkoxy, Cl-4
  • 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 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 Q)-8 alkyl) it shall be inte ⁇ reted as including those limitations given above for "alkyl” and "aryl.”
  • Designated numbers of carbon atoms e.g., Cl-10 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, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl.
  • alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.
  • R 1 , R 2 , R 3 , R 4 , R5, R6, R7, R8, R9, R!0, Rl 1 , Rl , Rl3 or R* 4 includes the definition Co (e.g., aryl C ⁇ -8 alkyl), the group modified by Co is not present in the substituent.
  • the group modified by the variable is not present; for example, when s is zero, the group "-(CH2)s C ⁇ CH” is "-C ⁇ CH".
  • the Cl-6 alkyl groups can be the same (e.g., dimethylamino) or different (e.g., N(CH3)(CH2CH3)).
  • halogen shall include iodine, bromine, chlorine and fluorine.
  • oxy means an oxygen (O) atom.
  • thio means a sulfur (S) atom.
  • 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. Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a Cl -5 alkylcarbonylamino Cl-6 alkyl substituent is equivalent to
  • 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 used in the treatment of osteoporosis such as bisphosphonate bone reso ⁇ tion inhibitors; preferably, the bone reso ⁇ tion inhibitor is the bisphosphonate alendronate, now sold as FOSAMAX®.
  • Preferred combinations are simultaneous or alternating treatments of an ⁇ v ⁇ 3 receptor antagonist of the present invention and FOSAMAX®.
  • 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 associated diseases.
  • diseases include conditions which can benefit from a reduction in bone reso ⁇ tion.
  • a reduction in bone reso ⁇ tion should improve the balance between reso ⁇ tion and formation, reduce bone loss or result in bone augmentation.
  • a reduction in bone reso ⁇ tion can alleviate the pain associated with osteolytic lesions and reduce the incidence and/or growth of those lesions.
  • osteoporosis including estrogen deficiency, immobilization, glucocorticoid induced and senile
  • osteodystrophy Paget's disease
  • myositis ossificans Bechterew's disease
  • malignant hypercalcemia metastatic bone disease
  • metastatic bone disease periodontal disease
  • cholelithiasis nephrolithiasis
  • urolithiasis urolithiasis
  • urinary calculus hardening of the arteries (sclerosis), arthritis, bursitis, neuritis and tetany.
  • Increased bone reso ⁇ tion can be accompanied by pathologically high calcium and phosphate concentrations in the plasma, which would be alleviated by this treatment.
  • the present invention would be useful in increasing bone mass in patients with growth hormone deficiency.
  • preferred combinations are simultaneous or alternating treatments of an v ⁇ 3 receptor antagonist of the present invention and a growth hormone secretagogue, optionally including a third component comprising FOSAMAX®.
  • vitronectin receptor antagonist compounds of the present invention may be effectively administered in combination with one or more agents known to be cytoxic or antiproliferative, e.g, taxol and doxorubicin.
  • 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.
  • the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be inte ⁇ reted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating ocv ⁇ 3 related conditions includes in principle any combination with any pharmaceutical composition useful for treating osteoporosis.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or 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, elixers, tinctures, suspensions, syrups and emulsions. Likewise, they 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 inhibitor.
  • 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 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 5.0 mg/kg/day.
  • the compositions are preferably provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 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 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient.
  • the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be 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 intermittant 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.
  • suitable pharmaceutical diluents, excipients or carriers collectively referred to herein as 'carrier' materials
  • 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; for oral administration in liquid form, 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 inco ⁇ orated 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 benzoate, sodium acetate, sodium chloride and the like.
  • 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 unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcho lines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the 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 polyvinylpyrrolidone, 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 polyactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polyactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • novel compounds of the present invention were prepared according to the procedure of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples.
  • the most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus.
  • the following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.
  • the following Schemes and Examples describe procedures for making representative compounds of the present invention.
  • the iodide hi (2.4 g, 10 mmol) (J. Org. Chem., 1983, 48, 5381) was added to the orange solution and the resulting solution stirred for 2 h at -78°C, 3 h at -15°C and then 16 h at ambient temperature.
  • the reaction mixture was concentrated and then treated with IN HC1 (30 mL). The mixture was then basified with IN
  • TLC RF 0.74 (silica, 70:15:15 CHCl3/EtOAc/CH3 ⁇ H); - I l l -
  • TLC RF 0.71 (silica, 70:15:15 CHCI3/E1OAC/CH3OH);
  • TLC RF 0.71 (silica, 70:15:15 CHCl3/EtOAc/CH3 ⁇ H);
  • Analytical and preparative HPLC was carried out using a Waters 600E Powerline Multi Solvent Delivery System with 0.1 mL heads with a Rheodyne 7125 injector and a Waters 990 Photodiode Array Detector with a Gilson FC203 Microfraction collector.
  • analytical and preparative HPLC a Vydac peptide-protein C-18 column, 4.6 x 250 mm was used with a C-18 Brownlee modular guard column.
  • the acetonitrile used for the HPLC analyses was Fisher Optima grade.
  • the HPLC radiodetector used was a Beckman 170 Radioisotope detector.

Abstract

L'invention porte sur certains composés nouveaux et leurs dérivés, leur synthèse et leur utilisation en tant qu'antagonistes du récepteur de la vitronectine. Lesdits composés antagonistes du récepteur de la vitronectine sont des antagonistes αvβ3, des antagonistes αvβ5 ou des antagonistes doubles αvβ3/αvβ5, qui servent à inhiber la résorption osseuse, prévenir et traiter l'ostéoporose et inhiber la resténose, la rétinopathie diabétique, la dégénérescence maculaire, l'angiogénèse, l'athérosclérose, l'inflammation et la croissance de tumeurs.
PCT/US1997/014912 1996-08-29 1997-08-25 Antagonistes de l'integrine WO1998008840A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US09/242,885 US6211184B1 (en) 1996-08-29 1997-08-25 Integrin antagonists
EP97938568A EP0934305A4 (fr) 1996-08-29 1997-08-25 Antagonistes de l'integrine
JP51178398A JP2002511052A (ja) 1996-08-29 1997-08-25 インテグリンアンタゴニスト
AU40865/97A AU724191B2 (en) 1996-08-29 1997-08-25 Integrin antagonists
CA002263999A CA2263999A1 (fr) 1996-08-29 1997-08-25 Antagonistes de l'integrine

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US2512396P 1996-08-29 1996-08-29
US3357996P 1996-12-19 1996-12-19
GBGB9703015.9A GB9703015D0 (en) 1997-02-13 1997-02-13 Alpha v B3 antagonists
GB9703015.9 1997-02-13
US4717797P 1997-05-20 1997-05-20
US60/047,177 1997-05-20
US60/025,123 1997-05-20
US60/033,579 1997-05-20

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EP (1) EP0934305A4 (fr)
JP (1) JP2002511052A (fr)
AU (1) AU724191B2 (fr)
CA (1) CA2263999A1 (fr)
WO (1) WO1998008840A1 (fr)

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US6211184B1 (en) 1996-08-29 2001-04-03 Merck & Co., Inc. Integrin antagonists
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WO2001043743A1 (fr) * 1999-12-15 2001-06-21 Celgene Corp. Methodes et compositions de prevention et de traitement de l'atherosclerose, de la restenose et des troubles associes
US6297233B1 (en) 1999-02-09 2001-10-02 Bristol-Myers Squibb Company Lactam inhibitors of FXa and method
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US6410526B1 (en) 1999-06-02 2002-06-25 Merck & Co., Inc. αv integrin receptor antagonists
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US6472403B2 (en) 2000-01-20 2002-10-29 Merck & Co., Inc. αV integrin receptor antagonists
US6511973B2 (en) 2000-08-02 2003-01-28 Bristol-Myers Squibb Co. Lactam inhibitors of FXa and method
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US6555542B1 (en) 2001-01-30 2003-04-29 Bristol-Myers Squibb Company Sulfonamide lactam inhibitors of FXa and method
WO2003066624A1 (fr) * 2002-02-06 2003-08-14 Abbott Gmbh & Co. Kg Pyrimidinonesulfamoylurees en tant que ligansds de l'integrine
US6624180B2 (en) 2000-11-20 2003-09-23 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade
US6653316B1 (en) 1999-05-19 2003-11-25 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6660885B2 (en) 2000-03-13 2003-12-09 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade
US6664255B1 (en) 1999-05-19 2003-12-16 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
US6686484B2 (en) 2000-04-17 2004-02-03 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade
US6689754B1 (en) 1998-04-10 2004-02-10 G. D. Searle & Co. Heterocyclic glycyl β-alanine derivatives
US6693121B2 (en) 2000-04-05 2004-02-17 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade
US6716838B1 (en) 1999-05-19 2004-04-06 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents
US6750342B1 (en) 1999-05-19 2004-06-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
US6867217B1 (en) 1999-05-19 2005-03-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
US6875791B2 (en) 2000-04-05 2005-04-05 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade
US6969715B2 (en) 2001-10-03 2005-11-29 Pharmacia Corporation 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade
EP1589029A3 (fr) * 1998-06-11 2006-01-18 Johnson & Johnson Pharmaceutical Research & Development L.L.C. Inhibiteurs de protéase à base de pyrazine
US7015230B1 (en) 1999-05-19 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
US7015223B1 (en) 2000-11-20 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade
US7105559B2 (en) 2001-10-03 2006-09-12 Pharmacia Corporation Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade
US7119094B1 (en) 2000-11-20 2006-10-10 Warner-Lambert Company Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade
WO2007084670A2 (fr) 2006-01-18 2007-07-26 Merck Patent Gmbh Traitement specifique utilisant des ligands de l’integrine destine a traiter un cancer
WO2008087025A2 (fr) 2007-01-18 2008-07-24 Merck Patent Gmbh Thérapie spécifique et médicament utilisant des ligands d'intégrine ou traitant le cancer
WO2010136168A2 (fr) 2009-05-25 2010-12-02 Merck Patent Gmbh Administration continue de ligands d'intégrines pour le traitement du cancer
EP2292251A1 (fr) 2001-04-24 2011-03-09 Merck Patent GmbH Polythérapie à base d'agents antiangiogéniques et de facteur de nécrose tumorale TNF-alpha
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
WO2018160521A2 (fr) 2017-02-28 2018-09-07 Lazuli, Inc. Inhibiteurs de l'(alpha-v)(bêta-6) intégrine
US11021480B2 (en) 2018-08-29 2021-06-01 Morphic Therapeutic, Inc. Inhibiting (α-V)(β-6) integrin
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US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes
TWI834321B (zh) 2017-02-28 2024-03-01 美商莫菲克醫療股份有限公司 αｖβ６整合蛋白之抑制劑

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WO1999052872A1 (fr) 1998-04-09 1999-10-21 Meiji Seika Kaisha, Ltd. DERIVES D'AMINOPIPERIDINE COMME ANTAGONISTES D'INTEGRINE αvβ¿3?
US6689754B1 (en) 1998-04-10 2004-02-10 G. D. Searle & Co. Heterocyclic glycyl β-alanine derivatives
WO1999052896A1 (fr) * 1998-04-10 1999-10-21 G.D. Searle & Co. Derives heterocycliques de glycil beta-alanine agissant comme antagonistes de la vitronectine
WO1999052879A1 (fr) * 1998-04-14 1999-10-21 American Home Products Corporation Derives d'acylresorcinol inhibiteurs selectifs de la vitronectine
WO1999052551A1 (fr) * 1998-04-15 1999-10-21 King's College London Traitement de l'atherosclerose
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US6090944A (en) * 1998-08-13 2000-07-18 Merck & Co., Inc. Alkanoic acid derivatives as αv integrin receptor antagonists
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US6297233B1 (en) 1999-02-09 2001-10-02 Bristol-Myers Squibb Company Lactam inhibitors of FXa and method
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US7125883B1 (en) 1999-04-13 2006-10-24 Abbott Gmbh & Co. Kg Integrin receptor ligands
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US6444811B1 (en) 1999-07-19 2002-09-03 Merck Frosst Canada & Co. Pyrazinones, compositions containing such compounds and methods of use
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US6413955B1 (en) 1999-10-04 2002-07-02 Merck & Co., Inc. Integrin receptor antagonists
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US7166586B2 (en) 2001-01-30 2007-01-23 Bristol Myers Squibb Co. Sulfonamide lactam inhibitors of FXa and method
US6555542B1 (en) 2001-01-30 2003-04-29 Bristol-Myers Squibb Company Sulfonamide lactam inhibitors of FXa and method
EP2292251A1 (fr) 2001-04-24 2011-03-09 Merck Patent GmbH Polythérapie à base d'agents antiangiogéniques et de facteur de nécrose tumorale TNF-alpha
US7361679B2 (en) 2001-09-12 2008-04-22 Kaken Pharmaceutical Co., Ltd. 2-phenyl-3-heteroarylpropionic acid derivative or salt thereof and medicine containing the same
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US7105559B2 (en) 2001-10-03 2006-09-12 Pharmacia Corporation Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade
US6969715B2 (en) 2001-10-03 2005-11-29 Pharmacia Corporation 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade
WO2003066624A1 (fr) * 2002-02-06 2003-08-14 Abbott Gmbh & Co. Kg Pyrimidinonesulfamoylurees en tant que ligansds de l'integrine
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WO2007084670A2 (fr) 2006-01-18 2007-07-26 Merck Patent Gmbh Traitement specifique utilisant des ligands de l’integrine destine a traiter un cancer
WO2008087025A2 (fr) 2007-01-18 2008-07-24 Merck Patent Gmbh Thérapie spécifique et médicament utilisant des ligands d'intégrine ou traitant le cancer
EP2441464A1 (fr) 2007-01-18 2012-04-18 Merck Patent GmbH Thérapie spécifique et médicament utilisant des ligands d'intégrine pour traiter le cancer
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WO2010136168A2 (fr) 2009-05-25 2010-12-02 Merck Patent Gmbh Administration continue de ligands d'intégrines pour le traitement du cancer
US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
US10328082B2 (en) 2014-05-30 2019-06-25 Pfizer Inc. Methods of use and combinations
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WO2018160521A2 (fr) 2017-02-28 2018-09-07 Lazuli, Inc. Inhibiteurs de l'(alpha-v)(bêta-6) intégrine
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TWI834321B (zh) 2017-02-28 2024-03-01 美商莫菲克醫療股份有限公司 αｖβ６整合蛋白之抑制劑
EP4159727A1 (fr) * 2017-02-28 2023-04-05 Morphic Therapeutic, Inc. Inhibiteurs de l'intégrine (alpha-v)(bêta-6)
CN110573499B (zh) * 2017-02-28 2023-04-21 莫菲克医疗股份有限公司 αvβ6整合蛋白的抑制剂
US11827621B2 (en) 2017-02-28 2023-11-28 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
US11021480B2 (en) 2018-08-29 2021-06-01 Morphic Therapeutic, Inc. Inhibiting (α-V)(β-6) integrin
US11739087B2 (en) 2018-08-29 2023-08-29 Morphic Therapeutic, Inc. Inhibiting (α-v)(β-6) integrin
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes

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CA2263999A1 (fr) 1998-03-05
AU724191B2 (en) 2000-09-14
JP2002511052A (ja) 2002-04-09
EP0934305A4 (fr) 2001-04-11
AU4086597A (en) 1998-03-19

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