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WO1998018461A1 - Antagonistes de l'integrine - Google Patents

Antagonistes de l'integrine Download PDF

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Publication number
WO1998018461A1
WO1998018461A1 PCT/US1997/019349 US9719349W WO9818461A1 WO 1998018461 A1 WO1998018461 A1 WO 1998018461A1 US 9719349 W US9719349 W US 9719349W WO 9818461 A1 WO9818461 A1 WO 9818461A1
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Prior art keywords
alkyl
aryl
alkylene
alkylamino
mammal
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PCT/US1997/019349
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English (en)
Inventor
Mark E. Duggan
George D. Hartman
William F. Hoffman
Nathan C. Ihle
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from GBGB9626308.2A external-priority patent/GB9626308D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to JP52063998A priority Critical patent/JP2001504456A/ja
Priority to AU50884/98A priority patent/AU717283B2/en
Priority to EP97913775A priority patent/EP0946164A4/fr
Priority to CA002268916A priority patent/CA2268916A1/fr
Publication of WO1998018461A1 publication Critical patent/WO1998018461A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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

Definitions

  • the present invention is related to U.S. provisional applications Serial Nos. 60/029,223, filed October 30, 1996, the contents of which are hereby incorporated by reference.
  • 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 ⁇ antagonists or dual ⁇ v ⁇ 3/ ⁇ v ⁇ antagonists useful for inhibiting bone resorption, 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 resorption of mineralized tissue from the bone. More specifically, osteoclasts are believed to exist in at least two physiological states. In 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.
  • mineralized tissue chiefly calcium carbonate and calcium phosphate
  • osteoclasts The adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption. In the migratory or motile state, the osteoclasts migrate across bone matrix and do not take part in resorption 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 ⁇ v ⁇ 3, 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. There is increasing evidence to suggest that ⁇ 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 hyperparathyroidism
  • 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 resorption (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 ⁇ % 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., Cell, 79:1167-1164 (1994)).
  • 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; M.C. Friedlander, et.al., Science 270, I ⁇ 00-l ⁇ 02, 199 ⁇ .
  • compounds that antagonize ⁇ v ⁇ 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 ⁇ 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 and tumor growth.
  • the compounds of the present invention are useful for inhibiting bone resorption 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 compounds of the formula
  • Ring is a 4 to 10-membered mono-or polycyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, and either unsubstituted or substituted with R27 a nd R ⁇ 8;
  • X is selected from
  • Y is selected from
  • n are each independently an integer from 0 to 6;
  • A is selected from
  • Rl, R2, R3, R4 R ⁇ , R 6, R7, RH R 18, R 19, R20, R21, R22, R23 ? R24, R 2 ⁇ , R26, R27 ⁇ R28 ? R29 a nd R ⁇ O are each independently selected from hydrogen, halogen,
  • Ci-6 dialkylamino C ⁇ -8 alkyl aryl C ⁇ -6 alkylamino C ⁇ -6 alkyl, C ⁇ -4 alkoxyamino C ⁇ -8 alkyl, hydroxy Ci-6 alkylamino C ⁇ -8 alkyl,
  • R are each independently selected from hydrogen, aryl, halogen, aryl-(CH2)p-, hydroxyl,
  • Cl-8 alkylaminocarbonyl Cl-6 alkylcarbonyloxy, C3-8 cycloalkyl, amino, Cl-6 alkylamino, amino Cl-6 alkyl, arylaminocarbonyl, aryl Cl-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl 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,
  • Ci-6 alkylsulfonyl Ci-6 alkylsulfonyl, Ci-6 alkylsulfonyl Cl-6 alkyl, arylsulfonyl Cl-6 alkyl, aryl Cl-6 alkylsulfonyl, aryl Ci-6 alkylsulfonyl Ci-6 alkyl,
  • Ci-6 alkylcarbonyl Ci-6 alkylcarbonyl, Ci-6 alkylcarbonyl Cl-6 alkyl, arylcarbonyl Ci-6 alkyl, aryl Cl-6 alkylcarbonyl, aryl Ci-6 alkylcarbonyl Ci-6 alkyl,
  • RlO and RU are each independently selected from hydrogen, aryl, halogen, aryl-(CH 2 )p-, 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-5 alkoxycarbonyl, aminocarbonyl, Cl-5 alkylaminocarbonyl, Cl-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-3 alkylamino, amino Cl-3 alkyl, arylaminocarbonyl, aryl Cl-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Ci-4 alkyl, hydroxycarbonyl, or hydroxycarbonyl Cl-5 alkyl, HC ⁇ C(CH2)r -
  • H2C CH(CH2)r -
  • 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,
  • Ci-6 alkyl arylaminocarbonylamino Ci-6 alkyl, aryl Cl-8 alkylaminocarbonylamino, aryl Cl-8 alkylaminocarbonylamino Ci-6 alkyl, aminosulfonylamino Ci-6 alkyl, Ci-8 alkylaminosulfonylamino, Ci-8 alkylaminosulfonylamino Cl-6 alkyl, arylaminosulfonylamino Ci-6 alkyl, aryl Cl-8 alkylaminosulfonylamino, aryl Cl-8 alkylaminosulfonylamino Ci-6 alkyl, Ci-6 alkylsulfonyl, Ci-6 alkylsulfonyl C ⁇ _6 alkyl, arylsulfonyl Cl-6 alkyl, aryl Cl-6 alkylsulfonyl, aryl Cl-6 alkylsulfonylsulffonyl, aryl
  • R 2 wherein the polycyclyl may be unsubstituted or substituted with R31, R32 ; R33 and R34 ; and provided that the carbon atom to which R O and RU are attached is itself attached to no more than one heteroatom; or RlO and RU are combined to form oxo, in which case the carbon atom to which RlO and RU are attached can itself be attached to more than one heteroatom;
  • Rl2 is selected from hydroxy, Ci-8 alkyloxy, aryl C ⁇ -6 alkyloxy,
  • Rl3, R!4, Rl and Rl6 are each independently selected from hydrogen, Ci-10 alkyl, aryl C ⁇ -8 alkyl, thio, amino C ⁇ -8 alkyl, Ci-3 acylamino C ⁇ -8 alkyl, Ci-6 alkylamino C ⁇ -8 alkyl, Ci-6 dialkylamino Crj-8 alkyl, aryl C ⁇ -6 alkylamino C ⁇ -6 alkyl, Ci-4 alkoxyamino C ⁇ -8 alkyl, hydroxy Cl-6 alkylamino C ⁇ -8 alkyl, Ci-4 alkoxy C ⁇ -6 alkyl, carboxy C ⁇ -6 alkyl, Ci-4 alkoxycarbonyl C ⁇ -6 alkyl, carboxy Cfj-6 alkyloxy, hydroxy Ci-6 alkylamino C ⁇ -6 alkyl, hydroxy C ⁇ -6 alkyl, NR 23
  • Ring is not a 6-membered monocyclic aromatic ring
  • Ring is selected from isoxazole, isoxazoline, imidazole, imidazoline, benzofuran, benzothiophene, benzimidazole, indole, benzothiazole, benzoxazole,
  • Z is (CH2)m where m is an integer from 0 to 3; preferably, m is zero; and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
  • Ring is selected from
  • X is selected from
  • Y is selected from
  • A is selected from
  • p is an integer from 0 to 3;
  • Rl, R2, R3, R4 R ⁇ , R6, R17 > R18, R19, R20, R23, R24, R 2 ⁇ , R26, R27 and R 9 are each independently selected from hydrogen, Ci-10 alkyl, aryl C ⁇ -8 alkyl, amino C ⁇ -8 alkyl, Cl-3 acylamino C ⁇ -8 alkyl,
  • R8, R9> Rl , and RU are each independently selected from hydrogen, fluorine, Cl-8 alkyl, hydroxyl, C3-8 cycloalkyl, aryl C ⁇ -6 alkyl,
  • Rl2 is selected from hydroxy
  • Rl3, R!4, Rl ⁇ nd R16 a re each independently selected from hydrogen
  • Ci-io alkyl aryl C ⁇ -8 alkyl, amino C ⁇ -8 alkyl,
  • Rl4, Rl ⁇ a nd R16 are combined to form oxo; provided that when Ring is
  • X is selected from and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
  • Y is selected from C ⁇ -8 alkylene, C ⁇ -8 alkylene-NR 5 -C ⁇ -8 alkylene;
  • Rl2 is selected from hydroxy or Ci-8 alkyloxy; and all other variables are as defined above; and the pharmaceutically acceptable salts thereof .
  • Exemplifying the invention is the compound selected from
  • the compound is selected from [6-( ⁇ ,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-yl)naphthylen-2-yl]-carbonyl- 2(S)-phenylsulfonylamino- ⁇ -alanine;
  • Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier.
  • An example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • An 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 resorption, 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 ⁇ antagonizing effect or a dual ⁇ v ⁇ 3/ ⁇ v ⁇ antagonizing effect.
  • ⁇ v ⁇ antagonizing effects are inhibition of: restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.
  • dual ⁇ v ⁇ 3/ ⁇ v ⁇ 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 described above. More specifically exemplifying the invention is any of the compositions described above, further comprising a therapeutically effective amount of a second bone resorption inhibitor; preferably, the second bone resorption 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 resorption inhibitor; preferably, the second bone resorption inhibitor is alendronate.
  • 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
  • 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 resorption, tumor growth, cancer, restenosis, artherosclerosis, diabetic retinopathy and/or angiogenesis.
  • Another illustration of the invention is a drug which is useful for treating and/or preventing osteoporosis in a mammal in need thereof, the effective ingredient of the said drug being any of the compounds described above. More specifically illustrating the invention is a drug which is useful for treating and/or preventing: bone resorption, tumor growth, cancer, restenosis, artherosclerosis, diabetic retinopathy and/or angiogenesis in a mammal in need thereof, the effective ingredient of the said drug being any of the compounds described above.
  • 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 or antiproliferative, e.g., taxol and doxorubicin.
  • Representative compounds of the present invention are ⁇ v ⁇ 3 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 resorption, who are in need of such therapy.
  • Pharmacologically effective amounts of the compounds, including pharmaceutically 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:
  • 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, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate.
  • 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.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., quaternary ammonium salts.
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic 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 polymorphs 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, 198 ⁇ . 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.
  • bone resorption 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).
  • 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, Ci-io alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, Ci-3 acylamino, Ci-3 acylamino Cl-8 alkyl, Cl-6 alkylamino, Cl-6 alkylamino Cl-8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino-Ci-8 alkyl, Cl-4 alkoxy, Ci-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl, Cl-5 alkoxycarbonyl, Ci-3
  • 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, Ci-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
  • 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 C ⁇ -8 alkyl) it shall be interpreted as including those limitations given above for "alkyl” and "aryl.”
  • Designated numbers of carbon atoms e.g., Ci-io 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.
  • substituent Y, B, Rl to R28 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".
  • halogen shall include iodine, bromine, chlorine and fluorine.
  • oxy means an oxygen (0) 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.
  • 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 resorption inhibitors; preferably, the bone resorption 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 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 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, subcutaneous, intramuscular or transdermal (e.g., patch) form, topical (e.g., ocular eyedrop) 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, 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 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. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • 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 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 phosphatidylcholines.
  • 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, polyhydrox propylmethacrylamide-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.
  • BH3-DMS Borane • dimethyl sulfide.
  • BOC or Boc t-Butyloxycarbonyl .
  • BOP Benzotriazol-l-yloxytris(dimethylamino)- phosphonium hexafluorophosphate.
  • CBZ(Cbz) Carbobenzyloxy or benzyloxycarbonyl.
  • CDI Carbonyldiimidazole.
  • CH 2 C1 2 Methylene chloride.
  • CHC1 3 Chloroform.
  • DEAD Diethyl azodicarboxylate.
  • DIAD Diisopropyl azodicarboxylate.
  • DIBAH or DIBAL-H Diisobutylaluminum hydride.
  • DIPEA Diisopropylethylamine.
  • DMAP 4-Dimethylaminopyridine.
  • DME 1 , 2-Dimethoxy ethane.
  • DPFN 3, ⁇ -Dimethyl-l-pyrazolylformamidine nitrate.
  • EDC l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide.
  • Et Ethyl.
  • EtOAc Ethyl acetate.
  • HOAc Acetic acid
  • LDA Lithium diisopropylamide.
  • NEt3 Triethylamine.
  • NMM N-methylmorpholine
  • PCA-HC1 Pyrazole carboxamidine hydrochloride.
  • Pd/C Palladium on activated carbon catalyst.
  • Ph Phenyl.
  • pTSA or TsOH p-Toluene sulfonic acid.
  • tBu tertiary butyl.
  • TEA Triethylamine .
  • TFA Trifluoroacetic acid
  • THF Tetrahydrofuran
  • TMEDA N,N,N',N'-Tetramethylethylenediamine
  • 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.
  • CI2 gas was bubbled through a solution of 1-3 (1.2 g, 10.0 mmol; for preparation see J. Org. Chem. 48, 3401, 1983) in ether (100 ml) at ambient temperature for 4 ⁇ min.
  • the resulting yellow solid was collected by filtration and then resuspended in H2O.
  • the pH of the aqueous suspension was adjusted to pH 8 with 6N NaOH and the solid collected by filtration and then dried overnight to give 4 as a yellow solid.
  • borane- methyl sulfide complex (0.301 mL, 10.0 M in methyl sulfide) dropwise. After stirring at 0°C for several minutes, the ice bath was removed and the opaque, yellowish suspension was heated to reflux overnight. The resulting suspension was cooled to 0°C and quenched with aqueous IN Na2C ⁇ 3 solution (30 mL).
  • N-Boc-4-(6-Bromo-[l ( 81naphthyridin-2-yl)piperidine (3-4) A solution of bromide 3 (3.2 g, 15.8 mmol), ketone (3.0 g, 13.2 mmol), 20% KOH (2.0 ml) and EtOH was heated to reflux for 18 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 712 ⁇ 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 2 ⁇ 0 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.
  • 100 mg of compound 1 ⁇ 9 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
  • test procedures employed to measure avb3 binding and the bone resorption inhibiting activity of the compounds of the present invention are described below.
  • osteoclasts When osteoclasts engage in bone resorption, they will literally cause the formation of pits in the surface of bone that they are acting upon. Therefore, when testing compounds for their ability to inhibit osteoclasts, it is useful to measure the ability of osteoclasts to excavate these resorption pits when the inhibiting compound is present.
  • Consecutive 200 micron thick cross sections from a six mm cylinder of bovine femur diaphysis were cut with a low speed diamond saw (Isomet, Beuler, Ltd., Lake Bluff, II). Bone slices were pooled, placed in a 10% ethanol solution and refrigerated until further use.
  • bone slices Prior to experimentation, bone slices were ultrasonicated twice, 20 minutes each in H2O. Cleaned slices were placed in 96 well plates such that two control lanes and one lane for each drug dosage are available. Each lane represents either triplicate or quadruplicate cultures.
  • the bone slices in 96 well plates were sterilized by UV irradiation. Prior to incubation with osteoclasts, the bone slices were hydrated by the addition of 0.1 ml Medium 199, pH 6.9 containing l ⁇ % fetal bovine serum and 1% penicillin/streptomycin. Osteoclasts were isolated from the long bones of 1 to 3 day old rat pups (Sprague-Dawley) by modifications of Chambers et al. , (J. Cell.
  • the resulting suspension (0.7 ⁇ ml/bone) was gently triturated 90-120 times using a wide bore transfer pipet.
  • the cellular population was separated from bone fragments by a cell strainer with a 100 micron nylon mesh. 100 ⁇ l of the cell suspension was placed onto each bone slice. Test compounds were then added at the desired experimental concentrations.
  • Bone slices exposed to osteoclasts for 20-24 hrs were processed for staining. Tissue culture media was removed from each bone slice. Each well was washed with 200 ⁇ l of H2O, and the bone slices were then fixed for 20 minutes in 2.5% glutaraldehyde, 0.1 M cacodylate, pH 7.4. After fixation, any remaining cellular debris was removed by 2 min. ultrasonication in the presence of 0.25 M NH4OH followed by 2 X 15 min ultrasonication in H2O. The bone slices were immediately stained for 6-8 min with filtered 1% toluidine blue and 1% borax.
  • TBS buffer 50 mM Tris*HCl pH 7.2, 150 mM NaCl, 1% BSA, 1 mM CaCl2, 1 mM MgCl2).
  • the reaction mixture was then incubated for 1 h at room temp.
  • the unbound and the bound ⁇ v ⁇ 3 were separated by filtration using a Skatron Cell Harvester.
  • the filters pre wet in 1.5% poly- ethyleneimine for 10 mins) were then washed with the wash buffer (50 mM Tris HCl, ImM CaCl2/MgCl2, pH 7.2).
  • the filter was then counted in a gamma counter.
  • ⁇ v ⁇ 3 was purified from 293 cells overexpressing ⁇ v ⁇ 3 (Duong et al., J. Bone Min. Res., S:S378, 1993) according to Pytela (Methods in Enzymology, 144:475, 1987)
  • Binding buffer 50 mM HEPES, pH 7.8, 100 mM NaCl, 1 mM C a 2+/Mg2+, O. ⁇ mM PMSF
  • SPA beads Pretreatment of SPA beads: ⁇ OO mg of lyophihzed SPA beads were first washed four times with 200 ml of ⁇ O-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12. ⁇ ml of binding buffer.
  • binding buffer 25 ⁇ l of each of the following: compound to be tested, binding buffer for total binding or 5 for non-specific binding (final concentration 1 ⁇ M) (iii) 5-10 in binding buffer (25 ⁇ l, final concentration 40 pM) (iv) Binding buffer ( 125 ⁇ l)
  • Osteoblast-like cells (1.8 cells), originally derived from mouse calvaria, were plated in CORNING 24 well tissue culture plates in a MEM medium containing ribo- and deoxyribonucleosides, 10% fetal bovine serum and penicillin- streptomycin. Cells were seeded at 40,000/well in the morning. In the afternoon, bone marrow cells were prepared from six week old male Balb/C mice as follows:
  • mice were sacrificed, tibiae removed and placed in the above medium. The ends were cut off and the marrow was flushed out of the cavity into a tube with a 1 mL syringe with a 27. ⁇ gauge needle. The marrow was suspended by pipetting up and down. The suspension was passed through >100 ⁇ m nylon cell strainer. The resulting suspension was centrifuged at 3 ⁇ 0 x g for seven minutes. The pellet was resuspended, and a sample was diluted in 2% acetic acid to lyse the red cells. The remaining cells were counted in a hemacytometer. The cells were pelleted and resuspended at 1 x 10 ⁇ cells/mL.
  • ⁇ O ⁇ L was added to each well of 1.8 cells to yield ⁇ 0,000 cells/well and l,2 ⁇ -dihydroxy-vitamin D3(D3) was added to each well to a final concentration of 10 nM.
  • the cultures were incubated at 37°C in a humidified, ⁇ % C ⁇ 2 atmosphere.
  • test compounds were added with fresh medium containing D3 to quadruplicate wells. Compounds were added again after 48 h with fresh medium containing D3. After an additional 48 h the medium was removed, cells were fixed with 10% formaldehyde in phosphate buffered saline for 10 minutes at room temperature, followed by a 1-2 minute treatment with ethanol: acetone (1:1) and air dried. The cells were then stained for tartrate resistant acid phosphatase as follows:
  • the cells were stained for 10- l ⁇ minutes at room temperature with ⁇ O mM acetate buffer, pH ⁇ .O containing 30 mM sodium tartrate, 0.3 mg/mL Fast Red Violet LB Salt and 0.1 mg/mL Naphthol AS -MX phosphate. After staining, the plates were washed extensively with deionized water and air dried. The number of multinucleated, positive staining cells were counted in each well. Representative compounds of the present invention were tested and found to bind to human ⁇ v ⁇ 3 integrin. These compounds were found to have IC50 values in the range of 0.4 to 110 nM in the SPA assay.

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Abstract

Cette invention a trait à certains nouveaux composés ainsi qu'à leurs dérivés, leur synthèse et leur utilisation en tant qu'antagonistes du récepteur de la vitronectine. Les composés, selon l'invention, antagonistes du récepteur de la vitronectine sont des antagonistes de αvβ3, de αvβ5 ou des antagonistes doubles de αvβ3/αvβ5 qui se révèlent efficaces s'agissant d'inhiber la résorption osseuse, de traiter et de prévenir l'ostéoporose ainsi que d'inhiber la resténose, la rétinopathie diabétique, la dégénérescence maculaire, l'angiogenèse, l'athérosclérose, l'inflammation et la croissance tumorale.
PCT/US1997/019349 1996-10-30 1997-10-27 Antagonistes de l'integrine Ceased WO1998018461A1 (fr)

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JP52063998A JP2001504456A (ja) 1996-10-30 1997-10-27 インテグリン拮抗薬
AU50884/98A AU717283B2 (en) 1996-10-30 1997-10-27 Integrin antagonists
EP97913775A EP0946164A4 (fr) 1996-10-30 1997-10-27 Antagonistes de l'integrine
CA002268916A CA2268916A1 (fr) 1996-10-30 1997-10-27 Antagonistes de l'integrine

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US2922396P 1996-10-30 1996-10-30
US60/029,223 1996-10-30
GBGB9626308.2A GB9626308D0 (en) 1996-12-18 1996-12-18 av›3 antagonists
GB9626308.2 1996-12-18

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WO2000061551A3 (fr) * 1999-04-13 2000-12-28 Basf Ag Ligands de recepteurs d'integrine
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WO2001014338A1 (fr) * 1999-08-24 2001-03-01 Merck Patent Gmbh NOUVEAUX INHIBITEURS DE L'INTEGRINE αVβ¿3?
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JP2002530384A (ja) * 1998-11-24 2002-09-17 アベンティス ファルマ ソシエテ アノニム 新規なアシルグアニジン誘導体、それらの製造方法、薬剤としてのそれらの使用及びそれらを含有する製薬組成物
EP1227083A4 (fr) * 1999-10-08 2002-11-20 Meiji Seika Kaisha DERIVES DE 3-AMINOPIPERIDINE UTILISES COMME ANTAGONISTES DE L'INTEGRINE $g(a)v$g(b)3
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US6545029B2 (en) 2000-06-12 2003-04-08 Bayer Aktiengesellschaft Phenylserine derivatives as integrin antagonists
EP1252162A4 (fr) * 2000-01-20 2003-06-11 Merck & Co Inc Antagonistes du recepteur de l'integrine alpha v
EP1229910A4 (fr) * 1999-10-04 2003-10-01 Merck & Co Inc Antagonistes des recepteurs d'integrine
US6677360B2 (en) 1998-12-16 2004-01-13 Bayer Aktiengesellschaft Biphenyl and biphenyl-analogous compounds as integrin antagonists
WO2004058760A1 (fr) * 2002-12-20 2004-07-15 Pharmacia Corporation Composes de thiazole en tant que derives d'antagonistes des recepteurs de l'integrine
US6849639B2 (en) 1999-12-14 2005-02-01 Amgen Inc. Integrin inhibitors and their methods of use
US7141564B2 (en) 2001-05-25 2006-11-28 Smithkline Beecham P.L.C. Nitrogen-containing bicyclic heterocycles for use as antibacterials
US7176199B2 (en) 2001-03-19 2007-02-13 Dainippon Pharmaceutical Co., Ltd. Aryl-substituted alicyclic compound and medical composition comprising the same
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EP1425010A4 (fr) * 2001-01-29 2009-07-29 Ortho Mcneil Pharm Inc Indoles substitues et utilisation de ceux-ci comme antagonistes d'integrine
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
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US6048861A (en) * 1997-12-17 2000-04-11 Merck & Co., Inc. Integrin receptor antagonists
US6066648A (en) * 1997-12-17 2000-05-23 Merck & Co., Inc. Integrin receptor antagonists
US6297249B1 (en) 1997-12-17 2001-10-02 Merck & Co., Inc. Integrin receptor antagonists
US6268378B1 (en) 1997-12-17 2001-07-31 Merck & Co., Inc. Integrin receptor antagonists
US6211191B1 (en) 1997-12-17 2001-04-03 Merck & Co., Inc. Integrin receptor antagonists
US6017926A (en) * 1997-12-17 2000-01-25 Merck & Co., Inc. Integrin receptor antagonists
US6040311A (en) * 1998-07-29 2000-03-21 Merck & Co., Inc. Integrin receptor antagonists
US6090944A (en) * 1998-08-13 2000-07-18 Merck & Co., Inc. Alkanoic acid derivatives as αv integrin receptor antagonists
JP2002530384A (ja) * 1998-11-24 2002-09-17 アベンティス ファルマ ソシエテ アノニム 新規なアシルグアニジン誘導体、それらの製造方法、薬剤としてのそれらの使用及びそれらを含有する製薬組成物
US7094911B2 (en) 1998-12-16 2006-08-22 Bayer Aktiengesellschaft Biphenyl and biphenyl-analogous compounds as integrin antagonists
US6677360B2 (en) 1998-12-16 2004-01-13 Bayer Aktiengesellschaft Biphenyl and biphenyl-analogous compounds as integrin antagonists
US6291503B1 (en) 1999-01-15 2001-09-18 Bayer Aktiengesellschaft β-phenylalanine derivatives as integrin antagonists
US6589972B2 (en) 1999-01-15 2003-07-08 Bayer Aktiengesellschaft β-phenylalanine derivatives as integrin antagonists
US7125883B1 (en) 1999-04-13 2006-10-24 Abbott Gmbh & Co. Kg Integrin receptor ligands
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US6274620B1 (en) 1999-06-07 2001-08-14 Biochem Pharma Inc. Thiophene integrin inhibitors
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WO2001002399A1 (fr) * 1999-07-02 2001-01-11 Aventis Pharma Deutschland Gmbh Derives de purine a substitution en tant qu'inhibiteurs de l'adhesion cellulaire
EP1065207A1 (fr) * 1999-07-02 2001-01-03 Aventis Pharma Deutschland GmbH Dérivées de la naphthyridine, procédés pour leur preparation, leur utilisation, et compositions pharmaceutique les contenant
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US6514964B1 (en) 1999-09-27 2003-02-04 Amgen Inc. Fused cycloheptane and fused azacycloheptane compounds and their methods of use
EP1229910A4 (fr) * 1999-10-04 2003-10-01 Merck & Co Inc Antagonistes des recepteurs d'integrine
EP1227083A4 (fr) * 1999-10-08 2002-11-20 Meiji Seika Kaisha DERIVES DE 3-AMINOPIPERIDINE UTILISES COMME ANTAGONISTES DE L'INTEGRINE $g(a)v$g(b)3
US6849639B2 (en) 1999-12-14 2005-02-01 Amgen Inc. Integrin inhibitors and their methods of use
EP1252162A4 (fr) * 2000-01-20 2003-06-11 Merck & Co Inc Antagonistes du recepteur de l'integrine alpha v
US6545029B2 (en) 2000-06-12 2003-04-08 Bayer Aktiengesellschaft Phenylserine derivatives as integrin antagonists
WO2002014320A3 (fr) * 2000-08-11 2002-07-25 Basf Ag Nouveaux derives de diareno-azepine substitues servant de ligands d'integrine
EP1425010A4 (fr) * 2001-01-29 2009-07-29 Ortho Mcneil Pharm Inc Indoles substitues et utilisation de ceux-ci comme antagonistes d'integrine
US7176199B2 (en) 2001-03-19 2007-02-13 Dainippon Pharmaceutical Co., Ltd. Aryl-substituted alicyclic compound and medical composition comprising the same
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
US7141564B2 (en) 2001-05-25 2006-11-28 Smithkline Beecham P.L.C. Nitrogen-containing bicyclic heterocycles for use as antibacterials
WO2004058760A1 (fr) * 2002-12-20 2004-07-15 Pharmacia Corporation Composes de thiazole en tant que derives d'antagonistes des recepteurs de l'integrine
US7115596B2 (en) 2002-12-20 2006-10-03 Pharmacia Corporation Thiazole compounds as integrin receptor antagonists derivatives
EP2335733A1 (fr) 2006-01-18 2011-06-22 Merck Patent GmbH Thérapie spécifique utilisant des ligands d'intégrine pour traiter le cancer
WO2007084670A2 (fr) 2006-01-18 2007-07-26 Merck Patent Gmbh Traitement specifique utilisant des ligands de l’integrine destine a traiter un cancer
EP2338518A1 (fr) 2006-01-18 2011-06-29 Merck Patent GmbH Thérapie spécifique utilisant des ligands d'intégrine pour traiter le cancer
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US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof
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AU717283B2 (en) 2000-03-23
EP0946164A4 (fr) 2000-08-23
EP0946164A1 (fr) 1999-10-06
AU5088498A (en) 1998-05-22
JP2001504456A (ja) 2001-04-03

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