WO1998018461A1 - Integrin antagonists - Google Patents
Integrin antagonists Download PDFInfo
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- 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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- alkyl
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- alkylene
- alkylamino
- mammal
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- 0 CC([N+](*)[O-])OC Chemical compound CC([N+](*)[O-])OC 0.000 description 4
- PKSVTWBTROQHKP-POHAHGRESA-N CC(CC[IH]N1)=C1/N=C\C=C Chemical compound CC(CC[IH]N1)=C1/N=C\C=C PKSVTWBTROQHKP-POHAHGRESA-N 0.000 description 1
- AHHPJGXNLSYKID-UHFFFAOYSA-N CCCNC1=C(C)C=C[I]=N1 Chemical compound CCCNC1=C(C)C=C[I]=N1 AHHPJGXNLSYKID-UHFFFAOYSA-N 0.000 description 1
- LNJMHEJAYSYZKK-UHFFFAOYSA-N Cc1ncccn1 Chemical compound Cc1ncccn1 LNJMHEJAYSYZKK-UHFFFAOYSA-N 0.000 description 1
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- 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
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- 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
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- 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
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- 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
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- 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
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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
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.
Abstract
This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as vitronectin receptor antagonists. The vitronectin receptor antagonist compounds of the present invention are αvβ3 antagonists, αvβ5 antagonists or dual αvβ3/αvβ5 antagonists useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation and tumor growth.
Description
TITLE OF THE INVENTION INTEGRIN ANTAGONISTS
CROSS-REFERENCE TO RELATED APPLICATIONS
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.
FIELD OF THE INVENTION
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 αvβ3 antagonists, αvβδ antagonists or dual αvβ3/ αvβδ antagonists useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation and tumor growth.
BACKGROUND OF THE INVENTION
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 μm 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. 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 αvβ3, thought to interact in bone with matrix proteins that contain the RGD sequence. Antibodies to αvβ3 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process. There is increasing evidence to suggest that αvβ3 ligands can be used effectively to inhibit osteoclast mediated bone resoption in vivo in mammals.
The current major bone diseases of public concern are 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. However, 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 δ% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
There are currently 20 million people with detectable fractures of the vertebrae due to osteoporosis in the United States. In addition, there are 2δ0,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.
Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.
Additionally, αvβ3 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). Moreover, it has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor; thus, inhibition of angiogenesis can cause tumor regression in animal models. (See, Harrison's Principles of Internal Medicine. 12th ed., 1991). αvβ3 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)).
Moreover, compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor αvβδ. A monoclonal antibody for αvβδ has been shown to inhibit VEGF- induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model; M.C. Friedlander, et.al., Science 270, Iδ00-lδ02, 199δ. Thus, compounds that antagonize αvβδ are useful for treating and preventing macular degeneration, diabetic retinopathy, and tumor growth.
In addition, certain compounds of this invention antagonize both the αvβ3 and αvβδ receptors. These compounds, referred to as "dual αvβ3/αvβδ 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.
It is an object of the present invention to identify compounds which bind to the αvβ3 receptor, αvβδ receptor or both the αvβ3 and αvβδ receptors. It is a further object of the invention to identify compounds which act as antagonists of the αvβ3 receptor. It is another object of the invention to identify αvβ3 antagonist compounds which are useful agents for inhibiting: bone resorption mediated by osteoclast cells, restenosis, atherosclerosis, inflammation, diabetic retinopathy,
macular degeneration and angiogenesis in animals, preferably mammals, especially humans. Still another object of the invention is to identify αvβ3 antagonists which cause tumor regression and/or inhibit tumor growth in animals. A further object of the invention is to identify αvβ3 antagonists useful for preventing or treating osteoporosis. An additional object of the invention is to identify αvβ3 antagonists useful for treating cancer.
It has now been found that the compounds of the present invention, αvβ3 ligands, are useful for inhibiting bone resorption in mammals. Thus, the compounds of the present invention are useful for preventing or reducing the incidence of osteoporosis. Additionally, the αvβ3 ligands of the present invention are also useful for treating and/or inhibiting restenosis, diabetic retinopathy, macular degeneration, atherosclerosis and/or angiogenesis in mammals.
SUMMARY OF THE INVENTION
The present invention provides compounds of the formula
X-Y-Z-Ring-A-B
wherein:
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 and R^8;
X is selected from
NR2 NR2 NR2
II II II
-NR1 R2, -NR1-C-R3, -C-NHR4, -NR1-C-NR3R4,
NR1 NR2
-aryl-NR1 R2, -aryl-C-NR2R3, -aryl-NR1-C-NR3R4 or a 4- to 10- membered mono- or polycyclic aromatic or
nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, 0 and S and either unsubstituted or substituted with Rl3, Rl4, Rlδ or R16;
Y is selected from
Cθ-8 alkylene,
C3-10 cycloalkyl,
Co-8 alkylene-NR5-CO-Co-8 alkylene,
C0-8 alkylene-CONR5-Cθ-8 alkylene, Cθ-8 alkylene-O-Cθ-8 alkylene,
Cθ-8 alkylene-NR5-Co-8 alkylene,
Cθ-8 alkylene-S(0)θ-2-Cθ-8 alkylene,
Co-8 alkylene-S02-NR5-Co-8 alkylene,
Cθ-8 alkylene-NR5-S02-Co-8 alkylene, Cθ-8 alkylene-CO-Co-8 alkylene,
(CH2)0-6 aryl(CH2)0-6,
(CH2)0-6 aryl-CO-(CH2)0-6,
(CH2)0-6 aryl-CO-NR5-(CH2)0-6,
(CH2)0-6 aryl-NR5-CO-(CH2)0-6J or
OH I (CH2)o-8CH(CH2)o-8 .
Z is selected from
- δ
0 (CH2)m, (CH2)mO(CH2)nι (CH2)mNR6(CH2)n , (CH2)mNR6CNR7(CH2)n
(CH2)
(CH2)nι
S O
(CH2)mC(CH2)n, (CH2)mSθ2(CH2)nι (CH2)mS(CH2)nι
(CH2)mSO(CH2)nι (CH2)mS02NR6(CH2)n, (CH2)mNR6S02(CH2)n,
(CH2)mCR6=CR7(CH2)nι or (CH2)mC≡C- (CH2)n;
where m and n are each independently an integer from 0 to 6;
A is selected from
(CH2)qO(CH2)p, (CH2)qNR29(CH2)Pι
O 0 0
(CH2)qC " NR2α9(CH2)Pi (CH2)qNR2i9'C(CH2)p(CH2)qC ll (CH2)Pi
S O
II II
(CH2)qC(CH2)Pι (CH2)qS02(CH2)p, (CH2)qS(CH2)Pι
(CH2)qSO(CH2)Pι (CH2)qS02NR29(CH2)p, (CH2)qNR29S02(CH2)p!
(CH2)qCR29=CR30(CH2)p or (CH2)qC≡C-(CH2)p;
where p and q are each independently an integer from 0 to 6;
B is selected from
Rl, R2, R3, R4 Rδ, R6, R7, RH R18, R19, R20, R21, R22, R23? R24, R2δ, R26, R27^ R28? R29 and R^O are each independently selected from hydrogen, halogen,
Cl-10 alkyl, aryl Cθ-8 alkyl, amino Cθ-8 alkyl,
Cl-3 acylamino Cθ-8 alkyl,
Ci-6 alkylamino Cθ-8 alkyl,
Ci-6 dialkylamino Cθ-8 alkyl, aryl Cθ-6 alkylamino Cθ-6 alkyl, Cχ-4 alkoxyamino Cθ-8 alkyl, hydroxy Ci-6 alkylamino Cθ-8 alkyl,
Ci-4 alkoxy Cθ-6 alkyl, carboxy Cθ-6 alkyl,
Cl-4 alkoxycarbonyl Cθ-6 alkyl, carboxy Cθ-6 alkyloxy, hydroxy Ci-6 alkylamino Cθ-6 alkyl, hydroxy Cθ-6 alkyl,
NR17 II ^ NR18R19 f or
NR18 U -NR17^ NR19R20.
R are each independently selected from hydrogen, aryl, halogen, aryl-(CH2)p-, hydroxyl,
Cl-8 alkylcarbonylamino, aryl Cl-5 alkoxy, Cl-5 alkoxycarbonyl, aminocarbonyl,
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,
Cl-5 alkoxycarbonyl, aminocarbonyl, Cl-5 alkylaminocarbonyl, Cl-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, Ci-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 -
Ci-6 alkyl-C≡C(CH2)r -,
C3-7 cycloalkyl-C≡C(CH2)r -,
aryl-C≡C(CH2)r -, Cl-6 alkylaryl-C≡C(CH2)r -, H2C=CH(CH2)r -, Cl-6 alkyl-CH=CH(CH2)r -> C3-7 cycloalkyl-CH=CH(CH2)r -, aryl-CH=CH(CH2)r-, Cl-6 alkylaryl-CH=CH(CH2)r -, Cl-6 alkyl-S02(CH2)r-, Cl-6 alkylaryl-S02(CH2)r-, Cl-6 alkoxy, aryl Cl-6 alkoxy, aryl Cl-6 alkyl,
Cl-6 alkylamino Cl-6 alkyl, arylamino, arylamino Cl-6 alkyl, aryl Cl-6 alkylamino, aryl Cl-6 alkylamino Cl-6 alkyl, arylcarbonyloxy, aryl Cl-6 alkylcarbonyloxy, Cl-6 dialkylamino,
Cl-6 dialkylamino Cl-6 alkyl, Cl-6 alkylaminocarbonyloxy, Cl-8 alkylsulfonylamino, Cl-8 alkylsulfonylamino Cl-6 alkyl, arylsulfonylamino Cl-6 alkyl, aryl Cl-6 alkylsulfonylamino, aryl Cl-6 alkylsulfonylamino Cl-6 alkyl, Cl-8 alkoxycarbonylamino, Cl-8 alkoxycarbonylamino Cl-8 alkyl, aryloxycarbonylamino Cl-8 alkyl, aryl Cl-8 alkoxycarbonylamino, aryl Cl-8 alkoxycarbonylamino Cl-8 alkyl, Cl-8 alkylcarbonylamino, Cl-8 alkylcarbonylamino Cl-6 alkyl,
arylcarbonylamino Ci-6 alkyl, aryl Ci-6 alkylcarbonylamino, aryl Ci-6 alkylcarbonylamino Ci-6 alkyl, aminocarbonylamino Ci-6 alkyl, Cl-8 alkylaminocarbonylamino,
Cl-8 alkylaminocarbonylamino Ci-6 alkyl, arylaminocarbonylamino Cl-6 alkyl, aryl Cl-8 alkylaminocarbonylamino, aryl Cl-8 alkylaminocarbonylamino Ci-6 alkyl, aminosulfonylamino Ci-6 alkyl,
Cl-8 alkylaminosulfonylamino, Ci-8 alkylaminosulfonylamino Ci- alkyl, arylaminosulfonylamino Cl-6 alkyl, aryl Cl-8 alkylaminosulfonylamino, aryl Ci-8 alkylaminosulfonylamino Ci-6 alkyl,
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 Cl-6 alkyl, arylcarbonyl Ci-6 alkyl, aryl Cl-6 alkylcarbonyl, aryl Ci-6 alkylcarbonyl Ci-6 alkyl,
Cl-6 alkylthiocarbonylamino, Ci-6 alkylthiocarbonylamino Cι_6 alkyl, arylthiocarbonylamino Cι_6 alkyl, aryl Cl-6 alkylthiocarbonylamino, aryl Ci-6 alkylthiocarbonylamino Ci-6 alkyl,
Ci-8 alkylaminocarbonyl Ci-6 alkyl, arylaminocarbonyl Ci-6 alkyl, aryl Ci-8 alkylaminocarbonyl, or aryl Ci-8 alkylaminocarbonyl Cl-6 alkyl,
wherein the alkyl or N atoms may be unsubstituted or substituted with one or more substituents selected from R21 and R2 ; or R8 and R^ are combined to form oxo;
RlO and RU are each independently selected from hydrogen, aryl, halogen, aryl-(CH2)p-, hydroxyl,
Cl-8 alkylcarbonylamino, aryl Cl-5 alkoxy, Cl-5 alkoxycarbonyl, aminocarbonyl, Cl-8 alkylaminocarbonyl,
Cl-6 alkylcarbonyloxy, C3-8 cycloalkyl, amino,
Cl- 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, 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 -
Ci-6 alkyl-C≡C(CH2)r -,
C3-7 cycloalkyl-C≡C(CH2)r -, aryl-C≡C(CH2)r -, Cl-6 alkylaryl-C≡C(CH2)r -,
H2C=CH(CH2)r -,
Cl-6 alkyl-CH=CH(CH2)r -,
C3-7 cycloalkyl-CH=CH(CH2)r -, aryl-CH=CH(CH2)r-, Cl-6 alkylaryl-CH=CH(CH2)r -,
Cl-6 alkyl-S02(CH2)r-,
Cl-6 alkylaryl-S02(CH2)r-,
Cl-6 alkoxy, aryl Ci-6 alkoxy, aryl Cl-6 alkyl,
Cl-6 alkylamino Cl-6 alkyl, arylamino, arylamino Cl-6 alkyl, aryl Cl-6 alkylamino, aryl Cl-6 alkylamino Cl-6 alkyl, arylcarbonyloxy, aryl Cl-6 alkylcarbonyloxy,
Cl-6 dialkylamino,
Cl-6 dialkylamino Cl-6 alkyl, Cl-6 alkylaminocarbonyloxy,
Cl-8 alkylsulfonylamino, Cl-8 alkylsulfonylamino Cl-6 alkyl, arylsulfonylamino Cl-6 alkyl, aryl Cl-6 alkylsulfonylamino, aryl Cl-6 alkylsulfonylamino Cl-6 alkyl,
Cl-8 alkoxycarbonylamino, Cl-8 alkoxycarbonylamino Cl-8 alkyl, aryloxycarbonylamino Cl-8 alkyl, aryl Cl-8 alkoxycarbonylamino,
aryl Cl-8 alkoxycarbonylamino Cl-8 alkyl, Ci-8 alkylcarbonylamino, Ci-8 alkylcarbonylamino Ci-6 alkyl, arylcarbonylamino Ci-6 alkyl, aryl Ci-6 alkylcarbonylamino, aryl Cl-6 alkylcarbonylamino Ci-6 alkyl, aminocarbonylamino Cl-6 alkyl,
Ci-8 alkylaminocarbonylamino,
Cι_8 alkylaminocarbonylamino 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 ι_6 alkyl, arylsulfonyl Cl-6 alkyl, aryl Cl-6 alkylsulfonyl, aryl Cl-6 alkylsulfonyl Cl-6 alkyl, Ci-6 alkylcarbonyl, Ci-6 alkylcarbonyl Ci-6 alkyl, arylcarbonyl Cl-6 alkyl, aryl Cl-6 alkylcarbonyl, aryl Cl-6 alkylcarbonyl Cl-6 alkyl, Cl-6 alkylthiocarbonylamino, Cl-6 alkylthiocarbonylamino Ci-6 alkyl, arylthiocarbonylamino Cl-6 alkyl, aryl Cl-6 alkylthiocarbonylamino, aryl Cl-6 alkylthiocarbonylamino Ci-6 alkyl, Ci-8 alkylaminocarbonyl Ci-6 alkyl,
arylaminocarbonyl Cl-6 alkyl, aryl Cl-8 alkylaminocarbonyl, aryl Cl-8 alkylaminocarbonyl Cι_6 alkyl, C7-20 polycyclyl Cθ-8 alkylsulfonylamino Cθ-6 alkyl, C7-20 polycyclyl Cθ-8 alkylcarbonylamino Crj-6 alkyl,
C7-20 polycyclyl Cθ-8 alkylaminosulfonyolamino Cθ-6 alkyl, C7-20 polycyclyl Cθ-8 alkylaminocarbonylamino Cθ-6 alkyl, or C7-20 polycyclyl Cθ-8 alkyloxycarbonylamino Cø-6 alkyl wherein the alkyl or N atoms may be unsubstituted or substituted with one or more substituents selected from R21 and
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 Cθ-6 alkyloxy,
Cl-8 alkylcarbonyloxy Ci-4 alkyloxy, aryl Cθ-8 alkylcarbonyloxy Ci-4 alkyloxy,
Ci-6 dialkylaminocarbonylmethyloxy, aryl Cl-6 dialkylaminocarbonylmethyloxy or an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by Ci-6 alkyl; and
Rl3, R!4, Rl and Rl6 are each independently selected from hydrogen, Ci-10 alkyl, aryl Cθ-8 alkyl, thio,
amino Cθ-8 alkyl, Ci-3 acylamino Cθ-8 alkyl, Ci-6 alkylamino Cθ-8 alkyl, Ci-6 dialkylamino Crj-8 alkyl, aryl Cθ-6 alkylamino Cθ-6 alkyl, Ci-4 alkoxyamino Cθ-8 alkyl, hydroxy Cl-6 alkylamino Cθ-8 alkyl, Ci-4 alkoxy Cθ-6 alkyl, carboxy Cθ-6 alkyl, Ci-4 alkoxycarbonyl Cθ-6 alkyl, carboxy Cfj-6 alkyloxy, hydroxy Ci-6 alkylamino Cθ-6 alkyl, hydroxy Cθ-6 alkyl, NR23
Λ N, R24R25 or
NR24 11 -NR23^ NR25R26 . or Rl3, Rl4, Rl and Ri6 are combined to form oxo;
provided that Ring is not a 6-membered monocyclic aromatic ring;
provided further that when Ring is thiophene, then X is selected from
and the pharmaceutically acceptable salts thereof.
In one embodiment of the invention is the compound wherein Y is selected from
Cθ-8 alkylene,
C3-10 cycloalkyl,
Co-8 alkylene-NR5-CO-Co-8 alkylene,
Co-8 alkylene-CONR5-Cθ-8 alkylene, Cθ-8 alkylene-O-Cθ-8 alkylene,
Cθ-8 alkylene-NR5-Cθ-8 alkylene,
Cθ-8 alkylene-S(0)θ-2-Cθ-8 alkylene,
Cθ-8 alkylene-S02-NR5-Co-8 alkylene,
Cθ-8 alkylene-NR5-S02-Co-8 alkylene, Co-8 alkylene-CO-Cθ-8 alkylene,
(CH2)0-6 aryl(CH2)0-6,
(CH2)0-6 aryl-CO-(CH2)0-6,
(CH2)0-6 aryl-CO-NH-(CH2)0-6, or
OH I (CH2)0-8CH(CH )0-8
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.
In a class of the invention is the compound of the formula
X-Y-Ring-A-B
wherein Ring is selected from
X is selected from
NR2 NR' NR£
NR >11^D2, _ -MNCRJ 1'- PC._-DR3J, -C-NHR4, -NR'-C-NR^R4,
NR1 NR£
-phenyl-NR1R2, -phenyl-C-NR2R3, -phenyl-NR1-C-NR3R4
Y is selected from
Crj-8 alkylene,
Co-8 alkylene-NR5-CO-Co-8 alkylene, Co-8 alkylene-CONR5-Co-8 alkylene, Cθ-8 alkylene-O-Cθ-8 alkylene, Co-8 alkylene-NR5-Cθ-8 alkylene, Co-8 alkylene-S(0)θ-2-Cθ-8 alkylene, Cθ-8 alkylene-Sθ2-NR5-Cθ-8 alkylene, Co-8 alkylene-NR5-Sθ2-Cθ-8 alkylene or (CH2)0-6 aryl(CH2)0-6;
A is selected from
S02(CH2)p> S02NR29(CH2)P| NR29S02(CH2)p or C≡C-(CH2)p;
where p is an integer from 0 to 3;
Rl, R2, R3, R4 Rδ, R6, R17> R18, R19, R20, R23, R24, R2δ, R26, R27 and R 9 are each independently selected from
hydrogen, Ci-10 alkyl, aryl Cθ-8 alkyl, amino Cθ-8 alkyl, Cl-3 acylamino Cθ-8 alkyl,
Cl-6 alkylamino Cθ-8 alkyl, Cl-6 dialkylamino Cθ-8 alkyl, Ci-4 alkoxy Cθ-6 alkyl, carboxy Cθ-6 alkyl, Cl-4 alkoxycarbonyl Cθ-6 alkyl, carboxy Cθ-6 alkyloxy, hydroxy Cθ-6 alkyl, NR17
^ NR18R19 nr , or
NR18
-NR 17Λ NR19R20 ,
R8, R9> Rl , and RU are each independently selected from hydrogen, fluorine, Cl-8 alkyl, hydroxyl, C3-8 cycloalkyl, aryl Cθ-6 alkyl,
Cθ-6 alkylamino Cθ-6 alkyl,
Cθ-6 dialkylamino Cθ-6 alkyl,
Cl-8 alkylsulfonylamino Cθ-6 alkyl, aryl Cθ-6 alkylsulfonylamino Cθ-6 alkyl,
Cl-8 alkyloxycarbonylamino Cθ-8 alkyl, aryl Cθ-8 alkyloxycarbonylamino Cθ-8 alkyl,
Cl-8 alkylcarbonylamino Cθ-6 alkyl, aryl Cθ-6 alkylcarbonylamino Cθ-6 alkyl,
Cθ-8 alkylaminocarbonylamino Cθ-6 alkyl, aryl Cθ-8 alkylaminocarbonylamino Cθ-6 alkyl, Cθ-8 alkylaminosulfonylamino Cθ-6 alkyl, aryl Cθ-8 alkylaminosulfonylamino Cθ-6 alkyl, Ci-6 alkylsulfonyl Cθ-6 alkyl,
Cl-6 alkylcarbonyl Cθ-6 alkyl or aryl Cθ-6 alkylcarbonyl Cθ-6 alkyl;
Rl2 is selected from hydroxy,
Ci-8 alkyloxy, aryl Cθ-6 alkyloxy,
Ci-8 alkylcarbonyloxy Cι_4 alkyloxy or aryl Cθ-8 alkylcarbonyloxy Ci-4 alkyloxy;
Rl3, R!4, Rlδ nd R16 are each independently selected from hydrogen,
Ci-io alkyl, aryl Cθ-8 alkyl, amino Cθ-8 alkyl,
Ci-3 acylamino Cθ-8 alkyl,
Cl-6 alkylamino Cθ-8 alkyl,
Ci-6 dialkylamino Cθ-8 alkyl,
Ci-4 alkoxy Cθ-6 alkyl, carboxy Cθ-6 alkyl,
Ci-4 alkoxycarbonyl Cθ-6 alkyl, carboxy Cθ-6 alkyloxy, hydroxy CQ-6 alkyl,
NR 23
X NR24R25 or
-
or R 3, Rl4, Rlδ and R16 are combined to form oxo; provided that when Ring is
then X is selected from
and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
In a subclass of the invention is the compound wherein X is selected from
and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
Illustrative of the invention is the compound of the formula
Y is selected from Cθ-8 alkylene, Cθ-8 alkylene-NR5-Cθ-8 alkylene; and
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
[6-(δ,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-yl)naphthylen-2-yl]-carbonyl- 2(S)-phenylsulfonylamino-β-alanine ethyl ester;
[6-(δ,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-yl)naphthylen-2-yl]-carbonyl- 2(S)-phenylsulfonylamino-β-alanine;
6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)carbonyl-2(S)- phenylsulfonylamino-β-alanine ethyl ester;
6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)-carbonyl-2(S)- phenylsulfonylamino-β-alanine;
4-(δ,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)piperidin-l-yl-carbonyl-2(S)- phenylsulfonylamino-β-alanine t-butyl ester;
4-(δ,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)piperidin-l-yl-carbonyl-2(S)- phenylsulfonylamino-β-alanine;
6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl-carbonyl-2(S)- phenylsulfonyl-β-alanine ethyl ester;
6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl-carbonyl-2(S)- phenylsulfonyl-β-alanine; or
6-[(l,4,δ,6-Tetrahydropyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl- carbonyl-2(S)-phenylsulfonylamino-β-alanine;
and the pharmaceutically acceptable salts thereof.
Preferably, the compound is selected from
[6-(δ,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-yl)naphthylen-2-yl]-carbonyl- 2(S)-phenylsulfonylamino-β-alanine;
6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)carbonyl-2(S)- phenylsulfonylamino-β-alanine;
4-(δ,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)piperidin-l-yl-carbonyl-2(S)- phenylsulfonylamino-β-alanine; or
6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl-carbonyl-2(S)- phenylsulfonyl-β-alanine;
and the pharmaceutically acceptable salts thereof.
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.
Further illustrating the invention is a method of treating and/or preventing a condition mediated by antagonism of a vitronectin receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds described above. Preferably, 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. More specifically exemplifying the invention is a method of eliciting a vitronectin antagonizing effect 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. Preferably, the vitronectin antagonizing
effect is an αvβ3 antagonizing effect; more specifically the αvβ3 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. Most preferably, the αvβ3 antagonizing effect is inhibition of bone resorption. Alternatively, the vitronectin antagonizing effect is an αvβδ antagonizing effect or a dual αvβ3/αvβδ antagonizing effect. Examples of αvβδ antagonizing effects are inhibition of: restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation or tumor growth. Examples of dual αvβ3/αvβδ 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
- 2δ -
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 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.
DETAILED DESCRIPTION OF THE INVENTION
Representative compounds of the present invention are αvβ3 antagonists which display submicromolar affinity for the human αvβ3 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 αvβ3 receptor where such treatment is needed, as, for example, in the prevention or treatment of osteoporosis. For use in medicine, the 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:
Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate,
Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate. Furthermore, where the compounds of the invention carry an acidic moiety, 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 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. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, 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, 198δ. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
The term "therapeutically 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. The term "bone resorption," as used herein, refers to the process by which osteoclasts degrade bone.
The term "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.).
The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
The term "alkynyl" shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range.
The term "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).
The term "alkoxy," as used herein, 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.). The term "aryl," as used herein, 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 alkoxycarbonyl Cl-6 alkyl, hydroxycarbonyl Cl-6 alkyloxy, hydroxy, hydroxy Cl-6 alkyl, cyano, trifluoromethyl, oxo or Cl-5 alkylcarbonyloxy. Examples of aryl 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-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl-5 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl-6 alkyl, hydroxycarbonyl Cl-6 alkyloxy, hydroxy, hydroxy Cl-6 alkyl, cyano, trifluoromethyl, oxo or Cl-5 alkylcarbonyloxy. Preferably, 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.
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aryl Cθ-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.
The terms "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. The Cθ-m or Cl-m designation where m may be an integer from 1-10 or 2-10 respectively refers to the alkyl component of the arylalkyl or alkylaryl unit. Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.
When substituent Y, B, Rl to R28 includes the definition Co (e.g., aryl Cθ-8 alkyl), the group modified by Co is not present in the substituent. Similarly, when any of the variables m, q, r or s is zero, then 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 term "halogen" shall include iodine, bromine, chlorine and fluorine. The term "oxy" means an oxygen (0) atom. The term "thio" means a sulfur (S) atom. The term "oxo" shall mean =0.
The term "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.
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 Ci- 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. For example, 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 αvβ3 receptor antagonist of the present invention and FOSAMAX®. In accordance with the method of the present invention, 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 interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating αvβ3 related conditions includes in principle any combination with any pharmaceutical composition useful for treating osteoporosis.
As used herein, the term "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 αvβ3 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. For oral administration, 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, lδ.0, 2δ.O, δθ.0, 100 and δOO 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. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, 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.
Furthermore, 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. To be administered in the form of a transdermal delivery system, the dosage
administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, 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. For instance, for oral administration in the form of a tablet or capsule, 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 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. Furthermore, 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.
In the schemes and examples below, various reagent symbols and abbreviations have the following meanings:
AcOH: Acetic acid.
BH3-DMS: Borane • dimethyl sulfide.
BOC or Boc: t-Butyloxycarbonyl . BOP: Benzotriazol-l-yloxytris(dimethylamino)- phosphonium hexafluorophosphate. CBZ(Cbz): Carbobenzyloxy or benzyloxycarbonyl. CDI: Carbonyldiimidazole. CH2C12: Methylene chloride. CHC13: Chloroform.
DEAD: Diethyl azodicarboxylate. DIAD: Diisopropyl azodicarboxylate.
DIBAH or DIBAL-H: Diisobutylaluminum hydride.
DIPEA: Diisopropylethylamine.
DMAP: 4-Dimethylaminopyridine. DME: 1 , 2-Dimethoxy ethane.
DMF: Dimethylformamide.
DMSO: Dimethylsulfoxide.
DPFN: 3,δ-Dimethyl-l-pyrazolylformamidine nitrate.
EDC: l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide. Et: Ethyl.
EtOAc: Ethyl acetate.
EtOH: Ethanol.
HOAc: Acetic acid.
HOBT: 1-Hydroxybenzotriazole.
LDA: Lithium diisopropylamide.
MeOH: Methanol.
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.
TLC: Thin Layer Chromatography.
TMEDA: N,N,N',N'-Tetramethylethylenediamine
TMS: Trimethylsilyl.
The 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.
Moreover, by utilizing the procedures described in detail in PCT International Application Publication Nos. WO 9δ/32710, published 7 December 199δ, and WO 9δ/17397, published 29 June 199δ, in conjunction with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein.
More specifically, procedures for preparing the N-terminus of the compounds of the present invention are described in WO 9δ/32710. Additionally, for a general review describing the synthesis of β-alanines which can be utilized as the C-terminus of the compounds of the present invention, see Cole, D.C., Recent Stereoselective Synthetic Approaches to β- Amino Acids, Tetrahedron, 1994, δO, 9δl7-9δ82; Juaristi, E, et al., Enantioselective Synthesis of β-Amino Acids, Aldrichemica Acta, 1994, 27, 3. In particular, synthesis of the 3-methyl β-alanine is taught in Duggan, M.F. et al., J. Med. Chem., 199δ, 38, 3332-3341; the 3-ethynyl β- alanine is taught in Zablocki, J.A., et al., J. Med. Chem., 199δ, 38, 2378- 2394; the 3-pyrid-3-yl β-alanine is taught in Rico, J.G. et al., J. Org. Chem., 1993, δ8, 7948-79δl; and the 2-amino and 2-toslylamino β- alanines are taught in Xue, C-B, et al., Biorg. Med. Chem. Letts., 1996, 6, 339-344.
Scheme 1
1-1 1-3
a) oxalyl chloride, toluene, DMF Cl2, ether b) Me2Cd
Pt02> H2 HOAC, HCl
A suspension of the acid i (2.6 g, 11.5 mmol; for preparation, see Biotechnol. Lett. 17(7), 711-16, 1995) was suspended in toluene (50 mL) and treated sequentially with oxalyl chloride (1.5 mL, 17.δ mmol) and DMF (2 drops). After stirring at ambient temperature for 2 h, the reaction mixture was heated to 70°C for 30 min, cooled, and concentrated to dryness. The resulting acid chloride was redissolved in toluene (2δ mL) and added to a O.δ M solution of (CH3)2Cd in toluene/THF (3:1) at ambient temperature. [The O.δ M solution of (CH3)2Cd was prepared as follows: CdCl2 was added to MeMgBr (1.4 M in toluene/THF (75/25); 18.6 mL, 26 mmol) and the resulting mixture stirred at ambient temperature for 2 h] After warming the reaction mixture to 70 °C for 1 h the yellow mixture was poured onto ice. EtOAc was added to the aqueous mixture, followed by washing with 20% H2SO4, brine, and sat. NaHCθ3, drying (MgSθ4), and concentration. Flash chromatography (silica, CH2CI2) gave JU2 as a solid. TLC Rf = 0.21 (CH2CI2), iH NMR (300 MHz, CDCI3) δ 8.63 (s, IH), 8.49 (s, IH), 8.15-8.00 (m, 4H),
4.00 (s, 3H), 2.7δ (s, 3H).
2-Amino-3-carboxaldehvde-δ-chloro-pyridine (1-4)
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 4δ 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.
TLC Rf = 0.δ9 (50% EtOAc/hexanes), iH NMR (300 MHz, CDCI3) δ 9.83 (s, IH), 8.22 (s, IH), 7.79 (s, IH), 6.77 (bs, 2H).
2-Methoxycarbonyl-6-(6-chloro-[l,8]-naphthyridin-2-yl)naphthy- lene (1-5)
A mixture of 1^2 (274 mg, 1.2 mmol), (258 mg, 1.6 mmol), 20% KOH (3 drops), and ethanol (20 mL) was stirred at 80°C for 1 h. The cooled reaction mixture was filtered to give 1^ as a solid. iH NMR (300 MHz, DMSO) δ 9.13 (s, IH), 9.00 (s, IH), 8.73-8.00 (m, 8H), 4.41 (q, J=7Hz, 2H), 1.40 (t, J=7Hz, 3H).
2-Methoxycarbonyl-6-(δ,6,7,8-tetrahydro-[l,8]-naphthyridin-2-yl)- nanhthylene (1-6)
A mixture of 1£ (344 mg, 1.0 mmol), 10% Pd/C (170 mg), 6N
HCl (2δ mL), and AcOH (δO mL) was shaken under a hydrogen atmosphere (δO psi) for 48 h. Filtration through a celite pad and concentration of the filtrate gave 1^5 as a yellow gum. iH NMR (300 MHz, CD3OD) δ 8.70-7.20 (m, 8H), 4.00 (s, 3H), 3.60 (m, 2H),
2.94 (m, 2H), 2.0δ (m, 2H).
2-Carboxylic acid-6-(δ,6,7,8-tetrahydro-[l,8]-naphthyridin-2- vPnaphthylene (1-7) A mixture of ML (417 mg, 1.1 mmol) and 6N HCl (δO mL) was heated at 60 °C overnight. The heterogeneous reaction mixture was cooled and then filtered to give 1J. as yellow solid. iH NMR (300 MHz, CD3OD) δ 8.70-7.20 (m, 8H), 3.60 (m, 2H), 2.96 (m,
2H), 2.04 (m, 2H).
[6-(δ,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-yl)naphthylen-2-yl]-carbonyl-
2(S)-phenylsulfonylamino-β-alanine ethyl ester (1-8)
To a mixture of ϋ (170 mg, O.δO mmol), Ha (244 mg, 0.55 mmol; for preparation, see WO 95/32710, published 7 Dec. 1995), NMM (220 μL, 2.0 mmol), and DMF (10 mL) at ambient temperature was added BOP (243 mg, 0.5δ mmol). After 20 h, the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and then washed with sat. NaHCθ3, H2O, and brine, dried (MgSθ4), and concentrated. Flash chromatography (silica, 10%-20% acetone/CH2Cl2) gave 2& as a yellow foam.
TLC Rf = 0.61 (30% acetone/CH2Cl2), iH NMR (300 MHz, CD3OD) δ 8.40-7.10 (m, 13H), 4.27 (m, IH), 3.9δ (q, J=7Hz, 2H), 3.7δ (m, IH), 3.62 (m, IH), 3.43 (m, 2H), 2.80 (m, 2H), 1.9δ (m, 2H), 1.06 (t, J=7Hz, 3H).
[6-(δ,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-yl)naphthylen-2-yl]-carbonyl-
2(S)-phenylsulfonylamino-β-alanine hydrochloride (1-9)
A solution of (162 mg, 0.29 mmol) CH3OH (10 mL), and
IN NaOH (3 mL) was stirred at ambient temperature for 16 h. The CH3OH was evaporated and the aqueous solution acidified with IN HCl to give JM) as a yellow solid. iH NMR (300 MHz, CD3OD) δ 8.40-7.20 (m, 13H), 4.30 (m, IH), 3.80 (m,
IH), 3.60 (m, 3H), 2.9δ (m, 2H), 2.03 (m, 2H).
Scheme 2
BH3 »DMS, toluene
1NUOH
2-([N-Pyridin-2-yl]aminocarbonyl)-6-methoxycarbonyl-naphthylene
(2-1)
To a suspension of naphthalene-2, 6-dicarboxylic acid monomethyl ester 1 (1.22 g, δ.30 mmol) in toluene (26. δ mL) under Ar was added DMF (one drop) followed by dropwise addition of oxalyl chloride (0.683 mL). Gas was evolved. The lumpy, suspended solid gradually became a fine white precipitate while stirring for 2 h. The reaction was concentrated and the residue was dissolved in dichloromethane (26. δ mL). Triethylamine (1.48 mL) and 2- aminopyridine (0.748 g) were then added, and the solution stirred under Ar overnight. The mixture was diluted with dichloromethane (250 mL) and washed with water (2 x 25 mL) and brine (25 mL), then dried (MgS04) and concentrated to give an off-white foam. This residue was adsorbed onto silica and purified by flash chromatography, eluting with 1:1 [25% EtOAc/Hexane : dichloromethane] to give 2^1 as a white solid. TLC Rf = 0.29 (silica, 1:1 25% EtOAc/hexane : dichloromethane), iH NMR (300 MHz, dβ-DMSO+DCl) δ 3.90 (s, 3H), 7.66 (dt, IH, J=12.3, 1.2Hz), 8.07 (dd, IH, J=8.6, 1.6Hz), 8.41-8.19 (m, 4H), 8.49-8.60 (m, 2H), 8.70 (s, IH), 9.06 (s, IH).
2-([N-Pyridin-2-yl]aminomethyl)-6-methoxycarbonyl-naphthylene ι
To a suspension of 0.84 g 2 (which had been azeotroped with benzene) in dry toluene (14 mL) at 0°C under Ar was added 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 Na2Cθ3 solution (30 mL). This mixture was extracted with ethyl acetate (300 mL) and the organic phase washed with water (30 mL) and brine (30 mL), then dried (MgSθ4) and concentrated. The residual solid was purified by flash chromatography on silica by eluting with 7% acetone- dichloromethane to give 2^2 as a white solid.
TLC Rf = 0.21 (silica; 7% acetone/dichloromethane),
iH NMR (400 MHz, dβ-DMSO) δ 3.91 (s, 3H), 4.67 (d, 2H, J=6.0Hz), 6.48 (t, IH, 6.0Hz), 6.δδ (d, IH, J=8.4Hz), 7.19 (t, IH, J=6.0Hz), 7.38 (dt, IH, J=7.7, 1.9Hz), 7.60 (dd, IH, J=8.4, l.δHz), 7.89 (s, IH), 7.94-7.98 (m, 2H), 8.08 (d, IH, J=8.42Hz), 8.60 (s, IH).
2-([N-Pyridin-2-yllaminomethyl)-6-carboxylic acid-naphthylene (2-3) A solution of (80 mg, 0.28 mmol) in aqueous 6N HCl solution (δ.O mL) was heated to 60 °C overnight, then stirred at room temperature an additional 24 h. The mixture was concentrated to give 3 as a white solid. iH NMR (300 MHz, dβ-DMSO) δ 4.8δ (d, 2H, J=δ.4Hz), 6.90 (t, IH, J=6.3
Hz), 7.1δ (d, IH, J=9.0Hz), 7.63 (dd, IH, J=8.δ, 1.6Hz), 7.91-8.00 (m, δH), 8.16 (d, IH, J=8.δHz), 8.61 (s, IH), 9.31 (br s, IH).
6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)carbonyl-2(S)- phenylsulfonylamino-β-alanine ethyl ester (2-4)
A solution of (0.080 g, 0.2δ mmol), 4-methylmorpholine (0.11 mL), BOP (0.17 g), and 17a (0.12 g) in DMF (δ.O mL) was stirred at room temperature under N2 overnight. The reaction was concentrated and the oily residue dissolved in ethyl acetate (lδO mL) and water (lδ mL). The organic phase was then washed with saturated NaHCθ3 solution (lδ mL) and brine (lδ mL), then dried with MgSθ4 and concentrated to a clear, yellowish oil. Purification by flash chromatography (silica), eluting with ethyl acetate, gave 2^4 as a white foam.
TLC Rf = 0.47 (silica, ethyl acetate), iH NMR (400 MHz, d6-DMSO) δ 0.93 (t, 3H, J=7.1Hz), 3.44 (m, IH), 3.δ6 (m, IH), 3.79 (q, 2H, J=7.1Hz), 4.14 (br t, IH J=6.6Hz), 4.66 (d, 2H, J=δ.9Hz), 6.48 (t, IH, J=5.8Hz), 6.54 (d, IH, J=8.4Hz), 7.17 (t, IH, J=δ.9Hz), 7.37 (m, IH), 7.δ3 (m, 3H), 7.7δ-7.96 (m, δH), 8.30 (s, IH), 8.47 (br s, IH), 8.67 (t, IH, J=δ.8Hz).
6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)-carbonyl-2(S)- phenylsulfonylamino-β-alanine trifluoroacetate (2-5)
To a solution of 2A (0.10 g, 0.188 mmol) in THF (1.9 mL) under N2 was added aqueous IN LiOH solution (0.469 mL). The cloudy solution was stirred at room temperature overnight. The reaction was concentrated to an off-white residue which was then purified by HPLC (Delta pak Cχ8, 0 to 60% acetonitrile-water over 60 min, 0.1% TFA-H2O).
Lyophilization gave 2r5 as a fluffy, white solid. TLC Rf = 0.38 (silica, δ0% [20:1:1 EtOH/NH4θH/H2θ - δ0% EtOAc]), iH NMR (400 MHz, d6-DMSO) δ 4.03 (dd, IH, J=lδ.δ, 6.8 Hz), 4.69 (d, 2H, J=3.7Hz), 6.74 (t, IH, J=6.3Hz), 6.92 (d, IH, J=8.4Hz), 7.39 (m, 2H), 7.53 (dd, IH, J=8.5, 1.3Hz), 7.73 (m, 3H), 7.91 (m, 3H), 8.17 (d, IH, J=9.0Hz), 8.27 (s, IH), 8.δ6 (t, IH, J=δ.8Hz)
Scheme 3
Br2, ether
20% KOH, ethanol, reflux
To a stirred solution of aldehyde 1-3 (2.4 g, 20.0 mmol) and Et2θ (200 ml) was added Br2 (4.16 g, 26.0 mmol). After 30 minutes, the solid that formed was collected, dissolved in EtOAc and then washed with IN NaOH, brine, dried (MgSθ4) and concentrated providing bromide 34 as a yellow solid. TLC Rf = 0.88 (silica, 75% EtOAc/hexanes), iH NMR (300 MHz, CDCI3) δ 9.82 (s, IH), 8.29 (d, IH, J=2Hz), 7.89 (d, IH, J=2Hz), 6.73 (bs, 2H).
N-Boc-4-acetylpiperidine (3-3)
To a stirred suspension of amine 3 (δ.21 g, 31.8 mmol, Acros), NEt3 (5.32 ml, 38.2 mmol) and DMF (100 ml) at 0°C was added BOC2O followed by the removal of the cooling bath. After 18 h, the reaction was poured into 200 ml H2O and then extracted with EtOAc. The organic portion was washed with H2O, δ% KHSO4, sat. NaHCθ3, brine, dried (MgSθ4) and concentrated. Flash chromatography (silica,
30% EtOAc/hexanes) gave ketone 3^ as a colorless oil. TLC Rf = 0.3 (silica, 30% EtOAc/hexanes), iH NMR (300 MHz, CDCI3) δ 4.09 (bs, 2H), 2.78 (bt, 2H, J=12Hz), 2.45 (m, IH), 2.17 (s, 3H), 1.83 (m, 2H), 1.52 (m, 2H), 1.46 (s, 9H).
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.
The solution was concentrated. Flash chromatography (silica, 50%
EtOAc/hexanes) provided bromide 34 as a yellow solid.
TLC Rf = 0.45 (silica, 6.0% EtOAc/hexanes), iH NMR (300 MHz, CDCI3) δ 9.08 (d, IH, J=3Hz), 8.31 (d, IH, J=2Hz), 8.08
(d, IH, J=8Hz), 7.44 (d, IH, J=9Hz), 4.28 (m, 2H), 3.12 (m, IH), 1.93 (m,
4H), 1.49 (s, 9H).
4-(6-Bromo-ri.81naphthyridin-2-yl)piperidine (3-δ)
A solution of bromide (3.5 g, 8.92 mmol), CH2CI2 (20 ml) and TFA (10 ml) was stirred for 1.0 h. The reaction was concentrated and then azeotroped with toluene. The residue was dissolved in IN NaOH and then extracted with CHCI3. The CHCI3 portion was washed with brine, dried (MgSθ4) and concentrated providing amine 3_ as a brown solid.
TLC Rf = 0.25 (silica, 10:1:1 EtOH/NH4θH/H2θ), iH NMR (300 MHz, CD3OD) δ 9.05 (d, IH, 2Hz), 8.64 (d, IH, J=2Hz), 8.33 (d, IH, J=9Hz), 7.6δ (d, IH, J=9Hz), 3.31 (m, 3H), 2.80 (td, 2H, J=3Hz, 12Hz), 1.95 (m, 4H).
4-(6-Bromo-[l,8]naphthyridin-2-yl)piperidin-l-yl-carbonyl-2-(S)- phenylsulfonylamino-β-alanine t-butyl ester (3-6) To a stirred solution of amine 3 5 (100 mg, 0.3423 mmol,
DIPEA (75 ml, 0.4108 mmol) and CHCI3 (2.0 ml) was added triphosgene
(36 mg, 0.1198 mmol). After 20 minutes, amine 3J5a (115 mg, 0.3423 mmol; for preparation, see WO 95/32710, published 7 Dec. 1995) and DIPEA (150 μl, 0.8216 mmol) was added and the reaction was stirred for 18 h. The reaction was diluted with EtOAc and then washed with sat. NaHCθ3, brine, dried (MgS04) and concentrated. Flash chromatography (silica, EtOAc) provided urea 3^5 as a white solid. TLC Rf = 0.24 (silica, EtOAc), iH NMR (300 MHz, CDCI3) δ 9.09 (d, IH, 2Hz), 8.32 (d, IH, J=2Hz), 8.10 (d, IH, J=8Hz), 7.8δ (d, 2H, J=8Hz), 7.δδ (m, 4H), δ.69 (bd, IH, J=8Hz), δ.09 (m, IH), 4.14 (m, 2H), 3.88 (m, IH), 3.77 (m, IH), 3.22 (m, 2H), 3.00 (bt, 2H, J=12Hz), 2.0δ (m, 3H), 1.28 (s, 9H).
4-(δ,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)piperidin-l-yl-carbonyl-2-(S)- phenylsulfonylamino-β-alanine t-butyl ester (3-7)
A solution of bromide 3 (125 mg, 0.2021 mmol), 10% Pd/C (125 mg) and EtOH (δ ml) was stirred under 1 atm H2 for 1.0 h. The reaction mixture was then filtered through a celite pad and the filtrate concentrated to give urea 3J_ as a colorless oil. TLC Rf = 0.17 (silica, 10% CH3θH/EtOAc),
- δO -
iH NMR (300 MHz, CD3OD) δ 7.84 (d, 2H, J=8Hz), 7.δ3 (m, 4H), 6.70 (m, IH), 6.62 (d, IH), J=8Hz), 4.09 (m, 3H), 3.47 (t, 2H, J=6Hz), 3.21 (m, IH), 2.83 (m, δH), 1.91 (m, δH), 1.71 (m, 2H), 1.24 (s, 9H).
4-(δ,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)piperidin-l-yl-carbonyl-2-(S)- phenylsulfonylamino- β-alanine (3-8)
A solution of ester £Z (60 mg, 0.1106 mmol), TFA (2 ml) and CH2CI2 (2 ml) was stirred for 2.0 h. The reaction solution was concentrated and then azeotroped with toluene. Flash chromatography (silica, 25:10:1:1 15:10:1:1 EtOAc EtOH/NH4θH H2θ) gave acid
3-8 as a white solid.
TLC Rf = 0.16 (silica, 10:10:1:1 EtOAc/EtOH/NH4θH/H2θ), iH NMR (300 MHz, CD3OD) δ 7.85 (m, 2H), 7.42 (m, 3H), 7.14 (d, IH), J=8Hz), 6.37 (d, IH, J=7Hz), 4.09 (bd, 2H, J=13Hz), 3.63 (m, IH), 3.44 (m, 3H), 3.21 (m, IH), 2.81 (bt, 2H, J=13Hz), 2.70 (t, 2H, J=6Hz), 2.60 (m, IH), 1.88 (m, 4H), 1.60 (m, 2H).
Scheme 4
4-1 (Otsuka, A., etal., JACS, 115, 9439, 1993)
4-2
NaNH2, toluene reflux
-δ2
Scheme 4 continued
δ3
Methyl 6-bromomethylnaphthylene-2-carboxylate (4-2)
A benzene solution (50 ml) of alcohol 4Λ (1.08 g, 5.0 mmol; for preparation see Osuka, A., et al., JACS, 115, 9439, 1993) was treated with PBr3 and the solution refluxed for 1 h. The reaction was cooled and the solution decanted from a yellow residue and concentrated to a colorless solid which was partitioned between EtOAc and saturated NaHC03 solution. The organic layer was washed with brine and dried (MgSθ4). Evaporation gave 4^2 as a colorless solid. TLC Rf = 0.53 (silica, 4:1, hexane/EtOAc), iH NMR (300 MHz, CDCI3) δ 8.59 (s, IH), 8.08 (dd, J=9Hz, 2Hz, IH), 7.94 (d, J=9Hz, IH), 7.87 (s, H), 7.85 (d, J=9Hz, IH), 7.57 (dd, J=9Hz, 2Hz, IH), 4.66 (s, 2H), 3.98 (s, 3H).
Methyl 6-[(pyrimidinyl-2-yl)aminomethyl]naphthylene-2-carboxylate (4- 4)
A toluene solution (10 ml) of NaNH2 (161 mg, 4.1 mmol) and
4-3 (375 mg, 3.9 mmol) was heated at 110°C for 1 h before (1100 mg, 3.9 mmol) was added. The reaction was heated 3 h at 110°C, cooled and poured into EtOAc. The resulting mixture was washed with H2O, dried (MgSθ4) and concentrated to a yellow solid which was purified by flash chromatography (silica, 9:1, CH2Cl2/acetone) to provide 44 as a yellow solid.
TLC Rf 0.31 (silica, 9:1, CH2Cl2/acetone), iH NMR (300 MHz, CDCI3) δ 8.58 (s, IH), 8.32 (d, J=5Hz, 2H), 8.04 (dd, J=9Hz, 2Hz, IH), 7.92 (d, J=9Hz, IH), 7.84 (d, 8Hz, IH), 7.83 (s, IH), 7.δ4 (dd, J=8Hz, 2Hz, IH), 6.59 (t, J=5Hz, IH), δ.49 (bs, IH), 4.84 (d, J=6Hz, 2H), 3.98 (s, 3H).
6-r(Pyrimidinyl-2-yl)aminomethvnnaphthylene-2-carboxylic acid (4-δ) A methanol solution (20 mL) of 4-4 (107 mg, 0.36 mmol) and
1 NaOH (10 mL, 10 mmol) was stirred at 60°C for 1 h. The reaction was concentrated and the residue acidified with 6 N HCl to provide as a solid. iH NMR (300 MHz, CD3OD) δ 8.61 (s, IH), 8.03, (m, 3H), 7.93 (m, 3H), 7.61 (dd, J=9Hz, 2Hz, IH), 7.0δ (t, J=6Hz, IH), 4.9δ (s, 2H).
- δ4 -
6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylene-2-carbonyl-2-(S)- phenylsulfonyl- β-alanine ethyl ester (4-6)
A DMF solution (δ mL) of 4δ (114 mg, 0.36 mmol), Ma (178 mg, 0.40 mmol), NMM (176 ml, 1.6 mmol) and BOP (177 mg, 0.40 mmol) was stirred under ambient conditions for 18 h. The reaction was concentrated and the residue partitioned between EtOAc and H2O. The organic layer was washed with sat. NaHCθ3 solution, brine and dried (MgSθ4). Filtration and concentration gave a pale yellow foam which was purified by flash chromatography (silica, EtOAc) to provide 4-6 as a colorless foam. TLC Rf 0.2δ (silica, EtOAc), iH NMR (300 MHz, CDCI3) δ 8.22 (s, IH), 7.72-7.88 (m, 7H), 7.40-7.δ4 (m, 5H), 6.58 (t, J=δHz, IH), 4.81 (d, J=6Hz, 2H), 4.1δ (m, IH), 4.04 (q, J=7Hz, 2H), 3.9δ (m, IH), 3.78 (m, IH), 1.13 (t, J=7Hz, 3H).
6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylene-2-carbonyl-2-
(S)phenylsulfonyl-β-alanine (4-7)
A MeOH solution (δ mL) of IN NaOH (1.2 mL, 1.2 mmol) and 46 (129 mg, 0.24 mmol) was stirred under ambient condition for 18 h. The solution was neutralized with IN HCl and concentrated to provide 47 as a viscous gum. iH NMR (300 MHz, CD3OD) δ 8.30 (s, IH), 7.80-8.02 (m, 7H), 7.61 (dd,
J=7Hz, 2Hz, IH), 7.40 (m, 4H), 7.0δ (t, J=δHz, IH), 4.96 (s, 2H), 4.26 (m, IH), 3.80 (m, IH), 3.δ6 (m, IH).
6-[(l,4,5,6-Tetrahydropyrimidinyl-2-yl)aminomethyl]naphthylene-2- carbonyl-2(S)-phenylsulfonylamino-β-alanine (4-8)
An acetic acid solution (20 mL) containing 12N HCl (1 mL), (121 mg, 0.24 mmol) and 10% Pd/C (25 mg) was hydrogenated at 60 psi for 3 h. Filtration and concentration provided a gum which was purified by preparative HPLC (Delta-pak Ci8, 100% H2θ-0.1% TFA JE 50/δO H2θ/CH3CN-0.1% TFA, 40 min) to provide 48 as a colorless solid.
δδ
iH NMR (300 MHz, CD3OD) δ 8.32 (s, H), 8.01 (d, J=9Hz, IH), 7.82-7.97 (m, δH), 7.40-7.δδ (m, 4H), 4.δδ (s, 2H), 4.26 (m, IH), 3.82 (m, IH), 3.δδ (m, IH), 3.18-3.42 (m, 4H), 1.97 (m, 2H).
δ6
Scheme δ
5-1
H, dioxane
δ7
Scheme δ continued
5-5
53.
-δ8-
Scheme δ continued
-δ9-
N-(4-Iodo-phenylsulfonylamino)-L-asparagine (δ-2)
To a stirred solution of acid (4.39 g, 33.2 mmol), NaOH (1.49 g, 37.2 mmol), dioxane (30 ml) and H2O (30 ml) at 0°C was added pipsyl chloride (10.34 g, 34.2 mmol). After ~δ minutes, NaOH (1.49, 37.2 mmol) dissolved in lδ ml H2O, was added followed by the removal of the cooling bath. After 2.0 h, the reaction mixture was concentrated. The residue was dissolved in H2O (300 ml) and then washed with EtOAc.
The aqueous portion was cooled to 0°C and then acidified with concentrated HCl. The solid was collected and then washed with Et2θ to provide acid « 2 as a white solid. iH NMR (300 MHz, D2O) δ 7.86 (d, 2H, J=8HZ), 7.48 (d, 2H, J=8Hz) 3.70
(m, IH), 2.39 (m, 2H).
2(S)-(4-Iodo-phenylsulfonylamino)-β-alanine (δ-3) To a stirred solution of NaOH (7.14 g, 181.8 mmol) and H2O
(40 ml) at 0°C was added Br2 (1.30 ml, 24.9 mmol) dropwise over a ten minute period. After ~δ minutes, acid | 2 (9.9 g, 24.9 mmol), NaOH (2.00 g, 49.8 mmol) and H2O (35 ml) were combined, cooled to 0°C and then added in a single portion to the reaction. After stirring for 20 minutes at 0°C, the reaction was heated to 90°C for 30 minutes and then recooled to 0°C. The pH was adjusted to ~7 by dropwise addition of concentrated HCl. The solid was collected, washed with EtOAc, and then dried in vacuo to provide acid 5 as a white solid. iH NMR (300 MHz, D2O) δ 8.02 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 4.36 (m, IH), 3.δl (dd, IH, J=δHz, 13Hz) 3.21 (m, IH).
Ethyl 2(S)-(4-iodo-phenylsulfonylamino)-β-alanine-hvdrochloride (δ-4)
HCl gas was rapidly bubbled through a suspension of acid δ-3 (4.0 g, 10.81 mmol) in EtOH (δO ml) at 0°C for 10 minutes. The cooling bath was removed and the reaction was heated to 60°C. After 18 h, the reaction was concentrated to provide ester S as a white solid. iH NMR (300 MHz, CD3OD) δ 7.98 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz),
4.2δ (q, IH, J=δHz), 3.92 (m, 2H), 3.33 (m, IH), 3.06 (m, IH), 1.01 (t, 3H, J=7Hz). Ethyl 4-r2-(2-Aminopyridin-6-yl)ethyl1benzoate (5-5)
A mixture of ester δ-δa (700 mg, 2.63 mmol), (for preparation, see: Scheme 29 of PCT International Application Publication No. WO 9δ/32710, published December 7, 1995) 10% Pd/C (350 mg) and EtOH were stirred under 1 atm H2. After 20 h, the reaction was filtered through a celite pad and then concentrated to provide ester 5£ as a brown oil.
TLC Rf = 0.23 (silica, 40% EtOAc/hexanes), iH NMR (300 MHz, CDCI3) δ 7.9δ (d, 2H, J=8Hz), 7.26 (m, 3H), 6.43 (d, IH, J=7Hz), 6.3δ (d, IH, J=8Hz), 4.37 (m, 4H), 3.05 (m, 2H), 2.91 (m, 2H), 1.39 (t, 3H, J=7Hz).
4-r2-(2-Aminopyridin-6-yl)ethyllbenzoic acid hydrochloride (5-6)
A suspension of ester i 5 (62δ mg, 2.31 mmol) in 6N HCl (12 ml) was heated to 60°C. After ~20 h, the reaction was concentrated to give acid δ-6 as a tan solid. iH NMR (300 MHz, CD3OD) δ 7.96 (d, 2H, J=8Hz), 7.80 (m, IH), 7.33 (d,
2H, J=8Hz), 6.84 (d, IH, J=9Hz), 6.69 (d, IH, J=7Hz), 3.09 (m, 4H).
Ethyl 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodo- phenylsulfonylamino)-β-alanine (δ-7)
A solution of acid i 6 (400 mg, 1.43 mmol), amine 4
(686 mg, l.δ7 mmol), EDC (3δ8 mg, 1.86 mmol), HOBT (2δ2 mg, 1.86 mmol), NMM (632 μl, δ.72 mmol) and DMF (10 ml) was stirred for -20 h.
The reaction was diluted with EtOAc and then washed with sat NaHC03, brine, dried (MgSθ4) and concentrated. Flash chromatography (silica, EtOAC δ% isopropanol EtOAc) provided amide 5 as a white solid. TLC Rf = 0.4 (silica, 10% isopropanol/EtOAc), iH NMR (300 MHz, CD3OD) δ 7.79 (d, 2H, J=9Hz) 7.61 (d, 2H, J=8Hz), 7.52 (d, 2H, J=9Hz), 7.29 (m, IH), 7.27 (d, 2H, J=8Hz), 4.20 (m, IH), 3.95 (q, 2H, J=7Hz), 3.66 (dd, IH, J=6Hz, 14Hz), 3.49 (dd, IH, J=8Hz, 13Hz), 3.01 (m, 2H), 2.86 (m, 2H), 1.08 (t, 3H, J=7Hz).
4-[2-(2-Aminopyridm-6-yl)ethyl]benzoyl-2(S)-(4-iodophenyl- sulfonylamino)-β-alanine (5-8)
A solution of ester δ 7 (200 mg, 0.3213 mmol) and 6N HCl (30 ml) was heated to 60°C. After ~20 h, the reaction mixture was concentrated. Flash chromatography (silica, 20:20:1:1 EtOAc/EtOH/ NH4OH/H2O) provided acid δ^δ as a white solid. TLC Rf = 0.4δ (silica, 20:20:1:1 EtOAc/EtOH/NH4θHZH2θ), iH NMR (400 MHz, DMSO) δ 8.40 (m, IH), 8.14 (Bs, IH), 7.81 (d, 2H, J=8Hz), 7.62 (d, 2H, J=8Hz), 7.48 (d, 2H, J=8Hz), 7.27 (m, 3H), 6.34 (d, IH, J=7Hz), 6.2δ (d, IH, J=8Hz), δ.8δ (bs, 2H), 3.89 (bs, IH), 3.3δ (m, 2H), 2.97 (m, 2H), 2.79 (m, 2H).
4-[2-(2-Aminopyridin-6-yl)ethyl)benzoyl-2(S)-(4-trimethylstannyl- phenylsulfonylamino-β-alanine (δ-9)
A solution of iodide ££ (70 mg, 0.1178 mmol), (CH3Sn)2 (49 μl, 0.23δ6 mmol), Pd(PPh3)4 (δ mg) and dioxane (7 ml) was heated to 90°C. After 2 h, the reaction was concentrated and then purified by prep HPLC (Delta-Pak Cχ8 lδ μM 100A°> 40 x 100 mm; 9δ:δ δ:9δ H2O/CH3CN) provided the trifluoroacetate salt. The salt was suspended in H2O (10 ml), treated with NH4OH (δ drops) and then lyophihzed to provide amide S£ as a white solid. iH NMR (400 MHz, DMSO) δ 8.40 (m, IH), 8.18 (d, IH, J=8Hz), 7.67 (m, δH), 7.δ6 (d, 2H, J=8Hz), 7.29 (d, 2H, J=8Hz), 6.9δ-7.δ2 (m, 2H), 6.4δ (bs, 2H), 4.00 (m, IH), 3.δ0 (m, IH), 3.33 (m, IH), 2.97 (m, 2H), 2.86 (m, 2H).
4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4-12δiodo- phenylsulfonylamino-β-alanine (δ-10)
An iodobead (Pierce) was added to a shipping vial of δ mCi of Nal^ l (Amersham, IMS30) and stirred for five minutes at room temperature. A solution of 0.1 mg of in O.Oδ mL of 10% H2Sθ4/MeOH was made and immediately added to the Nal2δl/i0dobead vial. After stirring for three minutes at room temperature, approximately 0.04-0.0δ mL of NH4OH was added so the reaction mixture was at pH 6-7. The entire reaction mixture was injected onto the HPLC for purification [Vydac peptide-protein C-18 column, 4.6 x 2δ0 mm, linear gradient of 10% acetonitrile (0.1% (TFA):H2θ (0.1% TFA) to 90% acetonitrile (0.1% TFA):H2θ (0.1% TFA) over 30 minutes, 1 mL/min]. The retention time
of 8-10 is 17 minutes under these conditions. Fractions containing the majority of the radioactivity were pooled, lyophihzed and diluted with ethanol to give approximately 1 mCi of 8-10. which coeluted on HPLC analysis with an authentic sample of 8-8. Instrumentation: Analytical and preparative HPLC was carried out using a Waters 600E Powerline Multi Solvent Delivery System with 0.1 mL heads with a Rheodyne 712δ injector and a Waters 990 Photodiode Array Detector with a Gilson FC203 Microfraction collector. For analytical and preparative HPLC a Vydac peptide-protein C-18 column, 4.6 x 2δ0 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. A Vydac C-18 protein and peptide column, 3.9 x 2δ0 mm was used for analytical and preparative HPLC. Solutions of radioactivity were concentrated using a Speedvac vacuum centrifuge. Calibration curves and chemical concentrations were determined using a Hewlett Packard Model 84δ2A UV/Vis Diode Array Spectrophotometer. Sample radioactivities were determined in a Packard Aδδ30 gamma counter.
EXAMPLE OF A PHARMACEUTICAL FORMULATION
As a specific embodiment of an oral composition, 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.
The test procedures employed to measure avb3 binding and the bone resorption inhibiting activity of the compounds of the present invention are described below.
BONE RESORPTION-PIT ASSAY
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.
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 lδ% 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. Science, 66:383-399). The resulting suspension (0.7δ 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 μl 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 μl 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.
After the bone slices have dried, resorption pits were counted in test and control slices. Resorption pits were viewed in a Microphot Fx (Nikon) fluorescence microscope using a polarizing Nikon IGS filter cube. Test dosage results were compared with controls and resulting IC50 values were determined for each compound tested.
The appropriateness of extrapolating data from this assay to utility and use in mammalian (including human) disease states is supported by the teaching found in Sato, M., et al., Journal of Bone and Mineral Research, Vol. 5, No. 1, 1990. That article teaches that certain bisphosphonates have been used clinically and appear to be effective in the treatment of Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastases, and bone loss due to immobilization or sex hormone deficiency. These same bisphosphonates are then tested in the resorption pit assay described above to confirm a correlation between their known utility and positive performance in the assay.
EIB ASSAY
Duong et al., J. Bone Miner. Res. , 8:S 378, describe a system for expressing the human integrin αvβ3. It has been suggested that the integrin stimulates attachment of osteoclasts to bone matrix, since antibodies against the integrin, or RGD -containing molecules, such as echistatin (European Publication 382 451), can effectively block bone resorption.
Reaction Mixture:
1. 175 μl TBS buffer (50 mM Tris*HCl pH 7.2, 150 mM NaCl, 1% BSA, 1 mM CaCl2, 1 mM MgCl2).
2. 25 μl cell extract (dilute with 100 mM octylglucoside buffer to give 2000 cpm/25 μl).
3. 12δl-echistatin (2δ μl/δ0,000 cpm) (see EP 382 4δl).
4. 2δ μl buffer (total binding) or unlabeled echistatin (nonspecific binding).
The reaction mixture was then incubated for 1 h at room temp. The unbound and the bound αvβ3 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.
SPA ASSAY
MATERIALS:
1. Wheatgerm agglutinin Scintillation Proximity Beads (SPA): Amersham
2. Octylglucopyranoside: Calbiochem
3. HEPES: Calbiochem 4. NaCl: Fisher δ. CaCl2: Fisher
6. MgCl2: SIGMA
7. Phenylmethylsulfonylfluoride (PMSF): SIGMA
8. Optiplate: PACKARD 9. δJϋ (specific activity 500-1000 Ci mmole)
10. test compound
11. Purified integrin receptor: αvβ3 was purified from 293 cells overexpressing αvβ3 (Duong et al., J. Bone Min. Res., S:S378, 1993) according to Pytela (Methods in Enzymology, 144:475, 1987)
12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaCl, 1 mM Ca2+/Mg2+, O.δ mM PMSF
13. δO mM octylglucoside in binding buffer: δO-OG buffer
PROCEDURE:
1. Pretreatment of SPA beads: δOO mg of lyophihzed SPA beads were first washed four times with 200 ml of δO-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12. δ ml of binding buffer.
2. Preparation of SPA beads and receptor mixture
In each assay tube, 2.δ μl (40 mg/ml) of pretreated beads were suspended in 97.δ μl of binding buffer and 20 ml of δO-OG buffer, δ μl (~30 ng/μl) of purified receptor was added to the
beads in suspension with stirring at room temperature for 30 minutes. The mixture was then centrifuged at 2,δ00 rpm in a Beckman GPR Benchtop centrifuge for 10 minutes at 4°C. The pellets were then resuspended in δO μl of binding buffer and 2δ μl of δO-OG buffer.
3. Reaction
The following were sequentially added into Optiplate in corresponding wells: (i) Receptor/beads mixture (75 μl)
(ii) 25 μl of each of the following: compound to be tested, binding buffer for total binding or 5 for non-specific binding (final concentration 1 μM) (iii) 5-10 in binding buffer (25 μl, final concentration 40 pM) (iv) Binding buffer ( 125 μl)
(v) Each plate was sealed with plate sealer from PACKARD and incubated overnight with rocking at 4°C
4. Plates were counted using PACKARD TOPCOUNT
δ. % inhibition was calculated as follows: A = total counts B = nonspecific counts C = sample counts % inhibition = [{(A-B)-(C-B)}/(A-B)]/(A-B) x 100
OCFORM ASSAY
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. δ gauge needle. The marrow was suspended by pipetting up and down. The suspension was passed through >100 μm nylon cell strainer. The resulting suspension was centrifuged at 3δ0 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. δO μL was added to each well of 1.8 cells to yield δ0,000 cells/well and l,2δ-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, δ% Cθ2 atmosphere.
After 48 h, the medium was changed. 72 h after the addition of bone marrow, 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- lδ minutes at room temperature with δO mM acetate buffer, pH δ.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 αvβ3 integrin. These compounds were found to have IC50 values in the range of 0.4 to 110 nM in the SPA assay.
While the invention has been described and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred doses as set forth hereinabove may be applicable as a
consequence of variations in the responsiveness of the mammal being treated for severity of bone disorders caused by resorption, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
Claims
WHAT IS CLAIMED IS:
1. A compound of the formula
X-Y-Z-Ring-A-B
wherein:
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 R 7 and R28;
X is selected from
NR2 NR2 NR2
II II II
-NR1 R2, -NR1-C-R3, -C-NHR4, -NR1-C-NR3R4,
NR1 NR2
-aryl-NR1 R2, -aryl-C-NR2R3, -aryl-NR1-C-NR3R4
> or 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 Rl3, Rl4, Ri5 or Rl6;
Y is selected from
Cθ-8 alkylene,
C3-10 cycloalkyl,
Co-8 alkylene-NR5-CO-Co-8 alkylene,
Co-8 alkylene-CONR5-Cθ-8 alkylene, Cθ-8 alkylene-O-Cθ-8 alkylene,
Cθ-8 alkylene-NR5-Cθ-8 alkylene,
Cθ-8 alkylene-S(0)θ-2-Cθ-8 alkylene,
Cθ-8 alkylene-S02-NR5-Co-8 alkylene,
Cθ-8 alkylene-NR5-S02-Co-8 alkylene, Co-8 alkylene-CO-Cθ-8 alkylene,
(CH2)0-6 aryl(CH2)0-6, (CH2)0-6 aryl-CO-(CH2)0-6, (CH2)0-6 aryl-CO-NR5-(CH2)0-6, (CH2)0-6 aryl-NR5-CO-(CH2)0-6, or OH
(CH2)0.8CH(CH2)0-8
Z is selected from
O
(CH2)m, (CH2)mO(CH2)n, (CH2)mNR6(CH2)n , (CH2)mNR6CNR7(CH2)n
(CH2)
S O
(CH2)mC(CH2)n| (CH2)mS02(CH2)n> (CH2)mS(CH2)n)
(CH2)mSO(CH2)nι (CH2)mS02NR6(CH2)nι (CH2)mNR6S02(CH2)n>
(CH2)mCR6=CR7(CH2)n> or (CH2)mC≡C-(CH2)n;
where m and n are each independently an integer from 0 to 6;
A is selected from
O
(CH2)qO(CH2)p,
(CH2)qNR29CNR30(CH2
O O O
(CH2)qC 11 NR 2299(CH2)Pι (CH2)qNR 229C(CH2)p(CH2)qC " (CH2)p,
S O
II II
(CH2)qC(CH2)p, (CH2)qS02(CH2)Pι (CH2)qS(CH2)p>
(CH2)qSO(CH2)p> (CH2)qS02NR29(CH2)Pι (CH2)qNR29S02(CH2)p
(CH2)qCR29=CR30(CH2)p or (CH2)qC≡C-(CH2)p;
where p and q are each independently an integer from 0 to 6;
B is selected from
Rl, R2, R3, R4 Rδ, R6, R7, R17, R18 R19, R20, R21, R22, R23, R24, R2δ, R26, 27; R28> R29 ancι R30 are eacn independently selected from hydrogen, halogen, Ci-io alkyl, aryl Cθ-8 alkyl, amino Cθ-8 alkyl, Cl-3 acylamino Cθ-8 alkyl,
Cl-6 alkylamino Cθ-8 alkyl,
Cl-6 dialkylamino Cθ-8 alkyl, aryl Cθ-6 alkylamino Cθ-6 alkyl,
Ci-4 alkoxyamino Cθ-8 alkyl, hydroxy Ci-6 alkylamino Cθ-8 alkyl, Ci-4 alkoxy Cθ-6 alkyl, carboxy Cθ-6 alkyl,
Ci-4 alkoxycarbonyl Cθ-6 alkyl, carboxy Cθ-6 alkyloxy, hydroxy Cl-6 alkylamino Cθ-6 alkyl, hydroxy Cθ-6 alkyl,
NR17
0
^ NR18R19 nr , or
R9 are each independently selected from hydrogen, aryl, halogen, aryl-(CH2)p-, hydroxyl,
Cl-8 alkylcarbonylamino, aryl Cl-5 alkoxy,
Ci-5 alkoxycarbonyl, aminocarbonyl, Cl-8 alkylaminocarbonyl, Cl-6 alkylcarbonyloxy, C3-8 cycloalkyl, amino,
Cl-6 alkylamino, amino Ci-6 alkyl, arylaminocarb onyl ,
aryl Cl-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Cl- alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl,
Ci- 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 alkylamino- carbonyl, Cl-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, Ci-3 alkylamino, amino Cl-3 alkyl, arylaminocarbonyl, aryl Cl-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Cι_4 alkyl, hydroxycarbonyl, or hydroxycarbonyl Cl-5 alkyl, HC≡C(CH2)r -
Ci-6 alkyl-C≡C(CH2)r -, C3-7 cycloalkyl-C≡C(CH2)r -, aryl-C≡C(CH2)r -, Ci-6 alkylaryl-C≡C(CH2)r -, H2C=CH(CH2)r -,
Cl-6 alkyl-CH=CH(CH2)r -, C3-7 cycloalkyl-CH=CH(CH2)r -, aryl-CH=CH(CH2)r-, Ci-6 alkylaryl-CH=CH(CH2)r -, Ci-6 alkyl-S02(CH2)r-,
Cl-6 alkylaryl-S02(CH2)r-, Ci-6 alkoxy, aryl Ci-6 alkoxy, aryl Cl-6 alkyl, Cl-6 alkylamino Cl-6 alkyl, arylamino, arylamino Ci-6 alkyl, aryl Ci-6 alkylamino, aryl Ci-6 alkylamino Ci-6 alkyl,
arylcarbonyloxy, aryl Cl-6 alkylcarbonyloxy,
Cl-6 dialkylamino,
Cl-6 dialkylamino Cl-6 alkyl, Cl-6 alkylaminocarbonyloxy,
Cl-8 alkylsulfonylamino,
Cl-8 alkylsulfonylamino Cl-6 alkyl, arylsulfonylamino Cl-6 alkyl, aryl Cl-6 alkylsulfonylamino, aryl Cl-6 alkylsulfonylamino Cl-6 alkyl,
Cl-8 alkoxycarbonylamino,
Cl-8 alkoxycarbonylamino Cl-8 alkyl, aryloxycarbonylamino Ci-8 alkyl, aryl Cl-8 alkoxycarbonylamino, aryl Cl-8 alkoxycarbonylamino Cl-8 alkyl,
Cl-8 alkylcarbonylamino,
Cl-8 alkylcarbonylamino Cl-6 alkyl, arylcarbonylamino Cl-6 alkyl, aryl Cl-6 alkylcarbonylamino, aryl Cl-6 alkylcarbonylamino Cl-6 alkyl, aminocarbonylamino Cl-6 alkyl,
Cl-8 alkylaminocarbonylamino,
Cl-8 alkylaminocarbonylamino Cl-6 alkyl, arylaminocarbonylamino Cl-6 alkyl, aryl Cl-8 alkylaminocarbonylamino, aryl Cl-8 alkylaminocarbonylamino Cl-6 alkyl, aminosulfonylamino Cl-6 alkyl,
Cl-8 alkylaminosulfonylamino,
Cl-8 alkylaminosulfonylamino Cl-6 alkyl, arylamino sulfonylamino Cl-6 alkyl, aryl Cl-8 alkylaminosulfonylamino, aryl Cl-8 alkylaminosulfonylamino Cl-6 alkyl,
Cl-6 alkylsulfonyl,
Cl-6 alkylsulfonyl Cl-6 alkyl, arylsulfonyl Cl-6 alkyl,
aryl C -6 alkylsulfonyl, aryl Ci-6 alkylsulfonyl Ci-6 alkyl,
Ci-6 alkylcarbonyl,
Ci-6 alkylcarbonyl Ci-6 alkyl, arylcarbonyl Ci-6 alkyl, aryl Ci-6 alkylcarbonyl, aryl Ci-6 alkylcarbonyl Cl-6 alkyl,
Cl-6 alkylthiocarbonylamino,
Cl-6 alkylthiocarbonylamino Ci-6 alkyl, arylthiocarbonylamino Ci-6 alkyl, aryl Ci-6 alkylthiocarbonylamino, aryl Cl-6 alkylthiocarbonylamino Ci-6 alkyl,
Cl-8 alkylaminocarbonyl Ci-6 alkyl, arylaminocarbonyl Cι_6 alkyl, aryl Ci-8 alkylaminocarbonyl, or aryl Ci-8 alkylaminocarbonyl Ci-6 alkyl, wherein the alkyl or N atoms may be unsubstituted or substituted with one or more substituents selected from R21 and
R22; or R8 and R9 are combined to form oxo;
RlO and RU are each independently selected from hydrogen, aryl, halogen, aryl-(CH2)p-, hydroxyl,
Cl-8 alkylcarbonylamino, aryl Cl-5 alkoxy,
Cl-5 alkoxycarbonyl, aminocarbonyl,
Ci-8 alkylaminocarbonyl , Ci-6 alkylcarbonyloxy, C3-8 cycloalkyl, amino,
Ci-6 alkylamino, amino Ci-6 alkyl, arylaminocarbonyl, aryl Cl-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Cι_6 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl,
Ci-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 Ci-3 alkyl, arylamino- carbonyl, aryl Cl-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Cl-4 alkyl, hydroxycarbonyl, or hydroxycarbonyl Cι_5 alkyl, HC≡C(CH2)r - Ci-6 alkyl-C≡C(CH2)r -, C3-7 cycloalkyl-C≡C(CH2)r -, aryl-C≡C(CH2)r -, Ci-6 alkylaryl-C≡C(CH2)r -, H2C=CH(CH2)r -, Ci-6 alkyl-CH=CH(CH2)r -, C3-7 cycloalkyl-CH=CH(CH2)r -, aryl-CH=CH(CH2)r-, Cl-6 alkylaryl-CH=CH(CH2)r -, Ci-6 alkyl-S02(CH2)r-, Ci-6 alkylaryl-S02(CH2)r-, Ci-6 alkoxy, aryl Ci-6 alkoxy, aryl Ci-6 alkyl,
Ci-6 alkylamino Ci-6 alkyl, arylamino,
arylamino Ci-6 alkyl, aryl Ci-6 alkylamino, aryl Ci-6 alkylamino Cl-6 alkyl, arylcarbonyloxy, aryl Cl-6 alkylcarbonyloxy,
Ci-6 dialkylamino, Ci- dialkylamino Ci-6 alkyl, Ci-6 alkylaminocarbonyloxy, Ci- alkylsulfonylamino, Ci-8 alkylsulfonylamino Ci-6 alkyl, arylsulfonylamino Ci-6 alkyl, aryl Cl-6 alkylsulfonylamino, aryl Ci- alkylsulfonylamino Ci-6 alkyl, Cl-8 alkoxycarbonylamino, Ci-8 alkoxycarbonylamino Cl-8 alkyl, aryloxycarbonylamino Ci-8 alkyl, aryl Ci-8 alkoxycarbonylamino, aryl Ci-8 alkoxycarbonylamino Ci-8 alkyl, Cl-8 alkylcarbonylamino , Ci-8 alkylcarbonylamino Ci-6 alkyl, arylcarbonylamino Ci-6 alkyl, aryl Ci-6 alkylcarbonylamino, aryl Ci-6 alkylcarbonylamino Cι_6 alkyl, aminocarbonylamino Ci-6 alkyl, Ci-8 alkylaminocarbonylamino,
Ci- alkylaminocarbonylamino Ci-6 alkyl, arylaminocarbonylamino Ci-6 alkyl, aryl Ci-8 alkylaminocarbonylamino, aryl Ci-8 alkylaminocarbonylamino Ci-6 alkyl, aminosulfonylamino Ci-6 alkyl,
Ci-8 alkylaminosulfonylamino, Ci-8 alkylaminosulfonylamino Ci-6 alkyl, arylaminosulfonylamino Ci-6 alkyl, aryl Ci-8 alkylaminosulfonylamino,
aryl C -8 alkylaminosulfonylamino Cl-6 alkyl,
Cl-6 alkylsulfonyl,
Cl-6 alkylsulfonyl Ci-6 alkyl, arylsulfonyl Cl-6 alkyl, aryl Ci- alkylsulfonyl, aryl Ci-6 alkylsulfonyl Ci- alkyl,
Cl-6 alkylcarbonyl,
Cl-6 alkylcarbonyl Ci-6 alkyl, arylcarbonyl Ci-6 alkyl, aryl Ci-6 alkylcarbonyl, aryl Ci-6 alkylcarbonyl Ci- alkyl,
Cl-6 alkylthiocarbonylamino,
Cl-6 alkylthiocarbonylamino Ci-6 alkyl, arylthiocarbonylamino Cl-6 alkyl, aryl Cl-6 alkylthiocarbonylamino, aryl Ci-6 alkylthiocarbonylamino Ci- alkyl,
Cl-8 alkylaminocarbonyl Ci-6 alkyl, arylaminocarbonyl Ci- alkyl, aryl Ci-8 alkylaminocarbonyl, aryl Ci-8 alkylaminocarbonyl Cl-6 alkyl,
C7-20 polycyclyl Cθ-8 alkylsulfonylamino Cθ-6 alkyl,
C7-20 polycyclyl Cθ-8 alkylcarbonylamino Cθ-6 alkyl,
C7-20 polycyclyl Cθ-8 alkylaminosulfonyolamino Cθ-6 alkyl,
C7-20 polycyclyl Cθ-8 alkylaminocarbonylamino Cθ-6 alkyl, or C7-20 polycyclyl Cθ-8 alkyloxycarbonylamino Cθ-6 alkyl wherein the alkyl or N atoms may be unsubstituted or substituted with one or more substituents selected from R21 and
R wherein the polycyclyl may be unsubstituted or substituted with R31, R32? R33 and R34, and provided that the carbon atom to which RlO and U are attached is itself attached to no more than one heteroatom; or RlO and RU are combined to form oxo;
selected from hydroxy,
Ci-8 alkyloxy, aryl Cθ-6 alkyloxy,
Ci-8 alkylcarbonyloxy Ci-4 alkyloxy, aryl Cθ-8 alkylcarbonyloxy Ci-4 alkyloxy,
Ci-6 dialkylaminocarbonylmethyloxy, aryl Cl-6 dialkylaminocarbonylmethyloxy or an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by Ci-6 alkyl; and
Rl3, R!4, Rlδ and Rl > are each independently selected from hydrogen,
Ci-10 alkyl, aryl Cθ-8 alkyl, thio, amino Cθ-8 alkyl,
Ci-3 acylamino Cθ-8 alkyl,
Cl-6 alkylamino Cθ-8 alkyl,
Ci-6 dialkylamino Cθ-8 alkyl, aryl Cθ-6 alkylamino Cθ-6 alkyl,
Cl-4 alkoxyamino Cθ-8 alkyl, hydroxy Ci-6 alkylamino Cθ-8 alkyl,
Ci-4 alkoxy Cθ-6 alkyl, carboxy Cθ-6 alkyl, Ci-4 alkoxycarbonyl Cθ-6 alkyl, carboxy Cθ-6 alkyloxy, hydroxy Ci-6 alkylamino Cθ-6 alkyl, hydroxy Cθ-6 alkyl,
NR23 II
^ NR24R25 nr , or
NR24 II -NR^^NR^R26. or Rl3, Rl4> Rlδ and Rl6
are combined to form oxo;
R31, R32? R33 an(j R34 are eac independently selected from hydrogen, halogen, Ci-io alkyl, C3-8 cycloalkyl, oxo, 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 - Ci-6 alkyloxy, hydroxy, hydroxy Cl-6 alkyl, Cl-6 alkyloxy- Ci-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, Cl-8 alkyl-S(0)q, Cl-8 alkylaminocarbonyl, Cl-8 dialkylaminocarbonyl, Cl-8 alkyloxycarbonylamino, Cl-8 alkylaminocarbonyloxy or Ci-8alkylsulfonylamino;
provided that Ring is not a 6-membered monocyclic aromatic ring;
provided further that when Ring is thiophene, then X is selected from
provided further that when Ring is selected from isoxazole, isoxazoline, imidazole, imidazoline, benzofuran, benzothiophene, benzimidazole, indole, benzothiazole, benzoxazole,
then X is selected from
2. The compound of Claim 1, wherein
Y is selected from
Cθ-8 alkylene, C3-10 cycloalkyl,
Co-8 alkylene-NR5-CO-Co-8 alkylene,
Cθ-8 alkylene-CONR5-Co-8 alkylene,
Cθ-8 alkylene-O-Cθ-8 alkylene,
Co-8 alkylene-NR5-Cθ-8 alkylene, Cθ-8 alkylene-S(0)θ-2-Cθ-8 alkylene,
Co-8 alkylene-S02-NR5-Co-8 alkylene,
Co-8 alkylene-NR5-S02-Co-8 alkylene,
Cθ-8 alkylene-CO-Cθ-8 alkylene,
(CH2)0-6 aryl(CH2)0-6, (CH2)0-6 aryl-CO-(CH )0-6,
(CH2)0-6 aryl-CO-NH-(CH )0-6, or
OH I (C H2)0.8C H (C H2)0-8
Z is (CH2)m where m is zero; and
and the pharmaceutically acceptable salts thereof.
The compound of Claim 2, of the formula
X-Y-Ring-A-B
wherein Ring is selected from
X is selected from
NR2 NR' NR'
I ' ~ "
-NR1 R2, -NR1-C-R3, -C-NHR4, -NR1-C-NR3R4,
NR1 NR'
II -phenyl-NR1 R2, -phenyl-C-NR2R3, -phenyl-NR1-C-NR3 3RD4
Y is selected from
Co-8 alkylene,
Co-8 alkylene-NR5-CO-Co-8 alkylene, Co-8 alkylene-CONR5-Co-8 alkylene, Cθ-8 alkylene-O-Cθ-8 alkylene, Cθ-8 alkylene-NR5-Cθ-8 alkylene, Co-8 alkylene-S(0)θ-2-Cθ-8 alkylene, Co-8 alkylene-S02-NR5-Co-8 alkylene, Cθ-8 alkylene-NR5-Sθ2-Cθ-8 alkylene or (CH2)0-6 aryl(CH2)0-6;
A is selected from
0(CH2)p, NRϋ(CH2)p ,
(CH2)p>
S02(CH2)p, sθ2NR29(CH2)p> NR29S02(CH2)p or C≡C-(CH2)p;
where p is an integer from 0 to 3;
Rl, R2, R3, R4, Rδ; R6, R17} R18, R19, R20, R23, R24, R2δ, R26, R27 and R29 are each independently selected from
hydrogen, Ci-10 alkyl, aryl Cθ-8 alkyl, amino Cθ-8 alkyl, Ci-3 acylamino Cθ-8 alkyl,
Cl-6 alkylamino Cθ-8 alkyl, Cl-6 dialkylamino Cθ-8 alkyl, Cl-4 alkoxy Cθ-6 alkyl, carboxy Cθ-6 alkyl, Cl-4 alkoxycarbonyl Cθ-6 alkyl, carboxy Cθ-6 alkyloxy, hydroxy Cθ-6 alkyl, NR17 u
^ NR18R19
NR18
-NR NR19R20
RlO and RU are each independently selected from hydrogen, fluorine, Cl-8 alkyl, hydroxyl, C3-8 cycloalkyl, aryl Cθ-6 alkyl, Cθ-6 alkylamino Cθ-6 alkyl, Cθ-6 dialkylamino Cθ-6 alkyl, Cl-8 alkylsulfonylamino Cθ-6 alkyl, aryl Cθ-6 alkylsulfonylamino Cθ-6 alkyl,
Cl-8 alkyloxycarbonylamino Cθ-8 alkyl, aryl Cθ-8 alkyloxycarbonylamino Cθ-8 alkyl, Cl-8 alkylcarbonylamino Cθ-6 alkyl, aryl Cθ-6 alkylcarbonylamino Cθ-6 alkyl,
- 8δ -
Cθ-8 alkylaminocarbonylamino Cθ-6 alkyl, aryl Cθ-8 alkylaminocarbonylamino Cθ-6 alkyl, Cθ-8 alkylaminosulfonylamino Cθ-6 alkyl, aryl Cθ-8 alkylaminosulfonylamino Cθ-6 alkyl, Cl-6 alkylsulfonyl Cθ-6 alkyl,
Cl-6 alkylcarbonyl Cθ-6 alkyl or aryl Cθ-6 alkylcarbonyl Cθ-6 alkyl;
Rl2 is selected from hydroxy,
Ci-8 alkyloxy, aryl Cθ-6 alkyloxy,
Cl-8 alkylcarbonyloxy Cl-4 alkyloxy or aryl Cθ-8 alkylcarbonyloxy Ci-4 alkyloxy;
Rl3, R!4? Rlδ and RIG are each independently selected from hydrogen,
Ci-io alkyl, aryl Cθ-8 alkyl, amino Cθ-8 alkyl,
Cl-3 acylamino Cθ-8 alkyl,
Ci-6 alkylamino Cθ-8 alkyl,
Ci-6 dialkylamino Cθ-8 alkyl,
Ci-4 alkoxy Co-6 alkyl, carboxy Cθ-6 alkyl,
Ci-4 alkoxycarbonyl Cθ-6 alkyl, carboxy Cθ-6 alkyloxy, hydroxy Cθ-6 alkyl,
NR24
X
-NR23^^ NR25R26
' or Rl3, R!4? Rlδ and R 6 are combined to form oxo; provided that when Ring is
then X is selected from
4. The compound of Claim 3, wherein X is selected from
and the pharmaceutically acceptable salts thereof.
δ. The compound of Claim 4, of the formula
X is selected from
Y is selected from
Cθ-8 alkylene, Co-8 alkylene-NR5-Cθ-8 alkylene; and
Rl2 is selected from hydroxy or
Cl-8 alkyloxy;
and the pharmaceutically acceptable salts thereof .
6. The compound of Claim δ, selected from
[6-(δ,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-yl)naphthylen-2-yl]-carbonyl- 2(S)-phenylsulfonylamino-β-alanine ethyl ester;
[6-(δ,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-yl)naphthylen-2-yl]-carbonyl- 2(S)-phenylsulfonylamino-β-alanine;
6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)carbonyl-2(S)- phenylsulfonylamino-β-alanine ethyl ester;
6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)-carbonyl-2(S)- phenylsulfonylamino-β-alanine;
4-(δ,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)piperidin-l-yl-carbonyl-2(S)- phenylsulfonylamino- β-alanine t-butyl ester;
4-(δ,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)piperidin-l-yl-carbonyl-2(S)- phenylsulfonylamino-β-alanine;
6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl-carbonyl-2(S)- phenylsulfonyl-β-alanine ethyl ester;
6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl-carbonyl-2(S)- phenylsulfonyl-β-alanine; or
6-[(l,4,δ,6-Tetrahydropyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl- carbonyl-2(S)-phenylsulfpnylamino-β-alanine;
and the pharmaceutically acceptable salts thereof.
7. The compound of Claim 6, selected from
[6-(δ,6,7,8-Tetrahydro-[l,8]-naphthyridin-2-yl)naphthylen-2-yl]-carbonyl- 2(S)-phenylsulfonylamino-β-alanine;
6-([N-Pyridin-2-yl)aminomethyl)naphthylen-2-yl)carbonyl-2(S)- phenylsulfonylamino-β-alanine;
4-(δ,6,7,8-Tetrahydro-[l,8]naphthyridin-2-yl)piperidin-l-yl-carbonyl-2(S)- phenylsulfonylamino-β-alanine; or
6-[(Pyrimidinyl-2-yl)aminomethyl]naphthylen-2-yl-carbonyl-2(S)- phenylsulfonyl-β-alanine;
and the pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition made by combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
10. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
11. A method of eliciting a vitronectin antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of Claim 1.
12. The method of Claim 11, wherein the vitronectin antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration or inhibition of tumor growth.
13. The method of Claim 12, wherein the vitronectin antagonizing effect is the inhibition of bone resorption.
14. A method of treating or preventing a condition mediated by antagonism of a vitronectin receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of Claim 1.
lδ. The method of Claim 14, wherein the condition is selected from the group consisting of osteoporosis and cancer.
16. The method of Claim lδ, wherein the condition is osteoporosis.
17. A method of inhibiting bone resorption in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of Claim 1.
18. A method of treating osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of Claim 1.
19. A method of preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of Claim 1.
20. A method of eliciting a vitronectin antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 8.
21. A method of treating or preventing a condition mediated by antagonism of a vitronectin receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 8.
22. A method of inhibiting bone resorption in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 8.
23. A method of treating osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 8.
24. A method of preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 8.
2δ. The use of the compound of Claim 1 in the preparation of a medicament for the treatment or prevention of a condition selected from: osteoporosis, bone resorption, tumor growth, cancer, restenosis, artherosclerosis, diabetic retinopathy, macular degeneration or angiogenesis in a mammal in need thereof.
26. A drug which is useful for treating or preventing a condition selected from: osteoporosis, bone resorption, tumor growth, cancer, restenosis, artherosclerosis, diabetic retinopathy, macular degeneration or angiogenesis in a mammal in need thereof, the effective ingredient of the said drug being the compound of Claim 1.
27. A method of treating tumor growth in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of Claim 1 and one or more agents known to be cytotoxic or antiprolif erative.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU50884/98A AU717283B2 (en) | 1996-10-30 | 1997-10-27 | Integrin antagonists |
| EP97913775A EP0946164A4 (en) | 1996-10-30 | 1997-10-27 | Integrin antagonists |
| CA002268916A CA2268916A1 (en) | 1996-10-30 | 1997-10-27 | Integrin antagonists |
| JP52063998A JP2001504456A (en) | 1996-10-30 | 1997-10-27 | Integrin antagonist |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2922396P | 1996-10-30 | 1996-10-30 | |
| US60/029,223 | 1996-10-30 | ||
| GB9626308.2 | 1996-12-18 | ||
| GBGB9626308.2A GB9626308D0 (en) | 1996-12-18 | 1996-12-18 | av›3 antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998018461A1 true WO1998018461A1 (en) | 1998-05-07 |
Family
ID=26310673
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/019349 WO1998018461A1 (en) | 1996-10-30 | 1997-10-27 | Integrin antagonists |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0946164A4 (en) |
| JP (1) | JP2001504456A (en) |
| AU (1) | AU717283B2 (en) |
| WO (1) | WO1998018461A1 (en) |
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| US7176199B2 (en) | 2001-03-19 | 2007-02-13 | Dainippon Pharmaceutical Co., Ltd. | Aryl-substituted alicyclic compound and medical composition comprising the same |
| WO2007084670A2 (en) | 2006-01-18 | 2007-07-26 | Merck Patent Gmbh | Specific therapy using integrin ligands for treating cancer |
| WO2008087025A2 (en) | 2007-01-18 | 2008-07-24 | Merck Patent Gmbh | Specific therapy and medicament using integrin ligands for treating cancer |
| WO2010136168A2 (en) | 2009-05-25 | 2010-12-02 | Merck Patent Gmbh | Continuous administration of integrin ligands for treating cancer |
| EP2292251A1 (en) | 2001-04-24 | 2011-03-09 | Merck Patent GmbH | Combination therapy using anti-angiogenic agents and TNF-alpha |
| WO2015181676A1 (en) | 2014-05-30 | 2015-12-03 | Pfizer Inc. | Carbonitrile derivatives as selective androgen receptor modulators |
| US10266488B2 (en) | 2013-10-10 | 2019-04-23 | Eastern Virginia Medical School | 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase |
| US11426473B2 (en) | 2013-09-24 | 2022-08-30 | Fujifilm Corporation | Nitrogen-containing compound or salt thereof, or metal complex thereof |
| WO2023275715A1 (en) | 2021-06-30 | 2023-01-05 | Pfizer Inc. | Metabolites of selective androgen receptor modulators |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002520287A (en) * | 1998-07-10 | 2002-07-09 | ザ・ユニバーシティ・オブ・シドニー | Prophylactic treatment of angiogenesis in macular degeneration |
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| EP0963370B1 (en) * | 1996-12-09 | 2003-03-19 | Eli Lilly And Company | Integrin antagonists |
| JP2001524079A (en) * | 1997-04-07 | 2001-11-27 | メルク エンド カンパニー インコーポレーテッド | How to treat cancer |
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- 1997-10-27 AU AU50884/98A patent/AU717283B2/en not_active Ceased
- 1997-10-27 EP EP97913775A patent/EP0946164A4/en not_active Withdrawn
- 1997-10-27 WO PCT/US1997/019349 patent/WO1998018461A1/en not_active Application Discontinuation
- 1997-10-27 JP JP52063998A patent/JP2001504456A/en active Pending
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| US5416099A (en) * | 1991-10-29 | 1995-05-16 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
| WO1995032710A1 (en) * | 1994-05-27 | 1995-12-07 | Merck & Co., Inc. | Compounds for inhibiting osteoclast-mediated bone resorption |
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Also Published As
| Publication number | Publication date |
|---|---|
| EP0946164A1 (en) | 1999-10-06 |
| JP2001504456A (en) | 2001-04-03 |
| AU717283B2 (en) | 2000-03-23 |
| EP0946164A4 (en) | 2000-08-23 |
| AU5088498A (en) | 1998-05-22 |
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