Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • 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

Definitions

• the present invention provides novel compounds and derivatives thereof, their synthesis, and their use as vitronectin receptor ligands. More particularly, the compounds of the present invention are ⁇ v ⁇ 3 antagonists, ⁇ v ⁇ 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, viral disease, 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.
• osteoclasts are believed to exist in at least two physiological states.
• the secretory state osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone.
• the adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption.
• 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.
• integrin receptor 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 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
• ⁇ v ⁇ 3 ligands have been found to be useful in treating and/or inhibiting restenosis (recurrence of stenosis after corrective surgery on the heart valve), atherosclerosis, diabetic retinopathy, macular degeneration and angiogenesis (formation of new blood vessels), and inhibiting viral disease.
• restenosis currence of stenosis after corrective surgery on the heart valve
• atherosclerosis atherosclerosis
• diabetic retinopathy diabetic retinopathy
• macular degeneration and angiogenesis formation of new blood vessels
• 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, 1500-1502, 1995.
• 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, viral disease, atherosclerosis and/or angiogenesis in mammals.
• the present invention provides ⁇ v ⁇ 3 antagonist compounds of the formula
• Aryl is a 6-membered aromatic ring containing 0, 1, 2 or 3 nitrogen atoms and either unsubstituted or substituted with R ⁇ and ⁇ ;
• X is selected from
• a 9- to 14-membered polycyclic ring system wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, 0 or S, and wherein the polycyclic ring system is either unsubstituted or substituted with R 1 , R 2 , R3 and R 4 ;
• Y is selected from C ⁇ -8 alkylene
• Z and A are each independently selected from
• n are each independently an integer from 0 to 6;
• p is an integer from 1 to 3;
• R 1 , R 2 , R3, R4, R5, R8 ? 9, RIO, R11 an d R ⁇ 2 are each independently selected from hydrogen, halogen, Ci-10 alkyl, aryl C ⁇ -8 alkyl, amino C ⁇ -8 alkyl, Cl-3 acylamino C ⁇ -8 alkyl,
• Ci-6 alkyloxy Ci-6 alkylcarbonyl, aryl C ⁇ -6 alkylcarbonyl,
• R is selected from C ⁇ - o polycyclyl C ⁇ -8 alkylsulfonylamino C ⁇ -6 alkyl;
• Rl3 is selected from hydroxy
• the compound is not 4-[2-(l,2,3,4-Tetrahydro-l,8- naphthyridin-7-yl)ethyl]benzoyl-2(S)[l(S)10-camphorsulfonylamino] ⁇ - alanine ethyl ester (1-14) or 4-[2-(l,2,3,4-Tetrahydro-l,8-naphthyridin-7- yl)ethyl]benzoyl-2(S)-[l(S)10-camphorsulfonylamino] ⁇ -alanine (1-l ⁇ ).
• Aryl is a 6-membered aromatic ring containing 0, 1 or 2 nitrogen atoms wherein Aryl is unsubstituted or substituted with R ⁇ and R ⁇ ;
• X is selected from
• a 9- to 14-membered fused polycyclic ring system wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2 or 3 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with Rl and R 2 ;
• Y is selected from the group consisting of C ⁇ -8 alkylene
• Z and A are each independently selected from
• n are each independently an integer from 0 to 4.
• Ci-io alkyl aryl C ⁇ -8 alkyl, amino C ⁇ -8 alkyl,
• R ⁇ is selected from hydrogen, Cl-8 alkyl or aryl C ⁇ -6 alkyl; R is selected from
• the compound is not 4-[2-(l,2,3,4-Tetrahydro-l,8- naphthyridin-7-yl)ethyl]benzoyl-2(S)[l(S)10-camphorsulfonylamino] ⁇ - alanine ethyl ester (1-14) or 4-[2-(l,2,3,4-Tetrahydro-l,8-naphthyridin-7- yl)ethyl]benzoyl-2(S)-[l(S)10-camphorsulfonylamino] ⁇ -alanine (1-15).
• a class of the invention is the compound wherein
• Aryl is a phenyl or pyridyl ring wherein the phenyl or pyridyl ring is unsubstituted or substituted with ⁇ ;
• X is a 9- to 14-membered fused polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2 or 3 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with Rl and R 2 ;
• Y is selected from C ⁇ -6 alkylene
• C ⁇ -6 alkylene-NRlO-CO-Co-6 alkylene Co-6 alkylene-CONRlO-Co-6 alkylene, C ⁇ -6 alkylene-O-C ⁇ -6 alkylene, C ⁇ -6 alkylene-NRl°-C ⁇ -6 alkylene, C ⁇ -6 alkylene-S(0) ⁇ -2-C ⁇ -6 alkylene, Cfj-6 alkylene-S ⁇ 2-NRl°-C ⁇ -6 alkylene, or C ⁇ -6 alkylene-aryl-C ⁇ -6 alkylene;
• Rl, R 2 , R 3 , R4, R ⁇ ; R8 ; 9 ? RIO, R11 an d U 12 are each independently selected from hydrogen, halogen, Ci-io alkyl, aryl C ⁇ -8 alkyl, Cl-4 alkoxy C ⁇ -6 alkyl, or Cl-4 alkoxycarbonyl C ⁇ -6 alkyl;
• R ⁇ is hydrogen
• R ' is selected from C7-10 polycyclyl C ⁇ -6 alkylsulfonylamino C ⁇ -6 alkyl or C7-10 polycyclyl C ⁇ -6 alkylcarbonylamino C ⁇ -6 alkyl; wherein the polycyclyl may be unsubstituted or substituted with Rl4, Rl5, R16 ⁇ R17 ;
• Rl3 is selected from hydroxy or Ci-8 alkyloxy
• Rl4, R!5 ? R16 and ? are each independently selected from hydrogen, halogen, Cl-6 alkyl, C3-7 cycloalkyl, oxo, amino, amino Ci-8 alkyl, C1-3 acylamino, Ci-3 acylamino Ci-8 alkyl, Cl-6 alkylamino, Ci-6 alkylamino Ci-8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino Ci-8 alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl-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, Ci-8 alkylsulfonyl, Ci
• Ci-8 alkyloxycarbonylamino Ci-8 alkylaminocarbonyloxy or Ci-8alkylsulfonylamino;
• the compound is not 4-[2-(l,2,3,4-Tetrahydro-l,8- naphthyridin-7-yl)ethyl]benzoyl-2(S)[l(S)10-camphorsulfonylamino] ⁇ - alanine ethyl ester (1-14) or 4-[2-(l,2,3,4-Tetrahydro-l,8-naphthyridin-7- yl)ethyl]benzoyl-2(S)-[l(S)10-camphorsulfonylamino] ⁇ -alanine (1-l ⁇ ).
• X is selected from the group consisting of
• Y is selected from C ⁇ -6 alkylene
• Z is selected from (CH 2 ) m or (CH 2 )-0- (CH 2 ) n ;
• Rl4, Rl5, Rl6 and Rl? are each independently selected from hydrogen, halogen, Cl-6 alkyl, oxo or hydroxy;
• the compound is not 4-[2-(l,2,3,4-Tetrahydro-l,8- naphthyridin-7-yl)ethyl]benzoyl-2(S)[l(S)10-camphorsulfonylamino] ⁇ - alanine ethyl ester (1-14) or 4-[2-(l,2,3,4-Tetrahydro-l,8-naphthyridin-7- yl)ethyl]benzoyl-2(S)-[l(S)10-camphorsulfonylamino] ⁇ -alanine (1-l ⁇ ).
• q is an integer from 0 to 2;
• R!8 is selected from
• the compound is not 4-[2-(l,2,3,4-Tetrahydro-l,8- naphthyridin-7-yl)ethyl]benzoyl-2(S)[l(S)10-camphorsulfonylamino] ⁇ - alanine ethyl ester (1-14) or 4-[2-(l,2,3,4-Tetrahydro-l,8-naphthyridin-7- yl)ethyl]benzoyl-2(S)-[l(S)10-camphorsulfonylamino] ⁇ -alanine (1-l ⁇ ).
• Exemplifying the invention is the compound selected from
• 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.
• Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
• the condition is selected from bone resorption, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, viral disease, 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, inhibition of viral disease, 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, viral disease, or tumor growth.
• Additional examples of the invention are methods of inhibiting bone resorption and of treating and/or preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions decribed above.
• Additional illustrations of the invention are methods of inhibiting tumor growth and of treating and/or preventing cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions decribed above.
• compositions described above further comprising a therapeutically effective amount of a second bone resorption inhibitor; preferably, the second bone resorption inhibitor is alendronate.
• More specifically 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 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, inflammation, viral disease, diabetic retinopathy, macular degeneration 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 descibed above. More specifically illustrating the invention is a drug which is useful for treating and/or preventing: bone resorption, tumor growth, cancer, restenosis, artherosclerosis, inflammation, viral disease, diabetic retinopathy, macular degeneration 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. Further illustrative are methods of treating tumor growth wherein the compounds of the present invention are administered in conjunction with radiation therapy.
• VEGF vascular endothethial growth factor
• 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 condition caused or mediated by the ⁇ v ⁇ 3 receptor, 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, restenosis, tumor growth, artherosclerosis, inflammation, macular degeneration, diabetic retinopathy and angiogenesis.
• 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 or cancer.
• 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,
• 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. In general, such 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.
• 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.
• bone resorption refers to the process by which osteoclasts degrade bone.
• alkyl shall mean straight, branched or monocyclic alkanes, alkenes or alkynes of the specified number of carbon atoms.
• alkyl refers to straight or branced chain alkanes of Cl-10 carbon atoms, or any number within this range
• 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).
• polycyclic refers to unsubstituted or substituted fused or bridged polycyclic systems containing from 7 to 20 carbon atoms and which can contain one or more degrees of unsaturation.
• polycyclyl refers to unsubstituted or substituted fused or bridged bi- or tri-cyclic systems containing from 7-l ⁇ carbon atoms and which can contain one or two degrees of unsaturation.
• polycyclyl refers to unsubstituted or substituted fused or bridged bi- or tri-cyclic systems containing from 7-10 carbon atoms and which can contain one or two degrees of unsaturation.
• prefered polycyclyl systems include, but are not limited to, decaline, camphor, adamantyl and norbornyl.
• cycloheteroalkyl shall mean a 3- to 8-membered fully saturated heterocyclic ring containing one or two heteroatoms chosen from N, O, or S.
• cycloheteroalkyl groups include, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl.
• alkoxy refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., Cl-5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).
• alkylene shall include both straight and branched chain alkylenes (e.g., -CH2-, -CH(CH3)-, -CH(CH3)-CH2-, etc.).
• aryl refers to a monocyclic or polycyclic system composed of ⁇ - and 6-membered rings, such that the system comprises at least one fully unsaturated (i.e., aromatic) ring, wherein the rings contain 0, 1, 2, 3 or 4 heteroatoms chosen from N, O or S, and either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Cl-10 alkyl, C3-8 cycloalkyl, aryl, aryl Ci-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-Ci-8 alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C ⁇ _6 alkyl, Ci- 5 alkoxycarbonyl,
• aryl examples include, but are not limited to, phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, indolyl, thienyl, furyl, dihydrobenzofuryl, benzo(l,3) dioxolane, oxazolyl, isoxazolyl and thiazolyl, which are either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Cl-10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, Cl-3 acylamino, Cl-3 acylamino Cl-8 alkyl, Cl-6 alkylamino, Cl-6 alkylamino-Ci-8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino Cl-8 alkyl, Cl-4 al
• 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- 10 shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
• arylalkyl and “alkylaryl” include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
• arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl.
• alkylaryl examples include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.
• substituent Rl, R 2 , R , R4, R5, R6, R7, R8 ? R9, RIO substituent Rl, R 2 , R , R4, R5, R6, R7, R8 ? R9, RIO
• Rll, Rl 2 , Rl3 or R i4 includes the definition Co (e.g., aryl C ⁇ -8 alkyl), the group modified by Co is not present in the substituent.
• Co e.g., aryl C ⁇ -8 alkyl
• 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.
• L- or D-amino acids means naturally occurring L- or D-amino acids, for example, those naturally occurring L-amino acids present in humans, e.g. protein amino acids,, including L- alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L- glutamine, L-glutamic acid, L-glycine, L-histidine, L-isoleucine, L- leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine, and those naturally occurring D-amino acids which are non-protein amino acids, such as those found, for example, in antibiotic substances produced by bacteria and fungi, including D-valine, D-asparagine, D-glutamate, D-ornithine, D-phenyla
• 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.
• Ci-5 alkylcarbonylamino Cl-6 alkyl substituent is equivalent to
• the present invention is also directed to combinations of the compounds of the present invention with one or more agents useful in the prevention or treatment of osteoporosis.
• the compounds of the instant invention may be effectively administered in combination with effective amounts of other agents used in the treatment of osteoporosis such as bisphosphonate bone 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.
• compositions further comprising an active ingredient selected from the group consisting of a.) an organic bisphosphonate or a pharmaceutically- acceptable salt or ester thereof, b.) an estrogen receptor modulator, and c.) a cytotoxic/antiproliferative agent, and mixtures thereof.
• an active ingredient selected from the group consisting of a.) an organic bisphosphonate or a pharmaceutically- acceptable salt or ester thereof, b.) an estrogen receptor modulator, and c.) a cytotoxic/antiproliferative agent, and mixtures thereof.
• Such bisphosphonates include alendronate, etidronate, pamidronate, risedronate, and pharmaceutically acceptable salts and esters thereof.
• a particularly preferred bisphosphonate is alendronate, especially alendronate monosodium trihydrate.
• Nonlimiting examples of estrogen receptor modulators include estrogen, progesterin, estradiol, raloxifene, and tamoxifene.
• Nonlimiting examples of cytotoxic/antiproliferative agents are taxol and doxorubicin.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• the compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, topical (e.g., ocular eyedrop), subcutaneous, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
• An effective but non-toxic amount of the compound desired can be employed as an ⁇ v ⁇ 3 inhibitor.
• the dosage regimen utilizing-the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
• An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
• Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day.
• compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient.
• the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
• compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
• preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
• the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
• the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
• suitable pharmaceutical diluents, excipients or carriers collectively referred to herein as 'carrier' materials
• the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. 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, polyhydroxypropylmethacrylamide-phenol, polyhydroxy- ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
• the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polyactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
• a drug for example, polylactic acid, polyglycolic acid, copolymers of polyactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
• BOP Benzotriazol-l-yloxytris(dimethylamino)- phosphonium hexafluorophosphate.
• CBZ(Cbz) Carbobenzyloxy or benzyloxycarbonyl.
• CDI Carbonyldiimidazole.
• DIAD Diisopropyl azodicarboxylate.
• DIBAL-H Diisobutylaluminum hydride.
• DIPEA Diisopropylethylamine.
• DMSO Dimethylsulfoxide .
• DPFN 3, ⁇ -Dimethyl-l-pyrazolylformamidine nitrate.
• LDA Lithium diisopropylamide.
• NEt3 Triethylamine.
• NMM N-methylmorpholine
• PCA-HC1 Pyrazole carboxamidine hydrochloride.
• Pd/C Palladium on activated carbon catalyst.
• Ph Phenyl.
• pTSA p-Toluene sulfonic acid.
• TEA Triethylamine
• TFA Trifluoroacetic acid.
• THF Tetrahydrofuran.
• TMEDA N,N,N',N'-Tetramethylethylenediamine.
• TMS Trimethylsilyl.
• TsCl Tosyl chloride.
• 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.
• Amine _ ⁇ (760 mg, 3.27 mmol) was dissolved in 3 ⁇ mL CH2CI2 and cooled to 0°C. NMM (7 ⁇ mL, 6.87 mmol) and 10(+) camphorsulfonyl chloride (1.23 g, 4.9 mmol; Aldrich) were added. After stirring at 0°C for one hour, the reaction was concentrated, then diluted with EtOAc, washed with H2O, sat. NaHC ⁇ 3, 10% KHSO4 and brine, dried (MgS ⁇ 4), and concentrated to an oil. Flash chromatography
• Ester __5 (900 mg, 2.18 mmol) was dissolved in l ⁇ mL EtOAc and cooled to 0°C. HC1 (g) was bubbled through the reaction mixture for l ⁇ minutes. The reaction was removed from the cooling bath and purged with Ar (g) for 20 minutes followed by concentration to provide __. 6 as a foamly solid.
• Analytical and preparative HPLC was carried out using a Waters 600E Powerline Multi Solvent Delivery System with 0.1 mL heads with a Rheodyne 7125 injector and a Waters 990 Photodiode Array Detector with a Gilson FC203 Microfraction collector.
• analytical and preparative HPLC a Vydac peptide-protein C-18 column, 4.6 x 250 mm was used with a C-18 Brownlee modular guard column.
• the acetonitrile used for the HPLC analyses was Fisher Optima grade.
• the HPLC radiodetector used was a Beckman 170 Radioisotope detector.
• test procedures employed to measure ⁇ v ⁇ 3 binding and the bone resorption inhibiting activity of the compounds of the present invention are described below.
• activity of the compounds of the present invention for treating cancer and/or inhibiting tumor growth is confirmed utilizing the nude mouse tumor xenograft assay described in Kohl et al., PNAS 91 (1994) 9141-45.
• 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.
• 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 15% 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.. ( ⁇ __ Cell. Science. 66:383-399). The resulting suspension (0.75 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 firs 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. 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.
• ⁇ 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,
• Binding buffer ⁇ O mM HEPES, pH 7.8, 100 mM NaCl, 1 mM Ca2+/Mg2+, O. ⁇ mM PMSF
• SPA beads Pretreatment of SPA beads: ⁇ OO mg of lyophilized 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.
• Osteoblast-like cells (1.8 cells), originally derived from mouse calvaria, were plated in CORNING 24 well tissue culture plates in ⁇ MEM medium containing ribo- and deoxyribonucleosides, 10% fetal bovine serum and penicillin- streptomycin. Cells were seeded at
• 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. 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- l ⁇ minutes at room temperature with ⁇ O mM acetate buffer, pH 5.0 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. EXAMPLE OF A PHARMACEUTICAL FORMULATION
• 100 mg of compound 1 (shown in Table 1) is formulated with sufficient finely divided lactose to provide a total amount of ⁇ 80 to ⁇ 90 mg to fill a size O hard gel capsule.

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