WO1999015170A1 - Vitronectin receptor antagonist - Google Patents
Vitronectin receptor antagonist Download PDFInfo
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- WO1999015170A1 WO1999015170A1 PCT/US1998/019949 US9819949W WO9915170A1 WO 1999015170 A1 WO1999015170 A1 WO 1999015170A1 US 9819949 W US9819949 W US 9819949W WO 9915170 A1 WO9915170 A1 WO 9915170A1
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- 0 CC(C=*NCCCOc1ccc(CCC(N(Cc2ccc(C(F)(F)F)cc2)C2)=O)c2c1)=CC=*[O-] Chemical compound CC(C=*NCCCOc1ccc(CCC(N(Cc2ccc(C(F)(F)F)cc2)C2)=O)c2c1)=CC=*[O-] 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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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
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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- 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
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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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
Definitions
- This invention relates to a pharmaceutically active compound which inhibits the vitronectin receptor and is useful for the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis.
- Integrins are a superfamily of cell adhesion receptors, which are transmembrane glycoproteins expressed on a variety of cells. These cell surface adhesion receptors include gpllb /Ilia (the fibrinogen receptor) and oC y ⁇ (the vitronectin receptor). The fibrinogen receptor gpllb /Ilia is expressed on the platelet surface, and mediates platelet aggregation and the formation of a hemostatic clot at the site of a bleeding wound. Philips, et al., Blood., 1988, 71, 831.
- the vitronectin receptor oc v ⁇ 3 is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions.
- the ⁇ v B 3 receptor expressed on the membrane of osteoclast cells mediates the adhesion of osteoclasts to the bone matrix, a key step in the bone reso ⁇ tion process. Ross, et al., J. Biol. Chem., 1987, 262, 7703.
- a disease characterized by excessive bone resorption is osteoporosis.
- the GX y ⁇ ⁇ receptor expressed on human aortic smooth muscle cells mediates their migration into neointima, a process which can lead to restenosis after percutaneous coronary angioplasty. Brown, et al., Cardiovascular Res., 1994, 28, 1815. Additionally, Brooks, et al., Cell, 1994, 79, 1157 has shown that an G y ⁇ ⁇ antagonist is able to promote tumor regression by inducing apoptosis of angiogenic blood vessels. Thus, agents that block the vitronectin receptor would be useful in treating diseases, such as osteoporosis, restenosis and cancer.
- the vitronectin receptor is now known to refer to three different integrins, designated ⁇ v ⁇ , a v B 3 and a v B 5 .
- ⁇ v ⁇ j binds fibronectin and vitronectin.
- v ⁇ _ binds a large variety of ligands, including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand's factor, osteopontin and bone sialoprotein I.
- ⁇ v B5 binds vitronectin.
- the vitronectin receptor oc v B5 has been shown to be involved in cell adhesion of a variety of cell types, including microvascular endothelial cells, (Davis, et al., J. Cell. Biol., 1993, 51, 206), and its role in angiogenesis has been confirmed. Brooks, et al., Science, 1994, 264, 569. This integrin is expressed on blood vessels in human wound granulation tissue, but not in normal skin. The vitronectin receptor is known to bind to bone matrix proteins which contain the tri-peptide Arg-Gly-Asp (or RGD) motif. Thus, Horton, et al., Exp. Cell Res.
- a certain compound is a potent inhibitor of the oc v B3 and v B5 receptors.
- such a compound is a more potent inhibitor of the vitronectin receptor than the fibrinogen receptor.
- This invention comprises a compound of the formula (I) as described hereinafter, which has pharmacological activity for the inhibition of the vitronection receptor and is useful in the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis.
- This invention is also a pharmaceutical composition
- a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically carrier.
- This invention is also a method of treating diseases which are mediated by the vitronectin receptor.
- the compound of this invention is useful for treating atherosclerosis, restenosis, inflammation, cancer and diseases wherein bone resorption is a factor, such as osteoporosis.
- This invention comprises a novel compound which is a more potent inhibitor of the vitronectin receptor than the fibrinogen receptor.
- the novel compound comprises a benzazepine core in which a nitrogen-containing substituent is present on the aromatic six- membered ring of the benzazepine and an aliphatic substituent containing an acidic moiety is present on the seven-membered ring of the benzazepine.
- the benzazepine ring system is believed to interact favorably with the vitronectin receptor and to orient the substituent sidechains on the six and seven membered rings so that they may also interact favorably with the receptor.
- This invention comprises a compound of formula (I):
- This compound is (S)-8-[3-(4-methylpyridin- 2-ylamino)-l-propyloxy]-3-oxo-2-[4-(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-lH-2- benzazepine-4-acetic acid.
- the compound of formula (I) inhibits the binding of vitronectin and other RGD- containing peptides to the vitronectin receptor.
- Inhibition of the vitronectin receptor on osteoclasts inhibits osteoclastic bone reso ⁇ tion and is useful in the treatment of diseases wherein bone resorption is associated with pathology, such as osteoporosis and osteoarthritis.
- this invention is a method for stimulating bone formation which comprises administering a compound of formula (I) which causes an increase in osteocalcin release.
- Increased bone production is a clear benefit in disease states wherein there is a deficiency of mineralized bone mass or remodeling of bone is desired, such as fracture healing and the prevention of bone fractures.
- Diseases and metabolic disorders which result in loss of bone structure would also benefit from such treatment. For instance, hyperparathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastasis, bone loss due to immobilization or sex hormone deficiency, Behcet's disease, osteomalacia, hyperostosis and osteopetrosis, could benefit from administering a compound of this invention.
- the compound of the instant invention inhibits vitronectin receptors on a number of different types of cells, said compound would be useful in the treatment of inflammatory disorders, such as rheumatoid arthritis and psoriasis, and cardiovascular diseases, such as atherosclerosis and restenosis.
- inflammatory disorders such as rheumatoid arthritis and psoriasis
- cardiovascular diseases such as atherosclerosis and restenosis.
- the compound of formula (I) of the present invention may be useful for the treatment or prevention of other diseases including, but not limited to, thromboembolic disorders, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplant rejection, septic shock, eczema, contact dermatitis, inflammatory bowel disease, and other autoimmune diseases.
- the compound of the present invention may also be useful for wound healing.
- the compound of the present invention is also useful for the treatment, including prevention, of angiogenic disorders.
- angiogenic disorders as used herein includes conditions involving abnormal neovascularization. Where the growth of new blood vessels
- SUBST1TUTE SHEET (RULE 26) is the cause of, or contributes to, the pathology associated with a disease, inhibition of angiogenisis will reduce the deleterious effects of the disease.
- An example of such a disease target is diabetic retinopathy.
- inhibition of angiogenisis will reduce the blood supply to the tissue and thereby contribute to reduction in tissue mass based on blood supply requirements. Examples include growth of tumors where neovascularization is a continual requirement in order that the tumor grow and the establishment of solid tumor metastases.
- the compound of the present invention inhibit tumor tissue angiogenesis, thereby preventing tumor metastasis and tumor growth.
- the inhibition of angiogenesis using the compound of the present invention can ameliorate the symptoms of the disease, and, in some cases, can cure the disease.
- eye diseases chacterized by neovascularization include corneal neovascular disorders, such as corneal transplantation, herpetic keratitis, luetic keratitis, pterygium and neovascular pannus associated with contact lens use. Additional eye diseases also include age-related macular degeneration, presumed ocular histoplasmosis, retinopathy of prematurity and neovascular glaucoma.
- This invention further provides a method of inhibiting tumor growth which comprises administering stepwise or in physical combination a compound of formula (I) and an antineoplastic agent, such as topotecan and cisplatin.
- prodrugs of the compounds of this invention are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
- novel prodrugs which are also intermediates in the preparation of the formula (I) compound, of formula (II):
- C ⁇ alkyl as applied herein means an optionally substituted alkyl group of 1 to 6 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
- DCC refers to dicyclohexylcarbodiimide
- DMAP refers to dimethylaminopyridine
- DIEA refers to diisopropylethyl amine
- EDC refers to l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride.
- HOBt refers to 1-hydroxybenzotriazole
- THF refers to tetrahydrofuran
- DIEA diisopropylethylamine
- DEAD refers to diethyl azodicarboxylate
- PPh3 refers to triphenylphosphine
- DIAD diisopropyl azodicarboxylate
- DME dimethoxyethane
- DMF dimethylformamide
- NBS refers to N-bromosuccinimide
- Pd/C refers to a palladium on carbon catalyst
- PPA refers to polyphosphoric acid
- DPPA refers to diphenylphosphoryl azide
- BOP refers to benzotriazol-l-yloxy-tris(dimethyl- amino)phosphonium hexafluorophosphate
- HF refers to hydrofluoric acid
- TEA refers to triethylamine
- TFA trifluoroacetic acid
- PCC
- SUBSTJTOTE SHEET (RULE 26) Compound 1-1, prepared by the general procedures described in Bondinell, et al., PCT application WO 93/00095, published January 7, 1993 and Bondinell, et al., PCT application WO 94/14776, is reacted with 4-(trifluoromethyl)benzyl bromide in the presence of a suitable base, generally sodium hydride or lithium bis(trimethylsilyl)amide, in an aprotic solvent, preferably DMF, THF, or mixtures thereof, to afford the bis-alkylated product 1-2.
- a suitable base generally sodium hydride or lithium bis(trimethylsilyl)amide
- an aprotic solvent preferably DMF, THF, or mixtures thereof.
- the 4-(trifluoromethyl)benzyl ether of 1-2 can be conveniently removed by hydrogenolysis to provide the phenol 1-3.
- the reaction is mediated by the complex formed between diethyl azodicarboxylate and triphenylphosphine, and is conducted in an aprotic solvent, for instance THF, CH2CI2, or DMF.
- aprotic solvent for instance THF, CH2CI2, or DMF.
- the pyridine-N-oxide moiety of 1-4 is reduced to the corresponding pyridine 1-5 under transfer hydrogenation conditions using a palladium catalyst, preferably palladium metal on activated carbon, in an inert solvent, for instance methanol, ethanol, or 2-propanol.
- a palladium catalyst preferably palladium metal on activated carbon
- an inert solvent for instance methanol, ethanol, or 2-propanol.
- Cyclohexene, 1 ,4-cyclohexadiene, formic acid, and salts of formic acid, such as potassium formate or ammonium formate are commonly used as the hydrogen transfer reagent in this type of reaction.
- the methyl ester of 1-5 is hydrolyzed using aqueous base, for example, LiOH in aqueous THF or NaOH in aqueous methanol or ethanol, and the intermediate carboxylate salt is acidified with a suitable acid, for instance TFA or HCl, to afford the carboxylic acid 1-6.
- aqueous base for example, LiOH in aqueous THF or NaOH in aqueous methanol or ethanol
- a suitable acid for instance TFA or HCl
- the intermediate carboxylate salt can be isolated, if desired, or a carboxylate salt of the free carboxylic acid can be prepared by methods well-known to those of skill in the art.
- Acid addition salts of the compound are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic.
- Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
- Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH4 + are specific examples of cations present in pharmaceutically acceptable salts.
- compositions which comprises a compound according to formula (I) and a pharmaceutically acceptable carrier.
- the compound of formula (I) may be used in the manufacture of a medicament.
- Pharmaceutical compositions of the compound of formula (I) prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
- the liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
- Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternately, the compound may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
- Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
- Liquid carriers include syrup, peanut oil, olive oil, saline and water.
- the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
- the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
- the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
- a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
- Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
- the compound of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
- excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols
- the compound described herein is an antagonist of the vitronectin receptor, and is useful for treating diseases wherein the underlying pathology is attributable to ligand or cell which interacts with the vitronectin receptor.
- this compound is useful for the treatment of diseases wherein loss of the bone matrix creates pathology.
- the instant compound is useful for the treatment of ostoeporosis, hyperparathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastasis, bone loss due to immobilization or sex hormone deficiency.
- the compound of this invention is also believed to have utility as an antitumor, anti-angiogenic, antiinflammatory and anti- metastatic agent, and be useful in the treatment of atherosclerosis and restenosis.
- the compound is administered either orally or parenterally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone reso ⁇ tion, or other
- the pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.
- parenteral administration is preferred. An intravenous infusion of the peptide in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful.
- the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg.
- the compound is administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
- the precise level and method by which the compound is administered is readily determined by one routinely skilled in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
- This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises administering stepwise or in physical combination a compound of formula (I) and other inhibitors of bone reso ⁇ tion, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
- this invention provides a method of treatment using a compound of this invention and an anabolic agent, such as the bone morphogenic protein, iproflavone, useful in the prevention of bone loss and/or to increase bone mass.
- this invention provides a method of inhibiting tumor growth which comprises administering stepwise or in physical combination a compound of formula (I) and an antineoplastic agent.
- SUBST1TUTE SHEET (RULE 26) intravenous infusion.
- the preferred carrier is a dextrose/saline solution containing mannitol.
- the dose schedule of the platinum coordination compound may be on the basis of from about 1 to about 500 mg per square meter (mg/m ⁇ ) of body surface area per course of treatment. Infusions of the platinum coordiation compound may be given one to two times weekly, and the weekly treatments may be repeated several times.
- the course of therapy generally employed is from about 0.1 to about 300.0 mg/mr- of body surface area per day for about five consecutive days.
- the course of therapy employed for topotecan is from about 1.0 to about 2.0 mg/m ⁇ of body surface area per day for about five consecutive days.
- the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval.
- the pharmaceutical composition may be formulated with both the compound of formula (I) and the antineoplastic agent in the same container, but formualtion in different containers is preferred.
- both agents are provided in solution form, they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement.
- kits for convenient administration of the compound of formula (I) and the antineoplastic agent at the same or different times, comprising, in a single container, such as a box, carton or other container, individual bottles, bags, vials or other containers each having an effective amount of the compound of formula (I) for parenteral administration, as described above, and an effective amount of the antineoplastic agent for parenteral administration, as described above.
- kit can comprise, for example, both pharmaceutical agents in separate containers or the same container, optionally as lyophilized plugs, and containers of solutions for reconstitution.
- a variation of this is to include the solution for reconstitution and the lyophilized plug in two chambers of a single container, which can be caused to admix prior to use.
- the antineoplastic agent and the compound of this invention may be packaged separately, as in two containers, or lyophilized together as a powder and provided in a single container.
- both agents are provided in solution form, they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement.
- the compound of formula (I) may be in an i.v. injectable form, or infusion bag linked in series, via tubing, to the antineoplastic agent in a second infusion bag.
- a patient can receive an initial bolus-type injection or infusion of the compound of formula (I) followed by an infusion of the antineoplastic agent.
- the compound may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
- Solid-Phase [ ⁇ H]-SK&F-107260 Binding to a v ⁇ Human placenta or human platelet ⁇ v ⁇ 3 (0.1-0.3 mg/mL) in buffer T (containing 2 mM CaCl2 and 1% octylglucoside) was diluted with buffer T containing 1 mM CaCl2, 1 mM MnCl2, 1 mM MgCl2 (buffer A) and 0.05% NaN3, and then immediately added to 96-well ELISA plates (Corning, New York, NY) at 0.1 mL per well. 0.1 - 0.2 ⁇ g of ⁇ v ⁇ 3 was added per well. The plates were incubated overnight at 4°C.
- the wells were washed once with buffer A and were incubated with 0.1 mL of 3.5% bovine serum albumin in the same buffer for 1 hr at room temperature. Following incubation the wells were aspirated completely and washed twice with 0.2 mL buffer A.
- the plates were incubated for 1 hr at room temperature. Following incubation the wells were aspirated completely and washed once with 0.2 mL of ice cold buffer A in a well-to- well fashion.
- the receptors were solubilized with 0.1 mL of 1% SDS and the bound [ 3 H]-SK&F- 107260 was determined by liquid scintillation counting with the addition of 3 mL Ready Safe in a Beckman LS Liquid Scintillation Counter, with 40% efficiency. Nonspecific binding of H]-SK&F-107260 was determined in the presence of 2 ⁇ M SK&F-107260 and was consistently less than 1% of total radioligand input.
- the IC50 concentration of the antagonist to inhibit 50% binding of [ 3 H]-SK&F- 107260
- the Kj dissociation constant of the antagonist
- the compound of the present invention inhibits vitronectin binding to SK&F 107260 at a concentration of about 0.003 micomolar.
- the Compound of this invention is also tested for in vitro and in vivo bone resorption in assays standard in the art for evaluating inhibition of bone formation, such as the pit formation assay disclosed in EP 528 587, which may also be performed using human osteoclasts in place of rat osteoclasts, and the ovarectomized rat model, described by Wronski et al, Cells and Materials 1991, Sup. 1, 69-74.
- Rat or human aortic smooth muscle cells were used. The cell migration was monitored in a Transwell cell culture chamber by using a polycarbonate membrane with pores of 8 um (Costar). The lower surface of the filter was coated with vitronectin. Cells were suspended in DMEM supplemented with 0.2% bovine serum albumin at a concentration of 2.5 - 5.0 x 10*> cells/mL, and were pretreated with test compound at various concentrations for 20 min at 20°C. The solvent alone was used as control. 0.2 mL of the cell suspension was placed in the upper compartment of the chamber. The lower compartment contained 0.6 mL of DMEM supplemented with 0.2% bovine serum albumin.
- Incubation was carried out at 37°C in an atmosphere of 95% air/5% CO2 for 24 hr. After incubation, the non-migrated cells on the upper surface of the filter were removed by gentle scraping. The filter was then fixed in methanol and stained with 10% Giemsa stain. Migration was measured either by a) counting the number of cells that had migrated to the lower surface of the filter or by b) extracting the stained cells with 10% acetic acid followed by determining the absorbance at 600 nM.
- Each experimental group consists of 5-6 adult male Sprague-Dawley rats (250-400g body weight).
- the rats are thyroparathyroidectomized (by the vendor, Taconic Farms) 7 days prior to use. All rats receive a replacement dose of thyroxine every 3 days.
- On receipt of the rats circulating ionized calcium levels are measured in whole blood immediately after it has been withdrawn by tail venipuncture into heparinized tubes. Rats are included if the ionized Ca level (measured with a Ciba-Corning model 634 calcium pH analyzer) is ⁇ 1.2 mM/L.
- Each rat is fitted with an indwelling venous and arterial catheter for the delivery of test material and for blood sampling respectively.
- each rat is administered either control vehicle or human parathyroid hormone 1-34 peptide (hPTHl-34, dose 1.25 ug/kg/h in saline/0.1% bovine serum albumin, Bachem, Ca) or a mixture of hPTHl-34 and test material, by continuous intravenous infusion via the venous catheter using an external syringe pump.
- the calcemic response of each rat is measured at two-hourly intervals during the infusion period of 6-8 hours.
- the medium is aspirated and replaced with murine anti-HLA-DR antibody then diluted 1 :3 in RPMI- 1640 medium.
- the suspension is incubated for 30 mins on ice and mixed frequently.
- the cells are washed x2 with cold RPMI- 1640 followed by centrifugation (1000 rpm, 5 mins at 4°C) and the cells are then transferred to a sterile 15 ml centrifuge tube.
- the number of mononuclear cells are enumerated in an improved Neubauer counting chamber.
- Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG (Dynal, Great Neck, NY) are removed from their stock bottle and placed into 5 ml of fresh medium (this washes away the toxic azide preservative). The medium is removed by immobilizing the beads on a magnet and is replaced with fresh medium.
- the beads are mixed with the cells and the suspension is incubated for 30 mins on ice. The suspension is mixed frequently.
- the bead-coated cells are immobilized on a magnet and the remaining cells (osteoclast-rich fraction) are decanted into a sterile 50 ml centrifuge tube.
- Fresh medium is added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process is repeated xlO. The bead-coated cells are discarded.
- the viable osteoclasts are enumerated in a counting chamber, using fluorescein diacetate to label live cells.
- a large-bore disposable plastic pasteur pipet is used to add the sample to the chamber.
- the osteoclasts are pelleted by centrifugation and the density adjusted to the appropriate number in EMEM medium (the number of osteoclasts is variable from tumor to tumor), supplemented with 10% fetal calf serum and Ug/liter of sodium bicarbonate. • 3ml aliquots of the cell suspension (per compound treatment) are decanted into
- the slices are washed in six changes of warm PBS (10 ml / well in a 6- well plate) and then placed into fresh medium containing the compound treatment or control samples. The samples are incubated at 37°C for 48 hours.
- TRIP Tartrate resistant acid phosphatase
- the bone slices containing the attached osteoclasts are washed in phosphate buffered saline and fixed in 2% gluteraldehyde (in 0.2M sodium cacodylate) for 5 mins.
- the TRAP positive osteoclasts (brick red/ pu ⁇ le precipitate) are enumerated by bright-field microscopy and are then removed from the surface of the dentine by sonication. • Pit volumes are determined using the Nikon/Lasertec ILM21W confocal microscope.
- the human osteoclasts are enriched and prepared for compound screening as described in the initial 9 steps of Assay 1. For clarity, these steps are repeated hereinbelow.
- the medium is aspirated and replaced with murine anti-HLA-DR antibody then diluted 1 :3 in RPMI- 1640 medium.
- the suspension is incubated for 30 mins on ice and mixed frequently.
- the cells are washed x2 with cold RPMI-1640 followed by centrifugation (1000 rpm, 5 mins at 4°C) and the cells are then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells are enumerated in an improved Neubauer counting chamber.
- Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG (Dynal, Great Neck, NY) are removed from their stock bottle and placed into 5 ml of fresh medium (this washes away the toxic azide preservative). The medium is removed by immobilizing the beads on a magnet and is replaced with fresh medium.
- the beads are mixed with the cells and the suspension is incubated for 30 mins on ice. The suspension is mixed frequently. • The bead-coated cells are immobilized on a magnet and the remaining cells
- Fresh medium is added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process is repeated xlO. The bead-coated cells are discarded.
- the viable osteoclasts are enumerated in a counting chamber, using fluorescein diacetate to label live cells.
- a large-bore disposable plastic pasteur pipet is used to add the sample to the chamber.
- the osteoclasts are pelleted by centrifugation and the density adjusted to the appropriate number in EMEM medium (the number of osteoclasts is variable from tumor to tumor), supplemented with 10% fetal calf serum and 1 Jg/liter of sodium bicarbonate.
- osteoclast preparations are preincubated for 30 minutes at 37°C with test compound (4 doses) or controls. • They are then seeded onto bovine cortical bone slices in wells of a 48-well tissue culture plate and are incubated for a further 2 hours at 37°C.
- the bone slices are washed in six changes of warm phosphate buffered saline (PBS), to remove non-adherent cells, and are then returned to wells of a 48 well plate containing fresh compound or controls. • The tissue culture plate is then incubated for 48 hours at 37°C.
- PBS warm phosphate buffered saline
- the supernatants from each well are aspirated into individual tubes and are screened in a competitive ELISA that detects the c-telopeptide of type I collagen which is released during the resorption process.
- This is a commercially available ELISA (Osteometer, Denmark) that contains a rabbit antibody that specifically reacts with an 8- amino acid sequence (Glu-Lys-Ala-His- Asp-Gly-Gly-Arg) that is present in the carboxy-terminal telopeptide of the al -chain of type I collagen.
- the results are expressed as % inhibition of resorption compared to a vehicle control.
- Human osteoclast adhesion assay The human osteoclasts are enriched and prepared for compound screening as described above in the inital 9 steps of Assay 1. For clarity, these steps are repeated hereinbelow.
- SUBST1TUTESHEET(RULE26) • Aliquots of human osteoclastoma-derived cell suspensions are removed from liquid nitrogen strorage, warmed rapidly at 37°C and washed xl in RPMI- 1640 medium by centrifugation (lOOOrpm, 5 mins at 4°C).
- the medium is aspirated and replaced with murine anti-HLA-DR antibody then diluted 1 :3 in RPMI- 1640 medium.
- the suspension is incubated for 30 mins on ice and mixed frequently.
- the cells are washed x2 with cold RPMI- 1640 followed by centrifugation (1000 rpm, 5 mins at 4°C) and the cells are then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells are enumerated in an improved Neubauer counting chamber.
- Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG (Dynal, Great Neck, NY) are removed from their stock bottle and placed into 5 ml of fresh medium (this washes away the toxic azide preservative). The medium is removed by immobilizing the beads on a magnet and is replaced with fresh medium. • The beads are mixed with the cells and the suspension is incubated for 30 mins on ice. The suspension is mixed frequently.
- the bead-coated cells are immobilized on a magnet and the remaining cells (osteoclast-rich fraction) are decanted into a sterile 50 ml centrifuge tube.
- Fresh medium is added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process is repeated xlO. The bead-coated cells are discarded.
- the viable osteoclasts are enumerated in a counting chamber, using fluorescein diacetate to label live cells.
- a large-bore disposable plastic pasteur pipet is used to add the sample to the chamber.
- the osteoclasts are pelleted by centrifugation and the density adjusted to the appropriate number in EMEM medium (the number of osteoclasts is variable from tumor to tumor), supplemented with 10% fetal calf serum and 1 Jg/liter of sodium bicarbonate.
- Osteoclastoma-derived osteoclasts are preincubated with compound (4 doses) or controls at 37°C for 30 minutes. • The cells are then seeded onto osteopontin-coated slides (human or rat osteopontin,
- Non adherent cells are removed by washing the slides vigorously in phosphate buffered saline and the cells remaining on the slides are fixed in acetone.
- the osteoclasts are stained for tartrate-resistant acid phosphatase (TRAP), a selective marker for cells of this phenotype (see steps 15 -17), and are enumerated by light microscopy. The results are expressed as % inhibition of adhesion compared to a vehicle control.
- TRIP tartrate-resistant acid phosphatase
- HEK293 cells Human embryonic kidney cells (HEK293 cells) were obtained from ATCC (Catalog No. CRL 1573). Cells were grown in Earl's minimal essential medium (EMEM) medium containing Earl's salts, 10% fetal bovine serum, 1% glutamine and 1% Penicillin- Steptomycin.
- EMEM Earl's minimal essential medium
- the growth medium was supplemented with 450 ⁇ g/mL Geneticin (G418 Sulfate, GIBCO-BRL, Bethesda, MD). The cells were maintained in selection medium until the colonies were large enough to be assayed.
- the cells were immobilized on glass microscope slides by centrifugation, fixed in acetone for 2 min at room temperature and air dried. Specific reactivity with 23C6, a monoclonal antibody specific for the ⁇ v ⁇ 3 complex was demonstrated using a standard indirect immunofluorescence method.
- SUBST1TUTE SHEET (RULE 26) temperature. Excess stain was removed by extensive washing with deionized water. The toluidine blue incorporated into cells was eluted by the addition of 0.1 mL of 50% ethanol containing 50 mM HCl. Cell adhesion was quantitated at an optical density of 600 nm on a microtiter plate reader (Titertek Multiskan MC, Sterling, VA).
- the vitronectin receptor v ⁇ s was purified from human placenta. Receptor preparation was diluted with 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 1 mM CaCl 2 , 1 mM MnCl 2 , 1 mM MgCl 2 (buffer A) and was immediately added to 96-well ELISA plates at 0.1 ml per well. 0.1-0.2 ⁇ g of v ⁇ 3 was added per well. The plates were incubated overnight at 4°C. At the time of the experiment, the wells were washed once with buffer A and were incubated with 0.1 ml of 3.5% bovine serum albumin in the same buffer for 1 hr at room temperature.
- the receptors were solubilized with 0.1 ml of 1% SDS and the bound [ 3 H]-SK&F- 107260 was determined by liquid scintillation counting with the addition of 3 ml Ready Safe in a Beckman LS 6800 Liquid Scintillation Counter, with 40% efficiency.
- Nonspecific binding of [ 3 H] -SK&F- 107260 was determined in the presence of 2 ⁇ M SK&F- 107260 and was consistently less than 1% of total radioligand input.
- the IC5 0 concentration of the antagonist to inhibit 50% binding of [ 3 H]-SK&F-107260 was determined by a nonlinear, least squares curve-fitting routine, which was modified from the LUNDON-2 program.
- Kj dissociation constant of the antagonist
- the column was washed with 50 mL cold buffer A.
- the lectin-retained GPIIb-IIIa was eluted with buffer A containing 10% dextrose. All procedures were performed at 4°C.
- the GPIIb-IIIa obtained was >95% pure as shown by SDS polyacrylamide gel electrophoresis.
- a mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) were dried to the walls of a glass tube under a stream of nitrogen.
- Purified GPIIb-IIIa was diluted to a final concentration of 0.5 mg/mL and mixed with the phospholipids in a protein:phospholipid ratio of 1 :3 (w:w). The mixture was resuspended and sonicated in a bath sonicator for 5 min.
- the mixture was then dialyzed overnight using 12,000-14,000 molecular weight cutoff dialysis tubing against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaC12 (with 2 changes).
- the GPIIb-IIIa- containing liposomes wee centrifuged at 12,000g for 15 min and resuspended in the dialysis buffer at a final protein concentration of approximately 1 mg/mL. The liposomes were stored at -70C until needed.
- the binding to the fibrinogen receptor (GPIIb-IIIa) was assayed by an indirect competitive binding method using [ 3 H]-SK&F-107260 as an RGD-type ligand.
- the binding assay was performed in a 96-well filtration plate assembly (Millipore Co ⁇ oration, Bedford, MA) using 0.22 um hydrophilic durapore membranes.
- the wells were precoated with 0.2 mL of 10 ⁇ g/mL polylysine (Sigma Chemical Co., St. Louis, MO.) at room temperature for 1 h to block nonspecific binding.
- Various concentrations of unlabeled benzazepines were added to the wells in quadruplicate.
- [ ⁇ HJ-SK&F- 107260 was applied to each well at a final concentration of 4.5 nM, followed by the addition of 1 ⁇ g of the purified platelet GPIIb-IIIa-containing liposomes. The mixtures were incubated for 1 h at room temperature. The GPIIb-IIIa-bound [3H]-SK&F- 107260 was seperated from the unbound by filtration using a Millipore filtration manifold, followed by washing with ice-cold buffer (2 times, each 0.2 mL).
- IC50 concentration of the antagonist which inhibits specific binding of [ 3 H]-SK&F- 107260 by 50% at equilibrium.
- the compound of this invention has an affinity for the vitronectin receptor relative to the fibrinogen receptor of greater than 10: 1. This compound has a ratio of activity of greater than 100:1.
- the efficacy of the compound of formula (I) alone or in combination with an antineoplastic agent may be determined using several transplantable mouse tumor models. See U. S. Patent Nos. 5,004,758 and 5,633,016 for details of these models.
- NMR nuclear magnetic resonance
- Apex-ODS indicates an octadecylsilyl derivatized silica gel chromatographic support having a nominal particle size of 5 ⁇ , made by Jones Chromatography, Littleton, Colorado.
- YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan.
- PRP- 1 ® is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada.
- Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Co ⁇ ., Denver, Colorado.
- N-(4-trifluormethylbenzyl)aminomethyl]-4-methoxydihydrocinnamide (40.30 g, 64 mmol) in dry THF (300 mL) at -78 °C was added a solution of lithium bis(trimethylsilyl)amide (70 mL, 1 M in THF, 70 mmol) via syringe. After 30 min, methyl bromoacetate (30 mL, 317 mmol) was added via syringe. After another 30 min at -78 °C the reaction was allowed to warm to -20 °C and stirred for an additional 6 h.
- the resulting homogeneous solution was treated slowly with a solution of sodium sulfite (34.3 g, 272 mmol) in water (175 mL) at 0 °C, then was acidified with an ice-cold solution of concentrated HCl (35 L) in water (150 mL). The reaction was extracted with ethyl acetate (2x200 mL), and the combined organic layers were washed with brine (400 mL), dried (MgS ⁇ 4) and concentrated to dryness. The resulting residue was treated with 4.0 M HCl in dioxane (400 mL) with stirring at RT (slow gas evolution was observed).
- a preparation which contains 20 mg of the compound of Example 1 as a sterile dry powder is prepared as follows: 20 mg of the compound is dissolved in 15 mL of distilled water. The solution is filtered under sterile conditions into a 25 mL multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 mL of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume. Subsequent dilution may be made by addition of a metered volume of this dosage unit to another volume of D5W for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion or other injection-infusion system.
- D5W dextrose in water
- a capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Example 1 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.
- a tablet for oral administration is prepared by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 1 with a 10% gelatin solution.
- the wet granules are screened, dried, mixed with 10 mg starch, 5 mg talc and 3 mg stearic acid; and compressed into a tablet.
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Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR9813208-3A BR9813208A (en) | 1997-09-24 | 1998-09-24 | Vitronectin receptor antagonist |
JP2000512539A JP2002528380A (en) | 1997-09-24 | 1998-09-24 | Vitronectin receptor antagonist |
KR1020007003088A KR20010024247A (en) | 1997-09-24 | 1998-09-24 | Vitronectin Receptor Antagonist |
PL98339413A PL339413A1 (en) | 1997-09-24 | 1998-09-24 | Antagonistic vitronectin receptor |
HU0003949A HUP0003949A2 (en) | 1997-09-24 | 1998-09-24 | Vitronectin receptor antagonist and pharmaceutical composition containing the compounds |
CA002303846A CA2303846A1 (en) | 1997-09-24 | 1998-09-24 | Vitronectin receptor antagonist |
EP98949454A EP1017387A4 (en) | 1997-09-24 | 1998-09-24 | Vitronectin receptor antagonist |
IL13518998A IL135189A0 (en) | 1997-09-24 | 1998-09-24 | Vitronectin receptor antagonist |
AU95774/98A AU9577498A (en) | 1997-09-24 | 1998-09-24 | Vitronectin receptor antagonist |
NO20001514A NO20001514L (en) | 1997-09-24 | 2000-03-23 | Vitronectin receptor antagonist |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5983297P | 1997-09-24 | 1997-09-24 | |
US60/059,832 | 1997-09-24 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09509142 A-371-Of-International | 2000-03-22 | ||
US09/800,057 Continuation US20010014737A1 (en) | 1997-09-24 | 2001-03-05 | Vitronectin receptor antagonist |
Publications (1)
Publication Number | Publication Date |
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WO1999015170A1 true WO1999015170A1 (en) | 1999-04-01 |
Family
ID=22025570
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/019949 WO1999015170A1 (en) | 1997-09-24 | 1998-09-24 | Vitronectin receptor antagonist |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP1017387A4 (en) |
JP (1) | JP2002528380A (en) |
KR (1) | KR20010024247A (en) |
CN (1) | CN1273529A (en) |
AU (1) | AU9577498A (en) |
BR (1) | BR9813208A (en) |
CA (1) | CA2303846A1 (en) |
HU (1) | HUP0003949A2 (en) |
IL (1) | IL135189A0 (en) |
NO (1) | NO20001514L (en) |
PL (1) | PL339413A1 (en) |
TR (1) | TR200000792T2 (en) |
WO (1) | WO1999015170A1 (en) |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001023357A2 (en) * | 1999-09-27 | 2001-04-05 | Amgen Inc. | Fused cycloheptane and fused azacycloheptane compounds and their use as integrin receptor antagonists |
US6232308B1 (en) | 1999-02-03 | 2001-05-15 | Merck & Co., Inc. | Bezazepine derivatives as αv integrin receptor antagonists |
WO2002018340A1 (en) * | 2000-08-30 | 2002-03-07 | Pharmacia Corporation | GEM-SUBSTITUTED α v β 3 INTEGRIN ANTAGONISTS |
WO2002018377A1 (en) * | 2000-08-29 | 2002-03-07 | Pharmacia Corporation | Compounds containing a bicyclic ring system useful as alpha v beta 3 antagonists |
US6531494B1 (en) | 2001-08-29 | 2003-03-11 | Pharmacia Corporation | Gem-substituted αvβ3 antagonists |
WO2005120477A2 (en) | 2004-06-07 | 2005-12-22 | Merck & Co., Inc. | N- (2-benzyl) -2-phenylbutanamides as androgen receptor modulators |
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 |
WO2009063990A1 (en) | 2007-11-16 | 2009-05-22 | Ube Industries, Ltd. | Benzazepinone compound |
WO2010093706A2 (en) | 2009-02-10 | 2010-08-19 | The Scripps Research Institute | Chemically programmed vaccination |
WO2010113958A1 (en) | 2009-03-30 | 2010-10-07 | 宇部興産株式会社 | Pharmaceutical composition for treatment or prevention of ophthalmic diseases |
WO2010136168A2 (en) | 2009-05-25 | 2010-12-02 | Merck Patent Gmbh | Continuous administration of integrin ligands for treating cancer |
EP2257538A2 (en) * | 2008-03-06 | 2010-12-08 | GlaxoSmithKline LLC | Process |
EP2292251A1 (en) | 2001-04-24 | 2011-03-09 | Merck Patent GmbH | Combination therapy using anti-angiogenic agents and TNF-alpha |
EP2428226A1 (en) | 2001-10-22 | 2012-03-14 | The Scripps Research Institute | Antibody targeting compounds |
WO2015181676A1 (en) | 2014-05-30 | 2015-12-03 | Pfizer Inc. | Carbonitrile derivatives as selective androgen receptor modulators |
WO2023275715A1 (en) | 2021-06-30 | 2023-01-05 | Pfizer Inc. | Metabolites of selective androgen receptor modulators |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5572996B2 (en) * | 2009-05-15 | 2014-08-20 | 宇部興産株式会社 | Medicine containing benzazepinone compound as active ingredient |
CN103864765B (en) * | 2014-03-05 | 2016-02-10 | 天津药物研究院 | Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1998014192A1 (en) * | 1996-10-02 | 1998-04-09 | Smithkline Beecham Corporation | Vitronectin receptor antagonists |
WO1998015278A1 (en) * | 1996-10-07 | 1998-04-16 | Smithkline Beecham Corporation | Method for stimulating bone formation |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996000574A1 (en) * | 1994-06-29 | 1996-01-11 | Smithkline Beecham Corporation | Vitronectin receptor antagonists |
-
1998
- 1998-09-24 EP EP98949454A patent/EP1017387A4/en not_active Withdrawn
- 1998-09-24 BR BR9813208-3A patent/BR9813208A/en not_active Application Discontinuation
- 1998-09-24 HU HU0003949A patent/HUP0003949A2/en unknown
- 1998-09-24 JP JP2000512539A patent/JP2002528380A/en not_active Withdrawn
- 1998-09-24 AU AU95774/98A patent/AU9577498A/en not_active Abandoned
- 1998-09-24 PL PL98339413A patent/PL339413A1/en unknown
- 1998-09-24 IL IL13518998A patent/IL135189A0/en unknown
- 1998-09-24 TR TR2000/00792T patent/TR200000792T2/en unknown
- 1998-09-24 CN CN98809495A patent/CN1273529A/en active Pending
- 1998-09-24 CA CA002303846A patent/CA2303846A1/en not_active Abandoned
- 1998-09-24 WO PCT/US1998/019949 patent/WO1999015170A1/en not_active Application Discontinuation
- 1998-09-24 KR KR1020007003088A patent/KR20010024247A/en not_active Application Discontinuation
-
2000
- 2000-03-23 NO NO20001514A patent/NO20001514L/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998014192A1 (en) * | 1996-10-02 | 1998-04-09 | Smithkline Beecham Corporation | Vitronectin receptor antagonists |
WO1998015278A1 (en) * | 1996-10-07 | 1998-04-16 | Smithkline Beecham Corporation | Method for stimulating bone formation |
Non-Patent Citations (1)
Title |
---|
See also references of EP1017387A4 * |
Cited By (27)
Publication number | Priority date | Publication date | Assignee | Title |
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US6232308B1 (en) | 1999-02-03 | 2001-05-15 | Merck & Co., Inc. | Bezazepine derivatives as αv integrin receptor antagonists |
WO2001023357A3 (en) * | 1999-09-27 | 2002-01-24 | Amgen Inc | Fused cycloheptane and fused azacycloheptane compounds and their use as integrin receptor antagonists |
US6514964B1 (en) | 1999-09-27 | 2003-02-04 | Amgen Inc. | Fused cycloheptane and fused azacycloheptane compounds and their methods of use |
WO2001023357A2 (en) * | 1999-09-27 | 2001-04-05 | Amgen Inc. | Fused cycloheptane and fused azacycloheptane compounds and their use as integrin receptor antagonists |
WO2002018377A1 (en) * | 2000-08-29 | 2002-03-07 | Pharmacia Corporation | Compounds containing a bicyclic ring system useful as alpha v beta 3 antagonists |
WO2002018340A1 (en) * | 2000-08-30 | 2002-03-07 | Pharmacia Corporation | GEM-SUBSTITUTED α v β 3 INTEGRIN ANTAGONISTS |
EP2292251A1 (en) | 2001-04-24 | 2011-03-09 | Merck Patent GmbH | Combination therapy using anti-angiogenic agents and TNF-alpha |
US6531494B1 (en) | 2001-08-29 | 2003-03-11 | Pharmacia Corporation | Gem-substituted αvβ3 antagonists |
EP2428226A1 (en) | 2001-10-22 | 2012-03-14 | The Scripps Research Institute | Antibody targeting compounds |
WO2005120477A2 (en) | 2004-06-07 | 2005-12-22 | Merck & Co., Inc. | N- (2-benzyl) -2-phenylbutanamides as androgen receptor modulators |
EP2338518A1 (en) | 2006-01-18 | 2011-06-29 | Merck Patent GmbH | Specific therapy using integrin ligands for treating cancer |
WO2007084670A2 (en) | 2006-01-18 | 2007-07-26 | Merck Patent Gmbh | Specific therapy using integrin ligands for treating cancer |
EP2335733A1 (en) | 2006-01-18 | 2011-06-22 | Merck Patent GmbH | Specific therapy using integrin ligands for treating cancer |
EP2441464A1 (en) | 2007-01-18 | 2012-04-18 | Merck Patent GmbH | Specific therapy and medicament 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 |
EP2578225A1 (en) | 2007-07-18 | 2013-04-10 | Merck Patent GmbH | Specific Therapy and Medicament Using Integrin Ligands for Treating Cancer |
KR20100106391A (en) | 2007-11-16 | 2010-10-01 | 우베 고산 가부시키가이샤 | Benzazepinone compound |
US8377922B2 (en) | 2007-11-16 | 2013-02-19 | Ube Industries, Ltd. | Benzazepinone compound |
WO2009063990A1 (en) | 2007-11-16 | 2009-05-22 | Ube Industries, Ltd. | Benzazepinone compound |
EP2257538A2 (en) * | 2008-03-06 | 2010-12-08 | GlaxoSmithKline LLC | Process |
EP2257538A4 (en) * | 2008-03-06 | 2012-02-22 | Glaxosmithkline Llc | Process |
WO2010093706A2 (en) | 2009-02-10 | 2010-08-19 | The Scripps Research Institute | Chemically programmed vaccination |
WO2010113958A1 (en) | 2009-03-30 | 2010-10-07 | 宇部興産株式会社 | Pharmaceutical composition for treatment or prevention of ophthalmic diseases |
WO2010136168A2 (en) | 2009-05-25 | 2010-12-02 | Merck Patent Gmbh | Continuous administration of integrin ligands for treating cancer |
WO2015181676A1 (en) | 2014-05-30 | 2015-12-03 | Pfizer Inc. | Carbonitrile derivatives as selective androgen receptor modulators |
US10328082B2 (en) | 2014-05-30 | 2019-06-25 | Pfizer Inc. | Methods of use and combinations |
WO2023275715A1 (en) | 2021-06-30 | 2023-01-05 | Pfizer Inc. | Metabolites of selective androgen receptor modulators |
Also Published As
Publication number | Publication date |
---|---|
EP1017387A4 (en) | 2004-08-18 |
BR9813208A (en) | 2000-08-22 |
IL135189A0 (en) | 2001-05-20 |
AU9577498A (en) | 1999-04-12 |
HUP0003949A2 (en) | 2001-10-28 |
NO20001514D0 (en) | 2000-03-23 |
CA2303846A1 (en) | 1999-04-01 |
TR200000792T2 (en) | 2000-09-21 |
NO20001514L (en) | 2000-03-23 |
EP1017387A1 (en) | 2000-07-12 |
PL339413A1 (en) | 2000-12-18 |
KR20010024247A (en) | 2001-03-26 |
JP2002528380A (en) | 2002-09-03 |
CN1273529A (en) | 2000-11-15 |
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