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WO1998015278A1 - Procede de stimulation de la formation osseuse - Google Patents

Procede de stimulation de la formation osseuse Download PDF

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Publication number
WO1998015278A1
WO1998015278A1 PCT/US1997/018178 US9718178W WO9815278A1 WO 1998015278 A1 WO1998015278 A1 WO 1998015278A1 US 9718178 W US9718178 W US 9718178W WO 9815278 A1 WO9815278 A1 WO 9815278A1
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WIPO (PCT)
Prior art keywords
methyl
oxo
tetrahydro
benzodiazepine
carbonyl
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PCT/US1997/018178
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English (en)
Inventor
Fred H. Drake
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Smithkline Beecham Corporation
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Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to EP97945563A priority Critical patent/EP0946180A4/fr
Priority to JP10517727A priority patent/JP2001501951A/ja
Publication of WO1998015278A1 publication Critical patent/WO1998015278A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • 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
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/26—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a double bond between positions 10 and 11
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • This invention relates to a new method for treating bone-related disorders with compounds which stimulate bone-formation.
  • the bone matrix consists of inorganic mineral and organic matrix.
  • the mineral which constitutes 65% of bone, is mainly calcium and phosphorous in hydroxyapatite crystals.
  • the matrix, which constitutes 35% of the bone tissue consists primarily of type I collagen (90%) and an assortment of non-collagenous proteins including osteopontin, bone sialoprotein, fibronectin, thrombospondin, osteocalcin, osteonectin, proteoglycans, and glycosaminoglycans.
  • Osteocalcin appears to be restricted to the cells of calcified tissues and is regulated by l,25(OH) 2 D3. It has been suggested that serum osteocalcin may be a marker for bone formation. See Hauschka et al, Phys. Rev., 69, 990 (1989). and Charles et al., Calcified Tissue International, 51,406 (1992).
  • Bone is extremely dynamic. At the tissue level it is continuously being resorbed and rebuilt in order to maintain the strength and vitality of skeletal tissue and to meet the demands of mineral homeostasis. Resorption and formation are carried out by osteoclasts and osteoblasts, respectively, at discrete foci in the skeleton. These foci, or remodeling units, represent sites for a cycle of resorption followed by new bone formation. The remodeling cycle begins when an osteoclast initiates the resorptive phase. Over a period of weeks these cells resorb bone until a signal, as yet undefined, stops the resorptive process and initiates the formation phase by recruitment of osteoblasts to the site.
  • a number of diseases of the skeleton are characterized by such an imbalance, including osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, and Paget's disease.
  • Bone formation occurs by an ordered process of osteoblast-mediated matrix deposition and mineralization. These events are associated with commitment of osteoblast precursors to a differentiation pathway that leads through a series of stages to mature osteoblasts; these stages are defined by changes in expression of markers of differentiation such as alkaline phosphatase, type I collagen, and osteocalcin.
  • Integrins are a family of cell surface receptors that are involved in both cell-matrix and cell-cell interactions.
  • the receptors are heterodimers composed of one ⁇ and one ⁇ subunit, each of which contain large extracellular domains, a single transmembrane domain, and relatively short cytoplasmic tail. At least 14 ⁇ and 8 ⁇ subunits have been identified, although not all ⁇ and ⁇ subunits appear to interact to form functional receptors. At least 20 combinations have been described. Hynes, R.O., Cell, 69, 1 1 (1992).
  • osteoclasts are mediated through integrin receptor.
  • integrin receptor For instance, Davies, et al, J. Cell Biol, 1989, 109, 1817, disclose that the osteoclast functional antigen, which is implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor.
  • the vitronectin receptor, or the ⁇ 3 integrin is known to bind to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tri-peptide Arg- Gly-Asp (or RGD) motif.
  • RGD tri-peptide Arg- Gly-Asp
  • bone formation may be stimulated by treating osteoblasts with compounds which bind to a receptor on osteoblasts.
  • the ability of compounds to bind this receptor and to induce bone formation may be demonstrated by the release of osteocalcin from cell cultures of osteoblasts, in vitro mineralization of bone tissue, enhanced matrix deposition, and in vivo bone formation.
  • this invention is an assay for identifying compounds which stimulate bone formation or mineralization which comprises treating osteoblasts with a compound and assaying for an increase in osteocalcin release. This discovery has led to the further discovery that small molecules may act directly upon osteoblasts to induce bone formation.
  • the osteoblasts may be derived from a natural source, such as by isolating and culturing osteoblasts from the bone tissue of a mammal, or from an immortalized cell line, such as an osteosarcoma, or by differentiation of precursor cells, such as stromal cells, into osteoblasts.
  • Rat, mouse and human cells are particularly useful for this, although other mammals would also be useful.
  • ROS 17/2.8 osteoblasts are useful. Since osteoblasts generally produce osteocalcin at a basal level, one needs to quantitate the increase in osteocalcin production to obtain an indication of the extent of osteoblast activation.
  • the compounds of this invention like endogenous mediators of bone production (such as parathyroid hormone and di-(OH)2-vitamin D3), will induce a maximal two to three fold increase in osteocalcin production in a dose- related fashion.
  • endogenous mediators of bone production such as parathyroid hormone and di-(OH)2-vitamin D3
  • assaying for osteocalcin release mean measuring the increase in osteocalcin production relative to the basal and maximal level of osteocalcin release caused by a compound of this invention.
  • a convenient measure of the activity of a compound to stimulate osteoblasts and bone formation is the EC50 of a compound for eliciting osteocalcin release.
  • a convenient method for quantitating osteocalcin release is radioimmunoassay.
  • Antibodies to osteocalcin and kits for quantitating osteocalcin are commercially available, or may be prepared by routine methods.
  • this invention is a method for stimulating bone formation which comprises administering a compound which causes an increase in osteocalcin release.
  • this is a method for stimulating bone formation which comprises administering an integrin-binding compound.
  • the compound will cause at least a two fold increase in osteocalcin production, and will have an EC50 of less than 10 uM, more preferably below 1 uM and most preferably below 0.1 uM.
  • 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 osteoporosis, 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.
  • hyperparathyroidism for instance, hyperparathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastasis, and bone loss due to immobilization or sex hormone deficiency, could benefit from administering a compound of this invention.
  • Compounds as used herein is intended to mean any chemical compound, other than a natural endogenous ligand, such as vitamin D3 or parathyroid hormone, which stimulates osteocalcin release.
  • the compound may be a peptide, protein, antibody or a small organic molecule.
  • the compound binds to an integrin receptor.
  • the interaction that mediates the osteocalcin release and bone formation is believed to be an interaction with an integrin or a group of integrin receptors, since compounds which contain the -Arg-Gly-Asp- sequence, such as cyclo[Arg-Gly-Asp-D- Phe-Val] and Gly-Arg-Gly-Asp-Ser, are able to stimulate osteoblasts and cause bone formation.
  • the -Arg-Gly-Asp- motif is commonly found in integrin receptor ligands.
  • other compounds that are known to bind to integrin receptors have also been found to be useful in this invention. Accordingly, in a preferred embodiment compounds which bind to integrin receptors are of particular interest for use in the method of this invention.
  • Integrin-binding compounds that useful in this invention are conveniently identified by assaying their ability to induce osteocalcin release from osteoblasts.
  • the compounds will stimulate osteocalcin release with an EC50 of less than 10 uM, more preferably at less than 1 uM.
  • the compounds will have an EC50 of less than 0.1 uM.
  • this invention is a method for stimulating bone formation which comprises administering an integrin binding compound, particularly an ⁇ 3 binding compound, which causes the release of osteocalcin.
  • an integrin binding compound particularly an ⁇ 3 binding compound, which causes the release of osteocalcin.
  • Compounds which have a Ki for binding the ⁇ 3 receptor of less than 2 uM, more often less than 1 uM are often active in the assay.
  • Vitronectin receptor antagonists are often also potent stimulators of osteocalcin release. It should be appreciated, however, that the effect is not necessarily due to interaction with the vitronectin receptor, since pre-treatment of osteoblasts with neutralizing antibodies specific for the vitronectin receptor does not effect the release of osteocalcin, and does not mimic or block bone formation induced by the active compounds of this invention.
  • compounds which have the desired bone-forming activity will bind to the 0C ⁇ b ⁇ 3 receptor with a Ki of greater than 10 uM.
  • Compounds which have been found to elicit osteocalcin release have also been shown to induce mineralization in osteoblastic cell lines from murine, rat and human origin.
  • Table 1 illustrates the generality of the response to various osteoblastic cell lines to the osteocalcin-releasing compounds cyclo(Arg-Gly-Asp-D-Phe-Val) and 7-[(((2-benzimidazolyl)methyl)amino)carbonyl]- 2,3,4, 5-tetrahydro-4-methyl-3-oxo-lH-l,4-benzodiazepine-2-acetic acid: Table 1
  • cells of non-osteoblastic origin e.g., L929 cells
  • R 1 is H, C ⁇ _6 alkyl or Ar-Ci ⁇ alkyl;
  • R2 is (CH 2 ) n C ⁇ 2 R';
  • R 3 is H, Ci ⁇ alkyl, Ar-Co-6alkyl, Het-Co-6alkyl, or C3-6cycloalkyl-Co-6alkyl;
  • R 4 is W-(Q') p -(CR' 2 ) q -U-(CR' 2 ) s -;
  • R 5 and R 6 are H, Ci. ⁇ alkyl, Ar-Co- ⁇ alkyl, Het-Co-6alkyl or C3_6cycloalkyl-Co-6alkyl;
  • R' is H, C ⁇ .6alkyl, C 3 . 7 cycloalkyl-Co- 4 alkyl or Ar-Co- 4 a ⁇ kyl;
  • Q' is NR 5 , S or CR 5 ;
  • Q is NR', O or S; z_z indicates a single or double bond:
  • R b and R c are independently selected from H, - ⁇ lkyl, Ar-Co-6alkyl, Het-C 0- 6alkyl, or C 3- 6cycloalkyl-C 0- 6alkyl, halogen, OR 1 , SR 1 , COR 1 , OH, N0 2 , N(R !
  • Certain peptides containing the -Arg-Gly-Asp- sequence, or modifications of this sequence, have also been founds to stimulate the release of osteocalcin.
  • Representative peptides active in this invention are: cyclo [ Arg-Gly- Asp-D-Phe- Val] ;
  • integrin receptor ligands such as:
  • R 4 is as above for formula (I), and R x is Ar or C ⁇ _6alkyl, particularly phenyl or n-butyl, also cause the release of osteocalcin.
  • R x is Ar or C ⁇ _6alkyl, particularly phenyl or n-butyl, also cause the release of osteocalcin.
  • X-X' is CH 2 -CH or NR i CH.
  • R 2 is CH CO 2 R'; preferably CO 2 H.
  • R 3 is H, C ⁇ galkyl, CF3CH2 or or benzyl or phenylethyl optionally substituted by one to three CF3, CF 3 O, NO2, CN, methoxy, halo, -O-CH2-O-, C ⁇ -4 alkyl.
  • R 5 is H or methyl.
  • R 6 is H or Ci ⁇ alkyl optionally substituted by amino, CN, pyridyl, benzimidazolyl, Ar-CONH-, biotin-Ci ⁇ alkyl-CONH.
  • R 6 is H or methyl.
  • R a is H, methyl, methoxy or NHR 1 .
  • Preferred compounds of formula (I) and (II) are: ( ⁇ )-2,3,4,5-tetrahydro-7-[[[(4-azabenzimidazol-2-yl)methyl]methylamino]-carbonyl]-4- (3,3-dimethylbutyl)-3-oxo-lH-l,4-benzodiazepine-2-acetic acid;
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula
  • C]-4alkyl as applied herein is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.
  • C]-6alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any ⁇ alkyl or Cj- ⁇ alkyl group may be optionally substituted by R 7 unless otherwise indicated.
  • Co- 4 alkyl and Co-6alkyl additionally indicates that no alkyl group need be present (e.g., that a covalent bond is present).
  • C2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C2_6alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included. Any C 2 -6 l enyl group may be optionally substituted by R 7 unless otherwise indicated.
  • C2-6 alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C 2 - 6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne. Any sp 3 carbon atom in the C 2 -6 lkynyl group may be optionally substituted by R 7 .
  • C ⁇ _ 4 ⁇ xoalkyl refers to an alkyl group of up to four carbons wherein a CH 2 group is replaced by a C(O), or carbonyl, group. Substituted formyl, acetyl, 1-propanal, 2- propanone, 3-propanal, 2-butanone, 3-butanone, 1- and 4-butanal groups are representative. includes additionally the higher analogues and isomers of five and six carbons substituted by a carbonyl group.
  • C3-6 ⁇ xoalkenyl and C 3-6 ⁇ xoalkynyl refers to a Cs. ⁇ alkenyl or C3_6alkynyl group wherein a CH2 group is replaced by C(O) group.
  • C3.40Xoalkenyl includes l-oxo-2-propenyl, 3-oxo-l-propenyl, 2-oxo-3-butenyl and the like.
  • a substituent on a C ⁇ _6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl or C ⁇ _6 oxoalkyl group, such as R 7 may be on any carbon atom which results in a stable structure, and is available by conventional synthetic techniques.
  • R 7 is independently H, halo, -OR 8 , -SR 8 , -CN, -NR'R 8 , -NO 2 , -CF 3 , CF 3 S(0) , -CO 2 R', -CONR' 2 , R 9 -C 0- 6alkyl-, R 9 -C ⁇ -6 oxoalkyl-, R 9 -C 2- 6alkenyl-, R 9 -C 2- 6alkynyl-, R 9 -C 0- 6alkyloxy-, R 9 -C 0- 6alkylamino- or R 9 -C 0 -6alkyl-S(O) r ; wherein R 8 is R', -C(O)R', -C(O)NR' 2 , -C(O)OR 5 , -S(O) m R' or S(0) 2 NR' 2 , and R 9 is H, C 3-6 cycloalkyl, Het or Ar;
  • R 9 -Ci-6 alkyl refers to a C ⁇ .(, alkyl group wherein in any position a carbon- hydrogen bond is replaced by a carbon-R 9 bond.
  • R 9 -C 2 -6 alkenyl and R 9 -C 2- 6 alkynyl have a similar meaning with respect to C 2 _6 alkenyl and C 2 -.6 alkynyl.
  • Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three moieties R 7 .
  • R 7 may be C ⁇ -4 alkylthio, trifluoroalkyl, OH, F, Cl, Br or I.
  • Het, or heterocycle indicates an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicyclic ring containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis.
  • heterocycles are benzofuran, benzimidazole, benzopyran, benzothiophene, furan, imidazole, indole, indoline, morpholine, piperidine, piperazine, pyrrole, pyrrolidine, tetrahydropyridine, pyridine, thiazole, thiophene, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline.
  • a six membered ring heterocycle containing one or two nitrogens, such as piperidine, piperazine, tetrahydropyridine and pyridine, are preferred heterocycles for the moiety Z. Any accessible combination of up to three substituents, such as chosen from R 7 , on the Het ring that is available by chemical synthesis and is stable is within the scope of this invention.
  • C3-7cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds.
  • Typical of Cs. ⁇ cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents, such as chosen from R 7 , on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention.
  • the ring formed will generally be a five- or six-membered heterocycle selected from those listed above for Het, or will be a phenyl, cyclohexyl or cyclopentyl ring.
  • Benzimidazolyl, 4-azabenzimidazolyl, 5-azabenzimidazolyl and substituted derivatives thereof are preferred moieties for W when R b and R c are joined together to form a ring.
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxy carbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical
  • BrZ refers to the o-bromobenzyloxycarbonyl radical
  • C1Z refers to the o-chlorobenzyloxycarbonyl radical
  • Bn refers to the benzyl radical
  • 4-MBzl refers to the 4-methyl benzyl radical
  • Me refers to methyl
  • Et refers to ethyl
  • Ac refers to acetyl
  • Alk refers to Cj .4 alkyl
  • Nph refers to 1- or 2-naphthyl
  • cHex refers to cyclohexyl.
  • MeArg is N ⁇ -methyl
  • DCC refers to dicyclohexylcarbodiimide
  • DMAP refers to dimethylaminopyridine
  • DIEA refers to diisopropylethylamine
  • EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide.
  • HOBt refers to 1-hydroxybenzotriazole
  • THF refers to tetrahydrofuran
  • DMF refers to dimethyl formamide
  • NBS refers to N-bromo-succinimide
  • Pd/C refers to a palladium on carbon catalyst
  • DPPA diphenylphosphoryl azide
  • BOP refers to benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate
  • HF refers to hydrofluoric acid
  • PPA refers to polyphosphoric acid
  • TEA refers to triethylamine
  • TFA trifluoroacetic acid
  • PCC refers to pyridinium chlorochromate.
  • the compounds of formula (I) and (II) may be prepared by methods common to the art, such as disclosed in the Example section herein, and published in Blackburn, et al, WO 93/08174; Bondinell, et al, WO 95/18619; Bondinell, et al, WO 94/14776; Blackburn, et al.
  • Acid addition salts of the compounds 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. Certain of the compounds form inner salts or zwitterions which may be acceptable.
  • 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)-(X) and a pharmaceutically acceptable carrier. Accordingly, the compounds of formula (I)-(X) may be used in the manufacture of a medicament.
  • Pharmaceutical compositions of the compounds of formula (I)-(X) 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.
  • excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • these compounds 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 compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • the compound is administered either orally or parenterally to the patient, in a manner such that the concentration of drug is sufficient to promote bone formation.
  • the pharmaceutical composition containing the peptide 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.
  • This invention is a method for treating or preventing conditions where deficiency of mineralized bone mass creates pathology or where bone remodeling or healing is desired, which comprises administering a compound of this invention, as hereinbefore defined, especially a compound according to any one of formula (I) - (X).
  • the administration of a compound of this invention is indicated for fracture healing and the prevention of bone fractures.
  • Diseases and metabolic disorders which result in loss of bone structure also benefit from such treatment. For instance, hyperparathyroidism, Paget's disease, osteomalacia, hypercalcemia of malignancy, osteolytic lesions produced
  • the compounds of this invention may also be used in combination with other therapies for the treatment of diseases or pathologies of the bone.
  • a compound which inhibits the resorption of bone such as an inhibitor of osteoclast function.
  • Inhibitors of cathepsin K and vitronectin receptor antagonists are known to inhibit osteoclast function, and other such inhibitors are also known in the art.
  • the compounds of this invention may both inhibit bone resorption and stimulate bone formation.
  • the compounds may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
  • ROS 17/2.8 osteoblasts were routinely cultured in Ham's F-12 medium containing 5% FBS, 25 mM HEPES (pH 7.4), 1.1 mM CaCl 2 , penicillin (10 U/ml) and streptomycin (10 ug/ml). The cells were subcultured twice a week using 0.04 % trypsin containing 5mM EDTA to detach the cells.
  • 30,000 cells were plated per well in 24-well multidishes in 0.5 ml of HAM's F-12 medium containing 1 % FBS and allowed to adhere for 3-4 hr at 37°C in a humidified incubator with 5 % CO 2 .
  • Increasing concentrations of test compounds (0.01 - 100 mM) were then added to the wells (duplicate cultures per concentration tested) and the incubation continued for an additional 48 hr.
  • cultures supernatants were removed and assayed for osteocalcin levels using a rat RIA as per the manufacturer's instructions.
  • the lower limit of detection in this assay was 0.3 ng/ml.
  • Vitamin D3 (10 nM) and the peptide cyclo[Arg-Gly-Asp-D-Phe-Val] were tested as an internal controls. Typically, this concentration of Vitamin D3 and the cyclic peptide yielded a two to three fold increase over the basal level of osteocalcin. The osteocalcin levels under unstimulated conditions ranged from 0.3-0.5 ng/ml.
  • the EC50 value for each test compound was normalized against a fixed value for cyclo[Arg-Gly-Asp-D-Phe-Val] (0.74 uM; averaged from five experiments). Activity for each compound was expressed as the EC50 from the dose- response curve.
  • the EC50 were less than 1 uM.
  • Preferred compounds generally promote osteocalcin release at a concentration of less than 0.5 uM. More preferred compounds promote osteocalcin release at less than 0.05 uM.
  • MC3T3-E1 cells were obtained from ATCC.
  • Fetal bovine serum (FBS) was purchased from Hyclone Laboratories Inc. (Logan, UT). Long acting ascorbic was purchased from Wako Pure Chem Industries, Ltd (Japan) and ⁇ -glycerophosphate from Sigma Chemical Co. (St. Louis, MO).
  • [ 3 H]thymidine [20 Ci/mmol] was purchased from Amersham Life Sciences (Arlington Heights, IL) and, 45 CaCl 2 purchased from. NEN Research Products (Boston, MA).
  • Mouse osteocalcin RIA was obtained from British Biotechnology Ltd (Stoughton, MA).
  • Calcified nodules in actively mineralizing cultures were visualized by staining cell monolayers with Alizarin-Red-S (Sigma Chemical Co, St Louis, MO). Cell cultures were washed twice with PBS, fixed for 10 min in 50 percent ethanol, rehydrated with 1 ml of distilled water for 5 min and then stained for 1-3 min with 200 uL of 1 percent Alizarin Red S (aqueous). The monolayers were then washed extensively and very carefully using 1 ml H2O per wash. Calcified nodules which appeared a bright red color were identified by light microscopy.
  • alkaline phosphatase activity was determined in cell lysates using the colorimetric assay. Cells were washed twice with PBS using 1 ml/wash. Subsequently, the monolayers were transferred to ice and cells lysed in 0.2 ml of 0.1 %TX- 100.
  • the assay mixture contained 20 uL of the cell lysate (0.2-0.7 mg protein) and 80 uL of reaction buffer containing 0.1M 2-amino-2- methyl -1-propanol, 2mM MgCl 2 , 2 mM Na 2 p-nitro-phenylphosphate (Na 2 PNPP), The reactions were stopped with the addition of 100 uL of ice cold 0.25 N NaOH to each reaction and absorbance was read at 410 nm. Standard curves were prepared with known amounts of p-nitrophenol. Alkaline phosphatase activity was calculated as umol of substrate (p-nitrophenol) released/mg protein min. Osteocalcin assay:
  • Osteocalcin levels in the supernatants were determined at various time points during the assay using a mouse RIA as per the manufacturers instructions.
  • the lower limits of detection in this assay was 1.5 ng/ml.
  • 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. Following incubation the wells were aspirated completely and washed twice with 0.2 mL buffer A.
  • the IC 50 concentration of the antagonist to inhibit 50% binding of [ H]-SK&F- 107260
  • the K; dissociation constant of the antagonist
  • the compounds of Examples 1-34 generally inhibit vitronectin binding to SK&F 107260 at less than 1 micromolar.
  • Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.
  • CDC1 3 is deuteriochloroform
  • DMSO-d ⁇ is hexadeuteriodimethylsulfoxide
  • CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million ( ⁇ ) downfield from the internal standard tetramethylsilane.
  • ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. 5 ⁇ 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 Corp., Denver, Colorado.
  • Acetone (4.2 L) was chilled to 10°C, and a solution of 6-methoxy-l-phenylindene (271 g, 1.22 mole) in acetone (1.8 L) was added over 1.5 hr concurrently with Jones reagent (1.8 L, prepared from Cr ⁇ 3 (470 g, 4.70 mole), H O (1 L), and cone H 2 SO4 (405 mL)).
  • Jones reagent 1.8 L, prepared from Cr ⁇ 3 (470 g, 4.70 mole), H O (1 L), and cone H 2 SO4 (405 mL)
  • 4 % Aqueous OSO4 (153 mL) was added to the resulting mixture in two portions, one at the onset of addition and the second at the mid-point of the addition, maintaining the temperature of the reaction mixture below 15°C.
  • reaction mixture was warmed to 22°C and stirred for 1.5 h, during which time a mild exotherm increased the temperature to 28°C.
  • the reaction mixture was then cooled to below 20°C and isopropanol (1 L) was added, dropwise initially and rapidly after the initial exotherm diminished. Stirring became difficult during this phase.
  • the temperature reached 32°C during the isopropanol addition.
  • H O (2 L) was added and the mixture was transferred to a separatory funnel. Additional H 2 O was added to dissolve the precipitated chromous acid, and the mixture was extracted with CH 2 C1 2 (2 L). The organic (upper) layer was separated and the aqueous phase was extracted with CH 2 C1 2 (2 x 1 L).
  • This liquid was dissolved in CH 2 C1 2 to a total volume of 500 mL, and the solution and AICI3 (100.8 g, 0.756 mol) were added concurrently over 1 hr to CH C1 2 (3.7 L) with stirring under argon at ambient temperature. The temperature was 28°C at the completion of the addition. The reaction mixture was stirred for 16 h at ambient temperature, during which time a solid precipitated. H O (1 L) was added, initially dropwise, over a period of 30 min. The mixture was then separated and the organic phase was washed sequentially with H 2 O (1 L) and 5 % aqueous NaHCO3 (1 L). The CH 2 C1 2 solution was then concentrated to give a yellow solid (175.3 g). Recrystallization from EtOAc/hexane gave the title compound (128 g, 71%).
  • reaction mixture was stirred for 10 min, then a solution of 10,1 l-dihydro-3-methoxy- 5H-dibenzo[a,d]cyclohepten-10-one (119.2 g, 0.50 mol) in anhydrous THF (1.26 L) was added dropwise over 40 min. The temperature was maintained below -65°C during all of these additions.
  • the reaction mixture was stirred for 20 min at -65 to -70°C and then was poured into saturated aqueous NH4CI (6.2 L) with vigorous stirring. The organic layer was separated and the aqueous phase was extracted with EtOAc (2 x 1 L).
  • the reaction mixture was stirred at 25 to 30°C for 2.25 hr, at which point it was poured into ice-H 2 O.
  • the organic layer was separated, methanol (100 mL) was added, and the mixture was extracted with CH C1 2 (2 x 50 mL).
  • the combined CH 2 C1 2 extracts were washed with H 2 O (250 mL) and then were concentrated to give a viscous oil (8.6 g). This was taken up in Et 2 O (150 mL) and the ether was boiled off while replacing it with hexane.
  • the desired phenol first separated as an oil which crystallized on stirring at ambient temperature. Two crops of solid were collected to afford the title compound (7.1 g, 89 %).
  • Example 9(a) Following the procedure of Example 1(b), the compound of Example 9(a) was saponified and purified to give the title compound (0.11 g, 91%).
  • Example 10(d) Following the procedure of Example 1(b), the compound of Example 10(d) was saponified and purified to give the title compound (0.13 g, 60%).
  • Example 15(c) Following the procedure of Example 15(c), except substituting 2-phenylethylamine for n-butylamine, the title compound (0.100 g, 31 %) was prepared as a brown oil following silica gel flash chromatography (5% MeOH/CH 2 Cl 2 ).
  • Methyl (S)-7-[[[2-(5,6-methylendioxybenzimidazolyl)methyl]methylamino] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (102.5 mg, 0.21 mmol) was dissolved in MeOH, and 1.0 N NaOH (0.5 mL, 0.5 mmol) was added. The reaction was stirred at RT for 48 h, then was neutralized with 1.0 N HCl.
  • 2-Amino-6-picoline (5.1 g, 47.1 mmol) was weighed into a 500 mL round bottom flask, and the flask was cooled to -30°C. Concentrated H 2 SO 4 (20 mL) was added, which caused some fuming to occur. Concentrated HNO (10 mL, 160 mmol) was then added dropwise slowly. The reaction was allowed to warm to RT over 30 min, then was heated in an oil bath set at 80°C. After 90 min, the reaction was removed from the heating bath, and ice was added. 6.25 N NaOH (150 mL, 937.5 mmol) was added slowly, and the resulting yellow precipitate was collected on a sintered glass funnel. Drying in a vacuum desiccator gave the title compound (1.7 g, 24%).
  • Methyl ( ⁇ )-7- [ [ [2-(benzimidazolyl)methyl] amino] carbony 1-4- [2-(3 ,4- methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate was saponified according to the procedure of Example 5(b) to give the title compound (84%) as a white solid.
  • Example 23(a) The compound of Example 23(a) (0.16 g, 0.4 mmol) was dissolved in CH 3 OH (10 mL) and THF (1 mL), and treated with IN NaOH (0.5 mL). The mixture was stirred overnight, concentrated, and the residue was dissolved in H 2 O and extracted with CH 2 C1 2 . The pH of the aqueous phase was adjusted to 5.5-6 with dilute HCl, and the solid which formed was filtered, washed with H 2 O and Et 2 O, and dried to give the title compound.
  • Example 24(a) According to the procedure of Example 24(a), except substituting 3-(4- nitrobenzyloxycarbonylamino)-l -propanol for the 2-[(3-hydroxy-l-propyl)amino]pyridine-N- oxide, and substituting methyl ( ⁇ )-8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2- benzazepine-4-acetate for the methyl ( ⁇ )-8-hydroxy-3-oxo-2,3,4.5-tetrahydro-lH-2-benzazepine-4- acetate, the title compound was prepared as a colorless oil.
  • Example 25(d) According to the procedure of Example 25(d), except substituting methyl ( ⁇ )-8-[3- [(2-diazepin-2-yl)amino]-l-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2- benzazepine-4-acetate for the methyl( ⁇ )-8-[3-[(2-imidazolin-2-yl)amino]-l-propyloxy]-2- methyl-3-oxo-2,3.4,5-tetrahydro-lH-2-benzazepine-4-acetate the title compound was prepared.
  • Example 24(c) According to the procedure of Example 24(c) except substituting methyl ( ⁇ )-8-[2-(2- aminothiazol-4-yl)-l-ethoxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate for the ethyl ( ⁇ )-8-[3-(2-pyridylamino-l-propyloxy)-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4- acetate, the title compound was prepared as a white solid.
  • the aqueous layer was passed through a 0.45 ⁇ m Acrodisk filter, then was carefully acidified to pH 6 using 10% HCl in H 2 O at 0 °C. The precipitate was collected, washed with H 2 O, and dried under vacuum at 50 °C to give the title compound as a white solid (62 mg, 48%).
  • Example 31(a) According to the procedure of Example 31(a), except substituting 3-(4- nitrobenzyloxycarbonylamino)-l -propanol for the 2-[(3-hydroxy-l- propyl)amino]pyridine-N-oxide, and ethyl ( ⁇ )-10,l l-dihydro-3-hydroxy-5H- dibenzo[a,d]cycloheptene-10-acetate for ethyl (R)-10,l l-dihydro-3-hydroxy-5H- dibenzo[a,d]cycloheptene- 10-acetate, the title compound was obtained as amber oil.
  • a preparation which contains 50 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 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 100 mg of the compound 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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Abstract

L'invention concerne un procédé pour stimuler la formation osseuse. Ce procédé consiste à administrer des composés de liaison de l'intégrine, qui provoquent la libération de l'ostéocalcine à partir des ostéoblastes.
PCT/US1997/018178 1996-10-07 1997-10-07 Procede de stimulation de la formation osseuse WO1998015278A1 (fr)

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EP97945563A EP0946180A4 (fr) 1996-10-07 1997-10-07 Procede de stimulation de la formation osseuse
JP10517727A JP2001501951A (ja) 1996-10-07 1997-10-07 骨形成刺激方法

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US2776496P 1996-10-07 1996-10-07
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WO1999015170A1 (fr) * 1997-09-24 1999-04-01 Smithkline Beecham Corporation Antagoniste du recepteur de vitronectine
US6008214A (en) * 1994-08-22 1999-12-28 Smithkline Beecham Corporation Bicyclic compounds
US6008213A (en) * 1995-06-29 1999-12-28 Smithkline Beecham Corporation Integrin receptor antagonists
WO2000038707A1 (fr) * 1998-12-24 2000-07-06 Garvan Institute Of Medical Research Methode de traitement de la perte osseuse
WO2000046215A1 (fr) * 1999-02-03 2000-08-10 Merck & Co., Inc. Derives de la benzazepine utilises comme antagonistes du recepteur alpha-v de l'integrine
EP1025090A4 (fr) * 1997-09-19 2000-11-08 Smithkline Beecham Corp Antagonistes du recepteur de la vitronectine
EP1146874A4 (fr) * 1998-12-04 2002-06-05 Smithkline Beecham Corp Antagoniste de recepteur de vitronectine
US6429214B1 (en) 1999-07-21 2002-08-06 Wyeth Bicyclic antagonists selective for the αvβ3 integrin
US6576643B2 (en) 1997-09-19 2003-06-10 Smithkline Beecham Corporation Vitronectin receptor antagonists
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
US7199150B2 (en) 2002-01-11 2007-04-03 Sankyo Company, Limited Amino alcohol compounds
WO2007084670A2 (fr) 2006-01-18 2007-07-26 Merck Patent Gmbh Traitement specifique utilisant des ligands de l’integrine destine a traiter un cancer
WO2008087025A2 (fr) 2007-01-18 2008-07-24 Merck Patent Gmbh Thérapie spécifique et médicament utilisant des ligands d'intégrine ou traitant le cancer
WO2009063990A1 (fr) 2007-11-16 2009-05-22 Ube Industries, Ltd. Composé de benzazépinone
WO2010093706A2 (fr) 2009-02-10 2010-08-19 The Scripps Research Institute Vaccination programmée chimiquement
WO2010136168A2 (fr) 2009-05-25 2010-12-02 Merck Patent Gmbh Administration continue de ligands d'intégrines pour le traitement du cancer
EP2292251A1 (fr) 2001-04-24 2011-03-09 Merck Patent GmbH Polythérapie à base d'agents antiangiogéniques et de facteur de nécrose tumorale TNF-alpha
US7910617B2 (en) 2004-02-24 2011-03-22 Sankyo Company, Limited Method for suppressing the number of peripheral blood lymphocytes using an amino alcohol compound
EP2428226A1 (fr) 2001-10-22 2012-03-14 The Scripps Research Institute Composés de ciblage d'anticorps
CN103772273A (zh) * 2014-03-04 2014-05-07 定陶县友帮化工有限公司 2-boc-氨基-3-羟基-5-氯吡啶的合成方法
CN103772272A (zh) * 2014-03-04 2014-05-07 定陶县友帮化工有限公司 2-boc-氨基-3-羟基-5-溴吡啶的合成方法
CN103880739A (zh) * 2014-03-12 2014-06-25 定陶县友帮化工有限公司 一种2-boc-氨基-3-羟基吡啶的合成方法
EP2878339A1 (fr) 2013-12-02 2015-06-03 Siena Biotech S.p.A. Antagonistes SIP3
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes

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Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6008214A (en) * 1994-08-22 1999-12-28 Smithkline Beecham Corporation Bicyclic compounds
US6008213A (en) * 1995-06-29 1999-12-28 Smithkline Beecham Corporation Integrin receptor antagonists
EP1025090A4 (fr) * 1997-09-19 2000-11-08 Smithkline Beecham Corp Antagonistes du recepteur de la vitronectine
US6576643B2 (en) 1997-09-19 2003-06-10 Smithkline Beecham Corporation Vitronectin receptor antagonists
WO1999015170A1 (fr) * 1997-09-24 1999-04-01 Smithkline Beecham Corporation Antagoniste du recepteur de vitronectine
EP1146874A4 (fr) * 1998-12-04 2002-06-05 Smithkline Beecham Corp Antagoniste de recepteur de vitronectine
US6495560B1 (en) 1998-12-04 2002-12-17 Smithkline Beecham Corporation Vitronectin receptor antagonist
WO2000038707A1 (fr) * 1998-12-24 2000-07-06 Garvan Institute Of Medical Research Methode de traitement de la perte osseuse
WO2000046215A1 (fr) * 1999-02-03 2000-08-10 Merck & Co., Inc. Derives de la benzazepine utilises comme antagonistes du recepteur alpha-v de l'integrine
US6232308B1 (en) 1999-02-03 2001-05-15 Merck & Co., Inc. Bezazepine derivatives as αv integrin receptor antagonists
US6429214B1 (en) 1999-07-21 2002-08-06 Wyeth Bicyclic antagonists selective for the αvβ3 integrin
EP2292251A1 (fr) 2001-04-24 2011-03-09 Merck Patent GmbH Polythérapie à base d'agents antiangiogéniques et de facteur de nécrose tumorale TNF-alpha
EP2428226A1 (fr) 2001-10-22 2012-03-14 The Scripps Research Institute Composés de ciblage d'anticorps
US8067396B2 (en) 2002-01-11 2011-11-29 Sankyo Company, Limited Amino alcohol compounds or phosphonic acid derivatives thereof
US8101650B2 (en) 2002-01-11 2012-01-24 Daiichi Sankyo Company, Limited Method for treating a immunology-related disease
US7638551B2 (en) 2002-01-11 2009-12-29 Sankyo Company, Limited Amino alcohol compounds or phosphonic acid derivatives thereof
US7199150B2 (en) 2002-01-11 2007-04-03 Sankyo Company, Limited Amino alcohol compounds
US7910617B2 (en) 2004-02-24 2011-03-22 Sankyo Company, Limited Method for suppressing the number of peripheral blood lymphocytes using an amino alcohol compound
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
EP2338518A1 (fr) 2006-01-18 2011-06-29 Merck Patent GmbH Thérapie spécifique utilisant des ligands d'intégrine pour traiter le cancer
EP2335733A1 (fr) 2006-01-18 2011-06-22 Merck Patent GmbH Thérapie spécifique utilisant des ligands d'intégrine pour traiter le cancer
WO2007084670A2 (fr) 2006-01-18 2007-07-26 Merck Patent Gmbh Traitement specifique utilisant des ligands de l’integrine destine a traiter un cancer
WO2008087025A2 (fr) 2007-01-18 2008-07-24 Merck Patent Gmbh Thérapie spécifique et médicament utilisant des ligands d'intégrine ou traitant le cancer
EP2441464A1 (fr) 2007-01-18 2012-04-18 Merck Patent GmbH Thérapie spécifique et médicament utilisant des ligands d'intégrine pour traiter le cancer
EP2578225A1 (fr) 2007-07-18 2013-04-10 Merck Patent GmbH Thérapie spécifique et médicament utilisant des ligands dýintégrine pour traiter le cancer
KR20100106391A (ko) 2007-11-16 2010-10-01 우베 고산 가부시키가이샤 벤즈아제피논 화합물
WO2009063990A1 (fr) 2007-11-16 2009-05-22 Ube Industries, Ltd. Composé de benzazépinone
US8377922B2 (en) 2007-11-16 2013-02-19 Ube Industries, Ltd. Benzazepinone compound
WO2010093706A2 (fr) 2009-02-10 2010-08-19 The Scripps Research Institute Vaccination programmée chimiquement
WO2010136168A2 (fr) 2009-05-25 2010-12-02 Merck Patent Gmbh Administration continue de ligands d'intégrines pour le traitement du cancer
EP2878339A1 (fr) 2013-12-02 2015-06-03 Siena Biotech S.p.A. Antagonistes SIP3
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EP3689864A1 (fr) 2013-12-02 2020-08-05 Teva Pharmaceutical Industries Limited Antagonistes du s1p3
EP3896068A1 (fr) 2013-12-02 2021-10-20 Teva Pharmaceutical Industries Limited Antagonistes du s1p3
CN103772273A (zh) * 2014-03-04 2014-05-07 定陶县友帮化工有限公司 2-boc-氨基-3-羟基-5-氯吡啶的合成方法
CN103772272A (zh) * 2014-03-04 2014-05-07 定陶县友帮化工有限公司 2-boc-氨基-3-羟基-5-溴吡啶的合成方法
CN103880739A (zh) * 2014-03-12 2014-06-25 定陶县友帮化工有限公司 一种2-boc-氨基-3-羟基吡啶的合成方法
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
US10328082B2 (en) 2014-05-30 2019-06-25 Pfizer Inc. Methods of use and combinations
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes

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EP0946180A4 (fr) 2003-07-23
EP0946180A1 (fr) 1999-10-06

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