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WO1999011626A1 - Antagonistes des recepteurs d'integrines - Google Patents

Antagonistes des recepteurs d'integrines Download PDF

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Publication number
WO1999011626A1
WO1999011626A1 PCT/US1998/018379 US9818379W WO9911626A1 WO 1999011626 A1 WO1999011626 A1 WO 1999011626A1 US 9818379 W US9818379 W US 9818379W WO 9911626 A1 WO9911626 A1 WO 9911626A1
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Prior art keywords
alkyl
compound according
6alkyl
compound
compounds
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PCT/US1998/018379
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English (en)
Inventor
Dirk A. Heerding
James M. Samanen
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Smithkline Beecham Corporation
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Priority to CA002304117A priority Critical patent/CA2304117A1/fr
Priority to EP98944735A priority patent/EP1027337A4/fr
Priority to JP2000508666A priority patent/JP2001514253A/ja
Publication of WO1999011626A1 publication Critical patent/WO1999011626A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to pharmaceutically active compounds which bind to integrins, such as the vitronectin receptor and fibrinogen receptor. Such compounds are useful for inhibiting platelet aggregation and osteoclast attachment to bone.
  • Integrins are a family of heterodimeric proteins which generally mediate cell adhesion. Typical of such proteins are the vitronectin receptor (an ⁇ y ⁇ 3 heterodimer) and the fibrinogen receptor (an ⁇ b ⁇ heterodimer).
  • the natural ligands of these receptors e.g., vitronectin and fibrinogen
  • vitronectin and fibrinogen have been found to share a common -Arg-Gly-Asp- amino acid sequence, which appears to be critical for binding.
  • many of the integrin receptors appear to cross react with ligands which possess such an amino acid sequence.
  • the ct ⁇ b ⁇ 3 receptor reacts with fibronectin and vitronectin, thrombospondin and von Willebrand factor, as well as fibrinogen.
  • fibrinogen a dimer having two binding sites for ⁇ b ⁇ 3 . reacts with activated receptors found on the surface of platelets.
  • the binding of ⁇ b ⁇ 3 receptors on adjacent platelets, by fibrinogen leads to crosslinking and is considered to be a major factor in platelet aggregation.
  • Compounds which inhibit the binding of the ⁇ b ⁇ 3 receptor to fibrinogen have been shown to inhibit the platelet aggregation in vitro, and thrombus formation in vivo. See, for instance, EP- A 0 341 915.
  • the vitronectin receptor is found on a variety of cell types, such as on osteoclasts and the endothelial cells lining blood vessels. Recent studies have indicated that the attachment of osteoclasts to the bone matrix is mediated through these cell surface adhesion receptors. 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 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.
  • echistatin a snake venom peptide which contains the RGD sequence
  • echistatin is a potent inhibitor of bone resorption in tissue culture, and inhibits attachment of osteoclasts to bone.
  • Fisher, et al, Endocrinology 1993, 132, 1411 has further shown that echistatin inhibits bone resorption in vivo in the rat.
  • EP 528 587 and 528 586 report substituted phenyl derivatives which inhibit osteoclast mediated bone resorption.
  • Bondinell, et al, in WO 93/00095 (PCT/US92/05463) and WO 94/14776 (PCT/US93/ 12436) disclose that certain compounds which have a substituted 6-7 bicyclic ring system are useful for inhibiting the fibrinogen ( ⁇ n b ⁇ 3 ) receptor.
  • Other 6-7 bicyclic ring systems which inhibit the fibrinogen receptor are disclosed by Blackburn et al. in WO 93/08174 (PCT/US92/08788).
  • Blackburn et al, WO 95/04057 also disclose compounds which have a five- or six- membered ring fused to such 6-7 bicyclic ring to form a tricyclic ring system, which are useful as antagonists of the fibrinogen receptor.
  • Other compounds having 6-7 bicyclic ring systems that selectively inhibit the vitronectin receptor are disclosed in WO 96/00730 (PCT/US95/08306) and WO 96/00574 (PCT/US 95/08146). It has now been discovered that certain new tricyclic ring systems are useful templates for preparing integrin receptor antagonists. It has also been discovered that such a ring system may be used as a template, which may be suitably substituted to prepare compounds which are selective for either the fibrinogen receptor or the vitronectin receptor.
  • 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 in which the pathology may be modified by binding to an integrin receptor, especially the vitronectin or the fibrinogen receptor.
  • the compounds of this invention are useful for treating osteoporosis, atherosclerosis, restenosis, cancer and conditions in which it is desirable to inhibit platelet aggregation, such as stroke, transient ischemia attacks, myocardial infarction and rethrombosis following thrombolytic therapy.
  • This invention comprises compounds of formula (I):
  • A is C or N
  • E is a five- or six-membered heteroaromatic or heterocyclic ring, or a six-membered aromatic ring; xUs CHR 1 , C(O) or C(S);
  • X 2 is CR 5 R 5 , NR 5 , S(O) u or O;
  • R 1 is H, Ci-6alkyl, C 3 _ 7 cycloalkyl-Co_ 4 alkyl or Ar-Co ⁇ alkyl;
  • R 2 is -OR', -NRR", -NR'SO 2 R'", -NR'OR', -OCR' 2 C(O)OR', -OCR' 2 OC(O)- R', -OCR' 2 C(O)NR 2 , CF or -COCR' 2 R 2' ;
  • R 2' is -OR', -CN, -S(O) r R', S(O) 2 NR' 2 , -C(O)R' C(O)NR' 2 or -CO 2 R';
  • R' is H, Cj- ⁇ alkyl
  • R" is R', -C(O)R' or -C(O)OR 5 ;
  • R'" is Ci-6alkyl
  • R 5 and R 5' are independently H, C ⁇ _6alkyl, C3_ 7 cycloalkyl-Co-4alkyl or Ar-Co-4alkyl;
  • R6 is W-(CR' 2 ) q -Z-(CR'R 10 ) r U-(CR' 2 ) s -V- or W'-(CR' 2 ) q -U-(CR' 2 ) s -;
  • R 3 , R 4 and R 7 are independently H, halo, -OR 12 , -SR 12 , -CN, -NRK 12 , -NO 2 , -CF 3 , CF 3 S(O) , -CO 2 R', -CONR' 2 , Rl 4 -C 0 _6alkyl-, R 14 -C ⁇ _ 6 oxoalkyl-, R 14 -C 2 _6alkenyl-, R 14 -C 2 _ 6 alkynyl-, R 14 -C 0- 6alkyloxy-, R 14 -C 0- 6alkylamino- or Rl -Co -6 alkyl-S(O) r -;
  • R 8 is R', C(O)R', CN, NO 2 , SO R' or C(O)OR5;
  • R 9 is R', -CF 3 , -SR', or -OR';
  • R 10 is H, C ⁇ -4 alkyl or -NRTt"
  • R 12 is R', -C(O)R', -C(O)NR' 2 , -C(O)OR 5 , -S(O) m R' or S(O) 2 NR' 2 ;
  • R 14 is H, C3.6cycloalkyl, Het or Ar;
  • R 15 is H, Cj-ioalkyl, C3 -7 cycloalkyl-Co_8alkyl or Ar-Co-8alkyl;
  • Q is NR', O or S
  • R a is H, Ci- ⁇ alkyl, Ar-Co-6alkyl, Het-Co-6alkyl, or C3_6cycloalkyl-Co-6alkyl, halogen, OR 1 , SR 1 , COR 1 , OH, NO 2 , N(R!) 2, CO(NR 1 ) 2 , CH 2 N(R!) 2; R b and R c are independently selected from H, C ⁇ _6alkyl, Ar-Co- ⁇ alkyl, Het- C 0- 6alkyl, or C 3 .
  • Y is absent, S or O;
  • Z is (CH 2 ) t , Het, Ar or C 3-7 cycloalkyl; m is 1 or 2; n is 0, 1, 2 or 3; q is 0, 1, 2 or 3; r is 0, 1 or 2; s is 0, 1 or 2; t is 0, 1 or 2; u is 0, 1 or 2; v is 0, 1 or 2; and w is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable addition salts, complexes or 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.
  • this invention includes each unique nonracemic compound which may be synthesized and resolved by conventional techniques.
  • compounds may have unsaturated carbon- carbon double bonds
  • both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • compounds may exist in tautomeric forms, such as
  • keto-enol tautomers such as -"" ⁇ -. and -"" ⁇
  • NR' NR' 2 groups such as R"R'N A NR'-X- and R"R'N A N-X- , each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or locked in one form by appropriate substitution with R'.
  • the meaning of any substituent at any one occurrence is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
  • this invention is a carbocyclic formula (I) compound accordi
  • a ! is C.
  • X 1 is CH2 and X 2 is O.
  • R 2 is -OH.
  • R 3 and R 4 are H.
  • U is CONR 15 , NR 15 CO, CH 2 CH 2 , or CH 2 O, where R 15 is Ci-ioalkyl, optionally substituted by N0 2 , CN, CO 2 R', R 14 -Co- 6 alkyl or R 14 - Co- 6 alkylamino.
  • U when U is Ar, it is a phenyl ring, preferably 1,3 disubstituted.
  • R 15 is R'. More suitably R 15 is C ⁇ _6alkyl, most suitably H or methyl.
  • Suitable substituents for R 6 when fibrinogen antagonist acitivity is desired are: . (CH 2 ) 2-3 -U (CH2) 2 -U (CH 2 ) 2 -U
  • R' are H or C ⁇ -4 alkyl.
  • R' is methyl and R" is H.
  • R 6 Particularly preferred of such groups for R 6 are:
  • R b and R c are joined to form a cyclohexyl, phenyl or pyridyl ring.
  • R a is halogen or R -I.
  • -(CR' 2 ) q -U- is (CH 2 ) q -NR'CO, (CH 2 ) q -CH 2 O or (CH 2 ) q -CH 2 CH 2 .
  • Specific preferred R 6 substituents for enhancing vitronectin activity are
  • fibrinogen antagonist activity will be favored by an intramolecular distance of about 16 angstroms between the oxygen of the carbonyl moiety attached to the seven-membered ring, and the basic nitrogen moiety of W or W'; while vitronectin antagonist activity will be favored by about 14 angstroms between the respective acidic and basic centers.
  • a specific compound of this invention is 3-[3-(2-pyridyl)aminopropyloxy]-
  • the compounds of formula (I) inhibit the binding of vitronectin and other RGD-containing peptides to the vitronectin (a v 6 3 ) receptor.
  • Inhibition of the vitronectin receptor on osteoclasts inhibits osteoclastic bone reso ⁇ tion and is useful in the treatment of diseases wherein bone reso ⁇ tion is associated with pathology, such as osteoporosis and osteoarthritis.
  • the compounds of the instant invention inhibit vitronectin receptors on a number of different types of cells, said compounds would be useful in the treatment of inflammatory disorders, such as rheumatoid arthritis and psoriasis, and cardiovascular diseases, such as atherosclerosis and restenosis.
  • the compounds 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 compounds of the present invention may also be useful for wound healing.
  • the compounds of the present invention are useful for the treatment, including prevention, of angiogenic disorders.
  • angiogenic disorders includes conditions involving abnormal neovascularization.
  • 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 compounds of the present invention inhibit tumor tissue angiogenesis, thereby preventing tumor metastasis and tumor growth.
  • the inhibition of angiogenesis using the compounds of the present invention can ameliorate the symptoms of the disease, and, in some cases, can cure the disease.
  • a preferred therapeutic target for the compounds of the instant invention are eye diseases chacterized by neovascularization.
  • eye diseases include corneal neovascular disorders, such as corneal transplantation, he ⁇ etic 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.
  • C ⁇ -4 alkyl as applied herein is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.
  • Ci ⁇ alkyl additionally includes pentyl, n- pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any C ⁇ -4 alkyl or Ci ⁇ 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).
  • C 2 - 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.
  • C 2- 6 alkenyl 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 alkenyl group may be optionally substituted by R 7 unless otherwise indicated.
  • C 2 -6al ynyl 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 _6alkynyl group may be optionally substituted by R 7 .
  • C ⁇ -4 oxoalkyl 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.
  • C ⁇ _ 6 ⁇ xoalkyl includes additionally the higher analogues and isomers of five and six carbons substituted by a carbonyl group.
  • C 3 _ 6 ⁇ xoalkenyl and C 3 .6 ⁇ xoalkynyl refers to a C 3 _6 lkenyl or C 3 - 6 alkynyl group wherein a CH 2 group is replaced by C(O) group.
  • C 3-4 oxoalkenyl includes l-oxo-2-propenyl, 3-oxo-l- propenyl, 2-oxo-3-butenyl and the like.
  • a substituent on a .6 alkyl, C 2 -6 alkenyl, C 2- 6 alkynyl or Ci-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 14 -C ⁇ _ 6 alkyl refers to a Cj_ 6 alkyl group wherein in any position a carbon- hydrogen bond is replaced by a carbon-R 14 bond.
  • R 1 -C 2 _6 alkenyl and R 14 -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 1 . 4 a.kyl, C ⁇ - alkoxy, C ⁇ -4 alkthio, 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, mo ⁇ holine, 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.
  • C 3-7 cycloalkyl 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 C 3 _ 7 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.
  • G>— indicates a nitrogen heterocycle, which may be a saturated or unsaturated stable five-, six- or seven-membered monocyclic ring, or a seven- to ten-membered bicyclic ring containing up to three nitrogen atoms or containing one nitrogen atom and a heteroatom chosen from oxygen and sulfur, and which may be substituted on any atom that results in a stable structure.
  • the nitrogen atom in such ring may be substituted so as to result in a quaternary nitrogen.
  • the nitrogen heterocycle may be substituted in any stable position by R 20 , for instance H, C ⁇ _ 4 alkoxy, F, Cl, Br, I, NO 2 , NR' 2 , OH, CO 2 R', CONHR', CF 3 , R ]4 -C 0 _ 4 alkyl, aforementioned sustituents.
  • ⁇ -S Representative of ⁇ -S) are pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, piperidine, piperazine, mo ⁇ holine, pyridine, pyridinium, tetrahydropyridine, tetrahydro- and hexahydro-azepine, quinuclidine, quinuclidinium, quinoline,
  • 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'.
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl 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 C ⁇ alkyl
  • Nph refers to 1- or 2-naphthyl
  • cHex refers to cyclohexyl.
  • MeArg is N ⁇ -methyl arginine. Tet refers to 5-tetrazolyl. Certain reagents are abbreviated herein.
  • 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.
  • WO 93/08174 (PCT/US92/08788; Genentech), WO 93/08174 (PCT/US92/08788; Genentech), WO 96/00730 (PCT/US95/08306; SmithKline Beecham), WO 96/00574 (PCT/US95/08146; SmithKline Beecham), WO 93/00095 (PCT/US92/05463; SmithKline Beecham) and WO 94/14776 (PCT/US93/ 12436; SmithKline Beecham) generally disclose such reactions and are inco ⁇ orated herein by reference.
  • Hydroxy esters such as commercially available methyl 2-hydroxy-4- methoxybenzoate (I-l) is condensed with a fluoronitroarene, such as commercially available 2-fluoro-l -nitrobenzene (1-2), in the presence of a mild base, such as K2CO3, in a suitable solvent, such as EtOH, to give the di-aryl ether 1-3. If neccessary, the reaction may be heated to reflux to effect this condensation. The reduction of the nitro group is accomplished by hydrogenation over a suitable catalyst, such as 10% Pd/C, in a suitable solvent, such as MeOH. Many alternative methods of reducing the nitro group exist and can be found in reference volumes such as Larcock, "Comprehensive Organic Transformations" (published by VCH Publishers).
  • the resulting aminoester is heated in a suitable solvent, such as toluene, to give the ring closed procuct 1-4.
  • a suitable solvent such as toluene
  • the ester of 1-3 is first saponified with aqueous base, such as NaOH, in a polar solvent, such as MeOH.
  • the resulting carboxylate is activated in situ by standard reagents, such as DCC, and allowed to react in an intramolecular fashion to give the cyclic amide, 1-4.
  • Compound 1-4 is then deprotonated with a suitable base, such as NaH, in a suitable solvent, such as DMF, and allowed to react with a suitable halo-ester, such as methyl bromoacetate to give 1-8.
  • a suitable base such as NaH
  • a suitable solvent such as DMF
  • a suitable halo-ester such as methyl bromoacetate
  • the carbonyl group of 1-4 is reduced by standard methods, such as treating with lithium aluminum hydride in an aprotic polar solvent, such as THF.
  • THF aprotic polar solvent
  • Many alternative methods of reducing the amide carbonyl group exsist and can be found in reference volumes such as "Compendium of Organic Synthetic Methods", Vol. I- VI (published by Wiley Interscience).
  • amine 1-5 is reacted with a suitable halo-ester, such as methyl bromoacetate, in the presence of a mild base, such as triethylamine, in a polar solvent, such as THF, to give 1-6.
  • a suitable halo-ester such as methyl bromoacetate
  • a mild base such as triethylamine
  • a polar solvent such as THF
  • the methyl ether of the tricyclic compounds, such as 1-6 or 1-8, are deprotected with a Lewis acid, such as BBr3, in a suitable solvent, such as CH2CI2 to give the corresponding phenols, such as 1-7 and 1-9.
  • a Lewis acid such as BBr3
  • CH2CI2 a suitable solvent
  • the methyl ethers can be removed by treatment with AICI3 and a thiol, such as ethanethiol, in a suitable solvent , such as CH2CI2.
  • the resulting phenols, such as 1-7 or 1-9, are then reacted according to the procedures found in WO 97/01540 (PCT/US96/1 1108; SmithKline Beecham).
  • a suitable aryl carboxylic acid such as 4-methoxybenzoic acid
  • a suitable aminoalcohol such as 2-amino-2-methyl-l-propanol
  • a strong base such as s-butyl lithium
  • an aprotic polar solvent such as Et 2 O.
  • the resulting anion is the quenched with suitable electrophile, such as 2-methyl-4H-3,l-benzoxazin-4-one, to give the corresponding keto- amide II-4.
  • Hydrolysis of the oxazoline and acetamide is accomplished by treatment with a strong acid, such as aqueous hydrochloric acid, to give the amino acid II -5.
  • the carboxylic acid of II-5 is activated in situ by standard methods, such as DCC, and allowed to react in an intramolecular fashion to give the cyclic amide II-6.
  • the ketone and carbonyl group of the amide are reduced simultaneously with a strong reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as THF, to give the cyclic amine II-7. If neccessary, the reaction can be heated to reflux to affect the transformation.
  • II-7 can be prepared by a process analogous to that shown in
  • the methyl ether of II-8 is demethylated with a Lewis acid, such as BBr3, in a suitable solvent, such as CH 2 C1 2 , to give the corresponding phenol, such as II-9.
  • a Lewis acid such as BBr3
  • a suitable solvent such as CH 2 C1 2
  • the methyl ethers can be removed by treatment with AICI3 and a thiol, such as ethanethiol, in a suitable solvent , such as CH 2 C1 2 .
  • the resulting phenols, II-9 is then reacted with the previously described Arg-VNR according to the procedures found in WO 97/01540 (PCT/US96/11108; SmithKline Beecham).
  • 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 of the compounds of formula (I) may be used in the manufacture of a medicament.
  • Pharmaceutical compositions of the compounds 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.
  • 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 compounds described herein which are antagonists of the vitronectin receptor are useful for treating diseases wherein the underlying pathology is attributable to ligand or cell which interacts with the vitronectin receptor. For instance, these compounds are useful for the treatment of diseases wherein loss of the bone matrix creates pathology.
  • the instant compounds are useful for the treatment of ostoeporosis, hype ⁇ arathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastasis, bone loss due to immobilization or sex hormone deficiency.
  • the compounds of this invention are also believed to have utility as antitumor, antiinflammatory, anti-angiogenic and anti-metastatic agents, and be useful in the treatment of cancer, atherosclerosis and restenosis.
  • the compounds of this invention are useful for inhibiting restenosis following angioplasty.
  • the compounds of this invention which inhibit fibrinogen binding provide a method of inhibiting platelet aggregation and clot formation in a mammal, especially a human, which comprises the internal administration of a compound of formula (I) and a pharmaceutically acceptable carrier.
  • Indications for such therapy include acute myocardial infarction (AMI), deep vein thrombosis, pulmonary embolism, dissecting anurysm, transient ischemia attack (TIA), stroke and other infarct-related disorders, and unstable angina.
  • DIC disseminated intravascular coagulation
  • septicemia surgical or infectious shock
  • post-operative and post-partum trauma cardiopulmonary bypass surgery
  • incompatible blood transfusion abruptio placenta
  • thrombotic thrombocytopenic pu ⁇ ura TTP
  • snake venom and immune diseases
  • the compounds of this invention may be useful in a method for the prevention of metastatic conditions, the prevention or treatment of fungal or bacterial infection, inducing immunostimulation, treatment of sickle cell disease, and the prevention or treatment of diseases in which bone reso ⁇ tion is a factor.
  • This invention further provides a method for inhibiting the reocclusion of an artery or vein following fibrinolytic therapy, which comprises internal administration of a compound of formula (I) and a fibrinolytic agent.
  • Administration of a compound of formula (I) in fibrinolytic therapy either prevents reocclusion completely or prolongs the time to reocclusion.
  • fibrinolytic agent is intended to mean any compound, whether a natural or synthetic product, which directly or indirectly causes the lysis of a fibrin clot.
  • Plasminogen activators are a well known group of fibrinolytic agents.
  • Useful plasminogen activators include, for example, anistreplase, urokinase (UK), pro-urokinase (pUK), streptokinase (SK), tissue plasminogen activator (tPA) and mutants, or variants, thereof.
  • the compounds of this invention may also be used in vitro to inhibit the aggregation of platelets in blood and blood products, e.g., for storage, or for ex vivo manipulations such as in diagnostic or research use.
  • 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 inhibit platelet aggregation or other such indication.
  • 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 compound 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 compounds are 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 compounds are 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.
  • 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.
  • Human placenta or human platelet ⁇ v ⁇ 3 (0.1-0.3 mg/mL) in buffer T was diluted with buffer T containing 1 mM CaCl 2 , 1 mM MnCl 2 , 1 mM MgC (buffer A) and 0.05% NaN 3 , 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. 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 [ 3 H]-SK&F- 107260
  • the Kj dissociation constant of the antagonist
  • Compounds of the present invention inhibit vitronectin binding to SK&F 107260 in the concentration of about 0.1 micromolar.
  • Each experimental group consists of 5-6 male Sprague-Dawley rats.
  • the rats are parathyroidectomized (by the vendor, Taconic Farms) 7 days prior to use. Twenty four hours prior to use, 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 ionized Ca level (measured with a Ciba-Corning model 634 calcium pH analyzer) is • 1.2 mM/L. The rats are then put on a diet of calcium-free chow and deionized water. At the start of the experiment the rats weigh approximately lOOg.
  • Baseline Ca levels are measured and the rats are administered control vehicle (saline) or compound (dissolved in saline) as a single intravenous (tail vein) bolus injection followed immediately by a single subcutaneous injection of either human parathyroid hormone 1- 34 peptide (hPTHl-34, dose 0.2mg/kg in saline/0.1% bovine serum albumen, Bachem, Ca) or the PTH vehicle.
  • hPTHl-34 human parathyroid hormone 1- 34 peptide
  • the calcemic response to PTH is measured 2h after compound/PTH administration.
  • Each experimental group consists of 8-10 male Sprague-Dawley or Wistar rats of approximately 30-40g body weight at the start of the experiment.
  • the agent being tested is administered by an appropriate route as single or multiple daily doses for a period of seven days.
  • the rats Prior to administration of the first dose, the rats are given a single dose of a fluorescent marker (tetracycline 25mg/kg, or calcein lOmg/kg) that labels the position of bone forming surfaces at that point in time.
  • a fluorescent marker tetracycline 25mg/kg, or calcein lOmg/kg
  • the rats are killed and both forelimbs are removed at the elbow, the foot is removed at the ankle and the skin removed.
  • the sample is frozen and mounted vertically on a microtome chuck.
  • the rate of bone reso ⁇ tion is measured mo ⁇ hometrically in the medial-dorsal portion of the cortical bone. The measurement is done as follows: the amount of bone resorbed at the periosteal surface is equal to the distance by which the periosteal surface has advanced towards the fluorescent label which had been inco ⁇ orated at the endosteal bone formation surface on day zero; this distance is calculated by subtracting the width of bone between the label and the periosteal surface on day 7 from the width on day zero; the reso ⁇ tion rate in microns per day is calculated by dividing the result by 7.
  • HUMAN OSTEOCLAST RESORPTION ASSAY PIT ASSAY
  • the cells are washed x2 with cold RPMI-1640 by centrifugation (lOOO ⁇ m, 5 mins at 4°C) and the cells are 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, 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 osteoclasts are enumerated in a counting chamber, using a large-bore disposable plastic pasteur to charge the chamber with the sample.
  • the cells are pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xl0 4 /ml in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate.
  • the slices are washed in six changes of warm PBS (10 ml / well in a 6- well plate) and then placed into fresh treatment or control. Incubate at 37°C for 48 hours. tartrate resistant acid phosphatase (trap) procedure (selective stain for cells of the osteoclast lineage).
  • the slices are washed in phosphate buffered saline and fixed in 2% gluteraldehyde (in 0.2M sodium cacodylate) for 5 mins. • They are washed in water and incubated in TRAP buffer for 5 mins at 37°C.
  • the TRAP positive osteoclasts are enumerated by bright-field microscopy and are then removed from the surface of the dentine by sonication.
  • 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 ⁇ b ⁇ 3 was diluted to a final concentration of 0.5 mg/mL and mixed with the phospholipids in a proteimphospholipid 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-HCI, pH 7.4, 100 mM NaCl, 2 mM CaC12 (with 2 changes).
  • the ⁇ b ⁇ 3-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 -70°C until needed.
  • the binding to the fibrinogen receptor ( ⁇ b ⁇ 3 . 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
  • IC50 concentration of the antagonist which inhibits specific binding of [ H]-SK&F- 107260 by 50% at equilibrium.
  • Inhibition of platelet aggregation may be measured by the method described in WO 93/00095 (PCT/US/92/05463).
  • In vivo thrombus formation is demonstrated by recording the systemic and hemodynamic effects of infusion of the peptides into anesthetized dogs according to the methods described in Aiken et al., Prostaglandins, 19, 620 (1980).
  • the compounds of the instant invention were tested for their ability to inhibit the migration and proliferation of smooth muscle tissue in an artery or vein in order to assess their ability to prevent restenosis of an artery, such as that which typically occurs following angioplasty.
  • 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 6 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% CO 2 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.
  • Nuclear magnetic resonance spectra were obtained using either a Bruker AM 250 or Bruker AC 400 spectrometer. Chemical shifts are reported in parts per milliom ( ⁇ ) downfield from the internal standard tetramethylsilane. Mass spectra were taken on either VG 70 FE or VG ZAB HF instruments using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were performed by Quantitative Technologies Inc., Whitehouse, New Jersey.
  • 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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Abstract

L'invention se rapporte à des composés à sept éléments, pharmaceutiquement actifs, hétérocycliques, tricycliques, contenant au moins un azote, qui se lient aux intégrines, tels que le récepteur de vitronectine et le récepteur du fibrinogène. Ces composés s'avèrent utiles s'agissant d'inhiber l'agrégation plaquettaire et la fixation des ostéoclastes à l'os.
PCT/US1998/018379 1997-09-04 1998-09-03 Antagonistes des recepteurs d'integrines WO1999011626A1 (fr)

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CA002304117A CA2304117A1 (fr) 1997-09-04 1998-09-03 Antagonistes des recepteurs d'integrines
EP98944735A EP1027337A4 (fr) 1997-09-04 1998-09-03 Antagonistes des recepteurs d'integrines
JP2000508666A JP2001514253A (ja) 1997-09-04 1998-09-03 インテグリンレセプターアンタゴニスト

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Cited By (16)

* Cited by examiner, † Cited by third party
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WO2000048603A1 (fr) * 1999-02-17 2000-08-24 Merck & Co., Inc. DERIVES DE LA DIBENZO-AZEPINE EN TANT QU'ANTAGONISTES DU RECEPTEUR αV INTEGRINE
US6232308B1 (en) 1999-02-03 2001-05-15 Merck & Co., Inc. Bezazepine derivatives as αv integrin receptor antagonists
WO2001096312A1 (fr) * 2000-06-14 2001-12-20 Basf Aktiengesellschaft Ligands de l"integrine
WO2001024827A3 (fr) * 1999-10-06 2002-05-10 Basf Ag Inhibiteurs de voie de signalisation de l'endotheline et antagonistes de recepteurs de l'integrine pour traitement combine
WO2002014320A3 (fr) * 2000-08-11 2002-07-25 Basf Ag Nouveaux derives de diareno-azepine substitues servant de ligands d'integrine
US6514964B1 (en) 1999-09-27 2003-02-04 Amgen Inc. Fused cycloheptane and fused azacycloheptane compounds and their methods of use
EP1208101A4 (fr) * 1999-08-06 2003-03-19 Smithkline Beecham Corp Antagonistes du recepteur de la vitronectine utiles pour le traitement des accidents vasculaires cerebraux
WO2005072741A1 (fr) * 2004-01-31 2005-08-11 Bayer Healthcare Ag Derives d'acide ((11-oxo-10,11-dihydrodibenzo[b, f][1, 4]oxazepin-1-yl)oxy) acetique et composes apparentes comme agents cardiovasculaires pour le traitement de l'atherosclerose
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
US7105508B1 (en) 1999-08-09 2006-09-12 Abbott Gmbh & Co. Kg Integrin receptors antagonists
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
WO2010136168A2 (fr) 2009-05-25 2010-12-02 Merck Patent Gmbh Administration continue de ligands d'intégrines pour le traitement du cancer
EP2292251A1 (fr) 2001-04-24 2011-03-09 Merck Patent GmbH Polythérapie à base d'agents antiangiogéniques et de facteur de nécrose tumorale TNF-alpha
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes

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US4551451A (en) * 1982-03-15 1985-11-05 A. Menarini S.A.S. Tricyclic derivatives of 5,6-dihydro-11H-dibenzo (b,e) azepin-6-one having pharmacological activity
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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6232308B1 (en) 1999-02-03 2001-05-15 Merck & Co., Inc. Bezazepine derivatives as αv integrin receptor antagonists
WO2000048603A1 (fr) * 1999-02-17 2000-08-24 Merck & Co., Inc. DERIVES DE LA DIBENZO-AZEPINE EN TANT QU'ANTAGONISTES DU RECEPTEUR αV INTEGRINE
EP1208101A4 (fr) * 1999-08-06 2003-03-19 Smithkline Beecham Corp Antagonistes du recepteur de la vitronectine utiles pour le traitement des accidents vasculaires cerebraux
US7105508B1 (en) 1999-08-09 2006-09-12 Abbott Gmbh & Co. Kg Integrin receptors antagonists
US6514964B1 (en) 1999-09-27 2003-02-04 Amgen Inc. Fused cycloheptane and fused azacycloheptane compounds and their methods of use
WO2001024827A3 (fr) * 1999-10-06 2002-05-10 Basf Ag Inhibiteurs de voie de signalisation de l'endotheline et antagonistes de recepteurs de l'integrine pour traitement combine
WO2001096312A1 (fr) * 2000-06-14 2001-12-20 Basf Aktiengesellschaft Ligands de l"integrine
US7279468B2 (en) 2000-06-14 2007-10-09 Abbott Gmbh & Co. Kg Integrin ligands
WO2002014320A3 (fr) * 2000-08-11 2002-07-25 Basf Ag Nouveaux derives de diareno-azepine substitues servant de ligands d'integrine
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
WO2005072741A1 (fr) * 2004-01-31 2005-08-11 Bayer Healthcare Ag Derives d'acide ((11-oxo-10,11-dihydrodibenzo[b, f][1, 4]oxazepin-1-yl)oxy) acetique et composes apparentes comme agents cardiovasculaires pour le traitement de l'atherosclerose
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
WO2007084670A2 (fr) 2006-01-18 2007-07-26 Merck Patent Gmbh Traitement specifique utilisant des ligands de l’integrine destine a traiter un cancer
EP2335733A1 (fr) 2006-01-18 2011-06-22 Merck Patent GmbH Thérapie spécifique utilisant des ligands d'intégrine pour traiter le cancer
EP2338518A1 (fr) 2006-01-18 2011-06-29 Merck Patent GmbH Thérapie spécifique utilisant des ligands d'intégrine pour traiter le 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
WO2010136168A2 (fr) 2009-05-25 2010-12-02 Merck Patent Gmbh Administration continue de ligands d'intégrines pour le traitement du cancer
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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EP1027337A1 (fr) 2000-08-16

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