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WO1996000730A1 - Antagonistes du recepteur de la vitronectine - Google Patents

Antagonistes du recepteur de la vitronectine Download PDF

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Publication number
WO1996000730A1
WO1996000730A1 PCT/US1995/008306 US9508306W WO9600730A1 WO 1996000730 A1 WO1996000730 A1 WO 1996000730A1 US 9508306 W US9508306 W US 9508306W WO 9600730 A1 WO9600730 A1 WO 9600730A1
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WO
WIPO (PCT)
Prior art keywords
methyl
benzodiazepine
tetrahydro
oxo
carbonyl
Prior art date
Application number
PCT/US1995/008306
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English (en)
Inventor
Fadia Ali
William Bondinell
William Francis Huffman
M. Amparo Lago
Richard Mcculloch Keenan
Chet Kwon
William Henry Miller
Thomas Nguyen
Dennis T. Takata
Original Assignee
Smithkline Beecham Corporation
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Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU30010/95A priority Critical patent/AU702661B2/en
Priority to CZ963824A priority patent/CZ382496A3/cs
Priority to BR9508178A priority patent/BR9508178A/pt
Priority to JP8503462A priority patent/JPH10504808A/ja
Priority to NZ290008A priority patent/NZ290008A/en
Priority to MX9700041A priority patent/MX9700041A/es
Priority to US08/505,171 priority patent/US5977101A/en
Priority to EP95926152A priority patent/EP0767792A4/fr
Publication of WO1996000730A1 publication Critical patent/WO1996000730A1/fr
Priority to NO965608A priority patent/NO965608L/no

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    • 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
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • R6 is aryl, C3_6cycloalkyl, C4_ ⁇ oaralkyl, C ioalkoxyalkyl, C ⁇ -i oalkaryl, C ⁇ _ ⁇ ⁇ alkylthioalkyl, C ⁇ _ j oalkoxythioalkyl, C ⁇ _ ⁇ oalkylamino,
  • R h is (CH 2 ) q CO 2 R f , in Klinnick, et al., EP 0 635,492, published January 25, 1995.
  • Y is H, CMalkyl, C ⁇ alkoxy, C ⁇ alkoxycarbonyl, F, Cl, Br, I, CF3, OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f )2, CH 2 N(R f ) 2 , methylenedioxy, CN, CO 2 R f , OC(O)R f , or NHC(O)Rf;
  • L* is -C(O)NR 8 -(CH 2 )-, -C(O)-(CH 2 ) q -, NR 8 -(CH 2 ) q -, -O-(CH 2 ) q -, or S(O) k -(CH 2 ) q -, in Hartman, et al., EP 0 540 331, published May 5, 1993.
  • R d is Het-C ⁇ alkyl
  • Z" independently are hydrogen, C M alkyl, halo, OR f , CN, S(O) k R f , CO 2 R f , or OH, in Bovy, et al., EP 0 539 343, published April 28, 1993.
  • fibrinogen receptor templates for use in the present invention were taken from pending published patent applications. Reference should be made to such patent applications for their full disclosures, including the methods of preparing said templates and specific compounds using said templates, the entire disclosure of such patent applications being inco ⁇ orated herein by reference.
  • JP 05078344-A (Der 93-140339/17) Mar. 30, 1993: Describes Bis- amidinoheterocycles, eg. benzofurans.
  • WO 93/07170 Apr. 15, 1993: Describes cyclic-RGD-containing peptides.
  • EP 611765 (Der 94-265375/33) , Aug 24, 1994: Cozzi, P., et al. Describes 5-(2- pyrazinylmethyl-2-imidazol- 1 -yl)- 1 -cyclohexylethylidene)aminoxypentanoic acid.
  • JP 04208296-A (Der. 92-303598/38), Nov. 30, 1990, Describes RGD peptides.
  • JP 04213311-A (Der. 92-305482/38), Nov. 27, 1990, Describes multimeric RGD peptides.
  • JP 04217693-A (Der 92-312284/38), Oct. 23, 1990, Descirbes multimeric RGD peptides.
  • JP 04221394-A (Der. 92-313678/38), Oct. 26, 1990, Describes multimeric RGD peptides.
  • JP 04221395-A (Der. 92-313679/38), Oct. 26, 1990, Describes multimeric RGD peptides.
  • JP 04221396-A (Der. 92-313680/38), Oct. 26, 1990, Describes multimeric RGD peptides.
  • JP 04221397-A (Der. 92-313681/38), Dec. 20, 1990, Describes multimeric RGD peptides.
  • EP 503301-A2 Feb. 14, 1991, Kitaguchi, H. et al. Describes RGD peptides.
  • WO 90/15072 (Der 91007159): Describes RGD-containing peptides:
  • JP 05078244- A Mar. 30, 1993: Describes dibenzo(b,e)oxepine derivatives.
  • EP 0368486 (Der 90-149427/20), Nov. 10, 1988: Describes X-R-Tyr-D-Y analogs.
  • EP 0382451 (Der 90248531): Descirbes RGD-containing snake venom inhibitors.
  • EP 0382538 (Der 90248420): Descirbes RGD-containing snake venom inhibitors.
  • EP 0422937 Oct. 11, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides.
  • EP 0478328 Sept. 26, 1991, M. S. Egbertson, et al.: Describes tyrosine derivatives.
  • EP 0478362 Sept. 27, 1991 M. E. Duggan et al. : Describes X-Gly-(3- phenethyl) ⁇ Ala analogs.
  • EP 0512829 May, 7, 1992, Duggan, M. E., et al.: Describes chiral 3-hydroxy-6-(4- piperidinyl)heptanoyl- ⁇ -X- ⁇ -Ala-OH analogs, with variations on X and the central alkanoyl chain.
  • Egbertson, et al. Describes tyrosine sulfonamides as inhibitors of osteoclast-mediated bone reso ⁇ tion.
  • WO 93/24520 May 14, 1993, Harbeson, S. L., et al.: Describes cyclic RGD peptides.
  • EP 038,362 Feb. 19, 1990, M. Muller, et al.: Describes X-NHCHYCO-Gly-Asp- NHCHZCO 2 H analogs.
  • EP 0384362 August 29, 1990, Allig, L. et al.: Describes amidinophenyl-linked Gly- Asp-X semipeptides.
  • US 5273982-A (Der 94-006713/01) Dec.
  • EP 0319506 (Der 89-3195506) Dec. 2, 1988, S. P. Adams, et al.: Describes RGD-X analogs.
  • Bovy, et al. Describes amidinophenyl- amidopropionyl- ⁇ -X-AlaOH analogs. US 888686, May 22, 1992, Bovy, P. R. et al. CA 2099994, Sept. 7, 1992, Garland, R. B., et al. US 5254573, Oct. 6, 1992, Bovy, P. R., et al.: Describes amidinophenylamidopropionyl- ⁇ -X- ⁇ -Ala-OH. (PF54C06), EP 0539343, Oct. 14, 1992, P.R. Bovy et al.: Describes amidinophenylamidopropionyl- ⁇ -X- ⁇ -Ala-OH.
  • WO 93/12074 Nov. 27, 1992, N. A. Abood, et al.: Describes amidinophenylalkylamido-(R)-Asp-(i.e. retro- Asp)-alkyl and aryl amides and sulfonamides.
  • WO 93/12103 Dec. 11, 1992, P. R. Bovy et al.: Describes amidinophenylalkanoyl-
  • WO 9405694 (Der 94-101119/12) Mar. 17, 1994, Zablocki, et al.: Describes amidinophenylalkylamido-amino acid derivatives. US 5314902, May 24, 1994, Adams, S. P. et al.: Describes ami dinophenylamidoalkanoyl derivatives. WO 9418162, Aug, 18, 1994, Adams, S. P., et al.: Describes amidinophenylalkanoyl-amino acid derivatives. WO 9419341, Sept. 1, 1994, Tjoeng, F. S., et al.: Describes amidinophenylnipecotic acid derivatives.
  • JP 05230009 (Der 93-317431/40, Feb. 24, 1992: Describes amidino-Cbz-meta- aminophenylpropionate.
  • EP 0547517 Al (Der 93-198544) June 23, 1993, Soyka, R., et al.: Describes pyridyl compounds.
  • Receptor Antagonist BD3U 52 in Mice and Monkeys, Thromb. Haem. , 69,
  • this invention includes each unique nonracemic compound which may be synthesized and resolved by conventional techniques. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • the meaning of any substituent at any one occu ⁇ ence is independent of its meaning, or any other substituent's meaning, at any other occu ⁇ ence.
  • Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of this invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).
  • Ci-4alkyl as applied herein means an optionally substituted alkyl group of 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.
  • Ci_6alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • C ⁇ -4alkyl and C ⁇ -6alkyl additionally indicates that no alkyl group need be present (e.g., that a covalent bond is present).
  • Ci-4alkyl or C]-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or -6 oxoalkyl may be optionally substituted with the group R x , which may be on any carbon atom that results in a stable structure and is available by conventional synthetic techniques.
  • Suitable groups for R x are CMalkyl, OR-*, SR*, CMalkyl, Ci-4alkylsulfonyl, Ci-4alkylsulfoxyl, -CN, N(R 1 )2, CH2N(R!2, -NO2, -CF3,
  • Ar, or aryl as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three substituents, such as those defined above for alkyl, especially CMalkyl, Ci-4alkoxy, Ci-4alkthio, 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 benzofuryl, benzimidazole, benzopyran, benzothiophene, furan, imidazole, indoline, mo ⁇ holine, piperidine, piperazine, pyrrole, py ⁇ olidine, tetrahydropyridine, pyridine, thiazole, thiophene, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline. Any accessible combination of up to three substituents on the Het ring, such as those defined above for alkyl that are available by chemical synthesis and are stable are 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 C3-7cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents, such as those defined above for alkyl, on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention.
  • R D and R c When R D and R c are joined together to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring fused to the ring to which R D and R c are attached, 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.
  • 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
  • CIZ refers to the o-chlorobenzyloxycarbonyl radical
  • Bzl 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 CMalkyl
  • Nph refers to 1- or 2-naphthyl
  • cHex refers to cyclohexyl.
  • Tet refers to 5-tetrazolyl.
  • DCC refers to dicyclohexylcarbodiimide
  • DMAP refers to dimethylaminopyridine
  • DIEA refers to diisopropylethyl amine
  • EDC refers to l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, hydrochloride.
  • HOBt refers to 1-hydroxybenzotriazole
  • THF tetrahydrofuran
  • DIEA diisopropylethylamine
  • DME dimethoxyethane
  • DMF dimethylformamide
  • NBS N- bromosuccinimide
  • Pd/C a palladium on carbon catalyst
  • PPA 1- propanephosphonic acid cyclic anhydride
  • DPPA diphenylphosphoryl azide
  • BOP refers to benzotriazol-l-yloxy-tris(dimethyl-amino)phosphonium hexafluorophosphate
  • HF refers to hydrofluoric acid
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • PCC pyridinium chlorochromate.
  • Typical methods include coupling to form amide bonds, nucleophilic displacement reactions and palladium catalyzed couplings.
  • W when W contains an ether or amine linkage, the bond may be formed by a displacement reaction, and one of L-l and L 2 will contain an amino or hydroxy group and the other will contain a displaceable group, such as a chloro, bromo or iodo group.
  • W when W contains an amide bond, typically one of L and L 2 will contain an amino group, and the other will contain a carboxylic acid group.
  • L ⁇ may be an aryl or heteroaryl bromide, iodide or trifluoromethylsulfonyloxy derivative and L 2 may contain an amino group and the amide linkage may be formed by palladium- catalyzed aminocarbonylation with carbon monoxide in a suitable solvent such as dimethylformamide or toluene.
  • L 1 and L 2 will be dependent upon the site of the linkage being formed.
  • General methods for preparing the linkage -(CHR") r -U-(CHR") s -V- are described, for example, in EP-A 0 372486 and EP-A 0 381 033 and EP-A 0478 363, which are inco ⁇ orated herein by reference.
  • L 1 may be -NH2
  • L 2 may be OH (as in an acid) or Cl (as in an acid chloride)
  • R 6" may be W-(CR , 2)q-Z-(CR , R 10 ) r -U-(CR' 2 )s- C(O), with any functional groups optionally protected.
  • R 6 " may be (benzyloxycarbonyl-amidino)benzoyl- or (N ⁇ -Boc,NS uan -Tos)arginyl-.
  • L 2 is OH
  • a coupling agent is used.
  • L 1 may be -CO 2 H or CO-C1
  • L 2 may be -NH 2
  • R 6" may be W-(CR' 2 )q-Z-(CR'R 10 ) r -U-(CR' 2 )s-.
  • R 6" may be (benzyloxycarbonyl-amidino)phenyl, (benzyloxycarbonylamino)methylbenzyl- or 6- (benzyloxycarbonylamino)hexyl- .
  • V is NHSO2 .
  • L 1 may be SO2CI
  • L 2 may be -NH and R 6" may be as above.
  • V is SO2NH
  • L 1 may be -NH 2 and L 2 may be SO 2 Cl.
  • L 1 may be -CHO
  • R 6" may be W- (CR , 2)q-Z-(CR , R 10 ) r -U-(CR'2)s-.
  • L 2 may be CHO, e.g., R 6 " may be W-(CR' 2 ) q -Z-(CR'R 10 ) r -U-(CR'2)s-i-CHO.
  • V is CH2CH2
  • V is CH2CH2
  • R 6 " may be
  • L 1 may be -CH 2 Br and L 2 may be -OH, -NH or -C ⁇ C H, respectively.
  • L 1 may be Br, I or CF3SO3
  • L 2 may be C ⁇ C H and the coupling may be catalyzed by palladium and a base.
  • V is CHOHCH2
  • EDC and HOBT or SOCI 2 a reacted with an appropriate amine to afford the co ⁇ esponding amide 1-2.
  • Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - VI (published by Wiley-Interscience).
  • the methyl ester of 1-2 is hydrolyzed using aqueous base, for example, aqueous LiOH in THF or aqueous NaOH in methanol, and the intermediate carboxylate salt is acidified with a suitable acid, for instance TFA or HC1, to afford the carboxylic acid 1-3.
  • aqueous base for example, aqueous LiOH in THF or aqueous NaOH in methanol
  • the intermediate carboxylate salt is acidified with a suitable acid, for instance TFA or HC1, to afford the carboxylic acid 1-3.
  • the intermediate carboxylate salt can be isolated, if desired.
  • Conversion of the carboxylic acid moiety of 1 -Scheme II to an aldehyde can be accomplished by standard methodology, as described in "Compendium of Organic Synthetic Methods" (published by Wiley-Interscience). For example, after protection of the aniline nitrogen as its tert-butyl carbamate, the carboxylic acid is converted to the corresponding acid chloride with a suitable reagent, such as thionyl chloride. The tert-butyl carbamate is lost under these conditions. The resulting acid chloride is then reduced to aldehyde 3-Scheme II by hydrogenation over a suitable catalyst, for instance palladium on carbon in the presence of 2,6-lutidine.
  • a suitable catalyst for instance palladium on carbon in the presence of 2,6-lutidine.
  • the aldehyde 3-Scheme II is then converted to the amine 4-Scheme II by reaction with 2-(aminomethyl)benzimidazole in the presence of a suitable reducing agent, such as sodium cyanoborohydride.
  • a suitable reducing agent such as sodium cyanoborohydride.
  • Alternative methods for converting an aldehyde to an amine are described in "Compendium of Organic Synthetic Methods" (published by Wiley-Interscience).
  • the basic nitrogen atoms of 4-Scheme II are methylated under modified Eschweiler-Clarke conditions (Sondengam, B. L. et al, Tetrahedron Letters 1973, 261; Borsch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673).
  • Halogenation of the aromatic moiety of 1-Scheme III can be accomplished with an appropriate elctrophilic halogenating reagent, such as N-chlorosuccinimide.
  • an appropriate elctrophilic halogenating reagent such as N-chlorosuccinimide.
  • the resulting chlorinated derivative, 2-Scheme III is then conveted to 3-Scheme III by the methods described in Scheme I.
  • the core 6-7 fused ring system is prepared of formula (VI) by methods well known in the art, e.g., Hynes, et al, J. Het. Chem., 1988, 25, 1173; Muller, et al, Helv. Chim. Ada., 1982, 65, 2118; Mori, et al, Heterocycles, 1981, 16, 1491.
  • methods for preparing benzazepines, 1,4-benzothiazepines, 1,4- benzoxazepines and 1,4-benzodiazepines are known and are disclosed, for instance, in Bondinell, et al, International Patent Application WO 93/00095.
  • a representative method for preparing the benzodiazepine nucleus is given by Schemes IV and V.
  • a representative method for preparing a benzazepine nucleus is given by Scheme VI.
  • a representative method for preparing a benzothiazepine is given by Scheme VII.
  • An benzoxazepine nucleus may be prepared in the same manner as Scheme VII, except substituting a benzyl alcohol for a benzyl thiol.
  • Schemes VHI-XI are illustrative of the methods for preparing certain compounds of the instant invention.
  • schemes VIII - X a covalent bond of the group W is prepared by a nucleophilic displacement reaction.
  • ethyl 3-[4-(carboxy)phenyl]amino]propionic acid (2-Scheme XI) is prepared by Michael-type addition of 4-(carboxy)aniline (1 -Scheme XI) to ethyl acrylate in acetic acid as described in Chem. Ber., 91, 2239, 1958.
  • the carboxyl in compound 2-Scheme XI is converted to the acid chloride with thionyl chloride, and the acid chloride is condensed with 2-(aminomethyl)benzimidazole dihydrochloride hydrate with diisopropylethylamine in dichloromethane to form compound 3- Scheme XI.
  • the starting material for the fo ⁇ nula lg-Scheme XII compounds are prepared following the procedures in Egbertson et al., J. Med. Chem., 1994, 37, 2537- 3551 which discloses general methods to alkylate the phenol of an N-protected tyrosine derivative, remove the N-protecting group, and sulfonylate the amine.
  • benzyl 4-bromobutyrate as the alkylating agent
  • intermediate Id-Scheme XII was prepared. Removal of the benzyl ester and reaction with ortho- phenylenediamine under standard conditions afforded the benzimidazole lf-Scheme X ⁇ . Finally, saponification of the methyl ester yielded the target compound lg- Scheme x ⁇ .
  • Amide coupling reagents as used herein denote reagents which may be used to form peptide bonds.
  • Typical coupling methods employ carbodiimides, activated anhydrides and esters and acyl halides.
  • Reagents such as EDC, DCC, DPPA, PPA, BOP reagent, HOBt, N-hydroxysuccinimide and oxalyl chloride are typical.
  • Coupling methods to form peptide bonds are generally well known to the art.
  • the methods of peptide synthesis generally set forth by Bodansky et al, THE PRACTICE OF PEPTIDE SYNTHESIS, Springer- Veriag, Berlin, 1984, Ali et al. in J. Med. Chem., 29, 984 (1986) and J. Med. Chem., 30, 2291 (1987) are generally illustrative of the technique and are inco ⁇ orated herein by reference.
  • the amine or aniline is coupled via its free amino group to an appropriate carboxylic acid substrate using a suitable carbodiimide coupling agent, such as N,N' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP).
  • a suitable carbodiimide coupling agent such as N,N' dicyclohexyl carbodiimide (DCC)
  • catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP).
  • HABt 1-hydroxybenzotriazole
  • DMAP dimethylamino pyridine
  • Other methods such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl of a suitably protected acid substrate, and subsequent reaction with the free amine of a suitably protected amine, optionally in the presence of a base, are also suitable.
  • a protected Boc-amino acid or Cbz-amidino benzoic acid is treated in an anhydrous solvent, such as methylene chloride or tetrahydrofuran(THF), in the presence of a base, such as N-methyl morpholine, DMAP or a trialkylamine, with isobutyl chloroformate to form the "activated anhydride", which is subsequently reacted with the free amine of a second protected amino acid or aniline.
  • anhydrous solvent such as methylene chloride or tetrahydrofuran(THF)
  • a base such as N-methyl morpholine, DMAP or a trialkylamine
  • the compounds of formula (XIX) and (XX) are commercially available or are prepared by methods known in the art such as illustrated herein disclosed in standard reference books, like the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I- VI (Wiley-Interscience).
  • a generally applicable route to benzimidazoles is disclosed in Nestor et al, J. Med. Chem. 1984, 27, 320.
  • Representative methods for preparing compounds of formula (XX) are also common to the art and may be found, for instance, in EP-A 0 381 033.
  • 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 “1" “ , Mg “ * “” * " and NH4" 1" are specific examples of cations present in pharmaceutically acceptable salts.
  • compositions which comprises a compound according to formula (I)-(V) and a pharmaceutically acceptable carrier. Accordingly, the compounds of formula (I)-(V) may be used in the manufacture of a medicament.
  • Pharmaceutical compositions of the compounds of formula (I)-(V) 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 ca ⁇ iers include starch, lactose, calcium sulfate dihydrate, te ⁇ a 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 ca ⁇ ier When a liquid ca ⁇ ier 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 are antagonists of the vitronectin receptor, and 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, hyperparathyroidism, 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, anti-angiogenic, antiinflammatory and anti-metastatic agents, and be useful in the treatment of atherosclerosis and restenosis.
  • the compound is administered either orally or parenterally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone reso ⁇ tion, or other such indication.
  • 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 prefe ⁇ ed.
  • 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 0J 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.
  • 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 0J 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 receptors were solubilized with 0.1 mL of 1% SDS and the bound [ 3 H]-SK&F-107260 was determined by liquid scintillation counting with the addition of 3 mL Ready Safe in a Beckman LS Liquid Scintillation Counter, with 40% efficiency.
  • Nonspecific binding of [ 3 H]-SK&F- 107260 was determined in the presence of 2 ⁇ M SK&F- 107260 and was consistently less than 1% of total radioligand input.
  • the IC50 concentration of the antagonist to inhibit 50% binding of [ 3 H]-SK&F- 107260 was determined by a nonlinear, least squares curve-fitting routine, which was modified from the LUNDON-2 program.
  • Kj dissociation constant of the antagonist
  • 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 ca ⁇ ied out at 37°C in an atmosphere of 95% air/5% CO2 for 24 hr. After incubation, the non-migrated cells on the upper surface of the filter were removed by gentle scraping. The filter was then fixed in methanol and stained with 10% Giemsa stain. Migration was measured either by a) counting the number of cells that had migrated to the lower surface of the filter or by b) extracting the stained cells with 10% acetic acid followed by determining the absorbance at 600 nM.
  • Each experimental group consists of 5-6 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/0J% 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.
  • 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 l.SxMfl/ ⁇ 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.
  • TRIP Tartrate resistant acid phosphatase
  • 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.
  • the column was washed with 50 mL cold buffer A.
  • the lectin-retained GPIIb-IIIa was eluted with buffer A containing 10% dextrose. All procedures were performed at 4°C.
  • the GPIIb-IIIa obtained was >95% pure as shown by SDS polyacrylamide gel electrophoresis.
  • a mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) were dried to the walls of a glass tube under a stream of nitrogen.
  • Purified GPIIb-IIIa was diluted to a final concentration of 0.5 mg/mL and mixed with the phospholipids in a protei phospholipid ratio of 1:3 (w:w). The mixture was resuspended and sonicated in a bath sonicator for 5 mm.
  • the mixture was then dialyzed overnight using 12,000-14,000 molecular weight cutoff dialysis tubing against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaC12 (with 2 changes).
  • the GPIIb-IIIa-containing liposomes wee centrifuged at 12,000g for 15 min and resuspended in the dialysis buffer at a final protein concentration of approximately 1 mg/mL. The liposomes were stored at -70C until needed.
  • the binding to the fibrinogen receptor (GPIIb-IIIa) was assayed by an indirect competitive binding method using [ 3 H] -SK&F- 107260 as an RGD-type ligand.
  • the binding assay was performed in a 96- well filtration plate assembly (Millipore Co ⁇ oration, Bedford, MA) using 0.22 um hydrophilic durapore membranes.
  • the wells were precoated with 0.2 mL of 10 ⁇ g/mL polylysine (Sigma Chemical Co., St. Louis, MO.) at room temperature for 1 h to block nonspecific binding.
  • Various concentrations of unlabeled benzadiazapines were added to the wells in quadruplicate.
  • [ 3 H]-SK&F- 107260 was applied to each well at a final concentration of 4.5 nM, followed by the addition of 1 ⁇ g of the purified platelet GPIIb-IIIa-containing liposomes. The mixtures were incubated for 1 h at room temperature. The GPHb-IIIa-bound [3HJ-SK&F-107260 was seperated from the unbound by filtration using a Millipore filtration manifold, followed by washing with ice-cold buffer (2 times, each 0.2 mL).
  • Compounds of the present invention inhibit the vitronectin binding to SK&F 007260 with a Ki at the vitronectin receptor that is about ten-fold greater than that for the fibrinogen receptor.
  • Prefe ⁇ ed compounds have a Ki at the vitronectin receptor that is thirty-fold greater than that at the fibrinogen receptor.
  • the most prefe ⁇ ed compounds have a Ki at the vitronectin receptor that is a hundred-fold greater than that at the fibrinogen receptor.
  • 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,
  • YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan.
  • PRP-1® is a polymeric (styrene- divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada)
  • Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Co ⁇ ., Denver, Colorado.
  • the solution was acidified with TFA (0.2 mL) and concentrated.
  • the resulting solid was triturated with H2O to leave a nearly colorless solid, which was dissolved with warming in 1:1 CH3CN/H2O.
  • the solution was cooled to RT and diluted with several volumes of H 2 O/0.1 % TFA.
  • Methyl ( ⁇ )-7-[[[N-[2-(5(6)-chlorobenzimidazolyl)methyl]-N-methyl]amino] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate was saponified following the procedure of Example 4(d).
  • Methyl ( ⁇ )-l-(tert-butoxycarbonyl)-7-carboxy-4-methyl-3-oxo-2,3,4,5- tetrahydro- lH-l,4-benzodiazepine-2-acetate 400 mg, 1.02 mmol was suspended in toluene and SOCI2 (3 mL) was added. The reaction was heated at 80°C for 3 h.
  • Methylamine (5.0 g, 0J6 mole) was dissolved in a solution of Et2 ⁇ (100 mL) and EtOH (5 mL) at 0°C, and 2-chloromethylbenzimidazole (13.4 g, 0.08 mole) was added in small portions.
  • the reaction mixture was stirred at RT for 3 h, then was allowed to stand at RT overnight. More Et 2 O (200 mL) was added, and the reaction was cooled in an ice bath for 3 h before filtering off the precipitate. The filtrate was saturated with HCl and filtered, and the filtrate was concentrated.
  • Example 16(b) Following the procedure of Example 1(b), the compound of Example 16(b) was saponified and purified to give the title compound (7.8 mg, 10%): MS (ES) m/e 422.0 (M+H)+.
  • MS (ES) m/e 422.0 (M+H)+ Anal. Calcd for C 2 2H 2 3N 5 O 4 • 2 CF 3 CO 2 H • 2.5 H 2 O: C, 44.96; H, 4.35; N, 10.08. Found: C, 44.79; H, 4.21; N, 10.08.
  • Example 18(a) Following the procedure of Example 1(b), the compound of Example 18(a) was saponified and purified to give the title compound (0J 1 g, 91%): MS (ESMS) m/e 422.2 (M+H) + .
  • MS (ESMS) m/e 422.2 (M+H) + Anal. Calcd for C 2 2H 2 3N 5 O 4 • 3 H 2 O: C, 55.57; H, 6J5; N, 14.73. Found: C, 55.30; H, 6.13; N, 14.39.
  • N-(Benzyloxycarbonyl)glycine (2.72 g, 13.13 mmol) was dissolved in CH2CI2 and an excess of thionyl chloride at room temperature. After 2 h, the reaction was evaporated under vacuum and the residue was stripped with toluene twice and dried under vacuum. The white solid was taken into CH2CI2 and 4- methoxy-2-nitroaniline (2J819 g, 12.98 mmol) was added as a solid, followed by triethylamine (2.0 mL, 1.455 g, 14.38 mmol). The reaction was sti ⁇ ed at RT for 24 h, then was evaporated under vacuum. The residue was dissolved in EtOAc and washed with aqueous IN NaHCO3.
  • N-[N-(Benzyloxycarbonyl)glycyl]-4-methoxy-2-nitroaniline (1.0 g, 2.87 mmol) was dissolved in glacial acetic acid, and iron powder was added. The mixture was heated in an oil bath at about 65 °C with stirring. After 24 h, the reaction was evaporated under vacuum. The residue was evaporated with toluene, dried under vacuum, and adsorbed onto silica gel.
  • N-(Benzyloxycarbonyl)sarcosine (4J g, 18.5 mmol) was dissolved in dry THF, and triethylamine (3 mL, 21.6 mmol) was added, followed by isobutylchloroformate (2.5 mL, 19.27 mmol).
  • the solution was cooled to about - 20°C for 15 minutes, then a solution of 2,3-diaminopyridine (2.0767 g, 19.03 mmol) in dry THF was added slowly.
  • the reaction was kept stirring between -10°C to -20°C for 15 minutes, then was allowed to warm to RT. After 3 d, the reaction was evaporated under vacuum, and the residue was partitioned between EtOAc and IN NaHCO3.
  • N-(Benzyloxycarbonyl)sarcosine (4.07 g, 18.24 mmol) was dissolved in dry THF, and triethylamine (3.0 mL, 21.57 mmol) was added, followed by isobutylchloroformate (2.5 mL, 19.27 mmol).
  • the white mixture was cooled in an acetone/dry ice bath to about -20 °C.
  • a solution of 3,4- diaminopyridine (2.0319 g, 18.62 mmol) in THF was added. The yellow solution was kept stirring at -10 to -20°C for 15 min, then was allowed to warm slowly to RT.
  • LAH (20 mL, 1M solution in THF) was added dropwise through a syringe to a solution of ( ⁇ )-indoline-2-carboxamide (2.2 g, 13.6 mmol) in anhydrous THF (20 mL) with cooling, and the resulting solution was refluxed under argon for 5 h. More LAH (20 mL) was added, and reflux was continued for another 6 h. 10% aqueous THF was added dropwise with cooling to destroy excess LAH, and then Et2 ⁇ was added. After sti ⁇ ing for 10 min, the colorless precipitate was removed by filtration and washed with THF.
  • Methyl ( ⁇ )-7-carboxy-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro- IH- 1 ,4- benzodiazepine-2-acetate 400 mg, 1.04 mmol was suspended in anhydrous toluene (5 mL), then thionyl chloride (3 mL) was added and the reaction mixture was heated to reflux for 1.5 h. The solvent was then eliminated and more toluene was added (2 x 5 mL) and then distilled off.
  • Example 35(b) A solution of Example 35(b) in methanol (5 mL) was hydrogenated at RT in 10% Pd/C overnight. The catalyst was filtered through Celite. The filtrate was concentrated to give a yellow foam which was triturated in acetone to give the title compound as an off white solid (0J40 g, 90%): MS (ES) m/e 465 (M+H)+: Anal. Calcd for C23H23N5O6 • 1.2 H2O: C, 56.92; H, 5.26; N, 14.38. Found: C, 57.09; H, 5.33; N, 14.00.
  • Methyl ( ⁇ )-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4- benzodiazepine-2-acetate (308.5 mg, 1.06 mmol) was weighed into a 250 mL roundbottom flask. Dry DMF was added, followed by HOBt • H 2 O (159.1 mg, 1.18 mmol) and EDC (248.3 mg, 1.30 mmol).
  • Methyl (S)-7-[[[2-(5,6-methylendioxybenzimidazolyl)methyl]methylamino] carbonyl] -4-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,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. Concentration under vacuum left a residue which was diluted with water and allowed to stand at RT overnight.
  • Boc-sarcosine (3.6 g, 19J mmol) was dissolved in dry THF in a flame-dried 250 mL roundbottom flask, and Et3N (6 mL, 43.14 mmol) was added. The solution was cooled to 0°C to -5°C, and isobutylchloroformate (2.5 mL, 1.93 mmol) was added. The white mixture was stirred at - 5 °C for 15 min, then was cooled to -20 °C to -30 °C, and 4,5-diaminopyrimidine (2J g, 19.15 mmol.) was added as a solid. The cooling bath was removed and the reaction was allowed to warm to RT.
  • reaction was concentrated to dryness under vacuum, and the residue was purified by chromatography ( ODS, step gradient, 5% CH 3 CN/H 2 O-0J% TFA, 10% CH 3 CN/H 2 O-0J % TFA, 20% CH3CN/H2 ⁇ -0J% TFA).
  • ODS ODS, step gradient, 5% CH 3 CN/H 2 O-0J% TFA, 10% CH 3 CN/H 2 O-0J % TFA, 20% CH3CN/H2 ⁇ -0J% TFA).
  • One fraction was collected and concentrated under vacuum.
  • the residue was reconcentrated from toluene and dried under vacuum, then was dissolved in MeOH and precipitated with Et3N.
  • the reaction was sti ⁇ ed at RT for 15 min, then was added to a solution of 2,3-diaminopyridine (2.5 g, 22.7 mmol) in dry THF at -25°C.
  • the reaction was sti ⁇ ed at -20°C for 30 min, then was allowed to warm to RT. After 24 h, the reaction was concentrated under vacuum. The residue was taken up in EtOAc and washed with 1.0 N NaHCO3. The organic layer was dried (MgSU4), filtered and concentrated under vacuum. The residue was dissolved in glacial AcOH (200 mL) and heated in an oil bath set at 109 °C. After 20 h, the reaction was concentrated under vacuum, and the residue was reconcentrated from toluene.
  • 2-Amino-6-picoline (5J g, 47J mmol) was weighed into a 500 mL round bottom flask, and the flask was cooled to -30°C. Concentrated H2SO4 (20 mL) was added, which caused some fuming to occur. Concentrated HNO3 (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.
  • the reaction was sti ⁇ ed at RT, then was added to a solution of 4,5-dimethoxyphenylenediamine (6.06 mmol) in dry THF at -25°C.
  • the Cbz-sarcosine, mixed-anhydride solution was added to the cooled phenylenediamine solution.
  • the reaction was stirred at -25°C for 10 min, then was allowed to warm to RT. After 20 h, the reaction was concentrated under vacuum. The residue was taken up in EtOAc and washed with 1.0 N NaHCO3.
  • the organic layer was dried (MgSO4), filtered, concentrated under vacuum, and reconcentrated from toluene.
  • the yellow foam was dissolved in absolute EtOH (9 mL), and 1.0 N HCl (6 mL, 6 mmol) and 10% Pd/C (0.32 g, 0.3 mmol) were added. The mixture was shaken on a Pan apparatus at RT under H2 (50 psi) for 4 h, then was filtered through Celite®. The filtrate was concentrated on the rotavap to leave a light yellow solid.

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Abstract

L'invention concerne des composés constituant des antagonistes du récepteur de la vitronectine qui sont utiles dans le traitement de l'ostéoporose. Ces composés comprennent une matrice antagoniste de récepteur fibrinogène liée à une fraction hétérocyclique.
PCT/US1995/008306 1994-06-29 1995-06-29 Antagonistes du recepteur de la vitronectine WO1996000730A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU30010/95A AU702661B2 (en) 1994-06-29 1995-06-29 Vitronectin receptor antagonists
CZ963824A CZ382496A3 (en) 1994-06-29 1995-06-29 Compounds representing antagonists of vitronectin receptors, process of their preparation, intermediates of such process, pharmaceutical composition containing the compounds and their use
BR9508178A BR9508178A (pt) 1994-06-29 1995-06-29 Antagonistas de receptor de vitronectina
JP8503462A JPH10504808A (ja) 1994-06-29 1995-06-29 ビトロネクチン受容体拮抗物質
NZ290008A NZ290008A (en) 1994-06-29 1995-06-29 Vitronectin receptor antagonists, comprising a fibrinogen antagonist analogue linked to a heterocycle
MX9700041A MX9700041A (es) 1994-06-29 1995-06-29 Antagonistas de receptor de vitronectina.
US08/505,171 US5977101A (en) 1995-06-29 1995-06-29 Benzimidazoles/Imidazoles Linked to a Fibrinogen Receptor Antagonist Template Having Vitronectin Receptor Antagonist Activity
EP95926152A EP0767792A4 (fr) 1994-06-29 1995-06-29 Antagonistes du recepteur de la vitronectine
NO965608A NO965608L (no) 1994-06-29 1996-12-27 Vitronectin-reseptor-antagonister

Applications Claiming Priority (4)

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US26769594A 1994-06-29 1994-06-29
US08/267,695 1994-06-29
US42893395A 1995-04-25 1995-04-25
US08/428,933 1995-04-25

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EP (1) EP0767792A4 (fr)
JP (1) JPH10504808A (fr)
CN (1) CN1156995A (fr)
AU (1) AU702661B2 (fr)
BR (1) BR9508178A (fr)
CA (1) CA2193966A1 (fr)
CZ (1) CZ382496A3 (fr)
HU (1) HUT76344A (fr)
MX (1) MX9700041A (fr)
NO (1) NO965608L (fr)
NZ (3) NZ290008A (fr)
PL (1) PL318199A1 (fr)
WO (1) WO1996000730A1 (fr)

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CN1156995A (zh) 1997-08-13
PL318199A1 (en) 1997-05-26
NO965608L (no) 1997-02-27
AU3001095A (en) 1996-01-25
NO965608D0 (no) 1996-12-27
CA2193966A1 (fr) 1996-01-11
EP0767792A4 (fr) 2002-11-20
AU702661B2 (en) 1999-02-25
NZ290008A (en) 1998-08-26
BR9508178A (pt) 1997-11-18
EP0767792A1 (fr) 1997-04-16
NZ329656A (en) 2000-01-28
MX9700041A (es) 1997-04-30
JPH10504808A (ja) 1998-05-12
CZ382496A3 (en) 1997-12-17
HUT76344A (en) 1997-08-28
NZ329822A (en) 2000-02-28

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