WO1997026250A1 - Antagonistes du recepteur integrine - Google Patents

Antagonistes du recepteur integrine Download PDF

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Publication number
WO1997026250A1
WO1997026250A1 PCT/US1997/000572 US9700572W WO9726250A1 WO 1997026250 A1 WO1997026250 A1 WO 1997026250A1 US 9700572 W US9700572 W US 9700572W WO 9726250 A1 WO9726250 A1 WO 9726250A1
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Prior art keywords
alkyl
aryl
alanine
butanoyl
amino
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PCT/US1997/000572
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English (en)
Inventor
George D. Hartman
James J. Perkins
Mark E. Duggan
Cecilia A. Hunt
Amy E. Krause
Nathan C. Ihle
Benny C. Askew
John Hutchinson
Karen M. Brashear
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Merck & Co., Inc.
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Priority claimed from GBGB9603373.3A external-priority patent/GB9603373D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP09526121A priority Critical patent/JP2000516197A/ja
Priority to EP97902931A priority patent/EP0880511A4/fr
Priority to AU16990/97A priority patent/AU713676B2/en
Publication of WO1997026250A1 publication Critical patent/WO1997026250A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • 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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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

Definitions

  • the invention relates generally to modulating cell adhesion and to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp Ilb/IIIa fibrinogen receptor site.
  • Fibrinogen is a glycoprotein present in blood plasma that participates in platelet aggregation and in fibrin formation. Platelets are cell-like anucleated fragments, found in the blood of all mammals, that also participate in blood coagulation. Interaction of fibrinogen with the Ilb/IIIa receptor site is known to be essential for normal platelet function.
  • platelets When a blood vessel is damaged by an injury or other causative factor, platelets adhere to the disrupted subendothethial surface. The adherent platelets subsequently release biologically active constituents and aggregate. Aggregation is initiated by the binding of agonists, such as thrombin, epinephrine, or ADP to specific platelet membrane receptors. Stimulation by agonists results in exposure of latent fibrinogen receptors on the platelet surface, and binding of fibrinogen to the glycoprotein Ilb/IIIa receptor complex.
  • agonists such as thrombin, epinephrine, or ADP
  • arginine- glycine-aspartic acid containing tripeptides are recognized by at least one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane -spanning subunits.
  • integrins which are heterodimeric proteins with two membrane -spanning subunits. The authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition specificity.
  • Ruggeri et al. Proc. Nat'l Acad. Sci. U.S.A., 83, 5708- 5712 (1986) explore a series of synthetic peptides designed in lengths to 16 residues, that contain RGD and a valine attached to the aspartic acid residue of RGD that inhibit fibrinogen binding to platelets. See also Koczewiak et al., Biochem., 23, 1767-1774 ( 1984); Ginsberg et al., J. Biol. Chem., 260(7), 3931 -3936 (1985); and Haverstick et al., Blood, 66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App. Nos. 275,748 and 298,820.
  • Ilb/IIIa complex This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges.
  • these snake venom factors also have high affinity for other members of the adhesive protein receptor family including the vitronectin and fibronectin receptors so are not selective for the gp Ilb/IIIa complex.
  • 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp Ilb/IIIa receptor.
  • U.S. Pat. No. 5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation.
  • the application PCT/US90/02746 describes the use of antibody-poly-peptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
  • the application PCT/US91/00564 discloses the use of large cyclic peptides containing RGD flanked by proline residues which are platelet aggregation inhibitors.
  • the application PCT/US90/03788 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides containing the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle.
  • Rl is a guandidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.
  • a number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli.
  • Myocardial infarction, stroke, phlebitis and a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.
  • the invention is a compound of the formula:
  • a 9- to 10-membered polycyclic ring system wherein one or more of the rings is aromatic, containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S and either unsubstituted or substituted with R' or R ⁇ ,
  • Rl and R ⁇ are independently selected from the group consisting of hydrogen, F, Cl, Br, I, Cl-lO alkyl,
  • Z is O, NR 8 , or S; and R 8 is defined as R 1 above;
  • Ci-6alkyl either unsubstituted or substituted, with one or more groups selected from halogen, hydroxyl,
  • Cl-6 alkylamino Cl-6 alkyl aryl amino, aryl amino Cl-6 alkyl, aryl Cl-6 alkylamino, aryl Cl-6 alkylamino Cl-6 alkyl, aryl carbonyloxy, aryl Cl-6 alkylcarbonyloxy, Cl-6 dialkylamino,
  • Cl-8 alkylaminocarbonylamino Cl-8 alkylaminocarbonylamino, Cl-8 alkylaminocarbonylamino Cl-6 alkyl, aryl aminocarbonylamino Cl-6 alkyl, aryl Cl-8 alkylaminocarbonylamino, aryl Cl-8 alkylaminocarbonylamino Cl-6 alkyl, aminosulfonylamino Cl-6 alkyl, Cl-8 alkylaminosulfonylamino,
  • R D and R ⁇ are independently hydrogen, Cl-8 alkyl, aryl, aryl Cl-8 alkyl, hydroxy, Cl -8 alkyloxy, aryloxy, aryl Cl -6 alkyloxy, Cl -8 alkylcarbonyloxy Cl -4 alkyloxy, aryl C] -8 alkylcarbonyloxy Cl -4 alkyloxy, Cl -8 alkylaminocarbonylmethyleneoxy, or C l -8 dialky laminocarbonylmethyleneoxy where m and n are integers 0-6.
  • n is 2-4, and n' is 2 or 3, and wherein Rl and R2 are independently selected from the group consisting of hydrogen, F, Cl, Br, I,
  • Cl-6 alkylamino Cl-8 alkyl Cl-6 dialkylamino, Cl-6 dialkylamino Cl-8 alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl, Cl-3 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy and hydroxy, hydroxy Cl-6 alkyl;
  • R5j hydrogen, fluorine
  • Cl-6 alkylcarbonyl Cl-6 alkylcarbonyl, Cl-6 alkylcarbonyl C l -6 alkyl, aryl carbonyl Cl-6alkyl, aryl carbonyl, aryl Cl-6 alkylcarbonyl, aryl Cl-6 alkylcarbonyl Cl-6alkyl, Cl-6 alkylthiocarbonylamino,
  • alkyl groups and aryl groups may be unsubstituted or substituted with one or more substituents selected from Rl and R-;
  • R° and R ⁇ are independently hydrogen, Cl-8 alkyl, aryl Cl-8 alkyl, hydroxy,
  • n' is 2 or 3
  • R 1 and R2 are independently selected from the group consisting of hydrogen, F, Cl, Br, I,
  • R4 are independently hydrogen, a five or six membered mono or polycyclic aromatic ring system containing 0, 1 , 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and sulfur, either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, Cl -3 alkoxy, Cl-5 alkylcarbonyloxy, Cl-5 alkoxycarbonyl, Cl-5 alkyl, aminoCl -5 alkyl, hydroxycarbonyl, hydroxycarbonylCi -5 alkyl, or hydroxycarbonylCl -5 alkoxy,
  • Cl-6alkyl either unsubstituted or substituted, with one or more groups selected from halogen, hydroxyl,
  • R ⁇ is hydrogen, fluorine, Cl-8 alkyl, hydroxyl, hydroxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl,
  • alkyl groups and aryl groups may be unsubstituted or substituted with one or more substituents selected from Rl and R ⁇ ;
  • R° and R are independently hydrogen
  • R 1 and R ⁇ are independently selected from the group consisting of hydrogen or amino, amino Cl -8 alkyl; Y is
  • R ⁇ is hydrogen or aryl C ⁇ -8 alkyl
  • aryl is defined as a six membered monocyclic aromatic ring system, either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, Cl -3 alkoxy, Cl -5 alkylcarbonyloxy, C] -5 alkoxycarbonyl,
  • R 5 is hydrogen, aryl sulfonylamino Cl-6 alkyl, aryl sulfonylamino, aryl Cl-6 alkylsulfonylamino, aryl Cl-6 alkylsulfonylamino Cl-6 alkyl, Cl-8 alkylsulfonylamino,
  • alkyl groups and aryl groups may be unsubstituted or substituted with one or more substituents selected from R 1 and R2; R6 i i>s hydrogen,
  • n is an integer selected from 0 to 6.
  • R4j IS hydrogen, methyl
  • Compounds of the invention are also useful for inhibiting the bone resorption activity of mammalian osteoclast cells by administering a pharmacologically effective amount of the compound to a patient in need of such activity to inhibit the activity of mammalian osteoclasts.
  • Compounds of the invention are also useful for inhibiting tumor growth in mammals.
  • Pharmacologically effective amounts of the compounds, including pharamaceutically acceptable salts thereof are administered to the mammal, to inhibit tumor growth.
  • the growth of tumors depends on an adequate blood supply, which in turn depends on growth of new vessels into the tumor. New vessels are stimulated by factors secreted by the tumor. Inhibition of angiogenesis can cause tumor regression in animals.
  • Compounds of the invention are also useful for treating and preventing diabetic retinopathy in mammals. Pharmacologically effective amounts of the compounds, including pharmaceutically acceptable salts thereof, are administered to the mammal, to inhibit diabetic retinopathy.
  • Compounds are also useful in the prevention of restenosis of vessels.
  • bone resorption activity means the process by which osteoclasts solubilize bone minerals and increase the activity of enzymes that degrade bone matrix.
  • Compounds of the invention are useful for inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets.
  • the above-mentioned compounds can be used in a method of acting upon a fibrinogen receptor which comprises administering a therapeutically effective but non-toxic amount of such compound to a mammal, preferably a human.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, dispersed therein, an effective but non-toxic amount of such compound is another feature of this invention.
  • the invention also includes the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the aggregation of blood platelets, preventing platelet thrombosis, preventing thromboembolism or preventing reocclusion, in a mammal.
  • Fibrinogen receptor antagonist compounds of Formula I are useful in a method of inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets. Fibrinogen receptor antagonists of this invention are illustrated by compounds having the formula:
  • fibrinogen receptor antagonist activity is based on evaluation of inhibition of ADP- stimulated platelets. Aggregation requires that fibrinogen bind to and occupy the platelet fibrinogen receptor site. Inhibitors of fibrinogen binding inhibit aggregation.
  • human platelets are isolated from fresh blood, collected into acid citrate/dextrose by differential centrifugation followed by gel filtration on Sepharose 2B in divalent ion-free Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin.
  • Platelet aggregation is measured at 37°C in a Chronolog aggregometer.
  • the reaction mixture contains gel-filtered human platelets (2 x 10 ⁇ per ml), fibrinogen (100 micrograms per ml (ug/ml)), Ca2+ ( 1 mM), and the compound to be tested.
  • the aggregation is initiated by adding 10 mM ADP 1 minute after the other components are added.
  • the reaction is then allowed to proceed for at least 2 minutes.
  • the extent of inhibition of aggregation is expressed as the percentage of the rate of aggregation observed in the absence of inhibitor.
  • the IC50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound.
  • salts shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edi ylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide,
  • pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
  • anti-coagulant shall include heparin, and warfarin.
  • thrombolytic agent shall include agents such as streptokinase and tissue plasminogen activator.
  • platelet anti-aggregation agent shall include agents such as aspirin and dipyridamole.
  • alkyl means straight or branched alkane containing 1 to about 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like, straight or branched alkene containing 2 to about 10 carbon atoms, e.g., propylenyl, buten- 1 -yl, isobutenyl, pentenylen-1 -yl, 2,2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen- 1-yl, hepten- 1 -yl, and octen-1 -yl radicals and the like, or straight or branched alkyne containing 2 to about 10 carbon atoms, e.g., methyl,
  • aryl means a 5- or 6-membered aromatic ring containing 0, 1 , or 2 heteroatoms selected from O, N, and S.
  • aryl include phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole, thiazole, and amino- and halogen- substituted derivatives thereof.
  • alkyloxy or "alkoxy” include an alkyl portion where alkyl is as defined above. Examples of alkoxy include methyloxy, propyloxy, and butyloxy.
  • arylalkyl and “alkylaryl” include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
  • arylalkyl include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl.
  • alkylaryl examples include toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine, butylpyridine, butenylpyridine, and pentenylpyridine.
  • halogen includes fluorine, chlorine, iodine and bromine.
  • oxy means an oxygen (O) atom.
  • thio means a sulfur (S) atom.
  • Compounds of the invention where X is a 5-membered monocyclic aromatic ring system, e.g., a thiazole system, can be prepared by forming an alkyl ester substituted derivative of the ring, e.g., methyl 4-(2-aminothiazol-4-yl)butanoate, forming the corresponding acid with HCl, and reacting with an amine to form the final product.
  • an alkyl ester substituted derivative of the ring e.g., methyl 4-(2-aminothiazol-4-yl)butanoate
  • X is a 6-membered monocyclic aromatic ring system, e.g., a pyridine system
  • X is a 6-membered monocyclic aromatic ring system
  • Compounds of the invention where X is a 9-membered polycyclic aromatic fused ring system can be prepared by reacting a substituted 5-membered ring starting material such as 2-amino-3-bromo thiophene, 2-nitro-3-bromo thiophene, 2-amino-3-bromo pyrrole, and 2-amino-3-bromo furan, with an appropriate compound under suitable ring closure conditions to effect formation of the 9-membered fused ring system.
  • a substituted 5-membered ring starting material such as 2-amino-3-bromo thiophene, 2-nitro-3-bromo thiophene, 2-amino-3-bromo pyrrole, and 2-amino-3-bromo furan
  • Compounds of the invention where X is a 10-membered polycyclic aromatic ring system can be prepared using a starting material such as naphthyridin (Hamada, Y. et al., Chem. Pharm. Bull. Soc, 1971 , 19(9), 1857-1862), or by reacting an aminoaldehyde pyridine with a suitable ketone under suitable ring closure conditions to effect formation of the 10-membered fused ring system.
  • the examples illustrate procedures for preparing compounds of the invention where Y is -(CH2)0-4, -0-, and -N(R")-.
  • EDC l -(3-Dimethylaminopropyl)-3-ethyicarbodiimide hydrochloride
  • Oxone potassium peroxymonosulfate
  • LDA Lithium diisopropylamide
  • PYCLU Chloro-N,N,N',N'-bis(pentamethylene)formamidinium hexafluorophosphate
  • the compounds of the present invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramusculsar form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent.
  • Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Ilb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of this invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli. Extraco oreal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit.
  • Adhesion is dependent on the interaction between gp Ilb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer. J. Physioi, 252(H), 615-621 ( 1987)). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be administered to prevent adhesion.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg kg/day) to about 100 mg/kg/day and preferably 0.01 -50 mg/kg/day and more preferably 0.01 -20 mg/kg/day, e.g. 0.1 mg/kg/day, 1.0 mg/kg/day, 5.0 mg/kg/day, or 10 mg/kg/day.
  • the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • compounds of the present invention may be administered in divided doses of two, three, or four times daily.
  • preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, or course, be continuous rather that intermittent throughout the dosage regime.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
  • suitable binders, lubricants, distintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy- ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • the compounds of the present invention can also be co- administered with suitable anticoagulation agents or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies. They may also be combined with heparin, aspirin, or warfarin.
  • suitable anticoagulation agents or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies. They may also be combined with heparin, aspirin, or warfarin.
  • novel compounds of the present invention were prepared according to the procedure of the following examples.
  • the most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus.
  • the following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted. SCHEME
  • N-Boc-glvcyl-2(S)-phenylsulfonamido- ⁇ -alanine t-butyl ester (1 -6)
  • N-Boc-glycine 255 mg, 1.5 mmol was dissolved in 7.4 mL EtOAc, cooled to -15°C, then NMM (179 ⁇ L, 1.6 mmol) and isobutyl chloroformate (21 1 ⁇ L, 1.6 mmol) were added.
  • amine _L5 500 mg, 1.5 mmol
  • additional NMM 422 ⁇ L, 3.2 mmol
  • Ester L8 (365 mg, 0.69 mmol) was dissolved in CH2CI2 (3.5 mL), then TFA (3.5 mL) was added. After 5 h the reaction mixture was concentrated, azeotroped with toluene, then purified by sequential flash chromatography (silica, 22:20: 1 : 1 EtOAc/EtOH/H2 ⁇ /NH4 ⁇ H, then silica, 4:1:1 CH2Cl2/MeOH/HOAc, then 7:1:1 CH2Cl2/MeOH/HOAc), providing L9 as a white solid.
  • Amino acid l -2a ( 1.0 g, 4.1 mmol) was suspended in 20 mL EtOH, cooled to 0°C, and SOC12 ( 1.5 mL, 21 mmol) was added dropwise. After stirring at RT overnight the mixture was concentrated, triturated with Et2 ⁇ (2x), and dried, providing 3 ⁇ 4 ( 1.26 g) as a hygroscopic yellow solid.
  • Ester 1-1 (220 mg, 0.51 mmol) and 1 N NaOH ( 1.3 mL, 1.3 mmol) were combined in 5 mL MeOH. After 3 d the reaction mixture was concentrated, purified by flash chromatography (silica, 9: 1 : 1 CH2Cl2/MeOH/HOAc), then preparative HPLC (Cl 8, 0.1 % TFA in CH3CN/H2O), providing, after lyophilization, acid 2 ⁇ 3 as a white solid.
  • N-Cbz-glycine (339 mg, 1.62 mmol) was dissolved in 8 mL EtOAc, cooled to -15°C, then NMM (196 ⁇ L, 1.8 mmol) and isobutyl chloroformate (230 ⁇ L, 1.8 mmol) were added. After 20 min, the mixed anhydride solution was added to amine ⁇ 4 (0.50 mg, 1.6 mmol) suspended in 5 mL EtOAc and the reaction was warmed to RT for 90 min. Following dilution with EtOAc, the mixture was washed with water, sat. NaHC ⁇ 3, 5% KHSO4, and brine, dried (MgS04), filtered and concentrated. Flash chromatography (silica, 75 % EtOAc/hexane) provided amide 3 ⁇ 5 as a colorless oil.
  • Ester 7 (59 mg, 0.12 mmol) was dissolved in 1 mL THF, then 1 N LiOH (0.29 mL, 0.29 mmol) was added. After stirring overnight the reaction was concentrated, the mixture was concentrated. Flash chromatography (silica, 22:20: 1 : 1 EtOAc/EtOH/H2 ⁇ /NH4 ⁇ H), followed by prep. HPLC (C-18, 0.1 % TFA/CH3CN/H2O) and lyophilization provided 3 ⁇ as a white solid.
  • Ester 4 2 (91 mg, 0.24 mmol) was dissolved in 2.4 mL EtOH, and 1 N NaOH (0.60 mL, 0.60 mmol) was added. After 45 min the mixture was concentrated, then diluted with EtOAc, washes with 10 % KHSO4 and brine, dried (MgS ⁇ 4) filtered and reconcentrated, providing acid 4 ⁇ 3 as a glass.
  • Ester 4-5 (20 mg, 34 ⁇ mol) was dissolved in 350 ⁇ L EtOH, then 1 N NaOH (85 ⁇ L, 85 ⁇ mol) was added. After 2 h the reaction was diluted with EtOAc, washed with 10 % KHSO4 and brine, dried (MgS ⁇ 4), filtered and concentrated. The residue was dissolved in 1 mL CH2CI2, treated with 1 mL TFA for 1 h, then concentrated and azeotroped with toluene. Flash chromatography (silica, 50: 1 : 1 , EtOH/H2 ⁇ /NH4 ⁇ H) provided 4-6 as an off-white solid.
  • Methylpyridine 5 ⁇ 2 (4.0 g, 19.2 mmol) was dissolved in 40 mL THF, cooled to -23°C, and LDA (2 M, 24 mL, 48 mmol) was added dropwise. After 30 min the mixture was cooled to -78°C and allyl bromide (2.49 mL, 2.88 mmol) was added dropwise. After 15 min more, the reaction was quenched with sat. NH4CI, warmed to RT, diluted with EtOAc, and the organic layer was washed with brine. After drying (MgS ⁇ 4), filtration and concentration, flash chromatography provided 5 ⁇ 3 as a yellow oil. TLC Rf 0.40 (silica, 75 % CH2Cl2/hexane)
  • Ester 6 ⁇ _ (324 mg, 1.22 mmol) was dissolved in 6 mL EtOH, then 1 N NaOH (2.4 mL, 2.4 mmol) was added. After stirring overnight the mixture was concentrated, rediluted with EtOAc, extracted into 10 % KHSO4, then concentrated, providing acid 6-2. along with inorganic salts.
  • Ester 6 ⁇ 3 (400 mg, 0.84 mmol) was dissolved in 4 mL EtOH, then 1 N NaOH (1 .7 mL, 1.7 mmol) was added. After 90 min the reaction was neutralized with 1 N HCl ( 1.7 mL, 1.7 mmol) and concentrated to an oil. Flash chromatography (silica, 50: 1 : 1 EtOH/H2 ⁇ /NH4 ⁇ H, then again with 12: 10: 1 : 1 EtOAc/EtOH/H2 ⁇ /NH4 ⁇ H) provided 6 .
  • Acid 4 ⁇ _ (0.86 g, 3.1 mmol), amine 7 2 (0.48 g. 3.4 mmol), NMM ( 1.35 mL, 12.3 mmol) and BOP (2.04 g, 4.61 mmol) were combined in 15 mL DMF. After stirring overnight the mixture was concentrated, redissolved in EtOAc, washed with water, 5 % KHSO4, sat. NaHC03 and brine, dried over MgS04, filtered and concentrated. Flash chromatography (silica, 50 % EtOAc/hexane) provided 7 ⁇ as a colorless oil.
  • aqueous phase was adjusted to pH 3 with aq. NaOH, then reextracted with EtOAc (2x).
  • the combined organic phases were washed with brine, dried (MgS04), filtered and concentrated, providing
  • Acid 7_ ⁇ _ (415 mg, 1.1 mmol), amine hydrochloride J (see procedure in EP 478 362 utilizing Boc-Gly(OEt) as starting material) (284 mg, 1.1 mmol), NMM (0.48 mL, 4.4 mmol) and BOP (729 mg, 1.65 mmol) were combined in 5 mL DMF. After stirring overnight the reaction was concentrated, redissolved in EtOAc, washed with water, 5 % KHS04, sat. NaHC ⁇ 3, and brine, dried (MgS ⁇ 4), filtered and concentrated. Flash chromatography (silica, EtOAc) provided 7 ⁇ 6 as a colorless waxy solid. TLC Rf 0.39 (silica, EtOAc)
  • Ester XL (100 mg, 0.18 mmol) was dissolved in 4 mL THF, then treated with 1 N LiOH (0.9 mL, 0.9 mmol). After stirring overnight the mixture was concentrated and purified by flash chromatography (silica, 15:20: 1 : 1 EtOAc/EtOH/H2 ⁇ /NH4 ⁇ H) to provide 7 ⁇ 8 as a white solid.
  • Ester R ⁇ _ (223 mg, 0.36 mmol) was dissolved in 4 mL EtOH, then 1 N NaOH (0.90 mL, 0.90 mmol) was added. After a few hours the reaction was diluted with EtOAc, extracted with water and the pH of the aq. phase was adjusted to 1 with 10 % KHSO4. The aqueous layer was extracted with EtOAc (2x), the combined organic layers were washed with brine, dried (MgS ⁇ 4), filtered and concentrated, providing 8-2 as an oil. TLC Rf 0.64 (silica, 9: 1 : 1 CH2Cl2/MeOH/HOAc)
  • Acid 7 ⁇ 4 100 mg, 0.26 mmol
  • NMM 1 17 ⁇ L, 1.1 mmol
  • BOP 176 mg, 0.40 mmol
  • the mixture was concentrated, redissolved in EtOAc, washed with water (2x), 5 % KHSO4, sat. NaHC ⁇ 3, and brine, dried (MgS ⁇ 4), filtered and concentrated. Flash chromatography (silica, EtOAc) provided 9 ⁇ 2 as a colorless oil.
  • ester 1N4 (1.8 g, 3.84 mmol), I N NaOH (6 ml, 6 mmol) and EtOH ( 10 ml) was stirred at ambient temperature for 30 minutes. The solution was acidified with 10% KHSO4 and then extracted with EtOAc. The EtOAc phase was washed with brine, dried (MgS ⁇ 4) and concentrated to furnish acid 1 1-5 as a yellow solid.
  • ester 12- 1 (2.5 g, 12.0 mmol) was dissolved in 10 ml
  • the alkoxy pyridine 12-3 (298 mg, 1.36 mmol) and amine 1 1 -3 (450 mg, 1.36 mmol) were combined with EDC (260 mg, 136 mmol), HOBT (208 mg, 136 mmol), in DMF (30 ml) and stirred at room temperature for 16 h. The solution was then diluted with ethyl acetate (200 ml) and washed with sat. NaHC ⁇ 3 (2 x 100 ml) and brine ( 100 ml). The organic layer was dried (Na2S04), filtered, and evaporated and the residue chromatographed on silica gel (3% CH3OH/CH2CI2) to give 12-4 as a colorless glass.
  • Acid salt 12-5 (352 mg, 0.93 mmol) and amino ester 7 ⁇ 5 (240 mg, 193 mmol), HOBT (142 mg, 0.93 mmol), EDC ( 198 mg, 0.93 mmol), and triethylamine (130 ⁇ l, 0.93 mmol) was dissolved in DMF (15 ml) and stirred at room temperature for 18 h. The solution was diluted with ethyl acetate (200 ml) washed with sat. NaHC03, water and brine (100 ml each), dried (Na2S ⁇ 4) and concentrated to give a colorless oil. Chromatography on silica gel afforded 12-6 as a colorless glass.
  • N-(t-butoxycarbonyl)glycine 14-3 (Aldrich) was coupled with 14-4 according to the procedure described for the preparation of
  • the title compound 14-6 was purified by column chromatography (silica, hexane/EtOAc 1 : 1 ). Rf (silica, hexane/EtOAc 1 : 1 ) 0.22.
  • N-(t-Butoxycarbonyl)glycine 14-3 (Aldrich) was coupled with 3(R)-methyl- ⁇ -alanine benzyl ester 0.5 H2SO4 1 1 -7 (Celgene) according to the procedure described for the preparation of 14-5.
  • the title product 15- 1 was then obtained by chromatography (silica, hexane/EtOAc 2:3). Rf (silica, hexane/EtOAc 1 : 1 ) 0.3.
  • Ethyl 3-aminobenzoate 16- 1 (Aldrich, 24.3 g, 0.147 mol) and bis (2-chloroethyl)amine hydrochloride 16-2 (Aldrich, 26.3 g, 0.147 mol) were heated at reflux in 500 mL n-butanol for 24 h. The solution was concentrated in vacuo, the residue was taken up in EtOAc and washed successively with saturated aqueous NaHC03 then brine.
  • the acid 17-1 was coupled with 3(S)-ethynyl- ⁇ -alanine ethyl ester hydrochloride (Zablocki et al., J. Med. Chem., 1995, 38, 2378-2394) using standard peptide coupling conditions. The product was then fully deprotected using previously described methodology to give, after reverse phase chromotography, 17-4 as the trifluoroacetate salt.
  • Ester 19-9 (69 mg, 0.17 mmol) was dissolved in 1 mL CH2CI2 at 0°C, 1 mL TFA was added, and the reaction was warmed to ambient temperature for 6 hr. After concentrating and azeotroping with toluene, flash chromatography (silica, 7:20: 1 : 1 EtOAc/EtOH/H2 ⁇ /NH4 ⁇ H) provided 19-10 as a white solid.

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Abstract

Des antagonistes du récepteur du fibrinogène ayant la formule (I) par exemple (a), sont utiles pour inhiber la liaison du fibrinogène aux plaquettes sanguines et pour inhiber l'agrégation des plaquettes sanguines.
PCT/US1997/000572 1996-01-16 1997-01-13 Antagonistes du recepteur integrine WO1997026250A1 (fr)

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AU16990/97A AU713676B2 (en) 1996-01-16 1997-01-13 Integrin receptor antagonists

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2327609A (en) * 1997-07-23 1999-02-03 Merck & Co Inc A method for eliciting an avß5 or dual avß3/avß5 antagonizing effect
WO1999031061A1 (fr) * 1997-12-17 1999-06-24 Merck & Co., Inc. Antagonistes du recepteur de l'integrine
US5919792A (en) * 1996-10-30 1999-07-06 Merck & Co., Inc. Integrin antagonists
US5952341A (en) * 1996-10-30 1999-09-14 Merck & Co., Inc. Integrin antagonists
WO1999052872A1 (fr) 1998-04-09 1999-10-21 Meiji Seika Kaisha, Ltd. DERIVES D'AMINOPIPERIDINE COMME ANTAGONISTES D'INTEGRINE αvβ¿3?
US5981546A (en) * 1996-08-29 1999-11-09 Merck & Co., Inc. Integrin antagonists
US6001855A (en) * 1998-01-02 1999-12-14 Hoffman-La Roche Inc. Thiazole derivatives
US6017925A (en) * 1997-01-17 2000-01-25 Merck & Co., Inc. Integrin antagonists
WO2000003973A1 (fr) * 1998-07-15 2000-01-27 Merck Patent Gmbh Derives de diacylhydrazine utilises comme inhibiteurs de l'integrine
US6048861A (en) * 1997-12-17 2000-04-11 Merck & Co., Inc. Integrin receptor antagonists
WO2000048996A2 (fr) * 1999-02-20 2000-08-24 Merck Patent Gmbh DERIVES DE LA β-ALANINE
WO2000069820A1 (fr) * 1999-05-14 2000-11-23 Combichem, Inc. Derives d'amine cycliques et leurs utilisations
US6211184B1 (en) 1996-08-29 2001-04-03 Merck & Co., Inc. Integrin antagonists
US6294549B1 (en) 1997-07-23 2001-09-25 Merck & Co., Inc. Method for eliciting an αvβ5 or dual αvβ3/αvβ5 antagonizing effect
WO2002016328A1 (fr) * 2000-08-23 2002-02-28 Merck Patent Gmbh Derives de biphenyle et leur utilisation en tant qu'inhibiteurs d'integrine
US6410526B1 (en) 1999-06-02 2002-06-25 Merck & Co., Inc. αv integrin receptor antagonists
US6489333B2 (en) 1998-04-01 2002-12-03 Bristol - Meyers Squibb Pharma Company Integrin antagonists
WO2003034995A3 (fr) * 2001-10-22 2003-09-12 Scripps Research Inst Composes de ciblage de l'integrine
US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
US7317019B2 (en) 2003-08-21 2008-01-08 Bristol Myers Squibb Co. N-alkylated diaminopropane derivatives as modulators of chemokine receptor activity
US11040955B2 (en) 2017-02-28 2021-06-22 Morphic Therapeutic, Inc. Inhibitors of (alpha-v)(beta-6) integrin
US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof
US11739087B2 (en) 2018-08-29 2023-08-29 Morphic Therapeutic, Inc. Inhibiting (α-v)(β-6) integrin
US11795167B2 (en) 2017-02-28 2023-10-24 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1307159C (zh) * 2000-05-31 2007-03-28 参天制药株式会社 TNF－α生成抑制剂

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3553227A (en) * 1968-08-05 1971-01-05 Parke Davis & Co S-2-((2-(2-thiazolylcarbamoyl)ethyl)amino)ethyl thiosulfate, salts thereof, and methods for their production
US4684722A (en) * 1986-01-06 1987-08-04 E. R. Squibb & Sons, Inc. Monosulfactams

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2008116C (fr) * 1989-02-23 2001-11-20 Thomas Weller Derives de glycine
US5332726A (en) * 1989-09-29 1994-07-26 Rhone-Poulenc Rorer Pharmaceuticals Inc. Antithrombotic peptides and pseudopeptides
US5051405A (en) * 1989-10-10 1991-09-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Anti-thrombotic peptides and pseudopeptides
HUT68769A (en) * 1991-05-07 1995-07-28 Merck & Co Inc FIBRINOGéN RECEPTOR ANTAGONIST COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM AS EFFECTIVE SUBSTANCE
DE4212304A1 (de) * 1992-04-13 1993-10-14 Cassella Ag Asparaginsäurederivate, ihre Herstellung und Verwendung
FR2692899B1 (fr) * 1992-06-30 1994-08-19 Adir Nouveaux dérivés peptidiques actifs dans les processus d'adhésion cellulaire, leur procédé de préparation et les compositions pharmaceutiques qui les renferment.
US5726192A (en) * 1992-12-29 1998-03-10 Smithkline Beecham Corporation Platelet aggregation inhibiting compounds
DE4309867A1 (de) * 1993-03-26 1994-09-29 Cassella Ag Neue Harnstoffderivate, ihre Herstellung und Verwendung
NZ262942A (en) * 1993-03-29 1997-07-27 Zeneca Ltd Pyridyl substituted piperazine and various other derivatives of azaheteroaryl substituted piperazines; pharmaceutical compositions
KR100323274B1 (ko) * 1993-10-19 2002-12-16 스미또모 세이야꾸 가부시키가이샤 2,3-디아미노프로피온산유도체
IL125034A0 (en) * 1995-12-29 1999-01-26 Smithkline Beecham Corp Vitronectin receptor antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3553227A (en) * 1968-08-05 1971-01-05 Parke Davis & Co S-2-((2-(2-thiazolylcarbamoyl)ethyl)amino)ethyl thiosulfate, salts thereof, and methods for their production
US4684722A (en) * 1986-01-06 1987-08-04 E. R. Squibb & Sons, Inc. Monosulfactams

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0880511A4 *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981546A (en) * 1996-08-29 1999-11-09 Merck & Co., Inc. Integrin antagonists
US6211184B1 (en) 1996-08-29 2001-04-03 Merck & Co., Inc. Integrin antagonists
US5919792A (en) * 1996-10-30 1999-07-06 Merck & Co., Inc. Integrin antagonists
US5952341A (en) * 1996-10-30 1999-09-14 Merck & Co., Inc. Integrin antagonists
US6017925A (en) * 1997-01-17 2000-01-25 Merck & Co., Inc. Integrin antagonists
GB2327609A (en) * 1997-07-23 1999-02-03 Merck & Co Inc A method for eliciting an avß5 or dual avß3/avß5 antagonizing effect
US6294549B1 (en) 1997-07-23 2001-09-25 Merck & Co., Inc. Method for eliciting an αvβ5 or dual αvβ3/αvβ5 antagonizing effect
US6048861A (en) * 1997-12-17 2000-04-11 Merck & Co., Inc. Integrin receptor antagonists
US6784190B2 (en) 1997-12-17 2004-08-31 Merck & Co., Inc. Integrin receptor antagonists
US6297249B1 (en) 1997-12-17 2001-10-02 Merck & Co., Inc. Integrin receptor antagonists
WO1999031061A1 (fr) * 1997-12-17 1999-06-24 Merck & Co., Inc. Antagonistes du recepteur de l'integrine
US6001855A (en) * 1998-01-02 1999-12-14 Hoffman-La Roche Inc. Thiazole derivatives
US6489333B2 (en) 1998-04-01 2002-12-03 Bristol - Meyers Squibb Pharma Company Integrin antagonists
WO1999052872A1 (fr) 1998-04-09 1999-10-21 Meiji Seika Kaisha, Ltd. DERIVES D'AMINOPIPERIDINE COMME ANTAGONISTES D'INTEGRINE αvβ¿3?
WO2000003973A1 (fr) * 1998-07-15 2000-01-27 Merck Patent Gmbh Derives de diacylhydrazine utilises comme inhibiteurs de l'integrine
WO2000048996A3 (fr) * 1999-02-20 2000-11-16 Merck Patent Gmbh DERIVES DE LA β-ALANINE
WO2000048996A2 (fr) * 1999-02-20 2000-08-24 Merck Patent Gmbh DERIVES DE LA β-ALANINE
US6576637B1 (en) 1999-02-20 2003-06-10 Merck Patent Gmbh β-alanine derivatives
AU760246B2 (en) * 1999-02-20 2003-05-08 Merck Patent Gmbh Beta-alanine derivatives
US7125895B1 (en) 1999-05-14 2006-10-24 Bristol-Myers Squibb Pharma Research Labs, Inc. Cyclic amine derivatives and their uses
WO2000069820A1 (fr) * 1999-05-14 2000-11-23 Combichem, Inc. Derives d'amine cycliques et leurs utilisations
US6410526B1 (en) 1999-06-02 2002-06-25 Merck & Co., Inc. αv integrin receptor antagonists
US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
WO2002016328A1 (fr) * 2000-08-23 2002-02-28 Merck Patent Gmbh Derives de biphenyle et leur utilisation en tant qu'inhibiteurs d'integrine
WO2003034995A3 (fr) * 2001-10-22 2003-09-12 Scripps Research Inst Composes de ciblage de l'integrine
KR101085784B1 (ko) * 2001-10-22 2011-11-25 더 스크립스 리서치 인스티튜트 인테그린 표적화 화합물
US7863333B2 (en) 2003-08-21 2011-01-04 Bristol-Myers Squibb Company N-alkylated diaminopropane derivatives as modulators of chemokine receptor activity
US7317019B2 (en) 2003-08-21 2008-01-08 Bristol Myers Squibb Co. N-alkylated diaminopropane derivatives as modulators of chemokine receptor activity
US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof
US11040955B2 (en) 2017-02-28 2021-06-22 Morphic Therapeutic, Inc. Inhibitors of (alpha-v)(beta-6) integrin
US11046669B2 (en) 2017-02-28 2021-06-29 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
RU2769702C2 (ru) * 2017-02-28 2022-04-05 Морфик Терапьютик, Инк. Ингибиторы интегрина avb6
US11795167B2 (en) 2017-02-28 2023-10-24 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
US11827621B2 (en) 2017-02-28 2023-11-28 Morphic Therapeutic, Inc. Inhibitors of (α-v)(β-6) integrin
US11739087B2 (en) 2018-08-29 2023-08-29 Morphic Therapeutic, Inc. Inhibiting (α-v)(β-6) integrin

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JP2000516197A (ja) 2000-12-05
EP0880511A1 (fr) 1998-12-02
CA2242877A1 (fr) 1997-07-24
AU1699097A (en) 1997-08-11
AU713676B2 (en) 1999-12-09
EP0880511A4 (fr) 1999-06-16

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