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WO1994018981A1 - Antagonistes des recepteurs de fibrinogene - Google Patents

Antagonistes des recepteurs de fibrinogene Download PDF

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Publication number
WO1994018981A1
WO1994018981A1 PCT/US1994/001881 US9401881W WO9418981A1 WO 1994018981 A1 WO1994018981 A1 WO 1994018981A1 US 9401881 W US9401881 W US 9401881W WO 9418981 A1 WO9418981 A1 WO 9418981A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
mmol
mammal
compound
substituted
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PCT/US1994/001881
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English (en)
Inventor
David Alan Claremon
John J. Baldwin
Nigel Liverton
Ben Askew
Original Assignee
Merck & Co., Inc.
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Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP94909745A priority Critical patent/EP0684823A4/fr
Priority to PL94310386A priority patent/PL310386A1/xx
Priority to US08/495,560 priority patent/US5821241A/en
Priority to AU62465/94A priority patent/AU680240B2/en
Priority to JP51922094A priority patent/JP3173792B2/ja
Priority to SK1024-95A priority patent/SK102495A3/sk
Publication of WO1994018981A1 publication Critical patent/WO1994018981A1/fr
Priority to BG99863A priority patent/BG99863A/xx
Priority to NO953270A priority patent/NO953270L/no
Priority to KR1019950703563A priority patent/KR960700722A/ko
Priority to FI953916A priority patent/FI953916L/fi

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A61K38/166—Streptokinase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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 Ilb/I ⁇ a 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.
  • fibrinogen fibrinogen, von Willebrand factor, and vitronectin.
  • 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.
  • a number of low molecular weight polypeptide factors have been isolated from snake venom. These factors apparently have high affinity for the gpllb/IIIa complex.
  • Huang et al., J. Biol Chem., 262. 16157-16163 (1987): Huang et al., Biochemistry 28. 661-666 (1989) describe the primary structure of the venom trigramin which is a 72 amino acid polypeptide that contains the RGD subunit.
  • Echistatin is another venom which has high affinity for the gpIIb/IIIa complex. This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges.
  • 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 gpIIb/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/US 91/00564 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.
  • the application PCT/US90/05367 published May 2, 1991, also discloses the use of peptides and
  • pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-L- aspartyl-L-valine that inhibit platelet aggregation and thrombus formation in mammalian blood.
  • the application Eur. Pat. App. No. 91 103462.7 discloses linear compounds which can include internal piperazinyl or piperidinyl derivatives.
  • Eur. Pat. App. No. 91300179.8, assigned to Merck & Co., Inc., and published on July 17, 1991 discloses linear polypeptide fibrinogen receptor antagonists.
  • R 1 is a guanidino 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 compounds have fibrinogen receptor antagonist activity.
  • Q is a 4-9 membered mono- or bi-cyclic ring system containing 1 , 2 or 3 heteroatoms chosen from N, O or S and either unsubstituted or substituted with R 8 ;
  • AB is a fused ring system sharing adjacent carbon and nitrogen atoms, wherein
  • A is a 5, 6 or 7 membered saturated or unsaturated ring
  • B is a 5, 6 or 7 membered saturated or unsaturated ring
  • R 1 is H, C 1 -4 alkyl, N(R 8 ) 2 , -N(R 8 )SO 2 R 7 , NR 8 CO 2 R 7 , NR 8 C(O)R 7 , NR 8 C(O)N(R 7 )R 8 , N(R 8 )SO 2 N(R 7 )R 8 , N(R 8 )SO 2 N(R 8 )C(O)OR 7 , C(O)N(R 7 ) 2 , or a cyclic group with R 6 as defined below;
  • R 2 is H, C 1 -4 alkyl, C 1 -4 branched alkyl, C 1 -4 alkyl aryl, or aryl;
  • R 4 is H, C 1 -4 alkyl, C 1 -4 branched alkyl, cyclic C 1 -4 alkyl or C 1 -4 alkenyl;
  • R 5 is CH, -CH(CH 2 ) n , a bond, or when R 5 is adjacent N(R 4 ),
  • O R 6 is COOH, CH 2 OH, C(O)NR 7 ) 2 , CO 2 R 9 , tetrazole, acylsulfonamide, or
  • R 7 is H, branched or straight chain C 1 -4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, C 1 -4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1 , 2, or 3 N, S, or O heteroatoms wherein substituted alkyl is hydroxy substituted or C 1 -4 alkoxy substituted alkyl, and wherein substituted aryl is substituted by one, two or three of the following groups: halogen, C 1 -4 alkoxy, hydroxy, or C 1 -4 alkyl; R 8 is H, branched or straight chain C 1 -4 alkyl;
  • R 9 is H, C 1 -4 alkyl or aryl; n is 0-7; n' is 0-3; and a is
  • the compounds have the formula
  • n' 0-3;
  • R 4 H, C 1-4 alkyl, C 1-4 branched alkyl, cyclic C 1-4 alkyl or C 1-4 alkenyl;
  • R 5 CH,-CH(CH 2 )n, or a bond
  • R 2 is H, C 1 -4 alkyl, C 1 -4 branched alkyl, C 1 -4 alkyl aryl, or aryl;
  • R 1 H, C 1 -4 alkyl, N(R 8 ) 2 , -N(R 8 )SO 2 R 7 , NR 8 CO 2 R 7 , NR 8 C(O)R 7 , NR 8 C(O)N(R 7 )R 8 , N(R 8 )SO 2 N(R 7 )R 8 , N(R 8 )SO 2 N(R 8 )C(O)OR 7 ,
  • R 6 COOH, CH 2 OH, C(O)NR 7 ) 2 , CO 2 R 9 , tetrazole, acylsulfonamide, or
  • R 7 H, branched or straight chain C 1 -4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, C 1 -4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or O heteroatoms
  • A a 5, 6 or 7 membered saturated, partially saturated, or unsaturated ring containing 1, 2 or 3 heteroatoms selected from O, S or N;
  • B a 5, 6 or 7 membered saturated, partially saturated, or unsaturated ring containing 1, 2 or 3 heteroatoms selected from O, S or N; wherein A and B form a fused ring system sharing adjacent carbon and nitrogen atoms.
  • the components having asymmetric centers occur as racemates, racemic mixtures, and as individual enantiomers and/or diastereomers. All isomeric forms are included in the present invention.
  • the compounds have the formula
  • AB is selected from the group of h
  • V is N or CR 7 , /
  • D is CH 2 , CH 2 -CH 2 ,
  • R 3 CN, C(O)N(R 7 )R 8 ,
  • AB is selected from the group of wherein V is N or C R 7
  • D is CH 2 , CH 2 -CH 2 ,
  • R 3 CN, C(O)N(R 7 )R 8 , r
  • AB is selected from wherein V is N or CR 7, and D is CH 2 , CH 2 -CH 2 ,
  • R 3 CN, C(O)N(R 7 )R 8 ,
  • 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, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methyln
  • 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 streptokinase and tissue plasminogen activator.
  • platelet anti-aggregation agent includes, for example, aspirin, ticlopidine, and dipyridamole.
  • alkyl means straight or branched alkane, alkene or alkyne.
  • aryl means a 5-10 membered unsaturated mono- or bicyclic ring group.
  • heteroaryl means aryl containing 1 , 2, 3 or 4 heteroatoms.
  • heteroatom means N, O, or S.
  • cyclic unless otherwise more specifically defined, means mono- or bicyclic saturated ring groups having 5-10 members.
  • heterocyclic means cyclic containing 1, 2, 3 or 4 heteroatoms.
  • heteroaryl groups and heterocyclic groups contain no more than 2 O atoms or 2 S atoms.
  • alkoxy includes an alkyl portion where alkyl is as defined above.
  • 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.
  • halogen includes fluorine, chlorine, iodine and bromine.
  • oxy means an oxygen (O) atom.
  • thio means a sulfur (S) atom.
  • Pd-C palladium on activated carbon catalyst.
  • HOAc acetic acid
  • BOP benzotriazol-1-yloxytris(dimethylamino)- phosphonium, hexafluorophosphate.
  • Oxone potassium peroxymonosulfate
  • Compounds of the invention may be used for inhibiting integrin protein-complex function relating to cell attachment activity. They may be administered to patients where inhibition of human or mammalian platelet aggregation or adhesion is desired.
  • Certain compounds of the invention are eliminated from circulation rapidly and are particularly useful in inhibiting platelet aggregation.
  • these compounds may find utility in surgery on peripheral arteries (arterial grafts, carotid endaterectomy) 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 thromboemboh. They may be administered to these surgical patients to prevent the formation of thrombi and
  • the compounds of the present invention can be
  • oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups, and emulsions.
  • 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
  • thromboemboh They may be administered to these surgical patients to prevent the formation of thrombi and thromboemboh.
  • Extracorporeal 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 gpIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer. J.
  • Platelets released from artificial surfaces show impaired hemostatic function.
  • Compounds of the invention may be administered to prevent adhesion.
  • 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 0.05-100 mg/kg/day and most preferably 0.1-20 mg/kg/day.
  • the most preferred doses will range from about 1 to about 10 ⁇ g/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, of 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, elixers, syrups and the like, and consistent with convention pharmaceutical practices.
  • 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, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated 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 polyvinlypyrrolidone, 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 anticoagulants, including antiplatelet agents such as heparin, aspirin, warfarin, dipyridamole and other compounds and agents known to inhibit blood clot formation, and thrombolytic agents such as plasminogen activators or streptokinase, to achieve beneficial effects in the treatment of various vascular pathologies.
  • suitable anticoagulants including antiplatelet agents such as heparin, aspirin, warfarin, dipyridamole and other compounds and agents known to inhibit blood clot formation, and thrombolytic agents such as plasminogen activators or streptokinase, to achieve beneficial effects in the treatment of various vascular pathologies.
  • 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.
  • 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)
  • Platelet aggregation is measured at 37°C in a Chronolog aggregometer.
  • the reaction mixture contains gel-filtered human platelets (2 x 10 8 per ml), fibrinogen (100 micrograms per ml (ug/ml)), Ca 2 + (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 IC 50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound.
  • L-Asparagine- ⁇ -butanesulfonamide (also N-(n-Butyl-sulfonyl)-L- asparagine)
  • A-2 A solution containing L-asparagine (6.45 g, 48.9 mmol) and NaOH (2.0 g, 50.0 mmol) in 100 ml of 50% aqueous dioxane was cooled to 0° in an ice bath. To this rapidly stirred mixture, a solution of NaOH (2.2 g, 55.0 mmol) in 50 ml of water and neat butane sulfonyl chloride (7.0 ml, 53.9 mmol) were added alternately over a period of 30 min.
  • reaction solution was concentrated to a volume of 50 ml at reduced pressure and aqueous residue was cooled, acidified with concentrated HCl, and extracted into ethyl acetate (3 x 100 ml). The organic extracts were dried over Na 2 SO 4 and concentrated to a volume of approximately 50 ml, anhydrous ether (50 ml) was added and the resulting white precipitate was isolated by vacuum filtration yielding A-2, mp. 154-155°.
  • a solution containing NaOH (6.04 g, 151 mmol) in 50 ml H 2 O was cooled to 0° and bromine (1.40 ml, 26.9 mmol) was added. The resulting solution was stirred at 0° for 5 min.
  • a cooled solution of A-2 (5.23 g, 20.7 mmol) and NaOH (1.66 g, 41.4 mmol) in 15 ml of H 2 O was added at once and mixture stirred at 0° for 5 min then heated to 80° for 15 min.
  • the solution was then cooled to 25° and acidified with 12N HCl (11 ml) and stirred until gas evolution ceased.
  • a solution of A-3 (3.83 g, 11.8 mmol) in 200 ml of ethyl acetate was cooled to 0°, HCl gas was bubbled through the solution for 5 min.
  • the solution was then warmed to 25° and stirred for 30 min then concentrated at reduced pressure to 50% of its volume and diluted with 100 ml of ether.
  • the resulting white solid was collected by vacuum filtration giving A-4 as a solid.
  • N-Tosyl-L-Asparagine (A-6) L-Asparagine (10.0 g, 75.7 mmol) was placed in a 500 ml round bottom flask equipped with a magnetic stir bar and an addition funnel. 1N Sodium hydroxide (85 ml, 1.1 eq.) was added. p-Toluenesulfonyl chloride (15.88g, 83.27 mmol) was dissolved in ethyl acetate (100 ml). This solution was added to the reaction flask with vigorous stirring. 1N Sodium hydroxide (85 ml, 1.1 eq.) was placed in the addition funnel, then added dropwise with vigorous stirring over a 2 h period.
  • reaction mixture was stirred an additional 2 h, at room temperature.
  • the organic and aqueous layers were separated and the aqueous layer was washed with ethyl acetate (2x50 ml).
  • the aqueous liquid was cooled to 0° then acidified with hydrochloric acid (cone). A white crystalline solid was obtained.
  • A-7 (5.0 g, 19.4 mmol) was suspended in Dioxane (100 ml) in a 1 liter pressure bottle. The bottle was cooled to -15°C and isobutylene (100 ml) was condensed into the dioxane. Concentrated H 2 SO 4 (5 ml) was added and the bottle sealed and stirred at room temperature for 36 h. The bottle was opened, and the excess
  • the crude tert-butyl ester was converted to the acid by treating with 15 mL of methylene chloride and 15 mL of trifluoroacetic acid at 0° and then warming to 25° for 1.2 h.
  • the mixture was concentrated to dryness under vacuum, added to water and extracted with ethyl acetate.
  • the organic portion was dried (Na 2 SO 4 ),
  • N-methyl morpholine-HCl was removed by filtration and the filtrate poured into a solution containing A-4 (4.30 g, 16.54 mmol), diisopropylethylamine (4.27 ml, 33.10 mmol) THF (60 ml) and H 2 O (20 ml).
  • the THF was then removed from the reaction solution at reduced pressure and the remaining aqueous portion acidified with sat. KHSO 4 and extracted with ethyl acetate (3 x 200 ml). Pooled extracts were dried over Na 2 SO 4 , filtered, and concentrated giving a red colored oil from which 3-4 formed as a white solid.
  • Acetic anhydride 70 ml, 0.76 mmol
  • 4-3 350 mg, 0.69 mmol
  • 10 ml THF 10 ml THF
  • the resulting solution was allowed to warm to room temperature and stirred for 18 h, then concentrated, and the residue was dissolved in 50 ml ethyl acetate and washed successively with NaHCO 3 , H 2 O, 10% KHSO 4 , H 2 O, and brine (25 ml each).
  • the organic layer was dried over
  • Compound 5-1 was obtained as a white crystalline solid using 1,3-dibromopropane in the procedure described for 3-2.
  • 6-1A was hydrolyzed with 1N NaOH in CH 3 OH/H 2 O as described for 1-6 to give the desired acid. This acid was coupled with ⁇ -alanine t-butyl ester as described for 2-8 to provide 6-2.
  • the alkyl bromide 8-2 (3.30 g, 10.4 mmol., 1.0 eq.), 2-4 (3.52 g, 15.5 mmol., 1.5 eq.), potassium iodide (5.18 g, 31.2 mmol), diisopropylethylamine (5.42 ml, 31.2 mmol., 3.0 eq.), and acetonitrile (50 ml) were combined.
  • the suspension was heated to reflux for 24 h, and then rotary evaporated to remove acetonitrile.
  • Saturated sodium bicarbonate solution (100 ml) was added, and the solution was extracted with ethyl acetate (5 x 50 ml).
  • ester 8-4 (180 mg, 0.347 mmol) and ethyl acetate (10 ml) were combined in a 50 ml round bottom flask. The suspension was cooled in an ice bath. Hydrogen chloride was bubbled through the suspension for 1.5 min. The reaction flask was warmed to room temperature, then solvent was removed by vacuum filtration giving 8-5 as a white solid, mp 248-249°.
  • This acid (500 mg, 1.62 mmol) was dissolved in 10 ml of CH 2 Cl 2 , HOBt (220 mg, 1.62 mmol) was added along with EDC (309 mg, 1.62 mmol), and 2-3 (356 mg, 1.63 mmol). The mixture was stirred under N 2 for 16 h then washed with 10% citric acid, H 2 O and brine (10 ml each) and dried over Na 2 SO 4 , concentrated and
  • This acid (300 mg, 0.78 mmol) was suspended in 50 ml of anhydrous DMF, A-8 (293 mg, 81 mmol), EDC (150 mg, 0.78 mmol), HOBt (105 mg, 0.78 mmol) and N-methyl morpholine (87 ml, 0.78 mmol) were added and the resulting clear solution was stirred at 25°C for 19 h.
  • the solution was diluted with 100 ml of EtOAc, washed successively with sat. NaHCO 3 , H 2 O, and brine (25 ml), dried over Na 2 SO 4 and evaporated to provide 12-3.
  • 12-3 was deprotected using TFA in CH 2 CI 2 and purified by reverse phase chromatography to give 12-4 as its TFA salt, mp 182- 185°.
  • ester 13-1 (1.5 g, 4.04 mmol) in 100 ml THF was treated with 1N LiOH (5.1 ml, 5.1 mmol) and 100 ml H 2 O and stirred at 25° for 1.5 h.
  • the THF was removed at reduced pressure and the aqueous residue acidified with 1N HCl.
  • the resulting precipitate was filtered and dried in vacuo to give the desired product as a white solid.
  • the acid 14-2 was coupled with A-9 as described for 13-2 to give the desired product as a white solid.
  • This material was dissolved in ethanol and residual over 10% Pd on C under a H 2 atmosphere to give 14-3 as a white solid.
  • A-7 (7.00 g, 27.1 mmol), THF (125 ml), and diisopropylethylamine (4.71 ml, 27.1 mmol) were combined in a 500 ml round bottom flask with a magnetic stir bar. Water was added in small portions until a clear solution resulted. The resulting solution was cooled in an ice bath. The mixed anhydride suspension was added in a single portion to the solution of 9 with vigorous mixing. After 20 min. stirring the reaction solution was concentrated to remove THF. The remaining aqueous material was acidified with 10% potassium bisulfate and the resulting precipitate was filtered to give white solid.
  • This hydrochloride salt of 15-2 was subjected to ion exchange chromatography using Dowex 50X8-200 ion exchange resin (110 g, 4.1 1 meq/g).
  • the resin was prepared by washing with water, methanol, water, 6N hydrochloric acid, and water (500 ml each). At this time the eluent was pH 7.
  • the hydrochloride was dissolved in water (30 ml) and then applied to the top of the column. The column was eluted with water. The pH of the eluant became strongly acidic. When the pH of eluant returned to 7, the column was eluted with ammoniun hydroxide:acetonitrile: water 50:25:25 (1.5L). Portions containing U.V. active material were combined then concentrated at high vacuum. The resulting white foam was dried for 8 h on the high vacuum to provide 15-2.
  • H 6 refers the hydrogen group at position 6 of the bicyclic structure

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Abstract

Les composés selon l'invention sont représentés par la formule (1) ou (2), par exemple (3). Lesdits composés ont une activité d'antagonistes des récepteurs de fibrinogène.
PCT/US1994/001881 1993-02-22 1994-02-22 Antagonistes des recepteurs de fibrinogene WO1994018981A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EP94909745A EP0684823A4 (fr) 1993-02-22 1994-02-22 Antagonistes des recepteurs de fibrinogene.
PL94310386A PL310386A1 (en) 1993-02-22 1994-02-22 Antagonists of factor i receptors
US08/495,560 US5821241A (en) 1994-02-22 1994-02-22 Fibrinogen receptor antagonists
AU62465/94A AU680240B2 (en) 1993-02-22 1994-02-22 Fibrinogen receptor antagonists
JP51922094A JP3173792B2 (ja) 1993-02-22 1994-02-22 フィブリノーゲンレセプターアンタゴニスト
SK1024-95A SK102495A3 (en) 1993-02-22 1994-02-22 Fibrinogen receptor antagonists and pharmaceutical agents containing them
BG99863A BG99863A (en) 1993-02-22 1995-08-15 Antagonists of fibrogenous receptor
NO953270A NO953270L (no) 1993-02-22 1995-08-21 Fibrinogenreceptorantagonister
KR1019950703563A KR960700722A (ko) 1993-02-22 1995-08-21 피브리노겐 수용체 길항제(Fibrinogen receptor antagonists)
FI953916A FI953916L (fi) 1993-02-22 1995-08-21 Fibrinogeenireseptoriantagonisteja

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2051793A 1993-02-22 1993-02-22
US020,517 1993-02-22

Publications (1)

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WO1994018981A1 true WO1994018981A1 (fr) 1994-09-01

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EP (1) EP0684823A4 (fr)
JP (1) JP3173792B2 (fr)
KR (1) KR960700722A (fr)
CN (1) CN1118139A (fr)
AU (1) AU680240B2 (fr)
BG (1) BG99863A (fr)
CA (1) CA2155123A1 (fr)
CZ (1) CZ210895A3 (fr)
FI (1) FI953916L (fr)
HU (1) HUT71796A (fr)
NO (1) NO953270L (fr)
NZ (1) NZ262664A (fr)
PL (1) PL310386A1 (fr)
SK (1) SK102495A3 (fr)
WO (1) WO1994018981A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5494921A (en) * 1994-09-16 1996-02-27 Merck & Co., Inc. Fibrinogen receptor antagonists
WO1997008145A1 (fr) * 1995-08-30 1997-03-06 G.D. Searle & Co. Derives de la meta-guanidine, de l'uree, de la thio-uree ou de l'acide aminobenzoique azacyclique utilises comme antagonistes de l'integrine
WO1997023480A1 (fr) * 1995-12-22 1997-07-03 The Du Pont Merck Pharmaceutical Company Nouveaux antagonistes de recepteurs d'integrines
WO1997035579A1 (fr) * 1996-03-27 1997-10-02 Merck & Co., Inc. Procede d'inhibition de la formation de caillots
US5811441A (en) * 1995-05-24 1998-09-22 The Dupont Merck Pharmaceutical Company Isoxazoline fibrinogen receptor antagonists
WO1998043962A1 (fr) * 1997-03-28 1998-10-08 Du Pont Pharmaceuticals Company Promedicaments heterocycliques inhibiteurs d'integrine
US5849736A (en) * 1993-11-24 1998-12-15 The Dupont Merck Pharmaceutical Company Isoxazoline and isoxazole fibrinogen receptor antagonists
US5900414A (en) * 1996-08-29 1999-05-04 Merck & Co., Inc. Methods for administering integrin receptor antagonists
WO2000006570A1 (fr) * 1998-07-27 2000-02-10 Ortho-Mcneil Pharmaceutical, Inc. Triazolopyridines pour traiter les dysfonctionnements thrombotiques
EP1023295A1 (fr) * 1997-02-06 2000-08-02 Merck & Co., Inc. Promedicaments antagonistes de recepteur de fibrinogene
US6100423A (en) * 1995-08-30 2000-08-08 G. D. Searle & Co. Amino benzenepropanoic acid compounds and derivatives thereof
US6291469B1 (en) 1995-09-29 2001-09-18 Eli Lilly And Company Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
CN1103775C (zh) * 1996-12-20 2003-03-26 赫彻斯特股份公司 玻连蛋白受体拮抗剂,其制备和用途
EP1572682A2 (fr) * 2002-12-20 2005-09-14 Pharmacia Corporation Composés de pyrazole acyclique
BG64902B1 (bg) * 1996-07-25 2006-08-31 Biogen, Inc. IIb/IIIa ИНХИБИТОРИ НА КЛЕТЪЧНА АДХЕЗИЯ, МЕТОД ЗАПОЛУЧАВАНЕ, ФАРМАЦЕВТИЧЕН СЪСТАВ И ИЗПОЛЗВАНЕ
WO2008006540A1 (fr) * 2006-07-12 2008-01-17 Syngenta Participations Ag Dérivés de triazolpyridine utilisés comme herbicides
WO2009137201A1 (fr) * 2008-04-04 2009-11-12 Cv Therapeutics, Inc. Dérivés de triazolopyridinone destinés à être utilisés comme inhibiteurs de la stéaroyl-coa désaturase
WO2010096722A1 (fr) * 2009-02-20 2010-08-26 Takeda Pharmaceutical Company Limited 3-oxo-2,3-dihydro-[1,2,4]triazolo[4, 3-a]pyridines utilisées comme inhibiteurs de l'époxyde hydrolase soluble (eh soluble)

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Publication number Priority date Publication date Assignee Title
HUP0203375A3 (en) * 1999-07-28 2005-03-29 Aventis Pharm Prod Inc Substituted oxoazaheterocyclyl compounds

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US5095018A (en) * 1989-06-06 1992-03-10 Burroughs Wellcome Co. 3-benzyl-1,2,4-triazolo[4,3-α] pyrazines
US5166154A (en) * 1989-10-17 1992-11-24 Boehringer Ingelheim Pharmaceuticals, Inc. Imidazo[1,2-a]piperazines
US5278161A (en) * 1990-06-28 1994-01-11 Hoffmann-La Roche Inc. Amino acid derivatives useful as renin inhibitors

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US5084466A (en) * 1989-01-31 1992-01-28 Hoffmann-La Roche Inc. Novel carboxamide pyridine compounds which have useful pharmaceutical utility

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US5095018A (en) * 1989-06-06 1992-03-10 Burroughs Wellcome Co. 3-benzyl-1,2,4-triazolo[4,3-α] pyrazines
US5166154A (en) * 1989-10-17 1992-11-24 Boehringer Ingelheim Pharmaceuticals, Inc. Imidazo[1,2-a]piperazines
US5278161A (en) * 1990-06-28 1994-01-11 Hoffmann-La Roche Inc. Amino acid derivatives useful as renin inhibitors

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See also references of EP0684823A4 *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5849736A (en) * 1993-11-24 1998-12-15 The Dupont Merck Pharmaceutical Company Isoxazoline and isoxazole fibrinogen receptor antagonists
US5494921A (en) * 1994-09-16 1996-02-27 Merck & Co., Inc. Fibrinogen receptor antagonists
US5811441A (en) * 1995-05-24 1998-09-22 The Dupont Merck Pharmaceutical Company Isoxazoline fibrinogen receptor antagonists
CN1085980C (zh) * 1995-08-30 2002-06-05 G·D·瑟尔公司 间－胍基、脲基、硫脲基或氮杂环氨基苯甲酸衍生物用作整合素拮抗剂
RU2196769C2 (ru) * 1995-08-30 2003-01-20 Джи. Ди. Сирл Энд Ко. Производные аминобензойной кислоты, фармацевтическая композиция
US6100423A (en) * 1995-08-30 2000-08-08 G. D. Searle & Co. Amino benzenepropanoic acid compounds and derivatives thereof
US6831199B1 (en) 1995-08-30 2004-12-14 G. D. Searle & Co. Pyrimidine compounds and derivatives thereof
WO1997008145A1 (fr) * 1995-08-30 1997-03-06 G.D. Searle & Co. Derives de la meta-guanidine, de l'uree, de la thio-uree ou de l'acide aminobenzoique azacyclique utilises comme antagonistes de l'integrine
US6291469B1 (en) 1995-09-29 2001-09-18 Eli Lilly And Company Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
US6693109B2 (en) 1995-09-29 2004-02-17 Eli Lilly And Company Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
US6528534B2 (en) 1995-09-29 2003-03-04 Millennium Pharmaceuticals, Inc. Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
WO1997023480A1 (fr) * 1995-12-22 1997-07-03 The Du Pont Merck Pharmaceutical Company Nouveaux antagonistes de recepteurs d'integrines
WO1997035579A1 (fr) * 1996-03-27 1997-10-02 Merck & Co., Inc. Procede d'inhibition de la formation de caillots
BG64902B1 (bg) * 1996-07-25 2006-08-31 Biogen, Inc. IIb/IIIa ИНХИБИТОРИ НА КЛЕТЪЧНА АДХЕЗИЯ, МЕТОД ЗАПОЛУЧАВАНЕ, ФАРМАЦЕВТИЧЕН СЪСТАВ И ИЗПОЛЗВАНЕ
US5900414A (en) * 1996-08-29 1999-05-04 Merck & Co., Inc. Methods for administering integrin receptor antagonists
CN1103775C (zh) * 1996-12-20 2003-03-26 赫彻斯特股份公司 玻连蛋白受体拮抗剂,其制备和用途
EP1023295A4 (fr) * 1997-02-06 2001-01-24 Merck & Co Inc Promedicaments antagonistes de recepteur de fibrinogene
EP1023295A1 (fr) * 1997-02-06 2000-08-02 Merck & Co., Inc. Promedicaments antagonistes de recepteur de fibrinogene
US6214834B1 (en) 1997-03-28 2001-04-10 Dupont Pharmaceuticals Company Integrin inhibitor prodrugs
WO1998043962A1 (fr) * 1997-03-28 1998-10-08 Du Pont Pharmaceuticals Company Promedicaments heterocycliques inhibiteurs d'integrine
US6303625B1 (en) 1998-07-27 2001-10-16 Ortho-Mcneil Pharmaceutical, Inc. Triazolopyridines for the treatment of thrombosis disorders
WO2000006570A1 (fr) * 1998-07-27 2000-02-10 Ortho-Mcneil Pharmaceutical, Inc. Triazolopyridines pour traiter les dysfonctionnements thrombotiques
EP1572682A2 (fr) * 2002-12-20 2005-09-14 Pharmacia Corporation Composés de pyrazole acyclique
EP1572682A4 (fr) * 2002-12-20 2008-01-23 Pharmacia Corp Composés de pyrazole acyclique
WO2008006540A1 (fr) * 2006-07-12 2008-01-17 Syngenta Participations Ag Dérivés de triazolpyridine utilisés comme herbicides
WO2009137201A1 (fr) * 2008-04-04 2009-11-12 Cv Therapeutics, Inc. Dérivés de triazolopyridinone destinés à être utilisés comme inhibiteurs de la stéaroyl-coa désaturase
US8088792B2 (en) 2008-04-04 2012-01-03 Gilead Sciences, Inc. Triazolopyridinone derivatives for use as stearoyl CoA desaturase inhibitors
US20120065227A1 (en) * 2008-04-04 2012-03-15 Gilead Sciences, Inc. TRIAZOLOPYRIDINONE DERIVATIVES FOR USE AS STEAROYL CoA DESATURASE INHIBITORS
WO2010096722A1 (fr) * 2009-02-20 2010-08-26 Takeda Pharmaceutical Company Limited 3-oxo-2,3-dihydro-[1,2,4]triazolo[4, 3-a]pyridines utilisées comme inhibiteurs de l'époxyde hydrolase soluble (eh soluble)

Also Published As

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HU9502028D0 (en) 1995-09-28
NO953270L (no) 1995-10-19
EP0684823A1 (fr) 1995-12-06
CN1118139A (zh) 1996-03-06
AU680240B2 (en) 1997-07-24
NO953270D0 (no) 1995-08-21
PL310386A1 (en) 1995-12-11
EP0684823A4 (fr) 1997-07-09
FI953916A0 (fi) 1995-08-21
SK102495A3 (en) 1997-01-08
CA2155123A1 (fr) 1994-09-01
NZ262664A (en) 1997-04-24
KR960700722A (ko) 1996-02-24
AU6246594A (en) 1994-09-14
FI953916L (fi) 1995-08-21
CZ210895A3 (en) 1996-02-14
JPH08507072A (ja) 1996-07-30
HUT71796A (en) 1996-02-28
BG99863A (en) 1996-02-29
JP3173792B2 (ja) 2001-06-04

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