WO1998034935A1 - Promedicaments antagonistes de recepteur de fibrinogene - Google Patents

Promedicaments antagonistes de recepteur de fibrinogene Download PDF

Info

Publication number
WO1998034935A1
WO1998034935A1 PCT/US1998/001998 US9801998W WO9834935A1 WO 1998034935 A1 WO1998034935 A1 WO 1998034935A1 US 9801998 W US9801998 W US 9801998W WO 9834935 A1 WO9834935 A1 WO 9834935A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
substituted
mammal
hydroxy
Prior art date
Application number
PCT/US1998/001998
Other languages
English (en)
Inventor
Melissa S. Egbertson
Steve D. Young
George D. Hartman
Jacquelynn J. Cook
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9707489.2A external-priority patent/GB9707489D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU61413/98A priority Critical patent/AU747293B2/en
Priority to JP53482498A priority patent/JP2001512439A/ja
Priority to CA002279927A priority patent/CA2279927A1/fr
Priority to EP98906092A priority patent/EP1023295A4/fr
Publication of WO1998034935A1 publication Critical patent/WO1998034935A1/fr

Links

Classifications

    • 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
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention relates generally to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp Hb/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 Hb/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 Hb/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 structurally related receptors
  • the authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition specificity.
  • Cheresh in Proc. Nat'l Acad. Sci. U.S.A., 84, 6471-6475, (1987) describes an Arg-Gly-Asp directed adhesion receptor expressed by human endothelial cells that is structurally similar to the Hb/IIIa complex on platelets but is antigenically and functionally distinct. This receptor is directly involved in endothelial cell attachment to fibrinogen, von Willebrand factor, and vitronectin.
  • a number of low molecular weight polypeptide factors have been isolated from snake venom. These factors apparently have high affinity for the gp Hb/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 compound which has high affinity for the gp Hb/IIIa complex. This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges.
  • Gan et al. J. Biol. Chem., 263, 19827-19832 (1988).
  • 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 Hb/IIIa receptor.
  • U.S. Pat. No. 5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation.
  • WO9014103 describes the use of antibody-poly-peptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
  • W09111458 discloses the use of large cyclic peptides containing RGD flanked by proline residues which are platelet aggregation inhibitors.
  • WO9101331 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.
  • U.S. Patent No. 5,051,405 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.
  • EP 445 796 discloses linear compounds which can include internal piperazinyl or piperidinyl derivatives.
  • EP437 367 discloses linear polypeptide fibrinogen receptor antagonists.
  • U.S. Patent No. 5,256,812 discloses compounds of the Rl-A-(W) a -X-(CH2)b- (Y) c -B-Z-COOR wherein Rl is a guandidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.
  • Fibrinogen receptor antagonist prodrugs having the structure, for example, of
  • Compounds of the invention, or pharmaceutically acceptable salts thereof, are useful in the manufacture of a medicament for inhibiting the aggregation of blood platelets, inhibiting angiogenesis, inhibiting osteoclast mediated bone resorption, preventing platelet thrombosis, preventing thrombo embolism or preventing reocclusion, in a mammal.
  • the invention relates to compounds having the formula
  • m and p are integers independently chosen from 0-6, q is an integer chosen from 1-6, and R ⁇ is selected from the group consisting of hydrogen, hydro xyl,
  • D and E are independently chosen from C, NH, N(CH3), N(CH2CH3), N(CHCH2CH2), O and S
  • R ⁇ is independently selected from the group consisting of hydrogen, Ci-io alkyl, aryl, aryl C 1-8 alkyl-, oxo, thio, amino, amino Ci-8 alkyl-,
  • Ci-6 dialkylamino- Ci-6 dialkylamino Cl-8 alkyl-, Ci-4 alkoxy Ci-4 alkoxy Ci-6 alkyl-, carboxy, carboxy Ci-6 alkyl-, Ci-3 alkoxycarbonyl-, C ⁇ -3 alkoxycarbonyl C ⁇ -6 alkyl-, carboxyoxy-, carboxy C ⁇ _6 alkyloxy-, hydroxy, and hydroxy C ⁇ _6 alkyl;
  • a and B which form a fused ring system sharing adjacent carbon and nitrogen atoms, are defined as follows:
  • A is 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 is a 5, 6 or 7 membered saturated, partially saturated, or unsaturated ring containing 1, 2 or 3 heteroatoms selected from 0, S or N;
  • Rl is hydrogen
  • Ci-6 alkyl carboxy, carboxy Ci-6 alkyl-, Ci-6 alkylcarboxy -,
  • Ci-8 alkyloxycarbonylamino- Ci-8 alkyloxycarbonylamino-, Ci-8 alkyloxycarbonylamino Ci-8 alkyl-, aryloxycarbonylamino- , aryloxycarbonylamino Cl-8 alkyl-, aryl Cl-8 alkyloxycarbonylamino-, aryl Cl-8 alkyloxycarbonylamino Cl-8 alkyl-, Cl-8 alkylcarbonylamino-,
  • R4 IS hydrogen
  • One class of compounds of the invention has the formula
  • R5 is independently selected from the group consisting of hydrogen
  • V 1 and V 2 is N or CR e and G is CH 2 , CH 2 -CH 2 ,
  • R" is H, branched or straight chain Ci-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, Ci-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 Cl-4 alkoxy- substituted alkyl, and wherein substituted aryl is substituted by one, two or three of the following groups: halogen, Cl-4 alkoxy, hydroxy, or C 1-4 alkyl; R ' is H, branched or straight chain Cl-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, Cl-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or O 5 heteroatoms wherein substituted alkyl is hydroxy- substituted or Cl-4 alkoxy-substituted alkyl, and where
  • R° is is H, branched or straight chain Cl-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, Cl-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or 0 heteroatoms 20 wherein substituted alkyl is hydroxy- substituted or Cl-4 alkoxy-substituted alkyl, and wherein substituted aryl is substituted by one, two or three of the following groups: halogen, Cl-4 alkoxy, hydroxy, or Cl-4 alkyl;
  • RlO is H, branched or straight chain Cl-4 alkyl
  • n and n' are 0-7;
  • n" is 0-3.
  • X is -CH2-, -0-, -CH2-0-, or -NH-C(O)-;
  • R4 is -CH2CH3 or -C(CH3)3.
  • the prodrugs may be administered in low amounts relative to the amounts of antagonist that would ordinarily be administered.
  • the prodrugs may be administered orally.
  • the prodrugs retain structural integrity while passing though the gastrointestinal system, and are effectively delivered to cells. They are subjected to metabolic reactions to form the active acid which then interacts with the platelet receptor site.
  • 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.
  • 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 108 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 i* 3 the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound.
  • the active amidine-acids of these compounds have been evaluated in vitro and found to have an IC50 for inhibiting platelet aggregation of between about 1.0 nM and 10,000 nM.
  • these compounds are useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy.
  • Pharmacologically effective amounts of the compounds, including pharmaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts.
  • these compounds are useful for treating angiogenesis (formation of new blood vessels). It has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor. Inhibition of angiogenesis can cause tumor regression in animal models. (See, Harrison's Principles of Internal Medicine. 12th ed., 1991). These compounds are therefore useful in the treatment of cancer for inhibiting tumor growth. (See e.g., Brooks et al., Cell, 79:1157-1164 (1994)).
  • 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, methyl
  • compositions and polymorphs of the general formula are within the present invention.
  • 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., ethynyl
  • aryl means a 5- or 6-membered aromatic ring containing 0, 1, or 2 heteroatoms selected from 0, N, and S, e.g. 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, e.g., 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 examples 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.
  • 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 are useful in the manufacture of a medicament for inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Hb/IIIa receptor, preventing platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy or after angioplasty or coronary artery bypass procedures, and preventing myocardial infarction in a mammal.
  • Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Hb/IIIa receptor is desired.
  • peripheral arteries arterial grafts, carotid endarterectomy
  • 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.
  • 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 gp Hb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer. J. Physiol, 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.
  • 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 0.01-100 mg kg/day and most preferably 0.01-20 mg/kg/day.
  • a typical 90 kg patient would receive oral dosages ranging between about 0.9 mg/day and about 9 g/day, most preferably between about 0.9 mg/day and 1.8 g/day.
  • Suitable pharmaceutical oral compositions such as tablets or capsules may contain , for example, 10 mg, 100 mg, 200 mg and 500 mg. Intravenously, 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 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 compound for oral administration in the form of a tablet or capsule, 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;
  • 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
  • the oral prodrug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, distintegrating 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.
  • Active drug can also be co-administered with the usual doses of suitable anticoagulation agents, such as heparin or warfarin (typically given in tablet doses between 1 and 20 mg daily during administration of the active drug), or thrombolytic agents such as tissue plasminogen activator (typically given in i.v. doses of between 20 and 150 mg over two hour period prior to or during administration of the active drug), to achieve beneficial effects in the treatment of various vascular pathologies.
  • suitable anticoagulation agents such as heparin or warfarin (typically given in tablet doses between 1 and 20 mg daily during administration of the active drug), or thrombolytic agents such as tissue plasminogen activator (typically given in i.v. doses of between 20 and 150 mg over two hour period prior to or during administration of the active drug)
  • Example 3-4 was prepared in a manner substantially the same as for example - Rf (EtOAc): 0.56.
  • Example 3 ⁇ 7 was prepared in a manner substantially the same as for example 1-5.
  • Rf 80% EtOAc / hexane: 0.40.
  • 4-6 was prepared substantially the same as for example 1-5.
  • iH NMR 400 MHz; DMSO-d 6 ) d 10.90 (bs, IH); 8.33 (t, IH); 8.27-8.25 (d, IH); 7.70-7.69 (m, 4H); 7.62-7.61 (m, 4H); 7.29-7.27 (d, 2H); 7.05-7.07 (d, 2H); 5.27 (s, 2H); 4.05 (m, IH); 3.49 (m, IH); 3.45 (m, IH); 2.3 (s, 3H); 0.96- 0.93 (t, 3H).
  • 5-5 was prepared in a manner substantially similiar as for example 1-5.
  • An intravenous dosage form of the above-indicated active compound is prepared as follows:
  • the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1994.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des promédicaments antagonistes de récepteur de fibrinogène ayant par exemple la structure représentée par la formule (I) et plus particulièrement par la formule (II).
PCT/US1998/001998 1997-02-06 1998-02-02 Promedicaments antagonistes de recepteur de fibrinogene WO1998034935A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU61413/98A AU747293B2 (en) 1997-02-06 1998-02-02 Fibrinogen receptor antagonist prodrugs
JP53482498A JP2001512439A (ja) 1997-02-06 1998-02-02 線維素原受容体拮抗薬プロドラッグ
CA002279927A CA2279927A1 (fr) 1997-02-06 1998-02-02 Promedicaments antagonistes de recepteur de fibrinogene
EP98906092A EP1023295A4 (fr) 1997-02-06 1998-02-02 Promedicaments antagonistes de recepteur de fibrinogene

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3690197P 1997-02-06 1997-02-06
US60/036,901 1997-02-06
GBGB9707489.2A GB9707489D0 (en) 1997-04-14 1997-04-14 Fibrinogen receptor antagonist prodrugs
GB9707489.2 1997-04-14

Publications (1)

Publication Number Publication Date
WO1998034935A1 true WO1998034935A1 (fr) 1998-08-13

Family

ID=26311371

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/001998 WO1998034935A1 (fr) 1997-02-06 1998-02-02 Promedicaments antagonistes de recepteur de fibrinogene

Country Status (5)

Country Link
EP (1) EP1023295A4 (fr)
JP (1) JP2001512439A (fr)
AU (1) AU747293B2 (fr)
CA (1) CA2279927A1 (fr)
WO (1) WO1998034935A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064397A1 (fr) * 1998-06-11 1999-12-16 G.D. Searle & Co. DOUBLES PROMEDICAMENTS D'ANTAGONISTES PUISSANTS DE GPIIb/IIIa
WO2000075129A1 (fr) * 1999-06-07 2000-12-14 Shire Biochem Inc. Inhibiteurs d'integrine thiophene
US6410594B1 (en) 1996-06-14 2002-06-25 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
US6503745B1 (en) 1998-11-05 2003-01-07 Biocryst Pharmaceuticals, Inc. Cyclopentane and cyclopentene compounds and use for detecting influenza virus
US6562861B1 (en) 1997-12-17 2003-05-13 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
CN111943818A (zh) * 2020-09-16 2020-11-17 天津市均凯化工科技有限公司 一种制备4,4′-双三氟甲基二苯醚的方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5422570B2 (ja) * 2008-02-21 2014-02-19 サノフイ 凝固第Ｘａ因子及びトロンビンの阻害剤としてのクロロチオフェン−アミド類

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2144762A1 (fr) * 1992-10-14 1994-04-28 George D. Hartman Antagonistes des recepteurs du fibrinogene
US5559127A (en) * 1992-10-14 1996-09-24 Merck & Co., Inc. Fibrinogen receptor antagonists
EP0673247A4 (fr) * 1992-12-01 1996-05-01 Merck & Co Inc Antagonistes des recepteurs du fibrinogene.
NZ262664A (en) * 1993-02-22 1997-04-24 Merck & Co Inc Heterocyclic substituted derivatives, and medicaments thereof
ES2147210T3 (es) * 1993-12-03 2000-09-01 Hoffmann La Roche Derivados de acido acetico como medicamentos.

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE STN REGISTRY 1 January 1900 (1900-01-01), "BENZENEPROPANOIC ACID, 3-Ä(HYDROXYAMINO)IMINOMETHYLÜ-.ALPHA.-Ä1-((4-(1-OXIDO-4-PYRIDINYL)BENZOYL)AMINO)ETHYLÜ-, METHYL ESTER, ÄR-(R*,R*Ü-(9CI)", XP002910817, Database accession no. 193153-12-7 *
DATABASE STN REGISTRY 1 January 1900 (1900-01-01), VOLKHARD, ET AL: "Preparation of Arylsulfonylaminobenzimidazoles as Inhibitors of Cell-Cell and Cell-Matrix Interactions", XP002910816, Database accession no. 203440-28-2 *
See also references of EP1023295A4 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6410594B1 (en) 1996-06-14 2002-06-25 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
US6562861B1 (en) 1997-12-17 2003-05-13 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
WO1999064397A1 (fr) * 1998-06-11 1999-12-16 G.D. Searle & Co. DOUBLES PROMEDICAMENTS D'ANTAGONISTES PUISSANTS DE GPIIb/IIIa
US6503745B1 (en) 1998-11-05 2003-01-07 Biocryst Pharmaceuticals, Inc. Cyclopentane and cyclopentene compounds and use for detecting influenza virus
WO2000075129A1 (fr) * 1999-06-07 2000-12-14 Shire Biochem Inc. Inhibiteurs d'integrine thiophene
US6274620B1 (en) 1999-06-07 2001-08-14 Biochem Pharma Inc. Thiophene integrin inhibitors
CN111943818A (zh) * 2020-09-16 2020-11-17 天津市均凯化工科技有限公司 一种制备4,4′-双三氟甲基二苯醚的方法

Also Published As

Publication number Publication date
EP1023295A4 (fr) 2001-01-24
EP1023295A1 (fr) 2000-08-02
AU747293B2 (en) 2002-05-16
CA2279927A1 (fr) 1998-08-13
AU6141398A (en) 1998-08-26
JP2001512439A (ja) 2001-08-21

Similar Documents

Publication Publication Date Title
AU719102B2 (en) Fibrinogen receptor antagonist prodrugs
US5334596A (en) Fibrinogen receptor antagonists
AU1699097A (en) Integrin receptor antagonists
US5932582A (en) Fibrinogen receptor antagonist prodrugs
EP0714295B1 (fr) Antagonistes du recepteur du fibrinogene
AU709631B2 (en) Fibrinogen receptor antagonist prodrugs
AU747293B2 (en) Fibrinogen receptor antagonist prodrugs
US5981584A (en) Fibrinogen receptor antagonist prodrugs
AU689961B2 (en) Fibrinogen receptor antagonists
US5990107A (en) Fibrinogen receptor antagonist prodrugs
AU742197B2 (en) Fibrinogen receptor antagonists
US6117842A (en) Fibrinogen receptor antagonists
AU719495B2 (en) Fibrinogen receptor antagonists
US5945545A (en) Fibrinogen receptor antagonists
US5789421A (en) Fibrinogen receptor antagonist
US5525617A (en) Fibrinogen receptor antagonists
AU702025B2 (en) Fibrinogen receptor antagonist

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GE GW HU ID IL IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK SL TJ TM TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1998906092

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2279927

Country of ref document: CA

Ref country code: CA

Ref document number: 2279927

Kind code of ref document: A

Format of ref document f/p: F

Ref country code: JP

Ref document number: 1998 534824

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 61413/98

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 1998906092

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998906092

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 61413/98

Country of ref document: AU