EP0912182A1 - Promedicaments antagonistes du recepteur de fibrinogene - Google Patents

Promedicaments antagonistes du recepteur de fibrinogene

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Publication number
EP0912182A1
EP0912182A1 EP97931396A EP97931396A EP0912182A1 EP 0912182 A1 EP0912182 A1 EP 0912182A1 EP 97931396 A EP97931396 A EP 97931396A EP 97931396 A EP97931396 A EP 97931396A EP 0912182 A1 EP0912182 A1 EP 0912182A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
carboxy
alkyloxy
amino
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97931396A
Other languages
German (de)
English (en)
Other versions
EP0912182A4 (fr
Inventor
Melissa S. Egbertson
George D. Hartman
William C. Lumma
John S. Wai
Steven D. Young
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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Filing date
Publication date
Priority claimed from GBGB9617983.3A external-priority patent/GB9617983D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0912182A1 publication Critical patent/EP0912182A1/fr
Publication of EP0912182A4 publication Critical patent/EP0912182A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • 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
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • 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, [167-1714 (1984); Ginsberg et al., f. 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.
  • WO9014103 describes the use of antibody-polypeptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
  • W091 1 1458 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.
  • the invention relates to compounds having the formula
  • X' is a moiety, comprising between 8 and 1 1 contiguous atoms selected from carbon and nitrogen, terminating at the non-A bond end in an amino, aliphatic amino, aromatic amino, amidino, or guanidino substituent having a pKa of between about 5-14, wherein the atom attached to A is selected from carbon and nitrogen; a 5 or 6 membered aromatic ring, having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R ⁇ , disubstituted on carbon and nitrogen atoms with R5 and R6, or trisubstituted on carbon and nitrogen with R ⁇ , R6, and R9, where R5, R6, and R9 are independently selected from the group consisting of hydrogen, halogen,
  • R5, R6, and R9 are independently selected from the group consisting of hydrogen, halogen, Cl- ⁇ o alkyl,
  • n 1 or 2
  • m 0, 1 , or 2; selected from the group consisting of hydrogen, halogen,
  • Cl-6 alkoxy Cl-6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl, Cl-3 alkoxycarbonyl,
  • R ⁇ is selected from the group consisting of hydrogen, -C(0)-Cl_8alkyl, -C(0)-C3-8cycloalkyl, -C(0)-aryl, and
  • the compounds are useful as prodrugs of fibrinogen receptor antagonists.
  • 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.
  • the invention relates to compounds having the formula
  • X' is a moiety, comprising between 8 and 1 1 contiguous atoms selected from carbon and nitrogen, terminating at the non-A bond end in an amino, aliphatic amino, aromatic amino, amidino, or guanidino substituent having a pKa of between about 5-14, wherein the atom attached to A is selected from carbon and nitrogen;
  • A is a 5 or 6 membered aromatic ring, having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R5, disubstituted on carbon and nitrogen atoms with R5 and R6, or trisubstituted on carbon and nitrogen with R5, R6 7 and R9, where R5, R6, and R9 are independently selected from the group consisting of hydrogen, halogen, Cl-10 alkyl,
  • a 9 or 10 membered fused aromatic ring having 0, 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R ⁇ , disubstituted on carbon and nitrogen atoms with R5 and R6, or trisubstituted on carbon and nitrogen with R5, R6 ? and R ⁇ , where R5, R6 ? and R9 are independently selected from the group consisting of hydrogen, halogen, Cl -10 alkyl,
  • R7 is selected from the group consisting of hydrogen, halogen, Cl -10 alkyl,
  • R ⁇ is selected from the group consisting of hydrogen, -C(0)-Cl-8alkyl, -C(0)-C3-8cycloalkyl, -C(0)-aryl, and -C(0)-Cl-3alkylaryl.
  • the compound has the formula
  • X is a 5, 6 or 7 membered aromatic or nonaromatic ring, having 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R! or disubstituted with Rl and R2, where Rl and R ⁇ are independently selected from the group consisting of hydrogen, halogen,
  • Cl-6 alkoxy Cl-6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl-6 alkyl, carboxy Cl-6 alkyl,
  • Cl-3 alkoxycarbonyl Cl-3 alkoxycarbonyl Cl _6 alkyl, carboxy, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl, or
  • a 9 or 10 membered fused aromatic or nonaromatic ring having 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with Rl or disubstituted with Rl and R2, where R l and R2 are independently selected from the group consisting of hydrogen, halogen,
  • a 5 or 6 membered aromatic or nonaromatic ring having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or substituted on carbon and nitrogen atoms with R ⁇ selected from the group consisting of halogen, Ci-10 alkyl,
  • A is a 5 or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R ⁇ , disubstituted on carbon and nitrogen atoms with R5 and R6, or trisubstituted on carbon and nitrogen with R5, R6 ? and R9, where
  • R5, R6 5 and R9 are independently selected from the group consisting of hydrogen, halogen, Cl -10 alkyl,
  • a 9 or 10 membered fused aromatic ring having 0, 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R ⁇ , disubstituted on carbon and nitrogen atoms with R5 and R° or trisubstituted on carbon and nitrogen with R5, R6, and R9, where R5, R6, and R9 are independently selected from the group consisting of hydrogen, halogen,
  • n is 1 or 2, and m is 0, 1 , or 2;
  • R7 is selected from the group consisting of hydrogen, halogen, Cl -10 alkyl,
  • R ⁇ is selected from the group consisting of hydrogen
  • X is a 6-membered aromatic or nonaromatic ring having 1 , 2 or
  • Y is a 6-membered aromatic or nonaromatic ring having 0, 1 , 2 or 3 nitrogen atoms
  • A is a 6-membered aromatic ring unsubstituted, monosubstituted with a moiety selected from the group consisting of halogen, Cl-3alkyl, and Cl -3alkylsulfonylamino, disubstituted with one or more moieties, same or different, selected from the group consisting of halogen, Cl -3alkyl, and Ci-3alkylsulfonylamino or trisubstituted with one or more moieties, same or different, selected from the group consisting of halogen, Cl-3alkyl, and Cl - 3alkylsulfonylamino,
  • X is a 6-membered aromatic or nonaromatic ring having 1 or 2 nitrogen atoms
  • Y is a 6-membered aromatic or nonaromatic ring having 0 or 1 nitrogen atoms
  • A is a 6-membered aromatic ring unsubstituted, monosubstituted with a moiety selected from the group consisting of Br, CH3, and NHSO2CH3, disubstituted with one or more moieties, same or different, selected from the group consisting of Br, CH3, and NHSO2CH3, or trisubstituted with one or more moieties, same or different, selected from the group consisting of Br, CH3, and NHSO2CH3; and
  • the active acids of these compounds have been evaluated in vitro and found to have an IC50 for inhibiting platelet aggregation of between about 0.008 ⁇ M and 2 ⁇ M.
  • the prodrugs may be administered in low amounts relative to achieve inhibition of fibrinogen binding to the fibrinogen receptor.
  • 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 oxidative enzymes such as alcohol and aldehyde dehydrogenase 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 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound.
  • 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 pharamaceutically 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: 1157-1 164 (1994)).
  • pharmaceutically acceptable 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, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate
  • the compounds of the invention are prodrugs of active acids which inhibit fibrinogen binding to the gpUb/IIIa platelet receptor site. For example, these acids form in vivo, subsequent to administration to the patient, according to successive alcohol dehydrogenase and aldehyde dehydrogenase reactions:
  • Compounds of the invention of the general formula R'-CH2 ⁇ R ⁇ , where R ⁇ is an acyl moiety may be esters which metabolize into the active acid.
  • 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 binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal.
  • a moiety comprising between 8 and 11 contiguous atoms means a series of sequentially bonded atoms, including a series of atoms that are sequentially bonded in linear relation, wherein none of the atoms are part of a cyclic moiety, and a series of atoms that are sequentially bonded in a linear relation, wherein some of the atoms are part of a cyclic moiety.
  • the above structure also has 12 continguous carbon or nitrogen atoms (atoms numbered 1 -12) bonded in linear relation, wherein 8 of the atoms are part of one or more cyclic moieties. Since the above structure has 11 continguous carbon or nitrogen atoms bonded in linear relation, wherein 7 of the atoms are part of one or more cyclic moieties, the structure falls within the definition of X'.
  • 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., ethyn
  • aryl means a 5- or 6-membered aromatic ring containing 0, 1 , or 2 heteroatoms selected from O, 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 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.
  • BOP benzotriazol- 1 -yloxytris(dimethy lamino)phosphonium, hexafluorophosphate
  • EDC 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Oxone potassium peroxymonosulfate
  • 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 intramuscular 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.
  • Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extraco ⁇ oreal 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. 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.
  • 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 0.01-100 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 10-500 mg, for example, 10 mg, 100 mg, 200 mg and 500 mg.
  • 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 form the active ingredient of the prodrug, 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.
  • the active ingredient prodrug 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 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 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.
  • 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)
  • field strength for NMR analysis is either 300 MHz or 400 MHz.
  • 4-aminophenol is reacted with halogenated ethanol to produce 4-aminophenoxy ethanol, which is combined with a piperazinyl benzoic acid to produce an alcohol prodrug of the invention.
  • ester 1 -4 (21.1 g, 61.1 mmol) 1 N NaOH (100 ml, 100 mmol) and EtOH (200 ml) was heated to 60°C for 2.0 h. The solution was acidifed with 10% KHSO4 and then extracted with EtOAc. The EtOAc phase was washed with brine, dried (MgS ⁇ 4) and concentrated to furnish acid J ⁇ 5 as a white solid.
  • Rf7-4a(5Q% EtOAc/hexanes) 0.45 lH NMR (400 MHz, CDCI3) ⁇ 8.0 (m, 2H), 7.8 (d, 2H), 7.5 (s, IH), 6.93 (d, 2H), 6.85 (d, IH), 4.6 (s, 2H), 4.3 (q, 2H), 3.6 (bs, 8H), 3.35 (m, 8H), 2.4 (s, 3H), 1.45 (s, 9H), 1.35 (t, 3H).
  • Rf7 (50% EtOAc/hexanes) 0.37 lH NMR (400 MHz, CDCI3) ⁇ 7.6 (d, 2H), 6.7 (d, 2H), 4.6 (s, 2H), 4.3
  • Ethyl isonipecotate (6.0g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9g, 38.66 mmol) and N-methylmorpholine (9.3g mL, 85.00 mmol), were dissolved in N-methylpyrrolidine (50 mL) and the resulting solution was heated at lOOoC for 48h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc and washed with water and brine (2 x 100 mL), then dried (Na2S04) and evaporated. The resulting residue was purified by flash chromatography (5% MeOH / CHCI3) to afford 8-1 as a crystalline solid.
  • All of the active compound, cellulose, and a portion of the com starch are mixed and granulated to 10% com starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
  • An intravenous dosage form of the above-indicated prodrug 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).
  • a pharmaceutical composition was prepared at room temperature using 2-(3-Methyl-4-(4-(l -piperazinyl)phenylcarbonyl- amino)phenoxy)-ethanol hydrochloride, a citrate buffer, and sodium chloride, to obtain a concentration of of 0.25 mg/ml.
  • the finished concentrated formulation is stored in a standard USP Type I borosilicate glass container at 30-40 degrees C. Prior to compound administration, the concentrated formulation is diluted in a 4: 1 ratio resulting in a finished concentration of 0.05 mg/ml and transfered to an infusion bag.
  • Additional alcohol prodrugs of the present invention can be prepared according to the procedure whereby diborane is used to reduce the acid to the corresponding alcohol:
  • Compounds of the invention may be administered to patients where inhibition of human or mammalian platelet aggregation or adhesion is desired.
  • Compounds of the invention are useful in inhibiting platelet aggregation and thus, they 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 interation of platelets with artificial surfaces, leads to platelet aggregation and consumption.
  • the aggregated platelets may form thrombi and thromboemboli.
  • Compounds of the invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.

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Abstract

Promédicaments à base d'alcool, antagonistes du récepteur de fibrinogène, répondant par exemple à la formule (I), et plus particulièrement aux formules (II) et (III).
EP97931396A 1996-06-28 1997-06-25 Promedicaments antagonistes du recepteur de fibrinogene Withdrawn EP0912182A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US2097696P 1996-06-28 1996-06-28
US20976P 1996-06-28
GBGB9617983.3A GB9617983D0 (en) 1996-08-28 1996-08-28 Fibrinogen receptor antagonist prodrugs
GB9617983 1996-08-28
PCT/US1997/011037 WO1998000144A1 (fr) 1996-06-28 1997-06-25 Promedicaments antagonistes du recepteur de fibrinogene

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EP0912182A1 true EP0912182A1 (fr) 1999-05-06
EP0912182A4 EP0912182A4 (fr) 1999-12-29

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AU (1) AU709631B2 (fr)
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US6310264B1 (en) * 1997-05-30 2001-10-30 Alcoa Nederland B.V. Method for processing material comprising aluminum and plastic

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AU721130B2 (en) * 1996-06-28 2000-06-22 Merck & Co., Inc. Fibrinogen receptor antagonists
GB0319150D0 (en) * 2003-08-14 2003-09-17 Glaxo Group Ltd Novel compounds
GB0421908D0 (en) * 2004-10-01 2004-11-03 Angeletti P Ist Richerche Bio New uses
ATE466838T1 (de) * 2005-06-06 2010-05-15 Hoffmann La Roche Sulfonamid-derivate als lebercarnitin-palmitoyl- transferase-hemmer
US8168658B2 (en) 2006-02-28 2012-05-01 Merck Sharp & Dohme Corp. Inhibitors of histone deacetylase
CA2866218C (fr) 2012-03-16 2020-06-09 Vitae Pharmaceuticals, Inc. Modulateurs du recepteur x du foie
DK2825542T3 (en) 2012-03-16 2017-01-09 Vitae Pharmaceuticals Inc LIVER-X-receptor modulators
CN107501202A (zh) * 2017-09-26 2017-12-22 杨文浪 微波法制备1,4苯并噁嗪酮的合成工艺

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US5256812A (en) * 1989-01-31 1993-10-26 Hoffmann-La Roche Inc. Carboxamides and sulfonamides
WO1994022834A1 (fr) * 1993-03-29 1994-10-13 Zeneca Limited Derives heterocycliques utilises comme inhibiteurs d'agregation plaquettaire
AU692439B2 (en) * 1993-03-29 1998-06-11 Zeneca Limited Heterocyclic compounds as platelet aggregation inhibitors
US5547671A (en) * 1995-09-20 1996-08-20 Duthinh; Phu Anti-intoxication composition

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See also references of WO9800144A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6310264B1 (en) * 1997-05-30 2001-10-30 Alcoa Nederland B.V. Method for processing material comprising aluminum and plastic

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EP0912182A4 (fr) 1999-12-29
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CA2257937A1 (fr) 1998-01-08
WO1998000144A1 (fr) 1998-01-08
AU3503397A (en) 1998-01-21

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