EP0612313A1 - Derives de piperidine acide acetique utilises comme inhibiteurs de l'agregation des plaquettes hematiques dependante du fibrinogene - Google Patents

Derives de piperidine acide acetique utilises comme inhibiteurs de l'agregation des plaquettes hematiques dependante du fibrinogene

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Publication number
EP0612313A1
EP0612313A1 EP92923116A EP92923116A EP0612313A1 EP 0612313 A1 EP0612313 A1 EP 0612313A1 EP 92923116 A EP92923116 A EP 92923116A EP 92923116 A EP92923116 A EP 92923116A EP 0612313 A1 EP0612313 A1 EP 0612313A1
Authority
EP
European Patent Office
Prior art keywords
physiologically acceptable
solvates
piperazinyl
acceptable salts
formula
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Withdrawn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
EP92923116A
Other languages
German (de)
English (en)
Inventor
Barry Porter
Colin David Eldred
Henry Anderson Kelly
James Russell Wheatcroft
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.)
Glaxo Group Ltd
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Glaxo Group Ltd
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Filing date
Publication date
Priority claimed from GB919124221A external-priority patent/GB9124221D0/en
Priority claimed from GB929201052A external-priority patent/GB9201052D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP0612313A1 publication Critical patent/EP0612313A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • This invention relates to acetic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing such compounds and to their use in medicine.
  • glycoprotein complex Gp ⁇ b/TJIa is the fibrinogen binding site on platelets that mediates the adhesive function required for platelet aggregation and thrombus formation.
  • X 1 and Y 1 which may be the same or different, represent CH or N;
  • X 2 represents CH or, when X 1 represents CH, may also represent N;
  • Y 2 represents N or, when Y 1 represents N, may also represent CH;
  • Z represents N or N *" R 5 ;
  • R 1 represents a hydrogen atom or a hydroxyl, C M alkyl or 2,2,2- trifluoroethyl group
  • R 2 represents a hydrogen atom or, when both X 1 and X 2 represent CH, may also represent a fluorine, chlorine or bromine atom or a C alkyl group;
  • R 3 represents a hydrogen atom or, when both Y 1 and Y 2 represent N, may also represent a C M alkyl or hydroxymethyl group.
  • R 4 represents a hydrogen atom or , when Z represents N, R 4 may also represent a C M alkyl
  • R 5 represents a C M alkyl or phenylC M alkyl group
  • R 6 represents a hydrogen atom or a C M alkyl group.
  • salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.
  • the compounds of formula (I) in which R 2 is other than hydrogen contain at least one chiral centre (shown as * in formula (I)) and that such compounds exist in the form of a pair of optical isomers (i.e- enantiomers).
  • the invention includes all such isomers and mixtures thereof including racemic mixtures.
  • Suitable physiologically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids (for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p- toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, salicylates, succinates, lactates, glutarates, glutaconates, acetates, tricarballylates, citrates, fi marates and maleates) and inorganic base salts such as alkali metal salts (for example sodium salts).
  • inorganic or organic acids for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p- toluenesulphonates, methanesulphonates, sulphamates, ascor
  • salts of the compounds of formula (I) include salts formed with trifluoroacetic acid.
  • the present invention encompasses all isomers of the compounds of formula (I) and their salts and solvates, including all tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures)- It is to be further understood that the present invention includes pharmacuetically acceptable derivatives of the compounds of formula (I).
  • pharmaceutically acceptable derivative is meant any pharmaceutically acceptable ester or salt or solvate of such ester of the compounds of formula (I) or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
  • the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds.
  • Such derivatives are compounds modified at the carboxyl or amidine functions.
  • compounds of interest include carboxylic acid esters of the compounds of formula (I).
  • esters include C M alkyl esters, more preferably C, .3 alkyl esters, such as ethyl esters.
  • Other compounds of interest as pharmaceutically acceptable derivatives include benzoylamidine, alkyloxycarbonyl amidine and dialkyloxyphosphinyl amidine derivatives of the compounds of formula (I), which may be prepared by transformation of the amidine group.
  • the pharmaceutically acceptable derivatives of the compounds of formula (I) may be derivatised at more than one position. It will be further appreciated by those skilled in the art that carboxylic acid ester derivatives of formula (I) may be useful as intermediates in the preparation of compounds of formula (I), or as pharmaceutically acceptable derivatives of formula (I), or both.
  • alkyl' as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n- propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
  • X 1 and X 2 both represent CH; Y 1 and Y 2 both represent N;
  • Z represents N or N *" R 5 , where R 5 represents a methyl or benzyl group; Z most preferably represents N; R 1 represents a hydrogen atom;
  • R 2 represents a hydrogen, fluorine or chlorine atom, or a C-_ 4 alkyl group; R 2 most preferably presents a hydrogen atom; R 4 represents a hydrogen atom; R 6 represents a hydrogen atom or a methyl group; and R ⁇ most preferably represents a hydrogen atom.
  • Whe 2 represents a chlorine or bromine atom or a C M alkyl group
  • R 2 is preferably in the position meta to the amidine function.
  • a particularly preferred compound of the invention is 4-[4-[4- (a ⁇ r ⁇ ino-- ⁇ nmomethyl)phenyl]-l-piperazinyl]-l-piperidineacetic acid and physiologically acceptable salts and solvates thereof.
  • 2-oxoethyl)-l-methylpiperidinium salts including physiologically acceptable salts and solvates thereof;
  • the compounds of the present invention are of interest for use in human and veterinary medicine, particularly in the treatment or prophylaxis of thrombotic disorders.
  • thrombotic disorders include occlusive vascular diseases such as myocardial infarction, cardiac fatalities, angina, transient ischaemic attacks and thrombotic stroke, arteriosclerosis, vessel wall disease, peripheral vascular disease, nephropathy, retinopathy, postoperative thrombosis, pulmonary embolism, deep vein thrombosis and retinal vein thrombosis.
  • the compounds of the invention are also of interest for use in the prophylaxis of peri- and postoperative complications following organ transplantation (particularly cardiac and renal), coronary artery bypass, peripheral artery bypass, angioplasty, thrombolysis and endarterectomy.
  • the compounds of the invention may also be useful for the treatment or prophylaxis of other conditions in which the glycoprotein complex Gp ⁇ b ⁇ ia or other integrin receptors are implicated.
  • the compounds of the invention may potentiate wound healing and be useful in the treatment of osteoporosis.
  • the compounds of the invention may also be useful for the treatment of certain cancerous diseases-
  • compounds of the invention may be of use to prevent or delay metastasis in cancer.
  • a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prophylaxis of thrombotic disorders-
  • a method of treating a human or animal subject suffering from or susceptible to a thrombotic disorder comprises administering to said subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
  • the compounds of formula (I) may advantageously be used in conjunction with one or more other therapeutic agents.
  • suitable agents for adjunctive therapy include thrombolytic agents or any other compound stimulating thrombolysis or fibrinolysis and cytotoxic drugs.
  • the present invention covers the use of a compound of formula ( ⁇ ) or a physiologically acceptable salt or solvate thereof in combination with one or more other therapeutic agents.
  • compositions comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof adapted
  • compositions for use in human or veterinary medicine.
  • Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
  • the compounds according to the invention may be formulated for administration in any suitable manner.
  • the compounds may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral or parenteral administration.
  • the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
  • the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously).
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • formulatory agents such as suspending, stabilising and/or dispersing agents.
  • For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle.
  • the compounds of the invention may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds of the invention may also be used in combination with other therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutic agent, in particular a thrombolytic agent.
  • Another therapeutic agent in particular a thrombolytic agent.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • a proposed daily dosage of a compound of formula (I) for the treatment of man is 0.01 mg/kg to 30 mg kg, which may be conveniently administered in 1 to 4 doses.
  • the precise dose employed will depend on the age and condition of the patient and on the route of administration.
  • a daily dose of O.lmg/kg to lOmg/kg may be suitable for systemic administration.
  • alkylation e.g. ethylation
  • a suitable alkylating agent such as an alcoholic solvent (e.g. methanol) at an elevated temperature (e.g. reflux)
  • a source of ammonia e.g. ammonium acetate
  • a suitable solvent such as an alcoholic solvent (e.g. methanol) at an elevated temperature (e.g. reflux)
  • the alkylation may conveniently be effected by employing an appropriate trialkyloxonium salt (e.g. triethyloxonium tetrafluoroborate) in a suitable solvent (e.g. dichloromethane) at room temperature.
  • an appropriate trialkyloxonium salt e.g. triethyloxonium tetrafluoroborate
  • suitable solvent e.g. dichloromethane
  • methylation or benzylation may conveniently be effected using an alkyl or benzyl halide (e.g. iodomethane) in a suitable solvent such as a ketone (e.g. acetone) at an elevated temperature (e.g. reflux).
  • a suitable solvent such as a ketone (e.g. acetone)
  • an elevated temperature e.g. reflux
  • hydroxylamine or an acid addition salt thereof e.g. hydroxyla ine hydrochloride
  • a suitable base such as an alkali or alkaline earth metal carbonate or bicarbonate (e.g. potassium carbonate) or an alkoxide such as potassium tert-butoxide and in a solvent such as an alcohol (e.g. methanol or tert-butanol), followed, where necessary, by removing any protecting groups present.
  • a suitable base such as an alkali or alkaline earth metal carbonate or bicarbonate (e.g. potassium carbonate) or an alkoxide such as potassium tert-butoxide
  • a solvent such as an alcohol (e.g. methanol or tert-butanol)
  • reaction 20 or an acid addition salt thereof may conveniently be effected at an elevated temperature (e.g. reflux) when a carbonate or bicarbonate is used.
  • elevated temperature e.g. reflux
  • the reaction may conveniently be effected at a temperature in the range of about 20° to 80°C.
  • compounds of formula (I) in which R' represents a hydroxyl, C M alkyl or 2,2,2-trifluoroethyl group may be prepared by treating
  • compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors.
  • compounds of formula (I) in which R 1 represents a hydrogen atom may be prepared from corresponding compounds of formula (I) in which R 1 represents a hydroxyl group by catalytic hydrogenation in a solvent such as an alcohol (e.g. ethanol), or acetic acid preferably in the presence of acetic anhydride.
  • a solvent such as an alcohol (e.g. ethanol), or acetic acid preferably in the presence of acetic anhydride.
  • Suitable catalysts include Raney Nickel or conventional palladium, platinum or rhodium catalysts.
  • compounds of formula (I) in which R 1 is hydrogen, C w alkyl or 2,2,2-trifluoroethyl and ring -C- represents
  • R l is hydrogen, C w alkyl or 2,2,2-trifluoroethyl
  • a platinum catalyst e.g. PtO
  • the reaction may conveniently be effected in a solvent such as an alcohol (e.g. ethanol), and optionally in the presence of an acid, such as hydrochloric acid.
  • Another process (G) for preparing compounds of formula (I) comprises deprotecting protected derivatives of compounds of formula (I).
  • compounds of formula (I) may be prepared from protected carboxyl derivatives of compounds of formula (I).
  • Suitable carboxyl protection groups include, for example, those described in
  • carboxyl protecting groups include, for example, carboxylic acid ester groups such as carboxylic acid alkyl or aralkyl esters, for example where the alkyl or aralkyl portion of the ester function is methyl, ethyl, tert-butyl, methoxymethyl, benzyl, diphenylmethyl, triphenylmethyl or p-nitrobenzyl.
  • carboxylic acid ester groups such as carboxylic acid alkyl or aralkyl esters, for example where the alkyl or aralkyl portion of the ester function is methyl, ethyl, tert-butyl, methoxymethyl, benzyl, diphenylmethyl, triphenylmethyl or p-nitrobenzyl.
  • ester is an unbranched alkyl (e.g. methyl) ester deprotection may be effected under conditions of acid hydrolysis, for example using hydrochloric acid.
  • Tert-butyl and triphenylmethyl ester groups may be removed under conditions of moderate acid hydrolysis, for example using formic or trifluoroacetic acid at room temperature or using hydrochloric acid in acetic acid.
  • Benzyl, diphenylmethyl and nitrobenzyl ester groups may be removed by hydrogenolysis in the presence of a metal catalyst (e.g. palladium).
  • reaction may conveniently be carried out in a solvent such as dimethylformamide or pyridine and in the presence of an organic base such as an amine (e.g. triethylamine).
  • a solvent such as dimethylformamide or pyridine
  • an organic base such as an amine (e.g. triethylamine).
  • Unprotected compounds of formula (HI) may also be prepared from compounds of formula ON) by removing the carboxylic acid protecting group R p according to the method described in process (E) hereinabove.
  • a mixture of compounds of formulae (V) and (NI) may be treated with a reducing agent such as a metal borohydride in the presence of a suitable acid and in a suitable solvent at about room temperature.
  • a reducing agent such as a metal borohydride
  • the reduction may conveniently be carried out using sodium cyanoborohydride in a solvent such as an alcohol (e.g. methanol) in the presence of an acid (e.g. hydrochloric acid) and preferably also with molecular sieves.
  • the reduction may be effected using sodium triacetoxyborohydride in a solvent such as tetrahydrofuran or dichloromethane in the presence of an acid (e.g. acetic acid).
  • Compounds of formula (NI) may be prepared from an ⁇ -protected (e.g. ⁇ -benzyl protected) piperidin-4-one, optionally substituted by C M alkyl, by removal of the protecting group followed by treatment with a reagent HalCHR 6 CO 2 R p preferably in the presence of a suitable base such as an alkali metal carbonate or bicarbonate (e.g. potassium carbonate) and in a solvent such as a nitrile (e.g. acetonitrile), conveniently at an elevated temperature (e.g. reflux).
  • a suitable base such as an alkali metal carbonate or bicarbonate (e.g. potassium carbonate)
  • a solvent such as a nitrile (e.g. acetonitrile)
  • the removal of the protecting group may be effected by hydrogenolysis in the presence of a suitable transition metal catalyst such as a palladium catalyst (e.g. Pd(OH) 2 ).
  • a suitable transition metal catalyst such as a palladium catalyst (e.g. Pd(OH) 2 ).
  • a base such as an alkali or alkaline earth metal carbonate or bicarbonate (e.g. sodium bicarbonate) and in a suitable solvent such as an aprotic polar solvent (e.g. dimethylformamide, acetonitrile or dimethylsulphoxide), conveniently at an elevated temperature.
  • a base such as an alkali or alkaline earth metal carbonate or bicarbonate (e.g. sodium bicarbonate)
  • a suitable solvent such as an aprotic polar solvent (e.g. dimethylformamide, acetonitrile or dimethylsulphoxide), conveniently at an elevated temperature.
  • aprotic polar solvent e.g. dimethylformamide, acetonitrile or dimethylsulphoxide
  • Compounds of formula (NHI) may be prepared from compounds of formula (VI) by reacting said compounds of formula (VI) with a suitable piperazine derivative, optionally protected (e.g. ⁇ -benzyl protected), under reducing conditions, for example as described above for the reaction between compounds of formulae (N) and (VI), followed, where appropriate, by the removal of any ⁇ -protecting group present using conventional conditions, for example as described above.
  • a suitable piperazine derivative optionally protected (e.g. ⁇ -benzyl protected)
  • SUBSTITUTE S may be prepared from compounds of formula (IX)
  • Compounds of formula (XI) may be prepared by reacting a 4- halopyridine derivative with 4-pyridylboronic acid, preferably in the presence of a suitable transition metal catalyst such as a palladium catalyst [e.g. tetrakis(triphenylphosphine)palladium(0)] and a suitable base such as an alkali metal carbonate (e.g. sodium carbonate).
  • a suitable transition metal catalyst such as a palladium catalyst [e.g. tetrakis(triphenylphosphine)palladium(0)]
  • a suitable base such as an alkali metal carbonate (e.g. sodium carbonate).
  • the reaction may conveniently be effected in a solvent such as an aqueous ether (e.g. aqueous 1,2-ethanediol dimethyl ether).
  • Compounds of formula (XV) may be prepared by reacting a suitable 4-halopyridine with a suitable piperazine under the conditions described above for preparing compounds of formula (IV) from compounds of formula (VII).
  • Suitable bases include alkali or alkaline earth metal carbonates or bicarbonates such as sodium bicarbonate or potassium carbonate.
  • the reaction may conveniently be effected in a solvent such as dimethylformamide or dimethylsulphoxide at an elevated temperature (e.g. 100°-200°C).
  • a solvent such as dimethylformamide or dimethylsulphoxide at an elevated temperature (e.g. 100°-200°C).
  • compounds of formula (XVI) are treated with benzyl bromide in an alcoholic solvent (e.g. ethanol) or a halogenated hydrocarbon (e.g. dichloromethane) at an elevated temperature to provide a salt of formula (XVII)
  • an alcoholic solvent e.g. ethanol
  • a halogenated hydrocarbon e.g. dichloromethane
  • borohydride reducing agent such as sodium borohydride in a suitable solvent such as an alcohol (e.g. ethanol) or dimethylformamide or a mixture of such solvents to a compound of formula (XVm)
  • Removal of the benzyl group and reduction of the double bond from a compound of formula (XVHI) provides the desired compounds of formula (V).
  • the removal of the benzyl group may conveniently be effected by hydrogenolysis in the presence of a palladium catalyst such as Pd(OH) 2 -on-carbon, or by reaction with 1-chloroethyl chloroformate in the presence of a base such as 'proton sponge' followed by treatment with methanol.
  • the reduction of the double bond may conveniently be effected by hydrogenation in the presence of a platinum catalyst such as platinum-on-carbon or platinum oxide or a palladium catalyst such as palladium hydroxide-on-carbon and optionally in the presence of an acid (e.g. hydrochloric acid).
  • the compound of formula (XX) is a known compound described by W. J. Thompson et al in J. Org. Chem., 1988, 53, 2052.
  • Compounds of formula (VII) are either known compounds or may be prepared from the known compounds of formula (VII) using conventional chemistry.
  • Compounds of formula (I) or intermediates thereto in which ring -A- represents a C M alkyl substituted phenyl group may conveniently be prepared by modification of the corresponding compound in which ring -A- represents a bromo substituted phenyl group.
  • the bromo substituted intermediate may be treated with a zinc reagent RZnBr (where R is C M alkyl) in the presence of a palladium catalyst such as lchloro[l, -bis(diphenylphosphino)ferrocene]paIlad ⁇ um Ql).
  • Alkylation may also be effected using a tin reagent R 4 Sn (where R is C M alkyl) in the presence of a palladium catalyst such as bis (triphenylphosphine)benzylpalladium chloride.
  • a palladium catalyst such as bis (triphenylphosphine)benzylpalladium chloride.
  • Compounds of formula (XXI) may be prepared by reacting compounds of formula (V) with an N-protected piperidin-4-one, optionally substituted by C M alkyl, under reducing conditions (for example as described above for the reaction between compounds of formulae (V) and (VI)), followed by removing the N-protecting group.
  • Suitable protecting groups include -CO 2 Alk (where Alk is an alkyl group such as t-butyl), or aralkyl, for example benzyl.
  • the former protecting group may be removed by acid hydrolysis (e.g. using trifluoroacetic acid at about room temperature), the latter under the conditions described above for the removal of the benzyl group from compounds of formula (XvTfl).
  • reaction may conveniently be effected in a solvent such as an aromatic hydrocarbon (e.g. toluene) and preferably in the presence of alumina at an elevated temperature.
  • a suitable inorganic nitrile such as sodium cyanide
  • a palladium catalyst e.g. tetrakis(triphenylphosphine)palladium(0).
  • the reaction may conveniently be effected in a solvent such as an aromatic hydrocarbon (e.g. toluene) and preferably in the presence of alumina at an elevated temperature.
  • Compounds of formula (XXII) may be prepared by reacting a 2,5- dihalopyridine (e.g. 2,5-dibromopyridine) with a compound of formula (V-QI) or a compound of formula
  • Compounds of formula (XXIV) may be prepared by reacting a 2,5- dihalopyridine (e.g.2,5-dibromopyridine) with a compound of formula (X) under the conditions described above for the reaction between compounds of formulae (VH) and (N-H).
  • a 2,5- dihalopyridine e.g.2,5-dibromopyridine
  • Compounds of formula (XXV) may be prepared by reacting a 2,5- dihalopyridine (e.g. 2,5-dibromopyridine) with a compound of formula (XV) under the conditions described above for the reaction between compounds of formulae (VH) and (VQI).
  • a 2,5- dihalopyridine e.g. 2,5-dibromopyridine
  • a compound of formula (XV) under the conditions described above for the reaction between compounds of formulae (VH) and (VQI).
  • Compounds of formula (XXIII) may be prepared by treating a compound of formula (X) with a reagent HalCHR 6 CO 2 R p under the conditions described above for preparing compounds of formula (VI).
  • Compounds of formula (XXNII) may be prepared by reacting a 2,5- dihalopyridine (e.g.2,5-dibromopyridine) with a compound of formula (XX) under the boronic acid coupling conditions described previously.
  • a 2,5- dihalopyridine e.g.2,5-dibromopyridine
  • Halopyridines and dihalopyridines described above are known in the art.
  • Alkyl substituted halopyridines are either known compounds described in Chem. Pharm. Bull., 1988, 36, 2244 and I. Het. Chem., 1988, 25, 81 or may be prepared according to the methods described therein.
  • the desired stereochemistry of the product may be obtained either by commencing with an optically pure starting material or by resolving the racemic mixture at any convenient stage in the synthesis.
  • an intermediate or a starting material may be effected by any suitable method known in the art: see for example 'Stereochemistry of Carbon Compounds' by E L Eliel (McGraw Hill, 1962) and 'Tables of Resolving Agents' by S HWilen- Certain intermediates described above are novel compounds, and it is to be understood that all novel intermediates herein form further aspects of the present invention. Compounds of formula (IV) are key intermediates and represent a particular aspect of the present invention.
  • acids of formula (I) are isolated following work-up as acid addition salts, e.g. trifluoroacetate salts.
  • Physiologically acceptable acid addition salts of the compounds of formula (I) may be prepared from the corresponding trifluoroacetate salts by exchange of ion using conventional means, for example by neutralisation of the trifluoroacetate salt using abase such as aqueous sodium hydroxide, followed by addition of a suitable organic or inorganic acid.
  • Inorganic base salts of the compounds of formula (I) may also be prepared from the corresponding trifluoroacetate salts by addition of a suitable strong base such as sodium hydride.
  • Solvates e.g. hydrates of a compound of formula (I) may be formed during the work-up procedure of one of the aforementioned process steps.
  • the following Preparations and Examples illustrate the invention but do not limit the invention in any way. All temperatures are in °C. Thin layer chromatography (T.l.c.) was carried out on silica plates. System A is dichloromethane-ethanol- 0.880 ammonia. System B is dichloromethane-methanol - 0.880 ammonia. Preparative high performance liquid chromatography (h.p.l.c.) was carried out using a Dynamax 60A C18 8 ⁇ M 25cm x 41.4mm i.d.
  • N-Benzyl-4-piperidone (lOg) was dissolved in absolute ethanol (100ml), treated with dilute hydrochloric acid (2N; 29ml) and hydrogenated at room temperature and pressure over Pearlmann's catalyst (lg) for 18h.
  • the catalyst was removed by filtering through "hyflo” and the solvent was removed in vacuo to leave the title compound
  • the title compound (a) as a white powder (65mg) having a mass spectrum [Mi ] of 416, and after R ⁇ 17.0 min the title compound (b) as a pale pink powder (lOOmg), also having a mass spectrum [MIT] of 416.
  • Methyl iodide (0.85ml) was added to a stirred suspension of Intermediate 10 (3.0g) in acetone (200ml) and the mixture was heated at reflux for 3h. The solvent was removed in vacuo and the residue dissolved in methanol (200ml). Trifluoroethylamine (1.15ml) was added and the mixture heated at ca. 60° under nitrogen for 5h. The solvent was removed in vacuo to leave a yellow foam which was purified by preparative h.plc. (gradient profile 10-70% (ii) in 18 min.) to give after R-. 11.07 min. the title compound as a white powder (182mg). Analytical h.plc. (gradient profile 10-90% (ii) in 25 min.) R-. 9.63 min.
  • Example 14 cis- 1.1 -Dimethylethyl 4-[4-[4-[aminof hydroxyimino)methyl]phenyl]- 1 - piperazinyl]-3-methyl- 1 -piperidineacetate
  • Example 8 (152mg) was treated with a mixture of trifluoroacetic acid and water (9:1; 50ml). The mixture was stirred at room temperature for 20min before the reagents were removed in vacuo to leave the title compound as a pink solid (120mg). Analysis Found : C-39.6; H.4.5; N,9.2; C 18 H 27 N 5 O 2 .3.65C 2 HF 3 O 2 requires : C,39.9; H,4.1; N,9.2%.
  • Example 16 fa) trans-4-[4-[4-f AminoiminomethvDphenyl]-! -piperazinyl]-! -f 2-hydroxy- 2-oxoethylVl-methylpiperidinium trifluoroacetate salt
  • fb cis-4-[4-[4- AminoiminomethvDphenyl]- 1 -piperazinyl]- 1 -f 2-hvdroxy-2-oxoethylV 1 - methylpiperidinium trifluoroacetate salt
  • Example la (58mg) was treated with trifluoroacetic acid and water (9:1; 25ml) and the mixture stirred at room temperature for 20min.
  • Example 2 A solution of Example 2 (0.12g) in trifluoroacetic acid (4.5ml) and water (0.5ml) was stirred at room temperature for 5h. The solution was evaporated under reduced pressure and the residue triturated under isopropyl acetate to yield the title compound as an off-white powder (0.2g).
  • Example 4 (44mg) was dissolved in trifluoroacetic acid-water (9:1, 10ml) and the mixture allowed to stand for 4h. The solvents were removed in vacuo and the residue triturated with dry ether to afford the title compound as a colourless solid (42mg). Analysis Found: C,37.65; H,4.0; N,9.9;
  • Example 5 (252mg) in trifluoroacetic acid-water (9:1, 20ml) was allowed to stand for 2h and the solvents evaporated in vacuo. The residue was triturated with dry ether
  • Example 6 (60mg) was dissolved in trifluoroacetic acid-water (9:1, 10ml) and the solution allowed to stand for 4h. The solvent was removed in vacuo and the residue triturated with dry ether (5ml). Purification by preparative h.plc. (gradient profile 5-20% (ii) over lOmin and 20% (ii) isochratic for 8min) afforded after R-.13.5 min. the title compound as a colourless solid (15mg).
  • Example 7 (82mg) was stirred at room temperature under nitrogen in a mixture of trifluoroacetic acid (4.5ml) and water (0.5ml) for 3.5h. The solvents were removed in vacuo to afford the title compound (67mg) as an off-white solid.
  • N.m.r. ( ⁇ , D 6 -DMSO) : 1.9-2.4 SH ⁇ C-E ⁇ s), 3-4 (lOH-H j O +
  • Example 15 (0.15g) was dissolved in ethanol (70ml) and hydrogen chloride gas was bubbled into the cooled (ice bath) solution for 20min, which was then stirred overnight at room temperature. The solvent was removed in vacuo to yield the title compound as a pale pink solid (lOOmg). Mass spectrum [MIT] 374.2.
  • Example 9 (lOOmg) was treated with a mixture of trifluoroacetic acid and water
  • Example 10 (97mg) was treated with trifluoroacetic acid and water (9:1, 25ml) and the mixture stirred at room temperature for 3h. The reagents were removed in vacuo to leave an oil which was triturated with ether to leave the title compound as a white solid
  • Example 26 4-[4-[4-f AminoiminomethyDphenyl]- 1 -piperazinyl]- ⁇ -methyl- 1 - piperidineacetic acid
  • Example 11 (1.45g) was dissolved in 2N hydrochloric acid ( ⁇ 100ml) and the mixture stirred at ca- 60° for 3 days. The solvent was removed in vacuo leaving the title compound as a pink solid (0.98g).
  • Example 27 r-[4-fAminoiminomethyl phenyl][4.4'-bipiperidine]-l-acetic acid, trifluoroacetate salt
  • Mass spectrum [MET] 345.5 A solution of Example 12 (105mg) in trifluoroacetic acid-water (9:1,15ml) was allowed to stand at 22° for 2.5h. The solvent was removed in vacuo and the residue purified by preparative h.plc. (gradient profile 5-20% (ii) in lOmin and 20% (ii) isochratic for 8 min.)
  • Example 13 (a) (30mg) was treated with trifluoroacetic acid and water (1:1) (10ml), and the mixture was stirred at room temperature for 18h. The solvent was removed in vacuo to give the title compound as an off white solid (26mg)
  • Example 13 (b) (86mg) was treated with trifluoroacetic acid and water (9:1, 10ml), and the mixture was stirred at room temperature for 18h. The solvent was removed in vacuo to give the title compound as a white solid f76mg).
  • Mass spectrum [MIT] 436 (86mg) was treated with trifluoroacetic acid and water (9:1, 10ml), and the mixture was stirred at room temperature for 18h. The solvent was removed in vacuo to give the title compound as a white solid f76mg).
  • Example 14 Acetic acid (10ml) and acetic anhydride (0.3ml) were added together to a mixture of Example 14 (0.9g) and 5% palladium on carbon (lOOmg) under nitrogen, and the mixture was hydrogenated at room temperature and pressure until hydrogen uptake had ceased.
  • the mixture was filtered through 5N HCl washed Hi-flow, and the filter cake washed with 5N hydrochloric acid (3 x 10ml). The filtrate was stirred under nitrogen for
  • Example 8 Sodium hydroxide solution (2N: 3ml) was added to Example 8 (0.7g) and the suspension evaporated to dryness- The solid residue was suspended in dry pyridine (15ml) and ethyl chloroformate (0.214ml) added. After lh, the solvent was removed in vacuo and the residue purified by preparative h.plc. (gradient profile 10-45% (ii) in 17 min) to give after - ⁇ 12.9 min the title compound as a beige solid (0.03g). Analytical h. ⁇ lc. (gradient profile 10-90% (ii) in 25 min) R ⁇ O. ⁇ min.
  • Example 31 A solution of Example 31 (0.032g), in trifluoroacetic acid (6ml) and water (1ml) was stirred at room temperature under nitrogen for 5h. The solvent was evaporated to give the title compound as a white solid (0.025g). Assay Found: C,37.3; H.3.6; N,6.8.
  • Example 8 A solution of Example 8 (0.4g) in dry dichlomethane (50ml) was treated with methyl chloroformate (0.05ml) and then sodium hydroxide solution (0. IN, 26.4m! and the mixture was stirred vigorously for 20 min. The organic layer was separated, dried (MgSO ⁇ and evaporated to yield the title compound as a yellow solid (0.3g). Tic. (System A, 9O:10:1) Rf 0.7.
  • Example 33 (0.4g) was dissolved in trifluoroacetic acid (18ml) and water (3ml) and the mixture was stirred at room temperature for lh. The mixture was concentrated in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 5-20% (ii) in 10 min and 20% (ii) isochratic for 8 min) to give after R.12 min the title compound as a beige solid (0.22g).
  • Example 8 Sodium hydroxide solution (2N, 20ml) was added to Example 8 (0.9g) and the solution evaporated to dryness. Dimethylformamide (10ml) followed by diethyl cyanophosphate (0.264ml) were added to the solid residue and the solution stirred at room temperature for 15h. The solution was filtered and the filtrate evaporated in vacuo to give the title compound as a red oil (0.6g).
  • Example 35 (0.6g) was stirred in trifluoroacetic acid (9ml) and water (1ml) for 2h at room temperature. The mixture was concentrated in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 5-40% (ii) in 17min) to give after R ⁇ 14.4 min the title compound as a foam (0.12g).
  • Example 8 (0.3g) in dichloromethane (20ml) was treated with benzoyl chloride (27 ⁇ l) and sodium hydroxide solution (0.1N; 14ml), and subsequently stirred vigorously for 2h. The organic layer was separated, dried (MgSO ⁇ , and evaporated in vacuo to yield a yellow residue which was purified by preparative h.plc. (gradient profile 10-55% (ii) in 17 min) to give after R-- 13.1 min the title compound as ayellow solid (O.llg) Mass Spectrum [-VttT] 506.
  • Example 37 (O.lg) was dissolved in trifluoroacetic acid (10ml) and water (1ml) and the mixture was stirred at room temperature for lh. The solvents were evaporated to give a yellow oil which was purified by preparative h.plc. (gradient profile 10-50% (ii) in
  • Example 39 A mixture of Example 39 (0.23g), acetic anhydride (78 ⁇ l) and 10% palladium on carbon (50mg) in glacial acetic acid (6ml) was hydrogenated at room temperature and pressure for lh. The catalyst was filtered off and the filtrate evaporated in vacuo. Purification by preparative h.p.l.c. (gradient profile 10-50% (ii) in 17 min) gave after R. 10.8 min the title compound f0.12 ) as a white solid. Mass Spectrum [MET] 402
  • Example 40 (0. lg) was stirred with trifluoroacetic acid (9ml) and water (1ml) at room temperature for 1.5h. The solvent was removed in vacuo to give an oily residue which was purified by preparative h.plc. (gradient profile 5-20% (ii) in 10 min and 20%
  • Inhibition of blood platelet aggregation by compounds of the invention was determined according to the following procedure. Citrated whole blood (1 part 3.8% trisodium citrate : 9 parts blood) was obtained from human volunteers, free of medication for at least 10 days prior to collection. The blood was incubated with 0. ImM aspirin and 0.05 ⁇ M prostacyclin and then centrifiiged at lOOOg for 4 minutes (20°C). The supernatant platelet rich plasma (PRP) was further centrifiiged at 1300g for 10 minutes (20°C) to sediment the platelets.
  • Citrated whole blood (1 part 3.8% trisodium citrate : 9 parts blood) was obtained from human volunteers, free of medication for at least 10 days prior to collection. The blood was incubated with 0. ImM aspirin and 0.05 ⁇ M prostacyclin and then centrifiiged at lOOOg for 4 minutes (20°C). The supernatant platelet rich plasma (PRP) was further centrifiiged at 1300g for 10 minutes (20°C)
  • the supernatant was discarded and the pellet washed with a physiological salt solution (HEPES 5mM, NaHCO 3 12mM, NaCl 140mM, 1&L_?0 4 0.74mM, D-Glucose 5.6mM, KC12.82mM and BSA 20g/l, pH 7.4) to remove residual plasma.
  • a physiological salt solution HPES 5mM, NaHCO 3 12mM, NaCl 140mM, 1&L_?0 4 0.74mM, D-Glucose 5.6mM, KC12.82mM and BSA 20g/l, pH 7.4
  • the platelets eluted within the void volume and were diluted to approximately 300,000 platelets ⁇ l in buffer.
  • Purified human fibrinogen Korean L.C. et al, 1981 Thromb.
  • Haemostasis, 46(3), 593-596 was added to a final concentration of 0.5mg/ml together with Ca2+ and Mg2+ at ImM and 0.5mM respectively.
  • Test compounds were incubated in GFP for 5 minutes at 37°C and the platelet aggregating agent adenosine diphosphate (ADP) was added to a final concentration of 1 x 10 5 M.
  • the potency of the compounds may be expressed as an IC 50 value defined as the concentration of compound required to produce 50% inhibition of platelet aggregation.
  • microcrystalline cellulose, lactose and cross-linked polyvinylpyrrolidone are sieved through a 500 micron sieve and blended in a suitable mixer.
  • the magnesium stearate is sieved through a 250 micron sieve and blended with the active blend.
  • the blend is compressed into tablets using suitable punches.
  • the compound of the invention, lactose and pregelatinised starch are blended together and granulated with water.
  • the wet mass is dried and milled.
  • the magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granule.
  • the resultant blend is compressed using suitable tablet punches.
  • the compound of the invention and pregelatinised starch are screened through a 500 micron mesh sieve, blended together and lubricated with magnesium stearate, (meshed through a 250 micron sieve).
  • the blend is filled into hard gelatine capsules of a suitable size.
  • the compound of the invention and lactose are blended together and granulated with a solution of polyvinylpyrrolidone.
  • the wet mass is dried and milled.
  • the magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granules.
  • the resultant blend is filled into hard gelatine capsules of a suitable size.
  • the hydroxypropyl methylcellulose is dispersed in a portion of hot purified water together with the hydroxybenzoates and the solution is allowed to cool to room temperature.
  • the saccharin sodium flavours and sorbitol solution are added to the bulk solution.
  • the compound of the invention is dissolved in a portion of the remaining water and added to the bulk solution. Suitable buffers may be added to control the pH in the region of maximum stability.
  • the solution is made up to volume, filtered and filled into suitable containers.
  • Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the compound of
  • SUBSTITUT the invention using dilute acid or alkali or by the addition of suitable buffer salts.
  • Antioxidants and metal chelating salts may also be included.
  • the solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass.
  • the injection is sterilised by heating in an autoclave using one of the acceptable cycles.
  • the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions.
  • the solution may be packed under an inert atmosphere of nitrogen.

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Abstract

Dérivés d'acide acétique de la formule (I), leurs dérivés pharmaceutiquement acceptables, et leurs sels et solvates. Dans ladite formule (I), X1 et Y1 sont identiques ou différents et représentent CH ou N; X2 représente CH ou, lorsque X1 représente CH, il peut également représenter N; Y2 représente N ou, lorsque Y1 représente N, il peut également représenter CH; Z représente N ou N+R5; R1 représente un atome d'hydrogène ou un groupe hydroxyle, alkyle C1-4 ou 2,2,2-trifluoroéthyle; R2 représente un atome d'hydrogène ou, lorsqu'à la fois X1 et X2 représentent CH, il peut également représenter un atome de fluor, de chlore ou de brome, ou un groupe alkyle C1-4; R3 représente un atome d'hydrogène ou, lorsqu'à la fois Y1 et Y2 représentent N, il peut également représenter un groupe alkyle C1-4 ou hydroxyméthyle; R4 représente un atome d'hydrogène ou, lorsque Z représente N, il peut également représenter un groupe alkyle C1-4; R5 représente un groupe alkyle C1-4 ou phénylalkyle C1-4; R6 représente un atome d'hydrogène ou un groupe alkyle C1-4. Les composés inhibent l'agrégation plaquettaire hématique dépendante du fibrinogène.
EP92923116A 1991-11-14 1992-11-10 Derives de piperidine acide acetique utilises comme inhibiteurs de l'agregation des plaquettes hematiques dependante du fibrinogene Withdrawn EP0612313A1 (fr)

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GB9124221 1991-11-14
GB919124221A GB9124221D0 (en) 1991-11-14 1991-11-14 Chemical compounds
GB929201052A GB9201052D0 (en) 1992-01-16 1992-01-16 Chemical compounds
GB9201052 1992-01-16
PCT/EP1992/002588 WO1993010091A2 (fr) 1991-11-14 1992-11-10 Derives de piperidine acide acetique utilises comme inhibiteurs de l'agregation des plaquettes hematiques dependante du fibrinogene

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MX9206541A (es) 1993-04-01
EP0542363A3 (en) 1993-07-14
IS3945A (is) 1993-05-15
AP9200447A0 (en) 1993-01-31
EP0542363A2 (fr) 1993-05-19
JPH07501063A (ja) 1995-02-02
WO1993010091A3 (fr) 1993-06-24
WO1993010091A2 (fr) 1993-05-27
AU2915892A (en) 1993-06-15
TW221996B (fr) 1994-04-01
CN1073169A (zh) 1993-06-16
IL103746A0 (en) 1993-04-04
AP330A (en) 1994-03-30

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