Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • 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
  • A61P9/08—Vasodilators for multiple indications
• • 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
  • 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

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 Ilb/IIIa 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 1-4 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 1-4 alkyl group;
• R 3 represents a hydrogen atom or, when both Y 1 and Y 2 represent N, may also represent a C 1-4 alkyl or hydroxymethyl group;
• R 4 represents a hydrogen atom or , when Z represents N, R 4 may also represent a C 1-4 alkyl group;
• R 5 represents a C 1-4 alkyl or phenyl C 1-4 alkyl group;
• R 6 represents a naphthyl group; a thiophenyl group; an unsubstituted phenyl group; a phenyl group substituted by C 1-4 alkyl, C 1-4 alkoxy, phenyl C 1-3 alkoxy, OH, halogen, where halogen is fluorine, chlorine, bromine or iodine, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NR 7 R 8 , NHSO 2 R 7 , CONR 7 R 8 or CO 2 R 7 ; a C 1-4 alkyl group substituted by one or more naphthyl, phenyl, OH or CO 2 R 7 ; a C 2-4 alkenyl group substituted by one or more naphthyl, phenyl, OH or CO 2 R 7 ; or a saturated or unsaturated C 5-7 cycloalkyl group; and
• R 7 and R 8 which may be the same or different represent H or C 1-4 aIkyl or, together with the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring.
• 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) contain at least one chiral centre (shown as * in formula (I)) and thus 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, fumarates 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, as
• 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).
• 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 1-6 alkyl esters, more preferably C 1-3 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.
• 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.
• the term '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 represents N
• Z preferably represents N
• R 1 represents a hydrogen atom or a hydroxyl group
• R 1 most preferably represents a hydrogen atom
• R 2 represents a hydrogen atom
• R 3 represents a hydrogen atom
• R 4 represents a hydrogen atom
• R 6 represents a naphthyl group; a thiophenyl group; an unsubstituted phenyl group; a phenyl group substituted by C 1-4 alkoxy, phenyl C 1-3 alkoxy, OH, fluorine, bromine, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NH 2 , N(C 1-4 alkyl) 2 ,
• R 6 most preferably represents an unsubstituted phenyl or a phenyl substituted in the 4- position by fluorine, bromine, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NH 2 , N(C 1-4 alkyl) 2 , NHSO 2 C 1-4 alkyl, CONR 7 R 8 (where R 7 and R 8 , together with the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring) or CO 2 H.
• R 2 represents a chlorine or bromine atom or a C 1-4 alkyl group
• R 2 is preferably in the position meta to the amidine function.
• Particularly preferred compound of the invention are: 4-[4-[4-(Aminoiminomethyl)phenyl]-1-piperazinyl]- ⁇ -phenyl-1-piperidineacetic acid and physiologically acceptable salts and solvates thereof;
• 1,1-Dimethylethyl 4-[4-[4-(aminoiminomethyl)phenyI]-1-piperazinyl]- ⁇ -(1- phenylethyl)-1-piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]-1-piperazinyl]- ⁇ -(phenylethyl)-1- piperidineacetic acid and 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
• the compounds of the invention may also be useful for the treatment or prophylaxis of other conditions in which the glycoprotein complex Gp Ilb/IIIa 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 use in human or veterinary medicine, particularly for use in 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. It is to be understood that the present invention covers the use of a compound of formula (I) 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 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
• 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.
• compositions 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 0.1 mg/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. hydroxylamine 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 and in a solvent such as an alcohol (e.g. methanol or tert-butanol), followed, where necessary, by removing any protecting groups present.
• the reaction with hydroxylamine or an acid addition salt thereof may conveniently be effected at an elevated temperature (e.g. reflux) when a carbonate or bicarbonate is used.
• an alkoxide the reaction
• compounds of formula (I) in which R1 represents a hydroxyl, C 1-4 alkyl or 2,2,2-trifluoroethyl group may be prepared by treating compounds of formula (II) with a suitable alkylating agent as described in process (A) above followed by reaction of the in situ formed thioimidate with an amine R 1 NH 2 , (where R 1 represents hydroxyl, C 1-4 alkyl or 2,2,2-trifluoroethyl), with subsequent removal of the carboxylic acid protecting group.
• the reaction with the amine R 1 NH 2 may conveniently be carried out in a suitable solvent such as an alcohol (e.g. methanol) or an ether (e.g.
• compounds of formula (I) may also be prepared by reacting a compound of formula (IV) hereinafter with an alcohol (e.g.
• 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.
• R 1 is hydrogen, C 1-4 alkyl or 2,2,2-trifluoroethyl
• a platinum catalyst e.g. PtO 2
• 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
• 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 'Protective Groups in Organic Synthesis' by Theodora W. Green, second edition, (John Wiley and Sons, 1991) which also describes methods for the removal of such groups.
• 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).
• the required isomer may conveniently be separated using preparative high performance liquid chromatography (h.p.l.c.) applied to the final products of processes (A)-(G) above or applied prior to any final deprotection step in said processes.
• preparative high performance liquid chromatography h.p.l.c.
• reaction may conveniently be carried out in a solvent such as dimethylforrnamide or pyridine and in the presence of an organic base such as an amine (e.g. triethylamine).
• a solvent such as dimethylforrnamide or pyridine
• an organic base such as an amine (e.g. triethylamine).
• Unprotected compounds of formula (III) may also be prepared from compounds of formula (IV) by removing the carboxylic acid protecting group R P according to the method described in process (E) hereinabove.
• R 6 is as defined above or a protected derivative thereof but is not a benzyl or napthylmethyl group
• a mixture of compounds of formulae (V) and (VI) 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.
• triacetoxyborohydride in a solvent such as tetrahydrofuran or dichloromethane in the presence of an acid (e.g. acetic acid).
• an acid e.g. acetic acid
• Compounds of formula (VI) may be prepared from an ⁇ -protected (e.g. ⁇ -benzyl protected) piperidin-4-one, optionally substituted by C 1-4 alkyl, by removal of the protecting group followed by treatment with a reagent LCHR 6 CO 2 R P (where R 6 is as defined in formula (VI) above and L is a leaving group, such as a halogen atom (e.g. bromine) or a sulphonate ester group (e.g. mesylate)).
• a reagent LCHR 6 CO 2 R P where R 6 is as defined in formula (VI) above and L is a leaving group, such as a halogen atom (e.g. bromine) or a sulphonate ester group (e.g. mesylate)).
• 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 ).
• compounds of formula (VI) in which R 6 represents a naphthyl, phenyl, naphthylC 2-4 alkyl or phenylC 2-4 alkyl group may be prepared by use of a reagent HalC ⁇ R 6 CO 2 R P (wherein R 6 represents a naphthyl, phenyl, naphthylC 2-4 alkyl or phenylC 2-4 alkyl group) as described above and 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 reagents of formula HalCHR 6 CO 2 R P are known compounds or may be prepared by either esterification of the corresponding ⁇ -halo carboxylic acid or by ⁇ -halogenation of the corresponding carboxylic acid ester, by standard methods.
• the ⁇ -halo carboyxlic acids and the carboxylic acid esters above are known compounds or are readily prepared using conventional chemistry.
• phenylC 1-3 alkoxy or protected hydroxy group or a halogen atom and RO 2 SO is a sulphonate ester group, such as a mesylate) as described above and preferably in the presence of a base such as an alkali metal hydrogen carbonate (e.g. sodium hydrogen carbonate) or carbonate (e.g. potassium carbonate).
• a base such as an alkali metal hydrogen carbonate (e.g. sodium hydrogen carbonate) or carbonate (e.g. potassium carbonate).
• the reaction is conveniently effectedin a polar, aprotic solvent, such as dimethylsulphoxide and preferably at elevated temperature (e.g. 80-100°C).
• reagents of formula RO 2 SOCHR 6 CO 2 R P may be prepared from the corresponding ⁇ -hdyroxy carboxylic acids, under standard conditions.
• ⁇ -Hydroxy carboxylic acids are known compounds or may be prepared by methods well known in the art.
• R 6 is as defined in formula (VI) above
• 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) and in 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 (VIII) may be prepared from compounds of formula (NI) 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 (V) 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)
• reducing conditions for example as described above for the reaction between compounds of formulae (V) and (VI)
• R 6 is as defined in formula (VI) above
• 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.
• 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 (XVIII)
• Removal of the benzyl group and reduction of the double bond from a compound of formula (XVIII) 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.
• Alkylation may also be effected using a tin reagent R 4 Sn (where R is C 1-4 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 1-4 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 (XVIII).
• 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 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 (VIII) or a compound of formula (XXIII),
• a 2,5- dihalopyridine e.g. 2,5-dibromopyridine
• reaction may conveniently be effected under the conditions described above for the reaction between compounds of formulae (VII) and (VIII).
• 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 (VII) and (VIII).
• 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 (VII) and (VIII).
• a 2,5- dihalopyridine e.g. 2,5-dibromopyridine
• Compounds of formula (XXVI) may be prepared by reacting a 2,5- dihalopyridine (e.g. 2,5-dibromopyridine) with a suitable piperazine derivative under the conditions described above for the reaction between compounds of formulae (VII) and (VIII).
• a 2,5- dihalopyridine e.g. 2,5-dibromopyridine
• a suitable piperazine derivative under the conditions described above for the reaction between compounds of formulae (VII) and (VIII).
• Compounds of formula (XXVII) 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
• a compound of formula (XX) under the boronic acid coupling conditions described previously.
• 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 J. Het. Chem., 1988, 25, 81 or may be prepared according to the methods described therein.
• a strong base such as a lithium amide (e.g. lithium bis(trimethylsilyl)amide or lithium diisopropylamide) at reduced temperature (e.g. -70°C) in a suitable solvent (e.g.
• alkylation may be effected by using, for example, a benzyl or naphthylmethyl halide (e.g. benzyl or naphthylmethyl bromide).
• a benzyl or naphthylmethyl halide e.g. benzyl or naphthylmethyl bromide
• 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.
• Resolution of the final product, 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 H Wilen.
• 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 a base 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.
• 4,4'-Bipiperidine dihydrochloride (3.2g) was dissolved in dimethylsulphoxide (80ml), potassium carbonate (5.0g) added and the mixture heated at 130°C for 20min.
• N-Benzyl-4-piperidone (10g) 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 (8.59g).
• Lithium bis(trimethylsilyl)amide (1M solution in tetrahydrofuran, 3.4ml) was added to a solution of intermediate 11 (1g) in dry tetrahydrofuran (25ml) at -72°C under nitrogen. The solution was stirred at -70°C for 15min. Benzyl bromide (0.309ml) in tetrahydrofuran (70ml) was added dropwise over 10min, and the solution was allowed to reach room temperature (18h). The solvent was removed in vacuo and saturated aqueous ammonium chloride (50ml) added.
• dichloromethane 50ml was treated dropwise at 0°C with methanesulphonyl chloride (0.904ml). The mixture was stirred at room temperature under nitrogen for 1h. The mixture was poured into water (100ml) and the aqueous layer extracted with
• Lithium diisopropylamide mono (tetrahydrofuran) complex (1.5M in cyclohexane, 29.6ml) was added to a stirred solution of ethyl 1- naphthaleneacetate (8g) in dry tetrahydrofuran (60 ml) at -70°, under nitrogen, and stirring was continued at -70° for 30 min.
• Carbon tetrabromide (14.6ml) was added, the vessel removed from the cold bath and the mixture was stirred at room temperature for 2h.
• Ammonium chloride (100 ml) was added and the solution extracted with ethyl acetate (3x150 ml).
• Lithium diisopropylamide mono tetrahydrofuran complex (1.5 M in cyelohexane, 9.02ml) was added to a stirred solution of intermediate 11 (4.0g) in dry tetrahydrofuran (75ml) at -75°C under nitrogen and stirring was continued for 1h.
• Chlorotitanium triisopropoxide (3.23ml) was added at -72°C and stirring was continued at -72°C for 30 mins.
• Acetophenone (1.37ml) was added and the mixture stirred at -70°C for 30 mins and allowed to warm up to room temperature overnight (16h). The solvent was removed in vacuo to leave an orange solid, which was partitioned between dichloromethane
• Lithium diisopropylamide mono tetrahydrofuran complex (1.5M in cyclohexane;
• Methane sulphonyl chloride (0.26ml) was added at 0° under nitrogen to a stirred solution of the aniline (940mg) in pyridine (10ml). After 1.5h the orange solution was cooled to ca 15°C and more methane sulphonyl chloride (0.13ml) was added. After 30 min. saturated sodium bicarbonate (50ml) was added and the mixture evaporated to dryness. Water (50ml) and ethyl acetate (50ml) were added to the residue and the aqueous layer was extracted again with ethyl acetate (50ml). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and evaporated to give an orange foam. Purification by column chromatography on silica gel (Merck 9385), eluting with 50-100% ethyl acetate in hexane gave the title compound as a yellow oil, (0.615mg).
• Example 7 A solution of Example 7 (0.500g) in 2N hydrochloric acid was stirred at 60°C for 21 h and at 80°C for 3 days. The acid was removed in vacuo and the residue dissolved in a minimum volume of distilled water. Purification by gradient preparative h.p.l.c.
• Example 9 (164mg) was dissolved in 2M hydrochloric acid (25ml) and the mixture heated at 80°C for 65 h. The solvent was removed in vacuo and the residue purified by preparative h.p.l.c (gradient profile 10-40% (ii) in 10 min and .40% (ii) isochratic for
• Example 11 A solution of Example 11 (0.140g) in 2N hydrochloric acid (30ml) was heated at 80°C under nitrogen for 3 days and at 90°C for 24h. The mbcture was concentrated in vacuo and the residue dissolved in a minimum volume of water. Purification by preparative h.p.l.c. (gradient profile 5-20% (ii) in 10min and 20% (ii) isochratic for 8min) gave after R T 14 min the title compound as a white solid (0.0975g).
• Example 12 (1.5g, crude) was treated with hydrochloric acid (5N, 150ml) and heated to 90°C for 18h. The mixture was concentrated in vacuo to leave a pale yellow solid which was purified by preparative h.p.l.c. (gradient profile 10-45% (ii) in 11min) to give after R t 10.5 min the title compound as a white solid (497mg).
• hydroxylamine hydrochloride (82mg) and potassium t- butoxide (126mg) were added after 0, 2 and 4h while heating under reflux, under nitrogen. Heating under reflux was continued for 17h, the mixture was concentrated to 20ml and further hydroxylamine hydrochloride (85mg) and potassium t-butoxide (128mg) were added. Heating under reflux was continued for 8h before further reagents, as above, were added. After heating under reflux overnight the mixture was concentrated to ca. 5ml and poured into water (100ml). The precipitate was filtered off, dried in vacuo and triturated with hot toluene (20ml). After cooling to ca. 40°C, the mixture was filtered to afford the title compound (1.17g) as a white solid.
• Example 8 (1.02g) was suspended in acetic acid (20ml) and acetic anhydride (0.8ml) added. The suspension was added to dry 10% palladium on carbon (800mg) in acetic acid
• Example 10 A mixture of Example 10 (0.450g), acetic anhydride (0.352ml) and 10% palladium on carbon (50mg) in glacial acetic acid (10ml) was hydrogenated at room temperature and pressure for lh. The catalyst was filtered off and the filtrate concentrated in vacuo: the residue was partitioned between dichloromethane (100ml) and 2N sodium carbonate (100ml). The aqueous layer was extracted with dichloromethane (2x100ml), and the combined organic extracts were dried (anhydrous potassium carbonate) and evaporated in vacuo to afford a dark brown solid (0.808g). Purification by flash chromatography on silica gel (Merck 9385, eluting with system B 89:10:1, 70:30:3, and finally 50:50:1) gave the title compound as a light brown solid (0.143g).
• Example 15 Acetic acid (8ml) containing acetic anhydride (0.57ml) was added to Example 13 (0.52g) and 10% palladium on carbon (75mg). The suspension was stirred under an atmosphere of hydrogen until uptake had ceased (1h). The suspension was filtered through hyflo and the filtrate evaporated in vacuo to give the title compound (0.5g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25 min) R.9.7min. Example 15
• Example 14 (ca 0.5g) was stirred in 5N hydrochloric acid (25ml) at 75° for 18h. The solvent was evaporated in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-60% (ii) in 17min) to give after R T 12.1 min the title compound as a beige solid
• Example 16 Acetic acid (10ml) containing acetic anhydride (0.324ml) was added to Example 16 (1.15g) and 10% palladium on carbon (150mg). The suspension was stirred under an atmosphere of hydrogen until uptake ceased (2h). The suspension was filtered through acid washed hyflo and the filtrate evaporated in vacuo to give the title compound as a red oil (0.8g).
• Example 17 (0.8g) was stirred in 5N hydrochloric acid (25ml) at 90° for 24h. The solvent was evaporated in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-60% (ii) in 17 min.) to give after R T 12.3 min the title compound as a beige solid (0.061g) Analysis Found C,50.7; H,4.8; N,9.1;
• Example 20 4-[4-[4-[Aminoiminomethyl)phenyl]-1-piperazinyl]- ⁇ -(1-naphthalenyl)-1-piperidineacetic acid trifluoroacetate salt
• Example 20 (1g) was stirred in 5N hydrochloric acid (20ml) at 90°C for 60h. The solvent was evaporated in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-60% (ii) in 17 min) to give after R T 1 1.9 min the title compound as a beige solid (0.410g).
• Example 22 A mixture of Example 22 (1g) acetic anhydride (0.786 ml) and 10% palladium on carbon (110mg) in acetic acid (25ml) was stirred under hydrogen for 1.75h. The catalyst was filtered off, the filtrate concentrated in vacuo and the residue partitioned between ethyl acetate (200ml) and 2N sodium carbonate (200ml). The aqueous layer was extracted with ethyl acetate (2x 100ml). The combined ethyl acetate extracts were washed with brine (250ml), dried (MgSO 4 ) and the solvent removed in vacuo to afford a brown solid. Purification by preparative h.p.l.c. (gradient profile 10-35% (ii) in 10 min and 35% (ii) isochratic for 8 min) gave after R T 11.5 min the title compound as a white solid (0.28g).
• Example 23 A solution of Example 23 (0.250g) in 2N hydrochloric acid (100ml) was heated at 80-90°C under nitrogen for 3 days. The mixture was concentrated to ca 10ml in vacuo and 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 t 13.8 min the title compound as an off white solid
• Example 25 Acetic acid (10ml) containing acetic anhydride (0.2ml) was added to Example 25 (795mg) and 10% palladium on carbon (100mg). The suspension was stirred in a hydrogen atmosphere until hydrogen uptake ceased, the catalyst filtered off through a small pad of acetic acid washed hyflo, and the filtrate was evaporated to give a red-brown gum. Purification by preparative h.p.l.c. (gradient profile 10-55% (ii) in 17min,) gave after R T 14.9 min the title compound as a beige solid (482mg).
• Example 26 A solution of Example 26 (480mg) in ethanol (15ml) and dimethylformamide (3 ml) was added to pre-reduced 10% palladium on carbon (100mg) in ethanol (6ml). The mixture was stirred in a hydrogen atmosphere at room temperature and atmospheric pressure for 3 hrs. The catalyst was removed by filtration through 'hyflo' and the filtrate evaporated to give the title compound as a beige solid (320mg).
• Example 27 A solution of Example 27 (235mg) in hydrochloric acid (4N, 15ml) was stirred at 80°C for 30hrs, evaporated to dryness and the residue triturated with isopropanol to give the title compound as a pink solid (114mg).
• Example 56 The title compound was prepared from Example 56 by a method analogous to that used for the preparation of Example 2 from Example 8 (via Example 9).
• Example 58 4-[4-[4-(Aminoiminomethyl)phenyl]-1-piperazinyl]- ⁇ -(4-aminophenyl)-1- piperidineacetic acid
• the title compound was prepared from Example 58 by a method analogous to that used for Example 57.
• 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 0.1 mM aspirin and 0.05 ⁇ M prostacyclin and then centrifuged at 1000g for 4 minutes (20°C). The supernatant platelet rich plasma (PRP) was further centrifuged 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 0.1 mM aspirin and 0.05 ⁇ M prostacyclin and then centrifuged at 1000g for 4 minutes (20°C). The supernatant platelet rich plasma (PRP) was further centrifuged at 1300g for 10 minutes (20°C) to sediment the platelets.
• the supernatant was discarded and the pellet washed with a physiological salt solution (HEPES 5mM, NaHCO 3 12mM, NaCl 140mM, KH 2 PO 4 0.74mM, D-Glucose 5.6mM, KCl 2.82mM and BSA 20g/1, pH 7.4) to remove residual plasma.
• a physiological salt solution HPES 5mM, NaHCO 3 12mM, NaCl 140mM, KH 2 PO 4 0.74mM, D-Glucose 5.6mM, KCl 2.82mM and BSA 20g/1, pH 7.4
• the compound of the invention 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.
• Compound of the invention 5.0mg
• 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.
• Compound of the invention 5.0mg
• 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 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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• 1993
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