EP0973720A1 - Derives d'acides benzoyle-cycloalkyl-1-carboxyliques-2-substitues - Google Patents

Derives d'acides benzoyle-cycloalkyl-1-carboxyliques-2-substitues

Info

Publication number
EP0973720A1
EP0973720A1 EP98910685A EP98910685A EP0973720A1 EP 0973720 A1 EP0973720 A1 EP 0973720A1 EP 98910685 A EP98910685 A EP 98910685A EP 98910685 A EP98910685 A EP 98910685A EP 0973720 A1 EP0973720 A1 EP 0973720A1
Authority
EP
European Patent Office
Prior art keywords
dichlorobenzoyl
cyclopropane
carboxylic acid
carboxylate
methyl
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Withdrawn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
EP98910685A
Other languages
German (de)
English (en)
Inventor
Mario Varasi
Antonio Giordani
Paolo Pevarello
Roberto Pellicciari
Carmela Speciale
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.)
Pfizer Italia SRL
Original Assignee
Pharmacia and Upjohn SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia and Upjohn SpA filed Critical Pharmacia and Upjohn SpA
Publication of EP0973720A1 publication Critical patent/EP0973720A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/18—Saturated compounds containing keto groups
    • C07C62/20—Saturated compounds containing keto groups with a saturated six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
    • C07C271/64—Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/38—Unsaturated compounds containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to 2- (substituted " benzoyl)- cycloalkyl-1-carboxylic acid derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use in therapy.
  • the compounds of the invention act as inhibitors of Kynurenine- 3-hydroxylase (KYN-OH) , an enzyme which forms part of the metabolic pathway of kynurenine.
  • KYN-OH Kynurenine- 3-hydroxylase
  • the compounds of the present invention fulfill such a need.
  • the present invention provides 2- (substituted benzoyl) -cycloalkyl-1-carboxylic acid compounds of formula (I)
  • the alkyl and alkoxy groups may be branched or straight groups .
  • E as a C ⁇ -C 4 alkylene chain is preferably a C ⁇ C;, alkylene chain, in particular a methylene (-CH 2 -) group.
  • C x -C 6 alkyl groups include C 1 -C 4 alkyl groups such as methyl, ethyl, n- and iso-propyl, n- , iso- , sec- and tert-butyl.
  • Representative examples of j ⁇ -Cg alkoxy groups include C ⁇ - C, alkoxy groups such as methoxy and ethoxy.
  • C 1 -C 6 alkylthio groups include C 1 -C 4 alkylthio groups such as methylthio and ethylthio.
  • C- ⁇ Cg alkanoyl groups include C 1 -C 4 alkanoyl groups such as acetyl and propionyl .
  • C- L -Cg alkoxycarbonyl groups include C 1 -C 4 alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl .
  • a halogen atom is fluorine, bromine, chlorine or iodine; in particular chlorine or fluorine.
  • Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acids or organic, e.g. acetic, trifluoroacetic , propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids, and salts with inorganic, e.g. alkali metal, especially sodium or potassium bases or alkaline-earth metal, especially calcium or magnesium bases, or with organic bases, e.g.
  • inorganic e.g. alkali metal, especially sodium or potassium bases or alkaline-earth metal, especially calcium or magnesium bases, or with organic bases, e.g.
  • acyclic or cyclic amines preferably methylamine, ethylamine, diethlamine, triethylamine or piperidine.
  • the compounds of the invention have asymmetric carbon atoms and therefore they can exist either as racemic mixtures or as individual optical isomers (enantiomers) .
  • the compounds of the invention can also be E- or Z- isomers or E-, Z- mixtures thereof.
  • the present invention also include within its scope all the possible isomers and their mixtures and both the metabolites and the pharmaceutically acceptable bio-precursors
  • Preferred compounds of the invention are the compounds of formula (I) wherein:
  • R 3 is hydroxy, C- L -C J alkoxy, benzyloxy, hydroxylamino or a group -N(R 12 R 13 ) wherein one of R 12 and R 13 is hydrogen and the other is hydrogen, C X - C alkyl, benzyl, phenyl or a S0 2 R 9 group in which R 9 is phenyl; and the pharmaceutically acceptable salts thereof.
  • R 3 is hydroxy, C ⁇ C,, alkoxy, hydroxylamino or a group -N(R 12 R 13 ) wherein one of R 12 and R 13 is hydrogen and the other is hydrogen, ⁇ ⁇ - ⁇ alkyl, benzyl, phenyl cr a S0 2 R 9 group in which
  • R 9 is phenyl; and the pharmaceutically acceptable salts thereof.
  • R 2 is hydrogen
  • R 3 is hydroxy, C - C 4 alkoxy, hydroxylamino or a group -N(R 12 R 13 ) wherein one of R 12 and R 13 is hydrogen and the other is hydrogen, C- L - C, alkyl, benzyl, phenyl or a S0 2 R 9 group in which R 9 is phenyl; and the pharmaceutically acceptable salts thereof.
  • Examples of preferred compounds of the invention are the following :
  • a further object of the present invention is also to provide a 2 -substituted benzoyl-cycloalkyl-1-carboxylic acid compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance, in particular as kynurenine-3 -hydroxylase enzyme inhibitor.
  • Object of the present invention is also the use of a compound of formula (I) , as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as kynurenine-3 -hydroxylase enzyme inhibitor.
  • the present invention also provides a method of treating a mammal, including human, in need of a kynurenine-3 -hydroxylase inhibitor, such method comprising adminstering thereto a therapeutically effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof .
  • the compounds of the invention and the salts thereof can be obtained, for instance, by a process comprising: a) reacting a compound of formula (II)
  • R 2 is as defined above and R 3 is C ⁇ Cg alkoxy, to obtain a compound of formula (I) wherein R 3 is CAC 6 alkoxy and E is an unsubstituted C x -alkylene (-CH 2 -) group; or b) reacting a compound of formula (IV)
  • R and R x are as defined above and BOC means tert- butoxycarbonyl , thus obtaining a compound of formula (I) wherein R 2 is -NHC0R 9 in which R 9 is tert-butoxy and R 3 is methoxy and E is an unsubstituted C alkylene chain; and, if desired converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of formula (I) into a salt thereof, and/or, if desired, converting a salt of a compound of formula (I) into a free compound of formula (I), and/or, if desired, separating a mixture of isomers of a compound of formula (I; into the single isomers.
  • the above process-variants a) , b) and c) are analogy processes which can be carried out according to well know methods in the art.
  • the reaction of a compound of formula (II) with a compound of formula (III) can be carried out, for example, in a suitable solvent such as, e. g. diethyl ether, in the presence of a suitable metal complex, e.g palladium (II) diacetate, at a temperature ranging from about -78°C to room temperature, for a time ranging from about 1 hours to about 24 hours.
  • a suitable metal complex e.g palladium (II) diacetate
  • the halogen atom X is preferably chlorine or bromine .
  • the reaction of a compound of formula (IV) with a compound of formula (V) can be carried out according to known methods; for example, following the procedure reported in: Sommerville L.F.,
  • this reaction can be performed in the presence of a suitable Lewis acid catalyst, in an inert solvent such as, e.g., dichloromethane or 1 , 2-dichloroethane , or m an appropriate aromatic hydrocarbon such as, e.g., chlorobenzene , nitrobenzene or in an excess of a compound of formula (V) itself; optionally in the presence of a co- solvent, e.g. nitromethane .
  • a suitable Lewis acid catalyst in an inert solvent such as, e.g., dichloromethane or 1 , 2-dichloroethane , or m an appropriate aromatic hydrocarbon such as, e.g., chlorobenzene , nitrobenzene or in an excess of a compound of formula (V) itself; optionally in the presence of a co- solvent, e.g. nitromethane .
  • an inert solvent such as, e.g., dichloromethane or 1 , 2-
  • a suitable Lewis acid may be, e.g. anhydrous aluminium trichloride, anhydrous zinc dichloride, typically anhydrous aluminium trichloride.
  • Deacylation of a compound of formula (VI) can be accomplished by treatment with a suitable deacylating agent, e.g. nydrazme hydrate, in a suitable solvent, e.g. anhydrous methanol .
  • the reaction may be carried out at a temperature ranging from about 0 to about 30°C, for a time between about 0.5 and about 24 hours .
  • the optional conversion of a compound of formula (I) into another compound of formula (I) can be carried out according to known methods .
  • hydrolysis of a compound of formula (I) wherein R 3 is C x -Cg alkoxy to obtain a compound of formula (I) wherein R 3 is hydroxy can be carried out according to well known methods in the art.
  • this reaction can be performed in an aqueous or hydroalcoholic alkali solution, for example sodium hydroxide, at a concentration ranging between 0.01 and 12N, at a temperature ranging from -20 °C to reflux temperature or by acid hydrolysis, for instance, using an aqueous solution of hydroholic acids, typically hydrochloric acid, in a suitable solvent, e.g. acetic acid, at a temperature ranging from about 0°C to reflux temperature.
  • aqueous or hydroalcoholic alkali solution for example sodium hydroxide
  • hydrolysis for instance, using an aqueous solution of hydroholic acids, typically hydrochloric acid, in a suitable solvent, e.g. acetic acid, at a temperature ranging from about 0°C to reflux temperature.
  • a compound of formula (I) wherein R 3 is hydroxy can be converted in another compound of formula (I) wherein R 3 is C- ⁇ Cg alkoxy, phenoxy or benzyloxy, by conventional alkylating methods, e.g. by treatment with a suitable alkylating agent, preferably a iodo derivative, in the presence of a base, e.g. potassium bicarbonate, in a suitable solvent, e.g. dimethylformamide , at a temperature ranging from about 0°C to about 60 °C.
  • a suitable alkylating agent preferably a iodo derivative
  • a base e.g. potassium bicarbonate
  • a suitable solvent e.g. dimethylformamide
  • a compound of formula (I) wherein R 3 is a N(R 7 R 8 ) wherein R ⁇ and R 3 are both hydrogen can be converted into a compound of formula (I) wherein R 7 and R 8 are, each independently, C ⁇ Cg alkyl, benzyl or phenyl, by alkylative procedures known in the literature.
  • R 7 and R 8 are, each independently, C ⁇ Cg alkyl, benzyl or phenyl, by alkylative procedures known in the literature.
  • the optional salification of a compound of formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.
  • the compounds of the invention have asymmetric carbon atoms and can have E/Z isomerism. Accordingly, they can be synthesized either as a mixture of isomers and then the desired isomer is separated by conventional techniques, or synthesis can be carried out by known stereospecific processes to obtain a single isomeric compound.
  • a compound of formula (II) as defined above can be obtained, for instance, by reacting a compound of formula (VII)
  • R and R are as defined above, with diazomethane , for example, in a suitable solvent such as, e.g. diethyl ether, at a temperature varying between -78°C and room temperature, for a time ranging between 1 and 24 hours.
  • a suitable solvent such as, e.g. diethyl ether
  • a compound of formula (IV) can be obtained by a multi-step process comprising the reaction of a compound of formula (VIII)
  • R 12 and E are as defined above.
  • a compound of formula (IX) can then be reacted with a halogenating agent to obtain a compound of formula (IV) as defined above.
  • the reaction of a compound of formula (VIII) to obtain a compound of formula (IX) can be accomplished by basic hydrolysis, i.e using an alcoholic solution of an alkali metal hydroxide, typically a potassium hydroxide solution in suitable alkoholic medium, i.e. methanol, at a suitable temperature, e.g. between 0 and 55°C, for a suitable time, e.g. 2-24 hours.
  • the reaction of a compound of formula (IX) to obtain a compound of formula (VI) can be accomplished in a suitable halogenating agent, i.e.
  • oxalyl chloride or bromide or thionyl chloride typically oxalyl chloride, in the presence or the absence of a solvent, at a suitable temperature, e.g. 0-40°C, for a suitable time, e.g. 1-6 hours.
  • a compound of formula (VI) can be obtained by a multi-step process comprising acid oxidation of a compound of formula (X)
  • R and R x are as defined above.
  • Acid oxidation of a compound of formula (X) can be accomplished for instance by using a dimethylsulfoxide (DMSO) solution of concentrated hydrobromic acid, e.g. aqueous 48% hydrobromic acid .
  • DMSO dimethylsulfoxide
  • reaction may be carried out at a temperature ranging from about 25 to about 100 °C, for a time between about 2 and about 48 hours.
  • a compound of formula (XI) can be then converted into a compound of formula (XII)
  • R and R x are as defined above, by treatment with a suitable hyppuric acid derivative in the presence of a suitable acylating agent, e.g. acetic anhydride.
  • a suitable acylating agent e.g. acetic anhydride.
  • the reaction may be carried out at a temperature ranging from about 50 to about 200°C, for a time between about 0.5 and about 24 hours.
  • a compound of formula (XII) if desired, can be converted into its isomer of formula (Xlla)
  • a compound of formula (XII) into a compound of formula (Xlla) can be accomplished using a suitable hydrohalic acid solution, e.g. 48% aqueous hydrobromic acid saturated with anhydrous hydrogen bromide gas, at a suitable temperature, e.g. between about -20 and about 25°C, for a suitable time, e.g. 15 minutes to 24 hours.
  • Cyclopropanation of a compound of formula (XII) or (Xlla) provides a compound of formula (XIII) and (Xllla) , respectively wherein R and R ⁇ are as defined above.
  • the reaction can be accomplished by treatment of a compound of formula (XII) or (Xlla), respectively, with an ethereal solution of diazomethane .
  • the reaction can be carried out at a temperature ranging from about -78 and about 25°C, for a time between about 2 and about 48 hours.
  • a compound of formula (XIII) or (Xllla) is then converted into a compound of formula (XIV) or (XlVa) , respectively
  • reaction can be accomplished by treatment with dimethylaminopyridme (DMAP) m methanol
  • DMAP dimethylaminopyridme
  • the reaction may be carried out at a temperature ranging from about 0 to about 50°C, for a time between about 10 minutes and 48 hours
  • a suitable solvent e g anhydrous dichloromethane
  • e g anhydrous dichloromethane provides a compound of formula 'VI) , which can be represented by the respective two isomeric compounds of formula (XV) and (XVa)
  • R and R x are as defined above.
  • the reaction can be carried out at a temperature ranging from about 0 to about 50°C, for a time between about 1 and 24 hours.
  • the isomeric compounds of formula (XV) and (XVa) are herein represented as a compound of formula (VI) .
  • the compounds of formula (X) and the above hyppuric acid derivatives are known compounds.
  • the compounds of the invention are active as kynurenine-3 - hydroxylase enzyme inhibitors and therefore are useful in the prevention and/or treatment of neuropathological processes, related to a deranged production of quinolinic acid and/or 3- hydroxykynurenine due to excessive activation of neuro- transmission mediated by excitatory amino acid receptors and/or oxidative stress.
  • neuropathological processes are neurodegenerative pathologies including, e.g.
  • Huntington's chorea Alzheimer's disease, Parkinson's disease, olivoponto cerebellar atrophy, non-Alzheimer's dementias, including the dementia like syndrome caused by Acquired Immunodeficiency Syndrome (AIDS) , multi-infarctual dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal and head trauma and epilepsy.
  • AIDS Acquired Immunodeficiency Syndrome
  • a human or animal in need of a kynurenine-3 -hydroxylase enzyme inhibitor can thus be treated by a method which comprises the administration thereto of a therapeutically effective amount of a compound of the invention or a salt thereof .
  • the condition of the human or animal can thereby be improved .
  • the efficacy of the compounds of the invention in the inhibition of the enzyme kynurenine-3 -hydroxylase was evaluated e.g., in rat liver mitochondrial extract following the method reported below, according to the procedure described in "Analytical Bioche . (1992), 205, 257-262", with minor modifications .
  • the assay for kynurenine 3 -hydroxylase is based on the enzymatic synthesis of tritiated water during the hydroxylation reaction. Radiolabeled water was quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal. Rat liver mitochondrial extract was used as enzymatic preparation for this assay.
  • the assay for kynurenine 3 -hydroxylase activity was carried out at 37°C for a time o 30 min .
  • the reaction mixture of a total volume of 30 ⁇ l was constituted of 44 ⁇ g of suspended extract, 100 mM Tris/Cl ' buffer pH 8.1 , 10 mM EDTA, 100 mM KCl, 0.8 mM NADPH, 0.025 mM L-Kynurenine , 0.3 ⁇ Ci L- (3 , 5 - 3 H) Kynurenine (10 Ci/mmol) and 3 ⁇ l of different concentration of inhibitor solutions.
  • the reaction was terminated by the addition of 300 ⁇ l of 7.5% (W/v) activated charcoal, vortexed and cent ⁇ fuged for 7 mm.. A 75 ⁇ l aliquot of supernatant was transferred to optiplate and 200 ⁇ l of liquid scintillation added. The optiplates were vortexed and the radioactivity counted in a scintillation counter.
  • the dosage level suitable for administration to a mammal, e.g. to humans, depends on the age, weight, conditions of the patient and on the administration route, for example, the dosage adopted for oral administration, for instance for the representative compound of the invention PNU 165853, may range from about 10 to about 500 mg pro dose, from 1 to 5 times daily.
  • the compounds of the invention can be administered m a variety of dosage forms, e.g orally, m the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally m the form of suppositories; parenterally, e.g. mtramuscolarly, or by intravenous and/or mtrathecal and/or mtraspmal injection or infusion.
  • the invention includes also pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent) .
  • the pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gum, gelatin, methylcellulose , carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arabic gum, gelatin, methylcellulose , carboxymethylcellulose or poly
  • a starch alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates , laurylsulphates ; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol .
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscolar injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride.
  • the solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, acqueous, isotonic saline solutions or they may contain as a carrier propylene glycol .
  • the suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • Oxalylchloride was removed by rotary evaporation and the corresponding 2- (3 , 4-dichlorobenzoyl ) - cyclopropyl-l-carboxylic acid chloride, dissolved in anhydrous dioxane (1.5 ml), was added to a dioxane (3.5 ml) solution containing R- ( - ) -phenylglycinol (0.093 g, 0.68 mmol) and triethylamine (0.1 ml, 0.7 mmol), maintained under magnetic stirring and argon atmosphere at 10°C.
  • acqueous layer was acidified with 10% hydrochloric acid, then extracted with ethyl acetate (4 x 5 ml) , the combined organic phases were washed with brine (1 x 5 ml) , dried over an. sodium sulfate and concentrated under vacuum to obtain the titled compound (50 mg,
  • Capsule each weighing 0.23 g and containing 50 mg of the active substance can be prepared as follows: Composition for 500 capsules: (E) -2- (3 , 4-dichlorobenzoyl) -cyclopropyl -
  • Magnesium stearate 5 g This formulation can be incapsulated in two hard gelatin capsules of two pieces, each with each capsule weighing 0.23 g.
  • a pharmaceutical injectable composition can be manifactured dissolving 50 g (E) -2- (3 , 4-dichlorobenzoyl) -cyclopropyl-l- carboxylic acid in sterile propyleneglycol (1000 ml) and sealed in 1-5 ml ampoules.
  • IDO Indolamineoxigenase
  • KYN-OH Kynurenine-3 -hydroxylase

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Psychology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des acides 2-(benzoyl substitué)-cycloalkyl-1-carboxyliques de formule (I), où E est une chaîne alcylène C1-C4 dans laquelle un atome de carbone est éventuellement substitué; chacun des radicaux R ou R1, qu'il soit identique ou différent, désigne hydrogène, halogène, hydroxy, trifluorométhyle, cyano, nitro, phényle, benzyle, alkyle C1-C6, alkoxy C1-C6, alcylthio C1-C6, SOR4 ou SO2R4; R2 désigne hydrogène ou -N(R7R8) où chacun des radicaux R7 ou R8 désigne indépendamment, hydrogène, alkyle C1-C6 benzyle, phényle, hydroxy, alkoxy C1-C6, benzyloxy ou un de R7 ou de R8 désigne hydrogène, l'autre désignant COR9; R3 désigne hydroxy, alkoxy C1-C6, phénoxy, benzyloxy ou un groupe -N(R12R13). L'invention concerne également leurs sels pharmaceutiquement acceptables. Ces dérivés et leurs sels ont une activité inhibitrice de l'enzyme cynurénine-3-hydroxylase.
EP98910685A 1997-03-11 1998-02-16 Derives d'acides benzoyle-cycloalkyl-1-carboxyliques-2-substitues Withdrawn EP0973720A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9705031 1997-03-11
GBGB9705031.4A GB9705031D0 (en) 1997-03-11 1997-03-11 2-substituted benzoyl-cycloalkyl-1-carboxylic acid derivatives
PCT/EP1998/000883 WO1998040344A1 (fr) 1997-03-11 1998-02-16 Derives d'acides benzoyle-cycloalkyl-1-carboxyliques-2-substitues

Publications (1)

Publication Number Publication Date
EP0973720A1 true EP0973720A1 (fr) 2000-01-26

Family

ID=10809053

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98910685A Withdrawn EP0973720A1 (fr) 1997-03-11 1998-02-16 Derives d'acides benzoyle-cycloalkyl-1-carboxyliques-2-substitues

Country Status (15)

Country Link
EP (1) EP0973720A1 (fr)
JP (1) JP2001514634A (fr)
KR (1) KR20000076096A (fr)
CN (1) CN1252049A (fr)
AU (1) AU6497998A (fr)
CA (1) CA2283184A1 (fr)
EA (1) EA199900809A1 (fr)
GB (1) GB9705031D0 (fr)
HU (1) HUP0001023A3 (fr)
IL (1) IL131676A0 (fr)
NO (1) NO994386L (fr)
PL (1) PL335601A1 (fr)
TW (1) TW407146B (fr)
WO (1) WO1998040344A1 (fr)
ZA (1) ZA981972B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1424333A1 (fr) * 2002-11-28 2004-06-02 Newron Pharmaceuticals S.p.A. Dérivés d'acide halothénoyl-cyclopropane-1-carboxylique
EP1475088A1 (fr) * 2003-05-05 2004-11-10 Newron Pharmaceuticals S.p.A. Inhibiteurs de la kynurenine-3-hydroxylase pour le traitement des désordres locomoteurs induits par la L-DOPA, dyskinésies, accoutumance aux médicaments, douleurs et cataract
EP1475385A1 (fr) * 2003-05-05 2004-11-10 Newron Pharmaceuticals S.p.A. Derivés de glycoside d'acide carboxylique de 2-(3,4-dichlorobenzoyl)-cyclopropane
WO2013151707A1 (fr) * 2012-04-05 2013-10-10 Chdi Foundation, Inc. Inhibiteurs de kynurénine-3-monooxygénase, compositions pharmaceutiques, et procédés d'utilisation de ceux-ci
CN103373911B (zh) * 2012-04-27 2016-12-14 中国科学院上海有机化学研究所 单氟代环丙烷类化合物及其制备方法和应用
CN104119246A (zh) * 2013-04-26 2014-10-29 中国科学院上海有机化学研究所 环丙烷衍生物及其制备方法和应用
WO2015047982A2 (fr) 2013-09-26 2015-04-02 Chdi Foundation, Inc. Inhibiteurs de kynurénine-3-monooxygénase, compositions pharmaceutiques et procédés d'utilisation de ces compositions
JP6449893B2 (ja) * 2013-09-26 2019-01-09 シーエイチディーアイ ファウンデーション，インコーポレーテッド キヌレニン−３−モノオキシゲナーゼ阻害薬、医薬組成物、及びこれらの使用方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3655667A (en) * 1968-04-04 1972-04-11 Smith Kline French Lab 1-(2-benzoylcyclopropylmethyl)-4-phenylpiperazines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9840344A1 *

Also Published As

Publication number Publication date
KR20000076096A (ko) 2000-12-26
AU6497998A (en) 1998-09-29
EA199900809A1 (ru) 2000-08-28
WO1998040344A1 (fr) 1998-09-17
JP2001514634A (ja) 2001-09-11
IL131676A0 (en) 2001-03-19
NO994386L (no) 1999-11-02
HUP0001023A3 (en) 2001-03-28
CA2283184A1 (fr) 1998-09-17
PL335601A1 (en) 2000-05-08
TW407146B (en) 2000-10-01
GB9705031D0 (en) 1997-04-30
ZA981972B (en) 1998-09-09
CN1252049A (zh) 2000-05-03
HUP0001023A2 (hu) 2000-09-28
NO994386D0 (no) 1999-09-10

Similar Documents

Publication Publication Date Title
HU215437B (hu) Gyulladáscsökkentő és vérlemezke-aggregációt gátló salétromsav-észterek és eljárás előállításukra
EP0662948B1 (fr) Derives de l'acide 2-amino-4-phenyl-4-oxobutyrique, ayant une activite inhibitrice de la cynureninase et/ou de la cynurenine-3-hydroxylase
US6048896A (en) 4-phenyl-4-oxo-2-butenoic acid derivatives with kynurenine-3-hydroxylase inhibiting activity
AU695852B2 (en) Polyarylcarbamoylaza -and- carbamoylalkanedioic acids
JP3542599B2 (ja) 置換（アリールアルコキシベンジル）アミノプロパンアミド誘導体及びその製造方法
US7531692B2 (en) Derivatives of 1-phenylalkanecarboxylic acids for the treatment of neurodegenerative diseases
EP0973720A1 (fr) Derives d'acides benzoyle-cycloalkyl-1-carboxyliques-2-substitues
JP2001501179A (ja) キヌレニン―３―ヒドロキシラーゼ抑制活性を有するｎ―置換―２―アミノ―４―フェニル―４―オキソ―ブタン酸
AU1808401A (en) Method for the stereoselective synthesis of cyclic amino acids
US6133302A (en) 5-(3-Phenyl-3-oxo-propyl)-1H-tetrazole derivatives
MXPA99008300A (en) 2-substituted benzoyl-cycloalkyl-1-carboxylic acid derivatives
US5973006A (en) Fluoro-substituted benzoylpropionic acid derivatives
EP1656340B1 (fr) Procédés de préparation de composés d'acide 1-carbamoylcycloalkylcarboxylique
EP0686145B1 (fr) Nouveaux composes
EP1025105A1 (fr) Composes benzothiopyraniques condenses

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19990920

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI NL PT SE

AX Request for extension of the european patent

Free format text: SI PAYMENT 19990920

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Withdrawal date: 20010223