Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
  • A61P25/00—Drugs for disorders of the nervous system
• • 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
  • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • 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
  • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
• • 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
• • 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
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• New phencyclidin derivatives processes for their preparation and pharmaceutical compositions containing them
• N- (1-phenylcyclohexyl) piperidine (or PCP), developed as an anesthetic agent and then withdrawn due to excessive psychotropic effects, is now only a pharmacological tool, interesting at least through of its derivatives or the like.
• One of the derivatives, N- (1- (2-thienyl) cyclohexyl) piperidine (or TCP) is, in its tritiated form, a ligand widely used as a marker for the PCP receptor.
• the present invention relates to new phencyclidine derivatives having a selective affinity for low affinity receptors, methods for their preparation, pharmaceutical compositions containing them and their use in particular as a protective agent for cells of the central or peripheral nervous system against acute or chronic degeneration, or as an anticonvulsant agent.
• Ar represents a carbocyclic or heterocyclic aryl radical, monocyclic with 5 or 6 members or consisting of condensed rings and optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkyl, alkenyl, alkynyl radicals , alkoxy, alkylthio, haloalkyl, hydroxyalkyl, having at most 6 carbon atoms; esterified or salified free carboxy; cyano; nitro; amino optionally substituted by one or two identical or different alkyl radicals containing at most 6 carbon atoms; Ri and R 2, which are identical or different, represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from hydroxyl, free esterified or salified carboxy, cyano, nitro or well Ri and R2 form with the nitrogen atom to which they are linked a radicals chosen from halogen atoms, hydroxyl, al
• n represents an integer from 0 to 2 and R3 and R'3 which are identical or different represent a hydrogen atom, a halogen atom or a hydroxyl radical, free esterified or salified carboxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxy alkyl having at most 6 carbon atoms;
• R4 has the same meaning as R3 or R'3;
• X, Y and Z are such that at least one represents a sulfur or oxygen atom and the others represent a methylene radical, with the exception of the compounds in which R3, R'3 and R4 each represent a d atom hydrogen and
• R 1 and R 2 form, with the nitrogen atom to which they are linked, a pyrrolidine radical
• Ar represents a phenyl or 2-thienyl radical and one of X, Y or Z represents an oxygen atom
• Ri and R 2 form with the nitrogen atom to which they are linked a piperidine radical
• Ar represents a phenyl, thienyl and benzothienyl radical
• Y represents a sulfur atom
• X and Z each represent a methylene radical
• Ri and R2 form with the nitrogen atom to which they are linked a piperidine radical
• Ar represents a phenyl, methoxyphenyl, benzothienyl and 2-thienyl radical
• Y represents an oxygen atom
• X and Z each represent a radical methylene
• Ri and R2 form with the nitrogen atom to which they are linked a piperidine radical
• Ar represents a phenyl, methoxyphenyl or 2-thienyl radical
• one of X or Z represents an oxygen atom
• l the other represents a methylene radical
• Y represents a methylene radical
• Ri and R2 form with the nitrogen atom to which they are linked a piperidine radical
• Ar represents a phenyl or 2 thienyl radical
• one of X or Z represents a sulfur atom
• the other represents a methylene radical
• Y represents a methylene radical
• Ri and R2 form with the nitrogen atom to which they are linked a pyrrolidine radical
• Ar represents a 2-thienyl radical
• one of X or Z represents a sulfur atom
• the other represents a methylene radical
• Y represents a methylene radical
• Ri and R2 form, with the nitrogen atom to which they are linked, an ethylamino or pyrrolidine radical, Ar represents a phenyl radical, Y represents a sulfur atom and X and Z each represent a methylene radical, either to one following formulas:
• a more particular subject of the invention is the compounds of general formula IA as defined above in which
• Ar represents a 5-membered monocyclic heterocyclic aryl radical or consisting of two condensed rings and optionally substituted by one or more identical or different alkyl or alkenyl radicals;
• Ri and R2 identical or different represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms or Ri and R2 form with the nitrogen atom to which they are linked a radical
• n is equal to 1 and R3 and R'3, which are identical or different, represent a hydrogen atom or a hydroxyl, alkyl or hydroxyalkyl radical having at most 6 carbon atoms.
• halogen represents a fluorine, chlorine, bromine or iodine atom.
• alkyl having at most 6 carbon atoms represents a linear or branched alkyl radical such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl radical.
• alkenyl radicals mention may be made of linear or branched alkyl radicals such as vinyl, allyl, 1-propenyl, butenyl, pentynyl or hexynyl.
• alkynyl radicals there may be mentioned the ethynyl, propargyl, butynyl, pentynyl or hexynyl radicals.
• the alkoxy radical linear or branched, preferably denotes the radicals in which the alkyl radical is as defined above.
• the methoxy, ethoxy, propoxy, isopropyloxy or butoxy radicals are preferred.
• the alkylthio radical preferably designates the radicals in which the alkyl radical is as defined above, for example methylthio or ethylthio.
• haloalkyl radical preferably designates the radicals in which the alkyl radical is as defined above and is substituted by one or more halogen atoms as defined above such as, for example, bromoethyl, trifluoromethyl, trifluoroethyl or alternatively pentafluoroethyl.
• the hydroxyalkyl radical preferably designates the radicals in which the alkyl radical is as defined above, for example hydroxymethyl or hydroxyethyl.
• the aryl radical can be carbocyclic or heterocyclic.
• the heterocyclic aryl radical can contain one or more heteroatoms, identical or different, chosen from oxygen, nitrogen and sulfur atoms.
• an aryl, carbocyclic or heterocyclic radical mention may be made of phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, diazolyl, oxadiazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl or indolyl radicals.
• a more particular subject of the invention is the compounds of general formula IA as defined above in which
• Ar represents the thienyl, furyl, benzothienyl, benzofuryl radical and optionally substituted by one or more methyl, ethyl, propyl or allyl radicals;
• Ri and R2 which are identical or different, represent a hydrogen atom or a methyl or ethyl radical, or else R and R2 form, with the nitrogen atom to which they are linked, a radical
• n is equal to 1 and R3 and R'3, which are identical or different, represent a hydrogen atom or a hydroxyl, hydroxymethyl, hydroxyethyl, methyl or ethyl radical.
• R3 and R'3 which are identical or different, represent a hydrogen atom or a hydroxyl, hydroxymethyl, hydroxyethyl, methyl or ethyl radical.
• the subject of the invention is also a process for preparing the compounds of general formula I as defined above, characterized in that it comprises
• the first step which consists in obtaining the compound of formula 2, is a conventional Grignard reaction whose conditions of implementation are known to those skilled in the art.
• the second step provides access to azide 3 from alcohol 2.
• the reaction takes place in the presence of an excess of protonating organic agent such as trichloroacetic acid, of an alkali azide in a solvent polar aprotic.
• the reaction takes place in the presence of an excess of trichloroacetic acid and sodium azide in chloroform.
• the conventional methods known to those skilled in the art for the reduction of azides can be used.
• the reduction can thus be carried out using, for example, Raney nickel in isopropanol at 60 ° C. or lithium aluminum hydride in diethyl ether or tetrahydrofuran.
• the alkaline conditions allow the acid formed to be trapped and can be obtained using, for example, potassium carbonate.
• the polar solvent used can be chosen from methanol, acetone, hexamethylphosphoramide or sulfolane and preferably hexamethylphosphoramide.
• the primary amine of formula 4 therefore corresponds to the compound of formula I in which R 1 and R 2 represent the hydrogen atom. If in the compound of formula I desired, R] and R 2 are identical or different and at least one of the two does not represent the hydrogen atom, then the compound of formula I is a secondary or tertiary amine depending on the values of Ri and R 2 ; these amines can be obtained from the corresponding primary amine of formula 4 according to the conventional methods known to those skilled in the art.
• the various isomeric, enantiomeric and diastereoisomeric forms can be obtained by splitting either the starting product or the final product according to methods known to those skilled in the art.
• the two diastereoisomers can be separated at the final stage by simple chromatography. This separation can also be carried out after obtaining the compounds of formula 4.
• the resolution can also be carried out by the use of optically active acids such as tartaric or mandelic acids.
• Another subject of the invention is another process for preparing the compounds of general formula I as defined above, characterized in that it comprises
• the reaction for obtaining the compound of formula 5 can be carried out in the presence of acetone cyanhydrin as a donor of cyanide ions; as dehydrating agent of the medium, one can use, for example, anhydrous magnesium sulfate.
• the reaction is preferably carried out in a basic polar solvent such as acetamide, methylacetamide, dimethylacetamide, acetylpiperidine or piperidine, and preferably dimethylacetamide or piperidine.
• the second stage of this second preparation process is a Bruylants reaction (P. Bruylants, Bull. Soc. Chim. Belg., 33, 467 (1924); P. Bruylants, A. Castille, Bull. Soc. Chim. Belg. ., 34, 261-284 (1925)).
• this reaction is stereospecific and leads to the introduction of the aryl radical in an equatorial position. Consequently, it will only be used for the synthesis of compounds of formula I which do not have any particular stereochemistry.
• this synthetic route will preferably be used in the case where R 4 represents a hydrogen atom.
• the starting compounds of formula 1 in which R4 represents the hydrogen atom and Y "represents a sulfur or oxygen atom or a methylene radical, are commercial products.
• the other starting compounds of formula 1 in which R4 represents the hydrogen atom can be prepared according to the scheme described by TE Young (J. Org. Chem., 38, 1562-1566 (1973)).
• the starting compounds in which R4 is different from the hydrogen atom can be obtained from the corresponding compounds of formula 1 in which R4 represents the hydrogen atom, according to the substitution methods known to man of art.
• the compounds of the present invention have very good affinity and selectivity for a new type of low affinity sites.
• the action on these sites inhibits the neurotoxicity induced by glutamate responsible for certain pathological consequences such as acute or chronic degeneration of cells of the central or peripheral nervous system.
• the compounds of the present invention can thus be used in various therapeutic applications.
• the compounds of the present invention can be used to protect the cells of the central or peripheral nervous system against acute degeneration induced by accidents such as trauma, ischemia or the action of endogenous and exogenous neurotoxic agents, directly or through secondary mechanisms.
• the compounds can also be used to protect the cells of the central or peripheral nervous system against chronic degenerations induced by neurodegenerative diseases and processes such as pathological aging, dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis. They can also be used as anticonvulsants or antidepressants or to stimulate alertness, to treat states of dependence on different substances such as drug addicts.
• the present application also relates, as medicaments, to the compounds of formula I as defined above, in all the isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral acids or pharmaceutically acceptable organic or inorganic or organic bases of said compounds of formula I, as well as pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined above.
• the invention thus relates to pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable acid or base additive salt thereof, in combination with a pharmaceutically acceptable carrier.
• the pharmaceutical composition can be in the form of a solid, for example, powders, granules, tablets, capsules or suppositories.
• the appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
• compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups.
• suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water, added to pharmaceutically acceptable oils or fats .
• the sterile liquid compositions can be used for intramuscular or subcutaneous injections and the sterile compositions can also be administered intravenously.
• the compositions according to the invention can also be administered by other conventional routes such as oral administration.
• a subject of the invention is also the use of the compounds of formula I ', characterized in that they correspond
• Ar ' represents a carbocyclic or heterocyclic aryl radical, 5 or 6-membered monocyclic or consisting of condensed rings and optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkyl, alkenyl, alkynyl radicals, alkoxy, alkylthio, haloalkyl, hydroxy alkyl, having at most 6 carbon atoms; esterified or salified free carboxy; cyano; nitro; amino optionally substituted by one or two identical or different alkyl radicals containing at most 6 carbon atoms; R'i and R'2 identical or different represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from hydroxyl radicals, free esterified or salified carboxy, cyano , nitro or R'i and R'2 form with the nitrogen atom to which they are linked a radicals chosen from halogen atom
• n represents an integer from 0 to 2 and R3 and R'3 which are identical or different represent a hydrogen atom, a halogen atom or a hydroxyl radical, free esterified or salified carboxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxy alkyl having at most 6 carbon atoms;
• R'4 has the same meaning as R3 or R'3;
• X ', Y' and Z ' are such that at least one represents a sulfur or oxygen atom or a methylene radical and the others represent a methylene radical, or to one of the following formulas: - N- [ l- (2-thienyl) -cyclohexan-1-yl] -3-hydroxymethyl-piperidine,
• the invention also relates to the use of the compounds of formula l as defined above, for the preparation of medicaments intended to protect the cells of the central or peripheral nervous system against the chronic degenerations induced by diseases or neurodegenerative processes such as pathological aging, dementia, Alzheimer's disease, Parkinson's disease, amyotrophic sclerosis, as well as anticonvulsant or antidepressant drugs or drugs to stimulate alertness, to treat states of dependence on various substances such than addicts like cocaine.
• diseases or neurodegenerative processes such as pathological aging, dementia, Alzheimer's disease, Parkinson's disease, amyotrophic sclerosis, as well as anticonvulsant or antidepressant drugs or drugs to stimulate alertness, to treat states of dependence on various substances such than addicts like cocaine.
• the invention relates more particularly to the use of the compounds of formula I'A as defined above in which
• Ar ' represents a 5-membered monocyclic heterocyclic aryl radical or consisting of two condensed rings and optionally substituted by one or more identical or different alkyl or alkenyl radicals;
• R'i and R'2 which are identical or different, represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms, or else Ri and R2 form, with the nitrogen atom to which they are linked, a radical
• n is equal to 1 and R3 and R'3 which are identical or different, represent a hydrogen atom or a hydroxyl, alkyl or hydroxyalkyl radical having at most 6 carbon atoms, for the preparation of medicaments as defined above .
• the invention relates more particularly also to the use of the compounds of formula A as defined above in which Ar 'represents the thienyl, furyl, benzothienyl, benzofuryl radical and optionally substituted by one or more methyl, ethyl, propyl radicals or allyl;
• R'i and R'2 identical or different, represent a hydrogen atom or a methyl or ethyl radical, or else Ri and R2 form, with the nitrogen atom to which they are linked, a radical
• n is equal to 1 and R3 and R'3 which are identical or different, represent a hydrogen atom or a hydroxyl, hydroxymethyl, hydroxyethyl, methyl or ethyl radical, for the preparation of medicaments as defined above. More particularly, the subject of the invention is the use of the compounds of formula I'A corresponding to the following formulas:
• Step 1 a 3-methyl-tetrahydro-4H-thiopyran-4-one
• diisopropylamine (8.4 ml, 60 mmol) and 74 ml of THF are introduced under nitrogen.
• NBuLi (37.5 ml, 60 mmol) is poured in dropwise and the mixture is stirred for an additional half hour at 25 ° C.
• the lithium diisopropylamide solution (0.5 M) obtained is cooled to -80 ° C.
• Tetrahydro-4H-thiopyran-4-one (6.96 g, 60 mmol) is added slowly. After half an hour, methyl iodide (5.6 ml, 90 mmol) is added and the temperature rises to 25 ° C.
• Step 1.b 4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-ols
• 2-thienylmagnesium bromide is prepared under nitrogen from magnesium (0.9 g, 37.2 mmol), 2-bromo-thiophene (6.1 g, 37.2 mmol) and 100 ml of ether anhydrous. The mixture is heated at 45 ° C. for 3 hours and then 3-methyltetrahydro-4H-thiopyran-4-one (4.2 g, 33 mmol) dissolved in ether (50 ml) is added at room temperature. The reaction medium is heated for 16 hours at reflux. After cooling, the reaction medium is poured into 100 ml of an aqueous solution saturated with NH4Cl.
• Step 1 4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl-azides
• lithium aluminum hydride (0.87 g, 23 mmol) is introduced into THF at 0 ° C.
• the mixture of azides obtained in the previous step (5.5 g, 23 mmol) dissolved in 30 ml of THF is poured in dropwise.
• the reaction medium is stirred for 24 hours at room temperature.
• the minimum ammonia (10%) is added very slowly in order to destroy the excess LiAlH 4 .
• Filtered on celite, the precipitate is washed with dichloromethane (300 ml) and concentrated to dryness.
• the brown oil obtained is taken up in ether and extracted with a HCl solution (10%) (3x100 ml).
• the aqueous phase is then neutralized with ammonia (20) and extracted with ether (3x100 ml).
• the organic phase is washed with water, dried over MgSO 4 and concentrated to dryness.
• the product obtained is purified by chromatography on silica, eluting with an EP / EA 50/50 mixture. A colorless oil (3.7 g) is thus obtained.
• the yellow oil obtained (6.2 g) is purified by chromatography on silica, eluting with an EP / EA mixture (90/10).
• the two diastereoisomers are thus obtained separately: the majority (2 g, 34%) and the minority (0.7 g, 12), both in the form of a white solid.
• Step 2 a 4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile
• magnesium sulfate 9.6 g, 80 mmol
• DMA 2 g, 23 mmol
• ⁇ -3-methylpiperidine
• tetrahydro-4H-thiopyran-4-one 2.3 g, 20 mmol
• acetone cyanohydrin 1.7 g, 20 mmol
• Step 2b ( ⁇ ) -N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl- piperidine
• 2-Thienylmagnesium bromide is prepared under nitrogen from magnesium in turnings (1 g, 40 mmol), 2-bromothiophene (6.52 g, 40 mmol) and 150 ml of anhydrous ether.
• the ether is refluxed for 3 hours and then raminonitrile obtained according to the preceding step (2.25 g, 10 mmol) is added at room temperature.
• the reaction medium is heated for 20 hours at reflux. After the usual treatment, a brown oil is obtained which is chromatographed on 100 g of alumina, eluting with an EP / EA mixture (95/5). A colorless oil (1.6 g) is thus obtained.
• Step 3 a S - (+) - 3-methyl-piperidine
• Step 3b S-4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile
• step 2a The procedure is identical to that illustrated in step 2a, using S - (-) - 3-methylpiperidine in place of ( ⁇ ) -3-methylpiperidine.
• Step 3 c S - (-) - N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl- piperidine
• step 2b The procedure is identical to that illustrated in step 2b, using S-4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile instead of ( ⁇ ) -4- ( 3-methyl- piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile.
• Step 4 a R - (-) - 3-methyl-piperidine
• Step 4b R-4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran- 4-carbonitrile
• step 2a The procedure is identical to that illustrated in step 2a, using R - (+) - 3-methylpiperidine in place of ( ⁇ ) -3-methylpiperidine.
• Step 4 c R - (+) - N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl- piperidine
• step 2b The procedure is identical to that illustrated in step 2b, using R-4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile instead of ( ⁇ ) -4- ( 3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile.
• a colorless oil (1.65 g) is obtained which crystallizes when cold.
• Mp 54-56 ° C.
• Step 8 a l- [l- (3-hydroxymethyl-piperidino) -cyclohexan-l-yl] -carbonitrile
• Step 8b N- [1- (2-thienyl) -cyclohexan-1-yl] -3-hydroxymethyl-piperidine
• 2-Thienylmagnesium bromide is prepared under nitrogen from magnesium (0.66, 27.2 mmol), 2-bromothiophene (4.4 g, 9.5 mmol) and 80 ml of anhydrous ether, heated at 45 ° C for 3 hours then added at room temperature l- [l- (3-hydroxymethyl-piperidino) -cyclohexan-1-yl] -carbonitrile (2 g, 9 mmol) dissolved in ether. The reaction medium is heated for 20 hours at reflux. After treatment of the reaction, 2.1 g of a yellow oil are obtained which is chromatographed on alumina, eluting with an EP / EA mixture (50/50). A colorless oil (1.4 g) is thus obtained.
• Step 9 a 4-piperidino-tetrahydro-4H-thiopyran-4-carbonitrile
• Step 9b N- [4- (2-furyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine
• a solution of MgBr 2 is prepared by adding dropwise and under nitrogen 1,2-dibromoethane (6.76 g, 36 mmol) diluted in 80 ml of anhydrous ether on magnesium in turns (0.88 g , 36 mmol). The solution is kept for 2 hours at room temperature.
• a solution of 2-lithio-furan is simultaneously prepared, at -20 ° C. and under nitrogen, by dropwise addition of a solution of 1.6 M n-butyllithium in hexane (28 ml, 45 mmol) on a mixture of furan (3.1 g, 45 mmol). This mixture is heated for 2 hours at reflux.
• the preparation process is identical to that of step 9b but using a 2-lithio-benzofuran solution instead of a 2-lithio-furan solution.
• the preparation process is identical to that of step 9b but using a solution of 2-lithio-5-methyl-thiophene in place of a solution of 2-lithio-furan.
• the preparation process is identical to that of step 9b but using a 2-Uthio-4-methyl-thiophene solution in place of a 2-lithio-furan solution.
• Step 13 a 4- (3-hydroxypiperidino) -tetrahydro-4H-thiopyran-4-carbonitrile
• 2-Thienylmagnesium bromide is prepared under nitrogen from magnesium (1.3 g, 53.2 mmol), 2-bromothiophene (8.7 g, 53.2 mmol) and 100 ml of anhydrous ether. The mixture is heated at 45 ° C. for 3 hours and then the aminonitrile obtained in step 13a (3 g, 13.3 mmol) dissolved in ether is added at room temperature. The reaction medium is heated for 20 hours at reflux. After treatment of the reaction, 2.3 g of a brown oil are obtained which is chromatographed on silica eluting with an EP / EA mixture (30/70). A white solid is thus obtained (42%).
• Step 14 a 4- (4-hydroxypiperidino) -tetrahydro-4H-thiopyran-4-carbonitrile
• Step 14b N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -4-hydroxy piperidine
• 2-Thienylmagnesium bromide is prepared under nitrogen from magnesium (0.45 g, 18.5 mmol), 2-bromothiophene (3 g, 18.5 mmol) and 50 ml of anhydrous ether. We heated at 45 ° C for 3 hours then raminonitrile obtained in step 14a (1.4 g, 6.2 mmol) dissolved in ether is added at room temperature. The reaction medium is heated
• Step 15 a Ethyl N-benzoyl-4-piperidone-3-carboxylate
• Benzamide (12.1 g, 0.1 mmol) in 200 ml of toluene is introduced under nitrogen into a 250 ml three-necked flask and sodium hydride (4 g, 0.1 mol) is added.
• the mixture is heated for one hour at reflux, then cooled to 0 ° C. and ethyl acrylate (32.6 ml, 0.3 moles) is poured rapidly.
• the reaction medium is stirred for 24 hours at 60 ° C. Cool to 0 ° C and add 100 ml of ice water. After 1/2 hour with stirring, the two phases are decanted and the aqueous phase is washed with 50 ml of ether.
• the aqueous phase is acidified to pH 3 and then extracted with dichloromethane (3x50 ml).
• the combined organic phases are dried over Na 2 SO 4 and concentrated to dryness.
• a yellow oil is thus obtained which is chromatographed on silica, eluting rapidly with anhydrous ether.
• An oil slightly colored red (9.4 g, 34) is thus obtained with traces of benzamide.
• Step 15b Ethyl N-benzoyl-4-piperidone-3-carboxylate
• Step 15 c 3-methyl-4-piperidone hydrochloride
• step 15b The compound from step 15b (7.7 g, 26.6 moles) is heated to reflux of an aqueous HCl solution (6N) for 72 hours.
• the precipitate of benzoic acid formed is filtered, the aqueous phase is extracted with ether (3 ⁇ 50 ml) and the aqueous phase is concentrated to dryness.
• the brown solid obtained is crystallized from ethanol and thus white crystals are obtained (2.85 g, 72%).
• Mp 180-182 ° C.
• Step 15 e l- (4-hydroxy-3-methyl-piperidino) -cycIohexan-l-carbonitrile
• step 15d The compound of step 15d (0.8 g, 7 mmol) is introduced into 10 ml of water in a 50 ml bicol. Cyclohexanone (2.7 g, 23.6 mmol) and a few drops of HCl are added. in order to bring the pH to 3. Then pour the potassium cyanide (0.47 g, 7.3 mmol). The pH of the medium is then close to 11. After 24 hours with stirring at room temperature, an extraction is carried out with dichloromethane, dried over Na2S ⁇ 4, filtered and concentrated to dryness. A colorless oil is thus obtained (1.43 g, 6.4 mmol) representing only one of the two diastereoisomers.
• Step 15 f N- [1- (2-thienyl) -cyclohexan-1-yl] -4-hydroxy-3-methyl piperidine
• 2-Thienylmagnesium bromide is prepared under nitrogen from magnesium (0.38 g, 15.7 mmol), 2-bromothiophene (2.57 g, 15.7 mmol) and 60 ml of anhydrous ether.
• the mixture is heated at 45 ° C. for 3 hours and then the aminonitrile obtained in step 15e (0.7 g, 3.15 mmol) dissolved in THF is added at room temperature.
• the reaction medium is heated for 20 hours at reflux. After treatment of the reaction, a brown oil is obtained which is chromatographed on alumina, eluting with anhydrous ether. A white solid is thus obtained (0.48 g, 54%).
• step 15e The aminonitrile from step 15e (0.7 g, 3.15 mmol) dissolved in 50 ml of anhydrous ether is poured in dropwise over a solution of 2-benzothiophenylmagnesium bromide (15.75 mmol). The mixture is heated under reflux of the ether for 16 hours. After the usual treatment, a yellow oil (0.85 g) is obtained which is chromatographed on alumina, eluting with an EP / EA mixture (20/80). A white solid is thus obtained (0.74 g, 71%).
• Step 17 a 1- (2-thienyl) -cyclohexanol
• 2-Thienylmagnesium bromide is prepared under nitrogen from magnesium (2.92 g, 120 mmol), 2-bromothiophene (19.6 g, 120 mmol) and 200 ml of anhydrous ether. The mixture is heated at 45 ° C. for 3 hours and then cyclohexanone (7.84 g, 80 mmol) dissolved in ether is added at ambient temperature. The reaction medium is heated for 16 hours at reflux. After cooling, the reaction medium is poured into 100 ml of an aqueous solution saturated with NH4Cl. It is stirred for 1/2 hour in order to destroy the magnesium complex, it is decanted and the aqueous phase is extracted with ether (3x50 ml).
• Step 17b 1- (2-thienyl) -cyclohexylazide
• the lithium aluminum hydride (2.28 g, 60 mmol) is introduced into 250 ml of THF at 0 ° C.
• the azide obtained in the preceding step 17b (13.5 g, 65 mmol) dissolved in 30 ml of THF is poured in dropwise.
• the reaction medium is stirred for 24 hours at room temperature.
• the minimum ammonia (10%) is added very slowly in order to destroy the excess LiAi ⁇ i. Filtered on celite, the precipitate is washed with dichloromethane (300 ml) and concentrated to dryness.
• the oil obtained is taken up in ether and extracted with a HCl solution (10%) (3x100 ml).
• the aqueous phase is then neutralized with ammonia (20%) and extracted with ether (3x100 ml).
• the organic phase is washed with water, dried over MgS ⁇ 4 and concentrated to dryness.
• the product obtained is purified by chromatography on alumina, eluting with an EP / EA mixture (60/40). A slightly yellow oil is thus obtained (8.1 g, 69%).
• Step 17 d N-acetoxy-1- (2-thienyl) -cyclohexylamine
• the amine from step 17c (3 g, 16.6 mmol) is introduced into the pyridine (100 ml) and the acetic anhydride (51 g, 50 mmol) is added dropwise. After 4 hours with stirring at room temperature, 100 ml of a HCl solution (10%) are added and the product formed is extracted with ether (3 ⁇ 50 ml). The organic phase is washed with an HCl solution (10%) (2x80 ml), then with water (2x80 ml), dried over MgS ⁇ 4 and concentrated to dryness. A white solid is thus obtained (3.1 g, 84%).
• Step 17 e N-ethyl-1- (2-thienyl) -cyclohexylamine
• the lithium aluminum hydride (0.51 g, 13.4 mmol) is introduced into 80 ml of THF at 0 ° C.
• the amine obtained in the preceding step 17d (3 g, 13.4 mmol) dissolved in 30 ml of THF is poured in dropwise.
• the reaction medium is stirred for 48 hours at reflux.
• the minimum ammonia (10%) is added very slowly in order to destroy the excess LiAlH-4. Filtered on celite, the precipitate is washed with dichloromethane (300 ml) and concentrated to dryness.
• the oil obtained is taken up in ether and extracted with a HCl solution (10%) (3x100 ml).
• a MgBr2 solution is prepared from 1,2-dibromoethane (6.76 g, 36 mmol,
• the mixture is brought to reflux for 16 hours, cooled to room temperature and then treated as follows: the mixture is poured gently into an ice-cold saturated NH4Cl solution, stirred for 30 minutes, extracted with ether; the ethereal phases are combined and then extracted three times with 10% HCl, and 20% NH4OH is added to the aqueous phase until neutral. The aqueous phase is extracted with ether, the organic phase washed with water, dried over Na 2 S04, filtered and concentrated in vacuo. The crude product is purified by chromatography on alumina with CH2Cl2 as eluent to give an oil (1.7 g, 76%).
• the affinity of the compounds for their potential binding site can be appreciated by quantifying their power of displacement of a tritiated marker specific for a given site. Binding experiments are carried out by competition between the molecule to be tested and the appropriate radioligand on a membrane preparation enriched in sites to be studied. The concentration of the tested derivative which inhibits 50% of the binding of the radioligand to the receptor is noted IC50.
• the tritiated marker used is [ 3 H] TCP and the tests carried out on membrane preparations originating from homogenates of anterior rat brains.
• the preparation comes from rat cerebellums. Having no specific marker, only [ 3 H] TCP can be used. A higher concentration of tritiated ligand (2.5 nM against 1 nM in the cortex) will be used in order to be sure to occupy all the PCP2 and PCP3 sites.
• the IC50 values are presented in Table 1 below.
• the tritiated marker used is [ 3 H] TCP and the tests are carried out on membrane preparations originating from the cerebral cortex of rats (Brain Res., 378, 133-141 (1986).

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