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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/20—Hypnotics; Sedatives
• • 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
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • 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
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered

Definitions

• the present invention relates to derivatives of N-cycloalkylpiperazine, methods for obtaining them and pharmaceutical compositions containing them.
• the present invention relates to N-cycloalkylpiperazine derivatives.
• the invention also relates to their use as pharmacological reagents.
• the subject of the invention is also the levorotatory and dextrorotatory derivatives of the N-cycloalkylpiperazine compounds, their preparation and their use as pharmacological reagents.
• the derivatives of the invention have interesting pharmacological properties on the central nervous system, in particular neuroleptic properties.
• the compounds of the invention are also good ligands for the 5-HT 1A serotonergic receptors and therefore have antidepressant, antihypertensive, aggressolytic, analgesic and anxiolytic properties.
• 5-HT 1A agonists have also been shown to decrease alcohol consumption in strains of alcohol-preferable rats (Drug. Dev. Res. 26, 319-341, 1992; Alcohol 6, 17-21, 1989; Alcohol 9 , 283-6, 1992; Pharraacol. Biochem. Behav. 34, 381-6, 1989; Alcohol 5, 147-152, 1988; Jpn. Psychiatr. Neurol. 46, 197-203, 1992), in monkeys (Alcohol 4, 49-56, 1987) and in humans (Psychopathology 22 (suppl. 1), 49-59, 1989; J. Clin. Psychopharmacol. 9, 379-380, 1989).
• the invention therefore relates to a new family of compounds which correspond to the following general formula (I): in which :
• - A is an amide group, or ,
• R 1, R 2, R 3, R 4 and R 5, identical or different, represent a hydrogen atom, halogen, aikyle group C 1 -C 6 alkoxy C 1 - C 6 , a trifluoromethyl group or a benzene ring,
• - m is an integer between 1 and 3
• - n is an integer equal to 2 or 3.
• - C 1 -C 6 alkyl the residues of saturated aliphatic hydrocarbons with straight or branched chain, containing 1 to 6 carbon atoms.
• the preferred alkyl group is the methyl group.
• halogen designates the four halogens F, Cl, Br and I.
• halogen designates the four halogens F, Cl, Br and I.
• R 1 , R 2 , R 3 , R 4 and R 5 when they represent a halogen, are F or Cl.
• - A is an amide group
• R 3 is a hydrogen atom, halogen, preferably fluorine or chlorine;
• the preferred derivatives for the purposes of the invention are the racemic and levorotatory compounds which correspond to the above description and, for which m is equal to 2.
• the compounds of formula (I) can be obtained by condensation of the substituted piperazines of formula (II) on the chlorinated derivatives of formula (III) below, in the presence of sodium or potassium carbonate and a catalytic amount of sodium or potassium iodide, in a ketone solvent such as methyl ethyl ketone (2 -butanone) or diethyl ketone.
• n, A, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
• the derivatives of the invention can also be prepared by condensation of
• X represents a halogen atom, preferably chlorine or bromine
• the compounds of formula (XVI) are easily obtained by condensation of commercial carbethoxypiperazine of formula (XVII) with the chlorinated derivatives of formula (III) in a mixture of methyl ethyl ketone and DMF, in the presence of potassium carbonate and sodium iodide according to the diagram:
• the chlorinated derivatives of formula (III) can easily be obtained by chlorination of the corresponding alcohol of formula (IV), in which m is defined as above, by thionyl chloride in an aromatic solvent such as benzene or toluene (BOGESO KP et al., J. Med. Chem., 1983, 26 (7), 944) or in a chlorinated solvent such as methylene chloride or chloroform:
• the alcohols of formula (IV) are prepared by reduction of the corresponding ketones of formula (V), available commercially, by sodium borohydride in an alcohol having from 1 to 6 carbon atoms, such as methanol or ethanol.
• the piperazines of formula (II) are obtained by hydrogenolysis of the corresponding benzylated derivatives of formula (VI), in which n, A, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, in the presence of palladium / carbon in an alcohol such as methanol or ethanol according to the scheme:
• benzylated compounds of formula (VI) are conventionally prepared by reaction of two equivalents of 4-benzylpiperazine of formula (VII) with the halogen amides of formula (VIII), in which X is as defined above, in dimethylformamide, in the presence sodim or potassium iodide.
• R 1 , R 2 , R 3 , R 4 and R 5 are as defined above,
• - A is an amide group
• 4-Benzyl-1- ( ⁇ -aminoalkyl) piperazine of formula (IX) is obtained by reduction of 4-benzyl-1- ( ⁇ -cyanoalkyl) piperazine of formula (XII) with double hydride of lithium and d aluminum (AlLiH 4 ) in a solvent such as tetrahydrofuran according to the diagram:
• the compound of formula (XII) is conventionally prepared by condensation of the corresponding halonitrile of formula (XIII) with the 4-benzylpiperazine of formula (VII) in the presence of potassium or sodium carbonate in dimethylformamide, X and n being such as previously defined
• R 1 , R 2 , R 3 , R 4 and R 5 are as defined above for the compounds of formula (I); - A is an amide group ,
• R 1 , R 2 , R 3 , R 4 and R 5 are as defined above for the compounds of formula (I);
• R 1 , R 2 , R 4 and R 5 represent a hydrogen atom
• R 3 is a hydrogen or halogen, fluorine or chlorine atom
• the compound of formula (XVIII) is easily obtained by treatment with hydrazine of the corresponding phthalimide (XIX) in solution in an alcohol having from 1 to 6 carbon atoms, such as methanol or ethanol.
• Phthalimide (XIX) results from the condensation of racemic or split 1- (1,2,3,4-tetrahydronapht-1-yl) piperazine (XV a ) with 2-chloro or 2-bromoethylphthalimide in a solvent such as DMF, acetonitrile or 2-butanone.
• the acid addition salts of the derivatives of formula (I) according to the invention can be obtained by conventional methods with acids commonly used to obtain pharmaceutically acceptable salts, such as hydrochloric, hydrobromic, maleic, fumaric acids.
• hydrochloric acid Preferably hydrochloric acid will be used.
• the derivatives of formula (I) have interesting pharmacological properties on the central nervous system. They present in animal pharmacology an atypical neuroleptic profile. Their affinity for the 5-HT 1A serotonergic receptors gives the derivatives according to the invention properties of the non-benzodiazepine anxiolytic, antidepressant, antihypertensive, analgesic, aggressiveolytic and anti-alcoholic type.
• a subject of the invention is also the pharmaceutical compositions containing, as active principle, a derivative of formula (I) in association with a pharmaceutically acceptable vehicle as well as the inclusion complexes such as those described in particular in Chem. Pharm. Bull., 1975, 23, 6, 1205; 1975, 23, 12, 3062; 1978, 26, 10, 2952.
• a pharmaceutically acceptable vehicle such as those described in particular in Chem. Pharm. Bull., 1975, 23, 6, 1205; 1975, 23, 12, 3062; 1978, 26, 10, 2952.
• inclusion complexes of the compounds of the invention in ⁇ -cyclodextrin.
• compositions according to the invention can be compositions which can be administered by the oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal route.
• Suitable administration forms include in particular oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, as well as administration forms -cutaneous, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.
• the invention relates to the use of derivatives of formula (I) as pharmacological reagents, as such or labeled with isotopes, optionally radioactive, in particular tritium or 14 C.
• Example 2 describes the preparation of the dextrorotatory derivative (+) of this same compound.
• Example 3 describes a general method for the preparation of racemic or optically pure derivatives (levogyres or dextrogyres), of general formula
• R 3 H, F, Cl.
• Examples 4 to 16 relate to the preparation of intermediate compounds which can be used to obtain the derivatives of formula (I).
• the base is dissolved in alcohol, hydrochloric alcohol is added, the salt crystallizes.
• F 228oC.
• the base is dissolved in alcohol, hydrochloric alcohol is added, the salt crystallizes.
• F 232oC.
• the product is purified on a silica column, eluent [AcOEt: Et 3 N 0.35%].
• the benzene is evaporated in vacuo.
• the solid is taken up in dichloromethane and then washed with ice water.
• the organic phase is dried and then concentrated in vacuo. 39 g of solid are obtained.
• dirbethoxypiperazine (317 g - 2 M), potassium carbonate (552 g - 4 M), sodium iodide (100 g - 0.66 M) are placed in solution in 1 1 of methyl ethyl ketone (2-butanone) and 400 ml of DMF.
• Chlorotetralin (302 g - 1.82 M) dissolved in 400 ml of methyl ethyl ketone is added slowly.
• the mixture is brought to reflux for 24 hours. After cooling, it is filtered and the solvents are evaporated.
• the residual oil is thrown into water and the product is extracted 3 times with ethyl acetate.
• the organic phase is concentrated and the residual oil is taken up in ethyl ether.
• Hydrochloric alcohol is then added.
• the hydrochloride formed is drained.
• the base is released in a methylene chloride-water mixture with sodium carbonate. After decantation, the organic phase is dried over Mg
• 1-carbethoxy-4- (1,2,3,4-tetrahydronapht-1-yl) piperazine 330 g - 1.14 M
• Potassium hydroxide 840 g - 15 M
• the mixture is brought to reflux.
• the reaction is followed by thin layer chromatography.
• the mixture After disappearance of the starting product, the mixture is cooled, filtered and then extracted with dichloromethane. The solvent is evaporated off and the residual oil is taken up in ethanol. Oxalic acid is then added. The oxalate formed is drained and then released in a methylene chloride-water mixture with sodium carbonate. After decantation, the organic phase is dried over MgSO 4 and the solvent is evaporated under vacuum.
• the mother liquors of the salt are evaporated to dryness to give 7.14 g of a product which is treated with 240 ml of an aqueous solution of NaOH 3 M.
• the aqueous phase is extracted with 3 times 200 ml of ethyl ether; the ethereal phase is dried over
• Free lamin is obtained by decomposition of the oxalate by 3 M sodium hydroxide.
• the tartrate thus obtained is decomposed with 220 ml of 3 M sodium hydroxide.
• the aqueous phase is extracted with 3 times 200 ml of ethyl ether; the organic phase is dried over MgSO 4 , filtered and evaporated to dryness.
• the procedure is as for the levorotatory enantiomer by preparing the oxalate of the amine (+) by adding an equivalent of oxalic acid in ethanol at 95%.
• the oxalate obtained is drained and then air dried.
• the solvent is evaporated to dryness, it is taken up in water, extracted with ethyl acetate and an acid-base washing is carried out.
• the neuroleptic activity of the derivatives of formula (I) was evaluated by the following tests:
• the product to be tested is administered intraperitoneally 60 min before the injection of apomorphine.
• Apomorphine is injected subcutaneously at a rate of 1 mg / kg.
• the mice are then isolated in separate cages.
• Atypical neuroleptics can have no effect on one or the other of the three parameters, or even on all three.
• the tail suspension test described by STERU et al. (Prog. Neuropsycho. Pharmacol. Biol. Psychiat. 1987, 11, 659-671; Arch. Int. Pharmacodyn. Ther. 1987, 288 (1). 11-30) was prepared to detect psychrotropic activities.
• the product to be tested is administered intraperitoneally 60 min before the mouse is hooked.
• this parameter based on the energy expended by the animals, is independent of the duration of the activity.
• Antidepressants conventionally decrease the time of immobility. Neuroleptics tend to increase it.
• the results are expressed as a percentage change compared to the untreated control.
• Synaptic membranes are prepared according to the method of JONES and MATUS (1980). The rats are decapitated and the brains (without the cerebellum) are quickly removed.
• the synaptic membranes are purified on a discontinuous sucrose gradient from a mitochondrial fraction lysed by hypotonic shock and stored at -70oC.
• the rat striatum membranes are prepared from different striatum under the same conditions.
• the measurements are carried out in the absence and in the presence of the derivatives to be studied. Each molecule is used at concentrations 10 -5 , 10 -7 and 10 -9 M.

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• 1992
  • 1992-07-16 FR FR9208808A patent/FR2693722B1/fr not_active Expired - Fee Related
• 1993
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