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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/64—Oxygen 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
  • 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
  • A61P25/06—Antimigraine agents
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/28—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
  • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
  • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
  • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
  • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
  • C07C255/43—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms the carbon skeleton being further substituted by singly-bound oxygen atoms
• • 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

Definitions

• the present invention relates to novel compounds derived from cyclopropylacetonitrile and their physiologically acceptable salts which are useful as medicaments.
• the compounds of the invention can also be used in the pharmaceutical industry as intermediates and for the preparation of medicaments.
• Calcium channel blockers are a group of substances that block the flow of calcium ions into the cell and can also inhibit the mobilization of calcium ions from calciosomes, thereby regulating the concentration of calcium ions inside of the cell.
• the movement of calcium is important in the process of muscle concentration and in the transmission of nerve impulses.
• Some calcium antagonists (such as nifedipine, verapamil, diltiazem) are hydrophilic compounds and are not useful for the treatment of brain damage, but they have shown their effectiveness in the treatment of cardiovascular diseases.
• certain drugs have lipophilic properties (such as nimodipine, emopamil, flunaricin) and are capable of rapidly and in sufficient quantity crossing the blood-brain barrier and thus reaching high levels of concentration in the tissue. cerebral and so are useful in the treatment of cerebral disorders.
• the compounds of the invention exhibit activity as antagonists of the serotonin 5-HT2 receptor.
• serotonin 5-HT2 receptor antagonists Given the known vasoconstrictive activity of serotonin, it has been proposed that the release of serotonin after ischemia may worsen the ischemic episode by constricting the cortical arteries. Serotonin 5-H 2 receptor antagonists have been shown to have positive effects in the face of ischemic attack.
• the cyclopropylacetonitrile derivatives which are the subject of the invention are calcium channel antagonists and 5-HT2 antagonists and exhibit properties of therapeutic utility as neuroprotectors, anxiolytics, tranquilizers, antipsychotics, anticonvulsants, antimigraine drugs, antiischemic agents, inhibitors of the syndrome. 'abstinence and are useful in dysfunctions in the field of knowledge such as senile dementia, memory dysfunctions, loss of consciousness, etc., as well as in the treatment of cardiovascular diseases.
• the compounds which are the subject of the invention correspond to the general formula (I)
• R4 represents a hydrogen atom or a linear alkyl radical.
• R5 represents a substituted phenyl radical represented by the general formula (II) or a substituted phenoxyl radical represented by the general formula (III), formulas in which
• two radicals in adjacent positions can form, combined, a methylenedioxy or ethylenedioxy group.
• Preferred halogen atoms in the R] _, R2, R3 R ⁇ / R 7 and R 8 are I and fluorine and chlorine.
• the linear or branched alkyl radicals preferred in R ⁇ _, R2 ; R3, R ⁇ R 7 and R 8 are methyl, ethyl, isopropyl and tert-butyl.
• R ⁇ , R2, R3, Rg, R 7 and Rg are methoxyl and ethoxyl.
• the new compounds of general formula (I) have an asymmetric carbon atom and therefore can be prepared as optical isomers or as racemates.
• the racemates of the compounds (I) can be split into their optical isomers by conventional methods, such as for example separation by chiral chromatography or by fractional crystallization of their diastereomeric salts. These salts can be prepared by reacting the compounds (I) with chiral acids.
• Optical isomers can be obtained by asymmetric synthesis in order to obtain optically active intermediates.
• the invention also relates to the physiologically acceptable salts of the compounds of general formula (I), in particular the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, malonic, succinic, glutaric, fumaric, malic, tatric, citric acids, ascorbic, maleic, benzoic, phenylacetic, cinnamic, and alkyl-, cycloalkyl- or aryl-sulfonic acids.
• the new derivatives of general formula (I) can be prepared by following the following methods: Process for the preparation of the new nitriles of general formula (IV):
• the reaction is carried out by adding potassium tert-butoxide to a solution of tosylmethyl isocyanide in dimethylsulfoxide cooled in an ice bath and in a nitrogen atmosphere. After having allowed to stand under these conditions for five minutes, methanol, ethanol or tert-butanol and the ketones of general formula (V) are added, leaving the solution to stand at room temperature overnight.
• Reaction times range from one hour to twenty-four hours.
• the temperature of the reaction rises to room temperature or to 45 ° C.
• the reaction can also be carried out by adding potassium tert-butoxide to a solution, cooled in an ice bath, of the ketone of general formula (V), of tosyl methyl isocyanide and of methanol, of ethanol or tert-butanol in an inert solvent and under a nitrogen atmosphere.
• R 4 and R5 have the meaning indicated above and X represents an leaving group, such as chloro, bromo, mesyloxy or tosyloxy.
• reaction is carried out by metallation of the ⁇ carbon of the cyclopropylacetonitrile derivative of general formula (IV) with a base in an inert solvent and then reacting the product with a compound of general formula (VI).
• the bases suitable for carrying out the reaction are alkali metal hydrides, alkali metal hydroxides, alkali metal alcoholates, alkali metal amides and organometallic compounds.
• the preferred bases are powdered or suspended sodium amide, potassium hydroxide powder, butyl lithium and lithium diisopropylamide.
• Suitable solvents for carrying out the reaction are aromatic and aliphatic hydrocarbons, as well as ethers and polar aprotic solvents.
• the preferred solvents are toluene and tetrahydrofuran.
• the reaction can be carried out under phase transfer catalysis conditions.
• Suitable catalysts are quaternary ammonium salts, phosphonium salts as well as crown ethers.
• the preferred catalysts are tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium acid sulfate, tetraphenylphosphonium bromide and dibenzo-18-crown-6 ether.
• the reaction temperature depends on the base used. Thus, when the reaction is carried out with powdered potassium hydroxide and a phase transfer catalyst, the temperature varies between 50 ° C and 90 ° C. When the reaction is carried out with lithium diisopropylamide, the temperature oscillates between -70 ° C. and the reflux temperature of tetrahydrofuran.
• Reductive amination can be carried out in the presence of hydrogen and a hydrogenation catalyst, as well as by means of the use of reducing agents such as sodium boron hydride or sodium cyanoborohydride in a solvent such as ethanol or methanol.
• reducing agents such as sodium boron hydride or sodium cyanoborohydride in a solvent such as ethanol or methanol.
• the reaction temperature varies between room temperature and the reflux temperature of the solvent used.
• R, R2 R3, Rg and R ⁇ Q have the meaning indicated above by means of hydrolysis with dilute acids such as aqueous oxalic acid at reflux, the reaction time being from one to three hours.
• the compounds of general formula (I) can be prepared by reaction under alkylation conditions of the amines of general formula (VIII) with the derivatives of general formula (XI):
• R] _, R2 and R3 have the meaning indicated above and X represents an outgoing group such as, for example, chloro, bromo, mesyloxy -or tosyloxy.
• This reaction can be carried out in a solution of (VIII) and (XI) in an inert solvent and in the presence of a base capable of capturing the acid which is released in the reaction.
• Suitable solvents can be toluene, ethanol or dimethylformamide.
• the reaction temperature ranges from 70 ° C to 130 ° C. Reaction times vary between 4 and 24 hours.
• the bromine derivative can be prepared by addition of hydrobromic acid under free radical conditions on the double bond of the compounds of general formula (XII)
• R ⁇ _, R2 and R3 have the meaning indicated above.
• the addition of hydrobromic acid is done by introduction of this body into a solution of the unsaturated derivative (XII) in an apolar solvent such as cyclohexane or toluene in the presence of a radical inducer such as dibenzoyl peroxide or azobisisobutyronitrile .
• the reaction temperature varies between 10 ° C and 60 ° C.
• the alcohols of general formula (XIII) can be obtained by reduction of the aldehydes of general formula (VII) with a reducing agent such as, for example, boron and sodium hydride.
• a reducing agent such as, for example, boron and sodium hydride.
• Example I-b 2-cyclopropyl-2- (4-chlorophenyl) -5- [N-methyl-N- (2-phenylethyl) amino] valeronitrile.
• Example VII-a 2-cyclopropyl-2-phenyl-5-oxovaléronitrile.
• Example I-a 2-cyclopropyl-2-phenyl-5- [N-methyl-N- (2-phenylethyl) amino] valeronitrile.
• a solution of 910 mg (4.27 mmol) of 2-cyclopropyl-2-phenyl-5-oxovaleronitrile, 576 ml (4.27 mmol) of N-methylphenethylamine and 5 ml of is kept at reflux for 1.5 hours. EtOH. Then the solution is cooled in an ice-water bath and 161 mg (4.27 mmol) of Na 2 B are added and the mixture is left to stand at room temperature for 1 hour.
• Example I-j 2-cyclopropyl-2-phenyl-5- [N- [2- (4-fluorophenyl) ethyl)] -N-methylamino] valeronitrile.
• the study substances are administered ip to mice. After one hour, BaCl2 (40 mg / kg, iv) is injected. Survival is determined 10 minutes after administration of BaCl2.
• a mouse cerebral cortex homogenate is used following a modification of the method of SS Nikam et al. , J. Med. Chem. , 31, 1965-1968 (1988).
• the radio ligand [ 3 H] -ketaneserine is used and to measure the non-specific union, methysergide is used.
• the incubation time is 15 minutes at a temperature of 37 ° C.
• the radio ligand united to the protein is separated by filtration on glass fiber filters and the radioactivity retained on the filter is determined by flickering. liquid.
• the inhibition constants (Ki, nM) are calculated by nonlinear regression analysis using the EBDA / LIGAND program (Munson & Rodbard, Analytical Biochemistry, 107, 220 (1980)). Table V represents the Ki of some of these products.
• mice The products are administered ip to the mice. After 30 minutes, the mice are subjected to a nitrogen atmosphere for one minute. The survival of the different groups is determined. Table 6 summarizes the results obtained with some of the examples. TABLE VI ED50 values of protection against mortality induced by exposure of mice to a nitrogen atmosphere for 1 minute. EXAMPLE 50 (mg / kg ip)
• compositions appropriate to the nature and extent of the condition to be treated.
• the daily dosage in human medicine is between 5 milligrams and 500 milligrams of product which can be administered in several doses.
• the compositions are prepared in forms compatible with the mode of administration used, such as, for example, tablets, dragees, capsules, suppositories, solutions or suspensions. These compositions are prepared by known methods and comprise from 1 to 60% by weight of active principle (compound of formula I) and from 40 to 99% by weight of suitable pharmaceutical vehicle compatible with the active principle and the physical form of the composition used.
• active principle compound of formula I
• suitable pharmaceutical vehicle compatible with the active principle and the physical form of the composition used.
• Example of formula for a tablet Example I-a 5 mg

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• 1994
  • 1994-03-16 FR FR9403073A patent/FR2717473B1/fr not_active Expired - Fee Related
• 1995
  • 1995-03-15 KR KR1019950705080A patent/KR960702430A/ko not_active Application Discontinuation
  • 1995-03-15 CA CA002162916A patent/CA2162916A1/fr not_active Abandoned
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  • 1995-03-15 JP JP7523852A patent/JPH08510476A/ja active Pending
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