Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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

Definitions

• the present invention relates to new 1,4-disubstituted piperidine derivatives having the general formula (I) :
• X is hydroxymethylene or methoxymethylene
• Y is a 3- membered methylene sequence
• R is a p-fluorophenyl group, as well as their pharmaceutically acceptable addition salts.
• THF Tetrahydrofuran is then formed, which enables to be handled safe from dialkylation in subsequent synthesis steps.
• the reduction of N-tert-butoxycarbonyl derivative with sodium borohydride in ethanol provides the corresponding secondary alcohol (IV) .
• Its methylation with iodomethane in the presence of a strong base in an ether-like solvent leads to the methoxy-derivative (V) .
• the strong base and the choice ether-like solvent are sodium hydride and tetrahydrofuran respectively.
• the following step is the unprotected reaction of (V) in acid medium. This reaction occurs conveniently by dissolving hydrogen chloride in a mixture of water and ethanol.
• US Patent No. 4588728 describes the treatment of psychosis with cis-9- [3- (3,5-dimethyl-piperazinyl) ropyl]carbazole.
• US Patent No. 4709094 describes the preparation of 1,3- disubstituted guanidines as well as their utility in the diagnosis and treatment of hallucinations associated with psychotic disorders and chronic mental depression.
• US Patent No. 5175174 describes the preparation of N-phenyl-piperidyl-4-a ine derivatives and their use as Class III antiarryhthmic agents, potassium channel blockers, antipsychotics, anticonvulsants and neuroprotectors.
• US Patent No. 5158947 describes the preparation of N-piperidyl-alkyl-benzazepine derivatives and their utility for the treatment of psychoneurosis.
• US Patent No. 5116995 describes the preparation of 4- (aminoalkyl) - carbazole and their use as antipsychotics.
• the closest compound to the compounds of this invention is 4- (p-fluorobenzoyl) -1- (3-p-fluorophenoxy)propylpiperidine (II), which is described in US Patent No. 3576810 (1971) .
• the compounds generically disclosed therein are claimed to be useful as tranquilizers, and as such, they show antianxiety activity. Obviously, no indication of a possible effect on sigma-receptors is given in this patent, insomuch as this term was introduced later on.
• a 2-nM solution of radioactive 3-PPP ((+) [ 3 H] 3- [3-hydroxyphenyl] -N- (1-propyl) -piperidine) , which acts as a specific ligand, was incubated with the membrane corresponding to 40 mg of guinea-pig total brain for 90 min at 25°C buffered at pH 8.5 with Tris.HCl. Thus, total binding of ligand to membranes was attained. Non-specific binding was then determined by adding a micromolar concentration of unlabelled 3-PPP. IC J0 values (inhibitory concentration 50%) were calculated from the inhibition rate of the specific binding obtained by adding eleven different concentrations of the compounds to be tested. After the incubation was completed, the samples were filtered through a glass fiber filter and then washed three times with Tris.HCl buffer. The amount of receptor-bound radioactivity was retained on the membrane and determined by liquid scintillation counting.
• D-, receptors A 2-nM solution of radioactive spiperone ( [ 3 H]spiperone) , which acts as a specific ligand, was incubated with the membrane corresponding to 20 mg of rat striatum for 20 min at 35°C buffered at pH 7.4 with Tris.HCl. The non-specific binding was then determined by addition of a micromolar concentration of unlabelled spiperone. IC J0 (inhibitory concentration 50%) was calculated from the inhibition rate of the specific binding obtained by addition of eleven different concentrations of the compounds to be tested. After the incubation was completed, the sample was filtered through a glass fiber filter and then washed three times with Tris.HCl buffer. The amount of receptor-bound radioactivity was retained on the membrane and determined by liquid scintillation counting.
• Stereotypy inhibition test Male Sprague-Dawley rats, weighing 200-300 g were used. The animals were weighed and then placed in individual transparent boxes. At time 0 the compounds to be tested were administered intraperitoneally. 0.25% agar was used as vehicle. After 30 min, apomorphine was injected subcutaneously at a dose of 1.5 mg/kg in a concentration of 0.6 mg/ l.
• stereotypy was scored from (-) to (+++) according to the following criteria: (-) absence of stereotypy or any abnormal movement; (+) presence of slight stereotyped movements of the head and intermittent sniffing; (++) intense movements of the head, mild licking interspersed with sniffing; and (+++) intense licking and/or gnawing. Results are expressed as ED 50 in mg/kg for a better quantification.
• Irwin test It consists in a package of tests intended to find out the properties of a compound as well as the magnitude of such properties which are completely unknown.
• the experimental results obtained suggest that the compounds of the invention can be useful in the treatment of sigma receptor-related nervous system diseases, and especially in anoxia, anxiety, convulsions, dyskinesia, drug addiction, schizophrenia, hypoxia, cerebral ischemia, mania, psychosis and stress.
• the compounds can be administered in combination with suitable vehicles via the oral, rectal or parenteral routes. These compounds are administered in doses ranging from 0.5 up to 100 mg per day, more preferably from 1 up to 30 mg per day.
• IR (KBr, cm “1 ): 3300-3700, 2400-2800, 1690, 1600, 1510, 1230.
• NMR (d ⁇ -D SO) : 2.0 (m, 4 H) ; 2.2 (m, 2 H) ; 3.15 (m, 2 H) ; 3.20 ( , 2 H) ; 3.6 (da, 2 H) ; 3.75 (m, 1 H) ; 4.05 (t, 2 H);6.98 (m, 2 H) ; 7.14 (t, 2 H) ; 7.4 (t, 2 H) ; 8.15 (dd, 2 H) .

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Neurosurgery (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Hydrogenated Pyridines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

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Family Cites Families (6)

• 1993
  • 1993-05-18 ES ES09301062A patent/ES2066721B1/es not_active Expired - Fee Related
• 1994
  • 1994-04-22 TW TW083103579A patent/TW252975B/zh active
  • 1994-05-03 ZA ZA943036A patent/ZA943036B/xx unknown
  • 1994-05-17 AU AU69284/94A patent/AU675332B2/en not_active Ceased
  • 1994-05-17 WO PCT/EP1994/001594 patent/WO1994026712A1/en not_active Application Discontinuation
  • 1994-05-17 JP JP6524990A patent/JPH07509255A/ja active Pending
  • 1994-05-17 NZ NZ267100A patent/NZ267100A/en unknown
  • 1994-05-17 KR KR1019950700196A patent/KR950702535A/ko not_active Application Discontinuation
  • 1994-05-17 EP EP94917641A patent/EP0651744A1/en not_active Withdrawn
  • 1994-05-17 CA CA002140260A patent/CA2140260A1/en not_active Abandoned
• 1995
  • 1995-01-06 NO NO950062A patent/NO301638B1/no unknown
  • 1995-01-17 FI FI950197A patent/FI950197A0/fi not_active Application Discontinuation

Non-Patent Citations (1)

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