WO1993014076A1 - Piperazine derivatives as 5-ht receptors antagonists - Google Patents

Piperazine derivatives as 5-ht receptors antagonists Download PDF

Info

Publication number
WO1993014076A1
WO1993014076A1 PCT/GB1992/002399 GB9202399W WO9314076A1 WO 1993014076 A1 WO1993014076 A1 WO 1993014076A1 GB 9202399 W GB9202399 W GB 9202399W WO 9314076 A1 WO9314076 A1 WO 9314076A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
cwhere
lower alkyl
Prior art date
Application number
PCT/GB1992/002399
Other languages
French (fr)
Inventor
Ian Anthony Cliffe
Original Assignee
John Wyeth & Brother Limited
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 John Wyeth & Brother Limited filed Critical John Wyeth & Brother Limited
Priority to EP93900365A priority Critical patent/EP0620817B1/en
Priority to JP51221993A priority patent/JP3274865B2/en
Priority to KR1019940702344A priority patent/KR100283345B1/en
Priority to DE69229834T priority patent/DE69229834T2/en
Priority to RU94039542A priority patent/RU2128653C1/en
Priority to US08/256,330 priority patent/US5532242A/en
Priority to BR9207030A priority patent/BR9207030A/en
Priority to AU31697/93A priority patent/AU668901B2/en
Publication of WO1993014076A1 publication Critical patent/WO1993014076A1/en
Priority to FI943247A priority patent/FI106200B/en

Links

Classifications

    • 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
    • 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
    • A61P25/22—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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to piperazine derivatives, to processes for their preparation, to their use and to pharmaceutical compositions containing them.
  • the novel compounds act on the central nervous system by binding to 5-HT receptors (as more fully explained below) and hence can be used as medicaments for treating humans and other mammals.
  • novel compounds of the invention are those of the general formula
  • A is an alkylene chain of 2 to 5 carbon atoms optionally substituted by one or more lower alkyl groups,
  • R is a monocyclic aryl or heteroaryl radical
  • R is cycloalkyl.
  • the term "lower” as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of “lower alkyl” radicals are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and isopentyl.
  • a cycloalkyl group can contain 3 to 12 carbon atoms.
  • a cycloalkyl group is cyclopentyl, cyclohexyl or cycloheptyl, most preferably cyclohexyl.
  • Cycloalkyl groups also include bicyclic, tricyclic and tetracyclic groups, eg adamantyl.
  • a monocyclic aryl radical means a phenyl radical which optionally may be substituted by one or more substituents and "a mono or bicyclic aryl radical” means an aromatic radical having 6 to 12 carbon atoms Ceg phenyl or naphthyl) which optionally may be substituted by one or more substituents.
  • Preferred substituents are lower alkyl, lower alkoxy Ceg methoxy, ethoxy, propoxy, butoxy), halogen, haloClower)alkyl Ceg trifluoromethyl) , nitro, nitrile, amido, lower)alkoxycarbonyl, a ino, Clower)alkylaitu.no or di lower)alkylamino substituents.
  • R is a phenyl radical containing a substituent in the ortho position.
  • a particularly pprreeffeerrrreedd eexxaammpple of R is o- lower)alkoxyphenyl eg o-methoxyphenyl
  • R is an optionally substituted phenyl radical.
  • monocyclic heteroaryl radical refers to a monocyclic aromatic radical containing one or more hetero atoms (eg oxygen, nitrogen, sulphur) and which may be optionally substituted by one or more substituents. ' Examples of suitable substituents are given above in connection with “aryl” radicals.
  • the monocyclic heteroaryl radical contains 5 to 7 ring atoms.
  • the hetero ring contains a nitrogen hetero atom with or without one or more further hetero atoms.
  • R is a heteroaryl radical it is preferably an optionally substituted pyrimidyl (particularly 2-pyrimidyl) radical.
  • Preferred compounds have the following substituents either independently or in combination:-
  • A is CCH 2 ) 2 -, -CCH 2 ) 3 - or -CCH 2 ) 4 *
  • R is o-methoxyphenyl
  • R is phenyl
  • the compounds of the invention may be prepared by methods known in the art from known starting materials or starting materials that may be prepared by conventional methods .
  • One method of preparing the compounds of the invention comprises acylating an amine of formula
  • acylating derivatives include the acid halides Ceg acid chlorides) azides, anhydrides, imidazolides Ceg obtained from carbonyldii idazole) , activated esters or O-acyl ureas obtained from a carbodiimide such as a dialkylcarbodiimide particularly . cyclohexylcarbodiimide.
  • the starting amine of formula CII) may -be prepared by a process such as that exemplified below:
  • Hal is halo, particularly chloro or bromo and A is an alkylene chain of 1 to 3 carbon atoms optionally substituted by one or more lower alkyl groups).
  • the reduction may be carried out with, for example, a boron reducing agent eg borane-dimethyl sulphide.
  • a second method of preparing the compounds of the invention comprises alkylating an amide of formula CIV)
  • the alkylating agent may be, for example, a compound of formula
  • A, R and R are as defined above and X is a leaving group such as halogen or an alkyl - or aryl-sulphonyloxy group.
  • a third method of preparing the compounds of the invention comprises alkylating a compound of formula
  • the starting compound of formula CV may, for example, be prepared as exemplified below
  • R is a group that is activated towards nucleophilic substitution
  • the compounds of the invention may be prepared by a further method which comprises reacting the appropriate fluoro compound of formula R F with a piperazine compound of formula
  • the processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds .
  • acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic, p-toluenesulphonic, oxalic and succinic acids.
  • the compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different steroisomeric forms.
  • the compounds can be, for example, racemates or optically active forms.
  • the optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
  • the compounds of the present invention possess pharmacological activity. In particular, they act on the central nervous system by binding to 5-HT receptors. In pharmacological testing it has been shown that the compounds particularly bind to receptors of the 5-HT- A type. In general, the compounds selectively bind to receptors of the 5-HT. type to a much greater extent than they bind to other receptors such as ⁇ . and D_ receptors. Many exhibit activity as 5-HT 1A antagonists in pharmacological testing.
  • the compounds of the invention can be used for the treatment of CNS disorders, such as anxiety in mammals, particularly humans. They may also be used as antidepressants, hypotensives, as agents for regulating the sleep/wake cycle, feeding behaviour and/or sexual function and for treating cognition disorders.
  • the compounds of the invention were tested for 5-HT, A receptor binding activity in rat hippocampal membrane homogenate by the method of B S Alexander and M D Wood, J Pharm Pharmacol, 1988, 4_0, 888-891.
  • Example 2 which is a representative compound of the invention, had a IC-.., of 4 nM in this test procedure.
  • the compounds are tested for 5-HT. , receptor antagonism activity in a test involving the antagonism of
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier Any suitable carrier known in the art can be used to prepare the pharmaceutical composition.
  • the carrier is generally a solid or liquid or a mixture of a solid or liquid.
  • Solid form compositions include powders, granules, tablets, capsules Ceg hard and soft gelatine capsules), suppositories and pessaries.
  • a solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl 15 cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • composition is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the 20 active ingredient Cwith or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.
  • Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and
  • the active ingredient for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • liquid carriers for oral and parenteral administration include water Cparticularly containing additives as above, eg cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols Ceg glycerol and glycols) and their derivatives, and oils Ceg fractionated coconut oil and arachis oil).
  • the 0 carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions which are sterile --* solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid 0 composition form.
  • the pharmaceutical composition is in unit dosage form, eg as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the ⁇ nit dosage forms can be packaged composition, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquid.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient.
  • Example 1 illustrates the preparation of an intermediate.

Abstract

Compounds of formula (I) where A is an alkylene chain of 2 to 5 carbon atoms optionally substituted by one or more lower alkyl groups, R represents hydrogen or one or two same or different lower alkyl groups, R1 is a monocyclic aryl or heteroaryl radical, R2 is a mono or bicycle aryl radical and R3 is cycloalkyl and the pharmaceutically acceptable acid addition salts are novel. They are 5-HT¿1A?-antagonists which may be used, for example, in treating anxiety.

Description

PIPERAZI E DERIVATIVES AS 5-HT RECEPTORS ANTAGONISTS
This invention relates to piperazine derivatives, to processes for their preparation, to their use and to pharmaceutical compositions containing them. The novel compounds act on the central nervous system by binding to 5-HT receptors (as more fully explained below) and hence can be used as medicaments for treating humans and other mammals.
The novel compounds of the invention are those of the general formula
Figure imgf000003_0001
and the pharmaceutically acceptable acid addition salts thereof.
In formula CI)
A is an alkylene chain of 2 to 5 carbon atoms optionally substituted by one or more lower alkyl groups,
R-represents hydrogen or one or two same or different lower alkyl groups,
R is a monocyclic aryl or heteroaryl radical,
2 R is a mono or bicyclic aryl radical
3 and R is cycloalkyl. The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of "lower alkyl" radicals are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and isopentyl.
A cycloalkyl group can contain 3 to 12 carbon atoms. Preferably a cycloalkyl group is cyclopentyl, cyclohexyl or cycloheptyl, most preferably cyclohexyl. Cycloalkyl groups also include bicyclic, tricyclic and tetracyclic groups, eg adamantyl.
When used herein "a monocyclic aryl radical" means a phenyl radical which optionally may be substituted by one or more substituents and "a mono or bicyclic aryl radical" means an aromatic radical having 6 to 12 carbon atoms Ceg phenyl or naphthyl) which optionally may be substituted by one or more substituents. Preferred substituents are lower alkyl, lower alkoxy Ceg methoxy, ethoxy, propoxy, butoxy), halogen, haloClower)alkyl Ceg trifluoromethyl) , nitro, nitrile, amido, lower)alkoxycarbonyl, a ino, Clower)alkylaitu.no or di lower)alkylamino substituents.
Preferably R is a phenyl radical containing a substituent in the ortho position. A particularly pprreeffeerrrreedd eexxaammpple of R is o- lower)alkoxyphenyl eg o-methoxyphenyl
2 Preferably R is an optionally substituted phenyl radical.
The term "monocyclic heteroaryl radical" refers to a monocyclic aromatic radical containing one or more hetero atoms (eg oxygen, nitrogen, sulphur) and which may be optionally substituted by one or more substituents.' Examples of suitable substituents are given above in connection with "aryl" radicals. Preferably the monocyclic heteroaryl radical contains 5 to 7 ring atoms. Preferably the hetero ring contains a nitrogen hetero atom with or without one or more further hetero atoms. When R is a heteroaryl radical it is preferably an optionally substituted pyrimidyl (particularly 2-pyrimidyl) radical.
Preferred compounds have the following substituents either independently or in combination:-
Ca) A is CCH2)2-, -CCH2)3- or -CCH2)4*
Cb) R is hydrogen
Cc) R is o-methoxyphenyl
2
Cd) R is phenyl
Ce) R is cyclohexyl
The compounds of the invention may be prepared by methods known in the art from known starting materials or starting materials that may be prepared by conventional methods .
One method of preparing the compounds of the invention comprises acylating an amine of formula
Figure imgf000006_0001
\ /
1 2 Cwhere A, R, R and R have the meanings given above) with an acid of formula
R3COOH CIII)
Cwhere R is as defined above) or with an acylating derivative thereof. Examples of acylating derivatives include the acid halides Ceg acid chlorides) azides, anhydrides, imidazolides Ceg obtained from carbonyldii idazole) , activated esters or O-acyl ureas obtained from a carbodiimide such as a dialkylcarbodiimide particularly . cyclohexylcarbodiimide.
The starting amine of formula CII) may -be prepared by a process such as that exemplified below:
Figure imgf000006_0002
R 1-N N-A--CONHR2 reduction
N-A-NHR
Figure imgf000006_0003
Cwhere R, R1, R2 and A are as defined above, Hal is halo, particularly chloro or bromo and A is an alkylene chain of 1 to 3 carbon atoms optionally substituted by one or more lower alkyl groups). The reduction may be carried out with, for example, a boron reducing agent eg borane-dimethyl sulphide.
A second method of preparing the compounds of the invention comprises alkylating an amide of formula CIV)
R2
I 3 HN.COR CIV)
with an alkylating agent providing the group
Figure imgf000007_0001
The alkylating agent may be, for example, a compound of formula
Figure imgf000007_0002
where A, R and R are as defined above and X is a leaving group such as halogen or an alkyl - or aryl-sulphonyloxy group.
A third method of preparing the compounds of the invention comprises alkylating a compound of formula
Figure imgf000008_0001
with a compound of formula
χ_A—NR2.CO.R3 CV)
Cwhere A, R, R 1,R2 and R3 and X are as defined above).
The starting compound of formula CV) may, for example, be prepared as exemplified below
X-A-Br + NHR2COR3 » CV)
Where R is a group that is activated towards nucleophilic substitution the compounds of the invention may be prepared by a further method which comprises reacting the appropriate fluoro compound of formula R F with a piperazine compound of formula
Figure imgf000008_0002
The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds .
Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic, p-toluenesulphonic, oxalic and succinic acids.
The compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different steroisomeric forms. The compounds can be, for example, racemates or optically active forms. The optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
The compounds of the present invention possess pharmacological activity. In particular, they act on the central nervous system by binding to 5-HT receptors. In pharmacological testing it has been shown that the compounds particularly bind to receptors of the 5-HT-A type. In general, the compounds selectively bind to receptors of the 5-HT. type to a much greater extent than they bind to other receptors such as α. and D_ receptors. Many exhibit activity as 5-HT1A antagonists in pharmacological testing. The compounds of the invention can be used for the treatment of CNS disorders, such as anxiety in mammals, particularly humans. They may also be used as antidepressants, hypotensives, as agents for regulating the sleep/wake cycle, feeding behaviour and/or sexual function and for treating cognition disorders.
The compounds of the invention were tested for 5-HT,A receptor binding activity in rat hippocampal membrane homogenate by the method of B S Alexander and M D Wood, J Pharm Pharmacol, 1988, 4_0, 888-891.
The compound of Example 2 which is a representative compound of the invention, had a IC-.., of 4 nM in this test procedure.
The compounds are tested for 5-HT. , receptor antagonism activity in a test involving the antagonism of
5-carboxamidotryptamine in the guinea-pig ileum in vitro Cbased upon the procedure of Fozard et al, Br J Pharmac, 1985, ^6, 601P). The results for compounds of the invention are given below. The compound of Example 2 had a pA-, of 8.2.
The invention also provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid or a mixture of a solid or liquid.
Solid form compositions include powders, granules, tablets, capsules Ceg hard and soft gelatine capsules), suppositories and pessaries. A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up
10 to 99%, eg from 0.03 to 99%, preferably 1 to 80% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl 15 cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the 20 active ingredient Cwith or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.
Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and
25 pressurised compositions. The active ingredient, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid
•*-(*' carrier can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water Cparticularly containing additives as above, eg cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols Ceg glycerol and glycols) and their derivatives, and oils Ceg fractionated coconut oil and arachis oil). For parenteral administration the 0 carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile --* solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid 0 composition form.
Preferably the pharmaceutical composition is in unit dosage form, eg as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the μnit dosage forms can be packaged composition, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquid. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient.
The following Examples illustrate the invention. Example 1 illustrates the preparation of an intermediate.
Example 1
N-Phenyl cyclohexane carboxamide
Cyclohexanecarbonyl chloride C14.66 g, 0.1 mol) was added dropwise to a stirred solution of aniline hydrochloride C12.96 g 0.1 mol) and N, N- diisopropylethylamine C15.20 g, 0.2 mol) in dichloromethane C100 ml). The solution was stirred under an atmosphere of argon for 18 h, washed with 0.1 N-HCl C3 x 50 ml) and dilute sodium hydrogen carbonate solution C50 ml), dried CMgSO.), and evaporated ij vacuo to give the product C18.6 g) as white crystals.
Example 2
N- 2-C4-C2-Methoxyphenyl)piperazin-l- yl)ethyl)-N-phenylc clohexanecarboxamide
A solution of the product of example 1 C2.03 g, 0.1 mol) in DMF C50 ml) was added dropwise to a suspension of potassium hydride, 35% dispersion in mineral oil 1.2 g, 0.011 mol) in DMF C20 ml). The suspension was stirred for 2 h, treated with l-C2-chloroethyl)-4-C2- methoxyphenyDpiperazine C2.53 g, 0.01 mol) stirred for 5 h at 80 C, cooled to room temperature, basified with dilute potassium carbonate solution, and evaporated in vacuo. The residue was dissolved in water C200 ml) and the solution extracted with ether C3 x 100 ml). The extracts were washed with water C100 ml), dried
CMgSO,), and evaporated in vacuo to give an oil which was purified by chromatography [silica; ethyl acetate-toluene C1:D] to give the product CO.41 g) as a yellow oil. Addition of ethereal hydrogen chloride and evaporation gave the dihydrochloride salt of the product as a white solid, m.p. 118-123°C. CFound: C, 62.6; H, 7.8; N, 8.2. C26H35N3°2" 2HCl.iH20 requires ,C, 62.6; H, 7.6; N, 8.4%).

Claims

1. A compound of the general formula
Figure imgf000016_0001
or a pharmaceutically acceptable acid addition salt thereof wherein
A is an alkylene chain of 2 to 5 carbon atoms optionally substituted by one or more lower alkyl groups,
R represents hydrogen or one or two same or different lower alkyl groups,
R is a monocyclic aryl or heteroaryl radical,
R 2 is a mono or bicyclic aryl radical
and R is cycloalkyl.
2. A compound as claimed in claim 1 in which A is - CH2 2-, -CCH2)3- or -CCH.,^-.
3. A compound as claimed in claim 1 or 2 in which R is o-methoxyphenyl.
4. A compound as claimed in any one of claims 1 to 3 in which R 2 i•s phenyl.
5. A compound as claimed in any one of claims 1 to 4 in which R is cyclohexyl.
6. A compound as claimed in claim 1 which is N-C2-C4-C2-methoxyphenyl)piperazin-1-yl)ethyl)-N- phenylcyclohexanecarboxamide or a pharmaceutically acceptable acid addition salt thereof.
7. A process for preparing a compound claimed in claim 1 which comprises
Ca) acylating an amine of formula CII)
Figure imgf000017_0001
Cwhere A, R, R 1 and R2 have the meanings defined in claim 1)
with an acid of formula
R3COOH (III)
Cwhere R is as defined in claim 1) or with an acylating derivative thereof
or
Cb) alkylating an amide of formula CIV)
Figure imgf000017_0002
- ~i
Cwhere R and are as defined in claim 1) with an alkylating agent providing the group
Figure imgf000018_0001
V_/
Cwhere A, R and R are as defined in claim 1)
or
Cc) alkylating a compound* of formula
Figure imgf000018_0002
with a compound of formula
X-A—NR2.CO.R3
Cwhere A, R 2 and R3 are as defined in claim 1 and X is a leaving group)
or
Cd) resolving a racemic compound claimed in claim 1 into an enantiomer
or
Ce) converting a base claimed in claim 1 into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable salt into the free base.
8. A pharmaceutical composition comprising a compound- claimed in claim 1 in association with a pharmaceutically acceptable carrier.
9. A pharmaceutical composition as claimed in claim 8 in which the compound is prepared by the process claimed in claim 7.
10. A process for preparing a pharmaceutical composition which comprises bringing a compound claimed in claim 1 into association with a pharmaceutically acceptable carrier.
11. A compound as claimed in claim 1 for use as a 5-HT-A antagonist.
12. A compound as claimed in claim 1 for use as an antidepressant, hypotensive, an agent for regulating the sleep/wake cycle, feeding behaviour or sexual function or for treating anxiety or cognition disorders.
PCT/GB1992/002399 1992-01-08 1992-12-24 Piperazine derivatives as 5-ht receptors antagonists WO1993014076A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP93900365A EP0620817B1 (en) 1992-01-08 1992-12-24 Piperazine derivatives as 5-ht receptors antagonists
JP51221993A JP3274865B2 (en) 1992-01-08 1992-12-24 Piperazine derivatives as 5-HT receptor antagonists
KR1019940702344A KR100283345B1 (en) 1992-01-08 1992-12-24 Piperazine Derivatives as 5-HT Receptor Antagonists, Methods for Making the Same, and Pharmaceutical Compositions Comprising the Same
DE69229834T DE69229834T2 (en) 1992-01-08 1992-12-24 PIPERAZINE DERIVATIVES AS 5-HT RECEPTOR ANTAGONISTS
RU94039542A RU2128653C1 (en) 1992-01-08 1992-12-24 Piperazine derivatives, method of their synthesis, pharmaceutical composition
US08/256,330 US5532242A (en) 1992-01-08 1992-12-24 Piperazine derivatives as 5-HT receptors antagonists
BR9207030A BR9207030A (en) 1992-01-08 1992-12-24 Piperazine derivatives as 5-HT receptor antagonists
AU31697/93A AU668901B2 (en) 1992-01-08 1992-12-24 Piperazine derivatives as 5-HT receptors antagonists
FI943247A FI106200B (en) 1992-01-08 1994-07-07 A process for the preparation of therapeutically useful piperazine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929200293A GB9200293D0 (en) 1992-01-08 1992-01-08 Piperazine derivatives
GB9200293.0 1992-01-08

Publications (1)

Publication Number Publication Date
WO1993014076A1 true WO1993014076A1 (en) 1993-07-22

Family

ID=10708249

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1992/002399 WO1993014076A1 (en) 1992-01-08 1992-12-24 Piperazine derivatives as 5-ht receptors antagonists

Country Status (21)

Country Link
US (1) US5532242A (en)
EP (1) EP0620817B1 (en)
JP (1) JP3274865B2 (en)
KR (1) KR100283345B1 (en)
AT (1) ATE183504T1 (en)
AU (1) AU668901B2 (en)
BR (1) BR9207030A (en)
CA (1) CA2125182A1 (en)
DE (1) DE69229834T2 (en)
ES (1) ES2134835T3 (en)
FI (1) FI106200B (en)
GB (2) GB9200293D0 (en)
HU (1) HUT70513A (en)
IL (1) IL104305A (en)
MX (1) MX9300031A (en)
NZ (1) NZ246205A (en)
PH (1) PH30268A (en)
RU (1) RU2128653C1 (en)
TW (1) TW265337B (en)
WO (1) WO1993014076A1 (en)
ZA (1) ZA93141B (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995024218A1 (en) * 1994-03-11 1995-09-14 The Trustees Of The University Of Pennsylvania Serotonin (5-ht1a) receptor ligands and imaging agents
US5451584A (en) * 1994-11-10 1995-09-19 American Home Products Corporation N-alkynyl carboxamides as sertonergic agents
US5541179A (en) * 1995-05-02 1996-07-30 American Home Products Corporation Tropon-2-one piperazine carboxamides as serotonergic agents
WO2002000259A1 (en) * 2000-06-27 2002-01-03 Taisho Pharmaceutical Co., Ltd. Remedial agent for anxiety neurosis or depression and piperazine derivative
US7737128B2 (en) 2004-06-10 2010-06-15 The Mclean Hospital Corporation Pyrimidines, such as uridine, in treatments for patients with bipolar disorder
US7863254B2 (en) 2000-03-16 2011-01-04 The Mclean Hospital Corporation Compounds for the treatment of psychiatric or substance abuse disorders
US7947661B2 (en) 2004-08-11 2011-05-24 The Mclean Hospital Corporation Compounds for the treatment of marihuana dependence, withdrawal, and usage
USRE43688E1 (en) 2006-01-25 2012-09-25 The Regents Of The University Of California Compositions and methods related to serotonin 5-HT1A receptors
CN103360342A (en) * 2012-04-09 2013-10-23 江苏恩华药业股份有限公司 3-Cyanoaniline alkyl aryl piperazine derivative and application in preparing medicaments

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE236882T1 (en) * 1992-12-21 2003-04-15 Smithkline Beecham Corp BICYCLIC FIBRINOGEN ANTAGONISTS
HUP9901680A3 (en) 1996-04-05 2000-12-28 Sod Conseils Rech Applic Use of piperazin-, piperidin- or hexahidropiridazin derivatives for the preparation of pharmaceutical compositions, new piperazin derivatives and pharmaceutical compositions containing these compounds
US5610164A (en) * 1996-07-24 1997-03-11 American Home Products Corporation (Thiophen-2-yl)-piperidin or tetrahydropyridin azabicyclocarboxamides
US6399614B1 (en) 1997-08-01 2002-06-04 Recordati S.A. Chemical And Pharmaceutical Company 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring
IT1293807B1 (en) * 1997-08-01 1999-03-10 Recordati Chem Pharm 1- (N-PHENYLAMINOALKYL) PIPERAZINE DERIVATIVES SUBSTITUTED AT POSITION 2 OF THE PHENYL RING
IT1293804B1 (en) 1997-08-01 1999-03-10 Recordati Chem Pharm DIARYLALKYL PIPERAZINS ACTIVE ON LOW URINARY TRACT
US6344458B1 (en) 1998-12-17 2002-02-05 American Home Products Corporation Piperazine ethylamide derivatives
BR9916263A (en) * 1998-12-17 2001-09-04 American Home Prod Piperazine ethylamide derivatives with activity on the 5-ht1a receptor
AR059898A1 (en) * 2006-03-15 2008-05-07 Janssen Pharmaceutica Nv DERIVATIVES OF 3-CIANO-PIRIDONA 1,4-DISUSTITUTED AND ITS USE AS ALLOSTERIC MODULATORS OF MGLUR2 RECEIVERS
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
TW200845978A (en) * 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
KR20100065191A (en) 2007-09-14 2010-06-15 오르토-맥닐-얀센 파마슈티칼스 인코포레이티드 1,3-disubstituted 4-(aryl-x-phenyl)-1h-pyridin-2-ones
CN101801951B (en) 2007-09-14 2013-11-13 杨森制药有限公司 1',3'-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2h, 1'h-[1, 4'] bipyridinyl-2'-ones
TW200927731A (en) * 2007-09-14 2009-07-01 Ortho Mcneil Janssen Pharm 1,3-disubstituted-4-phenyl-1H-pyridin-2-ones
ES2637794T3 (en) * 2007-11-14 2017-10-17 Janssen Pharmaceuticals, Inc. Imidazo [1,2-A] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
RU2510396C2 (en) 2008-09-02 2014-03-27 Янссен Фармасьютикалз, Инк. 3-azabicyclo[3,1,0]hexyl derivatives as modulators of metabotropic glutamate receptors
BRPI0920354A2 (en) 2008-10-16 2017-06-27 Addex Pharmaceuticals Sa indole and benzomorpholine derivatives as metabotropic glutamate receptor modulators
AU2009319387B2 (en) 2008-11-28 2012-05-10 Addex Pharma S.A. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
RS53075B (en) 2009-05-12 2014-04-30 Janssen Pharmaceuticals Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use for the treatment or prevention of neurological and psychiatric disorders
JP5707390B2 (en) 2009-05-12 2015-04-30 ジャンセン ファーマシューティカルズ， インコーポレイテッド 1,2,4-Triazolo [4,3-a] pyridine derivatives and their use as positive allosteric modulators of the mGluR2 receptor
WO2011027656A1 (en) 2009-09-04 2011-03-10 Semiconductor Energy Laboratory Co., Ltd. Transistor and display device
EP2649069B1 (en) 2010-11-08 2015-08-26 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
EP2643320B1 (en) 2010-11-08 2015-03-04 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
EP2661435B1 (en) 2010-11-08 2015-08-19 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
JO3368B1 (en) 2013-06-04 2019-03-13 Janssen Pharmaceutica Nv 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
JO3367B1 (en) 2013-09-06 2019-03-13 Janssen Pharmaceutica Nv 1,2,4-TRIAZOLO[4,3-a]PYRIDINE COMPOUNDS AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
DK3431106T3 (en) 2014-01-21 2021-03-15 Janssen Pharmaceutica Nv COMBINATIONS INCLUDING POSITIVE ALLOSTERIC MODULATORS OR ORTHOSTERIC AGONISTS OF METABOTROP GLUTAMATERG SUBTYPE 2 RECEPTOR AND USE OF THESE
ES2860298T3 (en) 2014-01-21 2021-10-04 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators of metabotropic glutamatergic receptor subtype 2 and their use

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3037982A (en) * 1959-08-12 1962-06-05 Miles Lab Phenylpiperazinylalkyl propionanilides
EP0015615A1 (en) * 1979-03-01 1980-09-17 Duphar International Research B.V Phenyl piperazine derivatives, their preparation and antiagressive medicines containing them
EP0048043A1 (en) * 1980-09-12 1982-03-24 Duphar International Research B.V Phenyl piperazine derivatives having analgetic activity
EP0048045A1 (en) * 1980-09-12 1982-03-24 Duphar International Research B.V Phenyl piperazine derivatives having antiagressive activity
EP0343961A2 (en) * 1988-05-24 1989-11-29 American Home Products Corporation Aryl- and heteroaryl piperazinyl carboxamides having central nervous system activity
EP0496692A1 (en) * 1991-01-24 1992-07-29 Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. (Faes) 2-Methoxyphenylpiperazine derivatives

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0185429A1 (en) * 1984-12-21 1986-06-25 Duphar International Research B.V New bicyclic heteroaryl piperazines
US5010078A (en) * 1988-05-24 1991-04-23 American Home Products Corporation Aryl- and heteroaryl piperazinyl carboxamides having central nervous system activity
GB8909209D0 (en) * 1989-04-22 1989-06-07 Wyeth John & Brother Ltd Piperazine derivatives
US5340812A (en) * 1989-04-22 1994-08-23 John Wyeth & Brother, Limited Piperazine derivatives
KR0173310B1 (en) * 1989-04-22 1999-02-01 폴 에이 리쳐 Piperazine derivatives, their preparation method and pharmaceutical composition comprising thereof
FR2655988B1 (en) * 1989-12-20 1994-05-20 Adir Cie NOVEL DERIVATIVES OF NAPHT-1-YL PIPERAZINE, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
DK178590D0 (en) * 1990-07-26 1990-07-26 Novo Nordisk As 1,4-DISUBSTITUTED PIPERAZINES

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3037982A (en) * 1959-08-12 1962-06-05 Miles Lab Phenylpiperazinylalkyl propionanilides
EP0015615A1 (en) * 1979-03-01 1980-09-17 Duphar International Research B.V Phenyl piperazine derivatives, their preparation and antiagressive medicines containing them
EP0048043A1 (en) * 1980-09-12 1982-03-24 Duphar International Research B.V Phenyl piperazine derivatives having analgetic activity
EP0048045A1 (en) * 1980-09-12 1982-03-24 Duphar International Research B.V Phenyl piperazine derivatives having antiagressive activity
EP0343961A2 (en) * 1988-05-24 1989-11-29 American Home Products Corporation Aryl- and heteroaryl piperazinyl carboxamides having central nervous system activity
EP0496692A1 (en) * 1991-01-24 1992-07-29 Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. (Faes) 2-Methoxyphenylpiperazine derivatives

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5609849A (en) * 1994-03-11 1997-03-11 The Trustees Of The University Of Pennsylvania Serotonin (5-HT1A) receptor ligands and imaging agents
US5744121A (en) * 1994-03-11 1998-04-28 The Trustees Of The University Of Pennsylvania Serotonin (5-HT1A) receptor ligands and imaging agents
WO1995024218A1 (en) * 1994-03-11 1995-09-14 The Trustees Of The University Of Pennsylvania Serotonin (5-ht1a) receptor ligands and imaging agents
US5451584A (en) * 1994-11-10 1995-09-19 American Home Products Corporation N-alkynyl carboxamides as sertonergic agents
US5541179A (en) * 1995-05-02 1996-07-30 American Home Products Corporation Tropon-2-one piperazine carboxamides as serotonergic agents
US7863254B2 (en) 2000-03-16 2011-01-04 The Mclean Hospital Corporation Compounds for the treatment of psychiatric or substance abuse disorders
US8575219B2 (en) 2000-03-16 2013-11-05 The Mclean Hospital Compounds for the treatment of psychiatric or substance abuse disorders
US8030294B2 (en) 2000-03-16 2011-10-04 The Mclean Hospital Corporation Compounds for the treatment of psychiatric or substance abuse disorders
US6949552B2 (en) 2000-06-27 2005-09-27 Taisho Pharmaceutical Co., Ltd. Remedial agent for anxiety neurosis or depression and piperazine derivative
WO2002000259A1 (en) * 2000-06-27 2002-01-03 Taisho Pharmaceutical Co., Ltd. Remedial agent for anxiety neurosis or depression and piperazine derivative
US7737128B2 (en) 2004-06-10 2010-06-15 The Mclean Hospital Corporation Pyrimidines, such as uridine, in treatments for patients with bipolar disorder
US7947661B2 (en) 2004-08-11 2011-05-24 The Mclean Hospital Corporation Compounds for the treatment of marihuana dependence, withdrawal, and usage
USRE43688E1 (en) 2006-01-25 2012-09-25 The Regents Of The University Of California Compositions and methods related to serotonin 5-HT1A receptors
CN103360342A (en) * 2012-04-09 2013-10-23 江苏恩华药业股份有限公司 3-Cyanoaniline alkyl aryl piperazine derivative and application in preparing medicaments
CN103360342B (en) * 2012-04-09 2015-12-16 江苏恩华药业股份有限公司 3-cyano-aniline alkylaryl bridged piperazine derivatives and preparing the application in medicine

Also Published As

Publication number Publication date
HU9402042D0 (en) 1994-09-28
AU668901B2 (en) 1996-05-23
HUT70513A (en) 1995-10-30
NZ246205A (en) 1996-12-20
RU2128653C1 (en) 1999-04-10
ZA93141B (en) 1994-07-08
TW265337B (en) 1995-12-11
DE69229834T2 (en) 2000-01-13
KR100283345B1 (en) 2001-03-02
MX9300031A (en) 1993-07-01
PH30268A (en) 1997-02-20
GB2263110B (en) 1995-08-09
ES2134835T3 (en) 1999-10-16
DE69229834D1 (en) 1999-09-23
JP3274865B2 (en) 2002-04-15
GB9200293D0 (en) 1992-02-26
IL104305A (en) 1998-04-05
FI943247A (en) 1994-07-07
GB9227001D0 (en) 1993-02-17
US5532242A (en) 1996-07-02
AU3169793A (en) 1993-08-03
CA2125182A1 (en) 1993-07-22
FI106200B (en) 2000-12-15
IL104305A0 (en) 1993-05-13
BR9207030A (en) 1995-12-05
ATE183504T1 (en) 1999-09-15
FI943247A0 (en) 1994-07-07
RU94039542A (en) 1996-08-10
EP0620817B1 (en) 1999-08-18
EP0620817A1 (en) 1994-10-26
GB2263110A (en) 1993-07-14
JPH07502739A (en) 1995-03-23

Similar Documents

Publication Publication Date Title
US5532242A (en) Piperazine derivatives as 5-HT receptors antagonists
US5710149A (en) Piperazine derivatives as 5-ht antagonists
US4882432A (en) Polycyclic-carbamic acid piperazinoalkyl esters and amides
SK280133B6 (en) Piperazine derivatives, method of their preparation, pharmaceutial agent them containing, intermediate, and their use
AU700546B2 (en) Piperazine derivatives and their use as 5-HT1A antagonists
EP0678090B1 (en) Piperazine derivatives
US5430033A (en) Piperazine derivatives
CA2053709C (en) Piperazine derivatives
US5629323A (en) Amide derivatives as 5-HT1A ligands
WO1994003444A1 (en) Amide derivatives
EP0782574B1 (en) Bicyclic carboxamides as 5-ht1a receptors ligands
EP0687257B1 (en) 4-amino-2-(hetero)aryl-butanamides useful as 5-ht1a-antagonists
SK279528B6 (en) Piperazine derivatives, method of their preparation and pharmaceutical compositions them containing

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR CA CS FI HU JP KP KR LK MG MN MW NO NZ PL RO RU SD US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1993900365

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2125182

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 246205

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 943247

Country of ref document: FI

Ref document number: 08256330

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1993900365

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 1993900365

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 943247

Country of ref document: FI