GB2263110A - Pharmaceutically active piperazine derivatives - Google Patents

Pharmaceutically active piperazine derivatives Download PDF

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Publication number
GB2263110A
GB2263110A GB9227001A GB9227001A GB2263110A GB 2263110 A GB2263110 A GB 2263110A GB 9227001 A GB9227001 A GB 9227001A GB 9227001 A GB9227001 A GB 9227001A GB 2263110 A GB2263110 A GB 2263110A
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compound
formula
pharmaceutically acceptable
lower alkyl
compounds
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GB9227001D0 (en
GB2263110B (en
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Ian Anthony Cliffe
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John Wyeth and Brother Ltd
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John Wyeth and Brother Ltd
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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
    • 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

Abstract

Compounds of formula (I> <IMAGE> 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, R<1> is a monocyclic aryl or heteroaryl radical, R<2> is a mono or bicyclic aryl radical and R<3> is cycloalkyl and the pharmaceutically acceptable acid addition salts are novel compounds which are 5-HT1A-antagonists and may be used, for example, in treating anxiety.

Description

PIPERAZINE DERIVATIVES 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
and the pharmaceutically acceptable acid addition salts thereof.
In formula (I) A is an alkylene chain of 2 to 5 carbon atoms optionally substituted by one or more lower alkyl groups2 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 bicyclic aryl radical is and R3 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 (eg phenyl or naphthyl) which optionally may be substituted by one or more substituents.
Preferred substituents are lower alkyl, lower alkoxy (eg methoxy, ethoxy, propoxy, butoxy), halogen, halo(lower)alkyl (eg trifluoromethyl), nitro, nitrile, amido, (lower)alkoxycarbonyl, amino, (lower)alkylamino or di(lower)alkylamino substituents.
Preferably R1 is a phenyl radical containing a substituent in the ortho position. A particularly preferred example of R1 is o-(lower)alkoxyphenyl eg 0-methoxyphenyl.
Preferably R2 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 R1 is a heteroaryl radical is it is preferably an optionally substituted pyrimidyl (particularly 2-pyrimidyl) radical.
Preferred compounds have the following substituents either independently or in combination: (a) A is -CCH2)2-, -(CH2 3 or -CcH2)4 - (b) R is hydrogen (c) R1 is o-methoxyphenyl (d) R2 is phenyl 3 (e) R3 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
(where A, R, R1 and R2 have the meanings given above) with an acid of formula 3 R3COOH (III) 3 (where R3 is as defined above) or with an acylating derivative thereof. Examples of acylating derivatives include the acid halides (eg acid chlorides) azides, anhydrides, imidazolides (eg obtained from carbonyldiimidazole), activated esters or O-acyl ureas obtained from a carbodiimide such as a dialkylcarbodiimide particularly cyclohexylcarbodiimide.
The starting amine of formula (II) may be prepared by a process such as that exemplified below:
(where 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 (IV)
with an alkylating agent providing the group
The alkylating agent may be, for example, a compound of formula
where A, R and R1 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
with a compound of formula X-A-NR2.CO.R3 (V) (where A, R, R1,R2 and R3 and X are as defined above).
The starting compound of formula (V) may, for example, be prepared as exemplified below
Where R1 is a group that is activated towards is nucleophilic substitution the compounds of the invention may be prepared by a further method which comprises reacting the appropriate fluoro compound of formula R1F 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.
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-HT1A type. In general, the compounds selectively bind to receptors of the 5-HT1A type to a much greater extent than they bind to other receptors such as a1 and D2 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-HT1A receptor binding activity in rat hippocampal membrane homogenate by the method of B S Alexander and M D Wood, J Pharm Pharmacol, 1988, 40, 888-891.
The compound of Example 2 which is a representative compound of the invention, had a IC50 of 4 nM in this test procedure.
The compounds are tested for 5-HT1A receptor antagonism activity in a test involving the antagonism of 5-carboxamidotryptamine in the guinea-pig ileum in vitro (based upon the procedure of Fozard et al, Br J Pharmac, 1985, 86, 601P). The results for compounds of the invention are given below. The compound of Example 2 had a pA2 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 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 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 active ingredient (with 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 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 agents3 thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators.
Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, eg cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (eg glycerol and glycols) and their derivatives, and oils (eg fractionated coconut oil and arachis oil). For parenteral administration the 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 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 unit 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 (14.66 g, 0.1 mol) was added dropwise to a stirred solution of aniline hydrochloride (12.96 g 0.1 mol) and N, Ndiisopropylethylamine (15.20 g, 0.2 mol) in dichloromethane (100 ml). The solution was stirred under an atmosphere of argon for 18 h, washed with 0.1 N-HC1 (3 x 50 ml) and dilute sodium hydrogen carbonate solution (50 ml), dried CMgSO4), and evaporated in vacuo to give the product (18.6 g) as white crystals.
Example 2 N-(2-(4-(2-Methoxyphenyl)piperazin-l- yl)ethyl)-N-phenylcyclohexanecarboxamide A solution of the product of example 1 (2.03 g, 0.1 mol) in DMF (50 ml) was added dropwise to a suspension of potassium hydride, 35% dispersion in mineral oil (1.2 g, 0.011 mol) in DMF (20 ml). The suspension was stirred for 2 h, treated with 1-(2-chloroethyl)-4-(2methoxyphenyl)piperazine (2.53 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 (200 ml) and the solution extracted with ether (3 x 100 ml). The extracts were washed with water (100 ml), dried (MgSO4), and evaporated in vacuo to give an oil which was purified by chromatography [silica; ethyl acetate-toluene (1:1)1 to give the product (0.41 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. 118-1230C.
(Found: C, 62.6; H, 7.8; N, 8.2. C26H35N302.
2HC1.4H20 requires C, 62.6; H, 7.6; N, 8.4%).

Claims (12)

1. A compound of the general formula
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, R1 is a monocyclic aryl or heteroaryl radical, R2 is a mono or bicyclic aryl radical and R3 is cycloalkyl.
2. A compound as claimed in claim 1 in which A is -CCH2)2-, -(CH2)3- or -CCH2)4-.
3. A compound as claimed in claim 1 or 2 in which R1 is o-methoxyphenyl.
4. A compound as claimed in any one of claims 1 to 3 R 2.
in which R2 is phenyl.
5. A compound as claimed in any one of claims 1 to 4 R 3.
in which R3 is cyclohexyl.
6. A compound as claimed in claim 1 which is N-(2-(4-(2-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 (a) acylating an amine of formula (II)
(where A, R, R1 and R2 have the meanings defined in claim 1) with an acid of formula R3CoOH (III) R COOH (where R3 is as defined in claim 1) or with an acylating derivative thereof or (b) alkylating an amide of formula (IV)
(where R2 and R3 are as defined in claim 1) with an alkylating agent providing the group
(where A, R and R1 are as defined in claim 1) or tc) alkylating a compound of formula
with a compound of formula X-A-NR2.CO.R3 (where A, R2 and R3 are as defined in claim 1 and X is a leaving group) or (d) resolving a racemic compound claimed in claim 1 into an enantiomer or (e) converting a base claimed in claim 1 into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable salt into the free base.
8. A process for preparing a compound claimed in claim 1 substantially as hereinbefore described with reference to Example 2.
9. A compound as claimed in claim 1 whenever prepared by the process claimed in claim 7 or 8.
10. A pharmaceutical composition comprising a compound claimed in any one of claims 1 to 6 or 9 in association with a pharmaceutically acceptable carrier.
11. A compound as claimed in any one of claims 1 to 6 or 9 for use as a 5 HT1A antagonist.
12. A compound as claimed in any one of claims 1 to 6 or 9 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.
GB9227001A 1992-01-08 1992-12-24 Piperazine derivatives Expired - Fee Related GB2263110B (en)

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GB2263110A true GB2263110A (en) 1993-07-14
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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)
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037983A1 (en) * 1996-04-05 1997-10-16 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) α1-ADRENERGIC RECEPTOR ANTAGONISTS
WO1999006384A1 (en) * 1997-08-01 1999-02-11 Recordati S.A., Chemical And Pharmaceutical Company 1-(n-phenylaminoalkyl)-piperazine derivatives substituted at position 2 of the phenyl ring
WO2000035892A1 (en) * 1998-12-17 2000-06-22 American Home Products Corporation Piperazine ethylamide derivatives with 5-ht1a receptor activity
US6344458B1 (en) 1998-12-17 2002-02-05 American Home Products Corporation Piperazine ethylamide derivatives
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

Families Citing this family (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69332860T2 (en) * 1992-12-21 2004-03-11 Smithkline Beecham Corp. BICYCLIC FIBRINOGEN ANTAGONISTE
US5609849A (en) * 1994-03-11 1997-03-11 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
US5610164A (en) * 1996-07-24 1997-03-11 American Home Products Corporation (Thiophen-2-yl)-piperidin or tetrahydropyridin azabicyclocarboxamides
IT1293804B1 (en) 1997-08-01 1999-03-10 Recordati Chem Pharm DIARYLALKYL PIPERAZINS ACTIVE ON LOW URINARY TRACT
US8030294B2 (en) 2000-03-16 2011-10-04 The Mclean Hospital Corporation Compounds for the treatment of psychiatric or substance abuse disorders
WO2002000259A1 (en) * 2000-06-27 2002-01-03 Taisho Pharmaceutical Co., Ltd. Remedial agent for anxiety neurosis or depression and piperazine derivative
WO2005122767A1 (en) 2004-06-10 2005-12-29 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
US7731940B2 (en) 2006-01-25 2010-06-08 The Regents Of The University Of California Compositions and methods related to serotonin 5-HT1A receptors
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
TW200845978A (en) * 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
JP5433579B2 (en) * 2007-09-14 2014-03-05 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． 1,3-disubstituted-4-phenyl-1H-pyridin-2-one
TWI475995B (en) 2007-09-14 2015-03-11 Janssen Pharmaceuticals Inc 1',3'-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2h, 1'h-[1,4'] bipyridinyl-2'-ones
EA019085B1 (en) 2007-09-14 2014-01-30 Янссен Фармасьютикалз, Инк. 1,3-disubstituted 4-(aryl-x-phenyl)-1h-pyridin-2-ones
RU2492170C9 (en) * 2007-11-14 2013-12-27 Орто-Макнейл-Янссен Фармасьютикалз, Инк. Imidazo[1,2-a]pyridine derivatives and their application as positive allosteric modulators of mglur2 receptors
EP2344470B1 (en) 2008-09-02 2013-11-06 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
EP2346505B1 (en) 2008-10-16 2014-04-23 Janssen Pharmaceuticals, Inc. Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors
CA2744138C (en) 2008-11-28 2015-08-11 Ortho-Mcneil-Janssen Pharmaceuticals, Inc. 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
AU2010246607B2 (en) 2009-05-12 2012-09-27 Addex Pharma S.A. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
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WO2011027656A1 (en) 2009-09-04 2011-03-10 Semiconductor Energy Laboratory Co., Ltd. Transistor and display device
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
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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
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CN109999025A (en) 2014-01-21 2019-07-12 詹森药业有限公司 Positive allosteric modulator or the combination of normotopia agonist including metabotropic glutamate energy receptor subtype 2 and application thereof
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190472A1 (en) * 1984-12-21 1986-08-13 Duphar International Research B.V New pharmaceutical compositions having anti-psychotic properties
GB2230781A (en) * 1989-04-22 1990-10-31 Wyeth John & Brother Ltd Piperazine derivatives as 5-ht(1a) antagonists

Family Cites Families (11)

* 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
AU532411B2 (en) * 1979-03-01 1983-09-29 Duphar International Research B.V. Phenyl piperazine derivatives
NL8005131A (en) * 1980-09-12 1982-04-01 Duphar Int Res PHENYLPIPERAZINE DERIVATIVES WITH ANALGETIC ACTION.
NL8005133A (en) * 1980-09-12 1982-04-01 Duphar Int Res PHENYLPIPERAZINE DERIVATIVES WITH ANTIAGRESSIVE ACTION.
CA1340113C (en) * 1988-05-24 1998-11-03 Magid A. Abou-Gharbia Aryl-and heteroaryl piperazinyl carboxamides having central nervous system activity
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
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
ES2027898A6 (en) * 1991-01-24 1992-06-16 Espanola Prod Quimicos 2-Methoxyphenylpiperazine derivatives.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190472A1 (en) * 1984-12-21 1986-08-13 Duphar International Research B.V New pharmaceutical compositions having anti-psychotic properties
GB2230781A (en) * 1989-04-22 1990-10-31 Wyeth John & Brother Ltd Piperazine derivatives as 5-ht(1a) antagonists

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037983A1 (en) * 1996-04-05 1997-10-16 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) α1-ADRENERGIC RECEPTOR ANTAGONISTS
US6300499B1 (en) 1996-04-05 2001-10-09 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) α1-adrenergic receptor antagonists
WO1999006384A1 (en) * 1997-08-01 1999-02-11 Recordati S.A., Chemical And Pharmaceutical Company 1-(n-phenylaminoalkyl)-piperazine derivatives substituted at position 2 of the phenyl ring
US6071920A (en) * 1997-08-01 2000-06-06 Recordati S.A. Chemical And Pharmaceutical Company 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring
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
WO2000035892A1 (en) * 1998-12-17 2000-06-22 American Home Products Corporation Piperazine ethylamide derivatives with 5-ht1a receptor activity
US6344458B1 (en) 1998-12-17 2002-02-05 American Home Products Corporation Piperazine ethylamide derivatives

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GB9227001D0 (en) 1993-02-17
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FI106200B (en) 2000-12-15
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BR9207030A (en) 1995-12-05
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AU3169793A (en) 1993-08-03
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ATE183504T1 (en) 1999-09-15
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