IL23338A - N-phenylpiperazine compounds - Google Patents

N-phenylpiperazine compounds

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Publication number
IL23338A
IL23338A IL23338A IL2333865A IL23338A IL 23338 A IL23338 A IL 23338A IL 23338 A IL23338 A IL 23338A IL 2333865 A IL2333865 A IL 2333865A IL 23338 A IL23338 A IL 23338A
Authority
IL
Israel
Prior art keywords
group
formula
phenylpiperazine
hal
acid addition
Prior art date
Application number
IL23338A
Original Assignee
May & Baker Ltd
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 May & Baker Ltd filed Critical May & Baker Ltd
Publication of IL23338A publication Critical patent/IL23338A/en

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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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/20—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 acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Punching Or Piercing (AREA)

Description

P T PATENTS FORM NO. 3, PATENTS AND DESIGNS ORDINANCE SPECIFICATION puna's ie- E maiann WE, MAY & BAKER LIMITED, a British Company, of Dagenham, in the County of Essex, England, do hereby declare the nature of this invention and in what manner the same is to be performed, to be particularly described and ascertained in and by the following st - THIS INVENTION relates to new piperazine derivatives of therapeutic value, to processes for their preparation and to' pharmaceutical compositions containing them.
According to the present invention there are provided the new, therapeutically useful N-phenylpiperazine derivatives of the general formula: wherein 0 represents a group -(CH_) COOR {wherein m represents zero 2 m — or an integer from 1 to 6 inclusive and R represents an alkyl group containing from 1 to 6 carbon atoms) or a group -CH -(CH ) R. 2 2 01 i (wherein R^ represents a cyano or carboxyl group and m is as hereinbefore defined) and non-toxic acid addition salts thereof, and, when Rj represents a carboxyl group, non-toxic salts with bases such as alkali metal hydroxides and amines, for example N-methylglucamine and mono-, di and tri-ethanolamine.
The aforesaid compounds and non-toxic salts thereof possess pharmacological and psychotropic properties indicative of utility in the treatment of behavioural disorders, anxiety states and related psychiatric conditions. Preferred compounds are those of formula I in which Q represents a -(CH_) COOR grouping and especially those such 2 m compounds wherein m represents 2 and R represents a methyl or ethyl group, and those in which Q represents a grou -CH (CH ) CN, and more especially 2 o ID l-^-cyanoethy¾-4-(m-trifluoromethylphenyl )piperazine, and non-toxic acid addition salts thereof. Of particular importance are 1-(2nnethoxycarbonylethyl ) ■ 4-(m-trifluoromethylphenyl Jpiperazine and its non-toxic acid addition salts.
According to a feature of this invention, the compounds of formula I are prepared by the reaction of m-trifluoromethyl henyl -piperazine of the formula! with a compound of the formula Hal-Q, wherein Hal represents a halogen atom such as chlorine, bromine or iodine, and Q is as hereinbefore defined. The reaction is preferably effected by heating the reactants in an inert organic solvent, such as a benzene hydrocarbon, e.g. benzene, or a halogenated hydrocarbon, e,g. chloroform, in the presence of an acid-binding agent, e.g. an alkali metal or derivative thereof, such as an alkali metal carbonate, hydroxide, alkoxide, amide or hydride, or a tertiary base such as triethylamine.
According to a further feature of the invention, the compounds of formula I are prepared by the reaction of an aniline derivative of the formula: with a compound of the general formula: Y - Q IV wherein the symbols X and Y are such that when X represents a hydrogen atom Y represents a -CH CH Hal grouping, and when X represents a -CH CH Hal grouping Y represents a hydrogen atom, and Q and Hal are as hereinbefore defined. The reaction may be effected in the presence or absence of an acid-binding agent,, but is preferably effected by heating the reactants in an inert organic solvent, such as an alcohol (e.g. ethanol), a ketone (e.g. acetone)^ a benzene hydrocarbon (e.g. benzene) or a halogenated hydrocarbon (e.g. chloroform), and in the presence of an acid-binding agent, e.g. an alkali metal or derivative thereof such as an alkali metal carbonate, hydroxide, alkoxide amide or h dride or a tertiar base suh as trieth lamin According to a still further feature of the invention, the compounds of formula I in which Q represents a -CH CH T group (wherein T represents a cyano or carboxy group or a grouping -COOR, R being as hereinbefore defined) are prepared by the reaction of an acrylic compound of the formula CH^ » CH-T^ [wherein represents a cyano or carboxy group or an aldehyde (-CHO) or alcohol grouping (-CH OH) or a grouping - COOR, R being as herein-before defined] with m-trifluoromethylphenylpiperazine, and, when represents an aldehyde or alcohol grouping, oxidising by known methods that grouping in the intermediate product obtained to a compound of formula I wherein Q represents the group The reaction with the acrylic compound may be effected with or without an inert organic solvent, such as an alcohol (e.g, ethanol), a ketone (e.g. acetone), a benzene hydrocarbon (e.g. benzene), or a halogenated hydrocarbon (e.g. chloroform), and in the presence or absence of a condensing agent, but is preferably effected with an inert solvent such as those set out above and in the presence of a suitable condensing agent such as benzyltrimethylammonium hydroxide.
According to another feature of the invention, the compounds of general formula I in which Q represents a -CH_-(CH,_) CN group are 2 2 m prepared by the reaction of a corresponding halide of the formula* (wherein Hal is as hereinbefore defined) with a metallic cyanide such as cuprous, potassium or sodium cyanide or sodium or potassium cupro- or nickelo-cyanide.
The compounds of formula V may themselves be prepared from the corresponding alkanols of the formula: (wherein m is as hereinbefore defined) by reaction with a suitable halogenating gent such as thionyl chloride or bromide or phosphorus trichloride or tribromide. The alkanols of formula VI may be conveniently prepared by reaction of m-trifluoromethylphenylpiperazine with a hydroxyalkyl halide of the formula Hal-CH^CH^OH wherein m and Hal are as hereinbefore defined.
As indicated above the symbol Q may represent an alkoxy-carbonyl , alkoxycarbonylalkyl , cyanoalkyl or carboxyalkyl group.
It is within the scope of the present invention to prepare a compound having a desired substituent by first preparing a compound which has a substituent different from that desired and thereafter converting this substituent to the desired substituent. Thus, the compounds of formula I in which Q is a carboxyalkyl group can be prepared from the corresponding compounds of formula I, in which Q is a cyanoalkyl group, by known methods for the hydrolysis of nitriles, for example by reaction with an aqueous alkali metal hydroxide, such as sodium hydroxide. Such carboxyalkyl compounds of formula I can be converted into alkoxycarbonylalkyl compounds of formula I according to known methods of esterification, for example, by reaction with the corresponding alcohol in the presence of a mineral acid such as hydrochloric acid. The compounds of formula I, in which Q is an alkoxycarbonylalkyl group, may be converted into compounds of formula I, in which Q is carboxyalkyl group, according to known methods for the hydrolysis of esters, for example, by heating with aqueous sodium hydroxide solution. The expression "known methods" used in the specification and accompanying claims means methods heretofore used or described in the chemical literature.
When the compounds of general formula I are used for therapeutic purposes in the form of acid addition salts, it should be understood that only those such salts should in practice be employed as contain anions that are relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial physiological properties inherent in the parent compounds are not vitiated by side-effects ascribable to those anions; in other words, only non-toxic salts are contemplated. Suitable acid addition salts include hydrohalides (for example, hydrochlorides), phosphates, nitrates, sulphates, maleates, fumarates, citrates, tartrates, methanesulphonates , isethionates and ethane disulphonates.
Such salts may be made from bases of formula I by the methods heretofore used in the art for making acid addition salts. For example, the acid addition salts may be made by mixing the base with an equivalent quantity of a non-toxic acid in a solvent and isolating the resultant salt by filtration after, if necessary, evaporation of part or all of the solvent. They may be purified by crystallisation or by any other method commonly used in the art. Non-toxic salts of the compounds of general formula I, wherein Q represents a carboxyalkyl group, with bases such as alkali metal hydroxides and amines may be prepared in a similar manner to acid addition salts by mixing the acid of formula I with an equivalent quantity of the base in a solvent and isolating the resultant salt by filtration after, if necessary, evaporation of part or all of the solvent.
The following Examples illustrate the invention.
EXAMPLE I m-Trifluoromethylphenylpiperazine (11.0 g.) was treated at ambient temperature with stirring with methyl acrylate (4.7 ml»| 4.56 g»). An exothermic reaction took place and the temperature of the reaction mixture rose to 48°C. during 5 minutes. The temperature then began to fall and at 38°C, one drop- of a 40% w/v ethanolic solution of benzyltrimethylammonium hydroxide was added but no further temperature change took place. The reaction mixture was allowed to stand at ambient temperature for 4o hours and then heated at 60°C. for 1 hour. The resulting oil was cooled and dissolved in isopropanol (100 ml.). Concentrated hydrochloric acid (4.1 ml.) was added to this solution to give a white crystalline solid which dissolved readily on warming. The solvent was removed by distillation under reduced pressure and the residue dried by azeotropic distillation with benzene. The white solid residue was crystallised from isopropanol (5p ml.), using charcoal and hot filtration, to give a white solid which was collected by filtration and dried in vacuo to yield l-(2-methoxycarbonylethyl)-4-(m-trifluoromethylphenyl)piperazine hydrochloride ( 15.0 g.{ 89%) , m.p. 176-177°C The m-trifluoromethylphenylpiperazine used as starting material was prepared as follows:" m-Trifluoromethylaniline (200 g.)» diethanolamine (132 g.) and 48/50% w/w hydrobromic acid (285 ml.) were heated together up to 180°C. during two hours, and the mixture then maintained at 180-200°C. for 3 hours. The solid product was allowed to cool and was then recrystallised, first from water and then from methanol to give m-trifluoromethylphenylpiperazine hydrobromide (215 g.; 56 %) , m.p. 250-253°C. m-Trifluoromethylphenylpiperazine hydrobromide (155 g.) excess 50% w/v aqueous sodium hydroxide solution (60 ml.). The resulting mixture was shaken with diethyl ether ( 100 ml.) and the two layers separated. The aqueous layer was re-extracted with diethyl ether (2 x 250 ml.) and the ethereal extracts ( 1500 ml.) combined, washed with water (2 x 250 ml.) and dried over anhydrous magnesium sulphate. The magnesium sulphate was removed by filtration and the filtrate evaporated to dryness to give m-trifluoromethylphenyl-piperazine as a straw-coloured oil (115 g»J 100% recovery^.
EXAMPLE II m-Trifluoromethylphenylpiperazine hydrobromide ( prepared as described in Example I) (20 g.) in water (100 ml.) was treated with 2N aqueous sodium hydroxide solution (70 ml.) and methyl chloroformate (6.08 g.) in chloroform (200 ml.) over 5 minutes at ambient temperature. The resulting suspension was stirred for minutes at ambient temperature, the two layers were separated and the aqueous layer re-extracted with chloroform (2 x 100 ml. portions). The chloroform extracts were combined, washed with water (50 ml.), dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue, which solidified, was recrystallised twice from ethyl acetate and cyclohexane to give 1-methoxycarbonyl -4-(m-trifluoromethylphenyl )-piperazine (4.6 g.) as off-white prisms, m.p. 58-60°C, Treatment of this base with excess methanesulphonic acid and recrystallisation of the salt from ethyl acetate and di-isopropyl ether gave 1-methoxycarbonyl -4-(ra~trifluoromethylphenyl )-piperazine methanesulphonate, m.p. 12 ~126°C, EXAMPLE III m-Trifluoromethylphenylpiperazine hydrobromide (prepared as described in Example I) ( 20 g.) was dissolved in water ( 100 ml.) and poured onto a mixture of crushed ice ( 100 g.) and an excess of ammonium hydroxide solution (d=0.88; 25 ml.). The oily base which separated was extracted into chloroform (2 x 50 ml.) and the combined chloroform extracts washed with water (50 ml.), dried over anhydrous magnesium sulphate and the solvent removed under reduced pressure. The residual m-trifluoromethylphenylpiperazine base was treated dropwise with acrylonitrile (4.7 ml.) followed by one drop of a 4θ% w/v alcoholic benzyltrimethylammonium hydroxide solution. The reaction temperature rose slowly from 27° to 34°C. over 1 hour. The mixture was then allowed to cool and stand at ambient temperature for 60 hours. The oily mixture was heated at 50°C. for 2 hours I dissolved in isopropyl alcohol (100 ml.) and concentrated hydrochloric acid (d=l.l8; 5·53 ml.) added. A solid separated and after cooling this solid was collected by filtration. It was recrystallised from a mixture of isopropyl alcohsl (250 ml.) and water (15 ml.) to give l-(2-cyanoethyl ) -4-(m-trifluoromethylphenyl )- piperazine monohydrochloride (15.0 g.; 73%) as a white solid, in.p. 227-228°C.
The pressnt invention further includes within its scope pharmaceutical compositions which comprise, as active ingredient, at least one compound of general formula I , or non-toxic acid addition salt or, when Q is a carboxyalkyl group, salt thereof, in association with a pharmaceutical carrier. The invention includes especially such compositions made up for oral or parenteral administration. In clinical practice the compounds of the present invention will normally be administered orally so that compositions suitable for oral administration are preferred.
Solid compositions for oral administration include compressed tablets, pills, dispersible powders, and granules. In such solid compositions one or more of the compounds of formula I is or are admixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid, or lactose. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
Liquid compositions for oral administration include pharmaceutically aceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions may also comprise adjuvants, such as wetting and suspending agents, and sweetening and flavouring agents.
The compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.
Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
These compositions may also contain adjuvants such as wetting, emulsifying and dispersing agents. They may be sterilised by, for example, filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents, by irradiation, or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously several unit dosage forms may be administered at about the same time. In general, the preparations of the present invention should normally contain at least 0.025$ by weight of active substance in the case of injectable solutions and at least 0,1% by weight of such substance in the case of oral preparations.
The following Example illustrates pharmaceutical compositions according to the invention.
EXAMPLE IV Tablets of the formula: l-(2-methoxycarbonylethyl )-4-(m-trifluoromethylphenyl )piperazine lOmg. lactose 9.5ro§. starch 20mg. dextrin 20mg. magnesium stearate 0.5mg. are prepared by intimately mixing the piperazine derivative, lactose, starch and dextrin and passing the mixture through a 60-mesh British Standard sieve. After addition of the magnesium stearate, the mixture is granulated to a suitable size and the granules compressed to form tablets.
Instead of the piperazine derivative specified in the above formulation any other piperazine derivative within the scope of general formula I may be employed, e.g. the compounds obtained as products in Examples II and III.

Claims (18)

* HAVING NOW particularly described and ascertained the nature of our said invention and in what manner the same is to ... be performed,' we declare that what we claim is
1. N-Phenylpiperazine derivatives of the general formula: wherein Q represents a group -(CH ) COO (wherein m represents zero or an integer from 1 to 6 inclusive and R is an alkyl group containing from 1 to 6 carbon atoms) or a group -CH -(CH ) R (wherein represents a cyano or carboxyl group and m is as hereinbefore defined) and non-toxic acid addition salts thereof and, when R^^ represents a carboxyl group, non-toxic salts with bases.
2. N-Phenylpiperazine compounds according to claim 1 wherein Q represents a -CH^^COOR group.
3. » N-Phenylpiperazine compounds according to claim 2 wherein ra represents 2 and R represents a methyl or ethyl group*
4. » N-Phenylpiperazine compounds according to claim 1 wherein Q represents a -CH -(CH ) CN group. 2
5. l-(2-Methoxycarbonylethyl ) -4-(m-trifluoromethylphenyl ) -piperazine and non-toxic acid addition salts thereof.
6. l-Methoxycarbonyl-4-(m-trifluoromethylphenyl )piperazine and non-toxic acid addition salts thereof.
7. » l-(2-Cyanoethyl )-4-(ra-trifluoromethylphenyl )piperazine and non-toxic acid addition salts thereof.
8. Process for the preparation of N-phenyl iperazine derivatives as claimed in claim 1 which comprises reacting m-trx-fluoromethylphenylpiperazine with a compound of the formula Hal-Q, wherein Hal re resents a halo en atom and Q is as defined in claim 1.
9. Process for the preparation of N-phenylpiperazi e derivatives as claimed in claim 1 which comprises reacting an aniline derivative of the formula: with a compound of the formula: wherein the symbols X and Y are such that when X represents a hydrogen atom Y represents a -CH CH Hal grouping , and when X represents a -CH CH Hal grouping Y represents a hydrogen atom, Hal represents 2 2 a halogen atom and Q is as defined in claim 1,
10. Process according to claim 8 or 9 wherein the reaction is effected in an inert organic solvent in the presence of an acid-binding agent*
11. · Process for the preparation of N-phenylpiperazine derivatives as claimed in claim 1 in which Q represents a -CH CH T group T representing a cyano or carboxy group or a 2 2 group -C00R wherein R is as defined in claim 1, which comprises reacting an acrylic compound of the formula CH =CH-T (wherein T «2 1 1 represents a cyano, carboxy, aldehyde or alcohol group, or a grouping -C00R) with m-trifluoromethylphenylpiperazine and, when represents an aldehyde or alcohol group, oxidising by known methods that group in the intermediate product obtained to fonn a N-phenylpiperazine derivative as claimed in claim 1 in which Q is the grouping -CH CH COOH.
12. · Process according to claim 11 wherein the reaction is effected in an inert organic solvent.
13. · Process according to claim ll or 12 wherein the reaction is effected in the presence of a condensing agent*
14. Process according to claim 1.3 wherein the condensing agent is benzyltrimethylammonium hydroxide.
15. 1 . Process for the preparation of N-phenylpiperazine derivatives as claimed in claim 1 in which Q represents a -CH^- (CH ) CN group which comprises reacting a corresponding halide 2 m of the formula: (wherein Hal represents a halogen atom and m is as defined in claim l) with a metallic cyanide.
16. Process according to claim 15 wherein the metallic cyanide is cuprous, potassium or sodium cyanide or sodium or potassium cupro- or nickelo-cyanide.
17. · Process according to any one of claims 8 to 16 followed by the step of converting by known methods a group Q in the product obtained into a different group within the definition of that symbol in claim 1.
18. Process for the preparation of N-phenylpiperazine compounds as claimed in claim 1 substantially as hereinbefore described with especial reference to Example Ij II or III. 19· N-Phenylpiperazine derivatives of the formula specified in claim 1 when prepared by the process claimed in any one of claims 8 to 18· 20i Pharmaceutical compositions which comprise * as active ingredient, at least one N-phenyl i erazine derivativei or non-toxic acid addition salt or salt thereof, as claimed in any one of claims 1 to 7 and 1 in association with a pharmaceutical carrier. 21* Pharmaceutical compositions as claimed in claim 20 substantially as hereinbefore described with especial reference to Example IV. Dated this 11th day of April, 1965 For the Applicants
IL23338A 1964-04-14 1965-04-12 N-phenylpiperazine compounds IL23338A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB15439/64A GB1105522A (en) 1964-04-14 1964-04-14 N-phenylpiperazine compounds

Publications (1)

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IL23338A true IL23338A (en) 1968-08-22

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US (1) US3326916A (en)
AT (4) AT257618B (en)
BE (1) BE662455A (en)
CH (2) CH444869A (en)
DE (1) DE1595933A1 (en)
ES (1) ES311825A1 (en)
FR (1) FR4239M (en)
GB (1) GB1105522A (en)
IL (1) IL23338A (en)
NL (1) NL6504788A (en)
NO (1) NO117423B (en)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE789255A (en) * 1971-09-30 1973-03-26 Synthelabo N-CYANO-ETHYL N'-M-CHLOROPHENYL PIPERAZINE AND ITS
FR2201084B1 (en) * 1972-09-29 1975-10-31 Bouchara Emile
US4202898A (en) * 1978-06-05 1980-05-13 Synthelabo Method of treating anxiety and depression
JPS574921A (en) * 1980-06-13 1982-01-11 Chugai Pharmaceut Co Ltd Remedy for cardiovascular disorder
DE19734516A1 (en) * 1997-08-08 1999-02-11 Bayer Ag Process for the preparation of N-aryl-N'-alkyl-piperazines
SE9904724D0 (en) * 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission I
SE9904723D0 (en) 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission II
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
EP1773772B1 (en) 2004-06-08 2010-06-02 NSAB, Filial af NeuroSearch Sweden AB, Sverige New disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission
SE0401465D0 (en) * 2004-06-08 2004-06-08 Carlsson A Research Ab New substituted piperdines as modulators of dopamine neurotransmission
US7851629B2 (en) * 2004-06-08 2010-12-14 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
DE602005017784D1 (en) * 2004-06-08 2009-12-31 Nsab, Filial Af Neurosearch Sweden Ab NEW DISUBSTITUTED PHENYLPIPERIDINES AS MODULATORS OF DOPAMINE AND SEROTONINE NEUROTRANSMISSION
MX2007004215A (en) * 2004-10-13 2007-12-12 Neurosearch Sweden Ab Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-n- propyl-piperidine.
CA2584833A1 (en) * 2004-10-13 2006-04-20 Neurosearch Sweden Ab Process for the synthesis of 4-(3-sulfonylphenyl)-piperidines
SE529246C2 (en) * 2005-10-13 2007-06-12 Neurosearch Sweden Ab New disubstituted phenyl-piperidines as modulators of dopamine neurotransmission
MX347209B (en) 2011-12-08 2017-04-19 Teva Pharmaceuticals Int Gmbh The hydrobromide salt of pridopidine.
CN104470585A (en) 2012-04-04 2015-03-25 爱华克斯国际有限公司 Pharmaceutical compositions for combination therapy

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BE662455A (en)
CH444869A (en) 1967-10-15
AT262293B (en) 1968-06-10
DE1595933A1 (en) 1970-02-12
US3326916A (en) 1967-06-20
CH435295A (en) 1967-05-15
AT257619B (en) 1967-10-10
NL6504788A (en) 1965-10-15
ES311825A1 (en) 1966-02-01
NO117423B (en) 1969-08-11
AT257618B (en) 1967-10-10
FR4239M (en) 1966-06-20
AT257620B (en) 1967-10-10
GB1105522A (en) 1968-03-06

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