GB2023594A - 1-substituted alkyl-4-(3- trifluoromethylthiophenyl)- piperazines - Google Patents

1-substituted alkyl-4-(3- trifluoromethylthiophenyl)- piperazines Download PDF

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GB2023594A
GB2023594A GB7921307A GB7921307A GB2023594A GB 2023594 A GB2023594 A GB 2023594A GB 7921307 A GB7921307 A GB 7921307A GB 7921307 A GB7921307 A GB 7921307A GB 2023594 A GB2023594 A GB 2023594A
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • 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
    • C07D295/08—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 bound oxygen or sulfur atoms
    • C07D295/084—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Abstract

Compounds having the general formula (I> <IMAGE> in which n is 1, 2 or 3 and R represents (i) a group of formula: <IMAGE> (A) in which R1 and R2 represent hydrogen atoms or together represent a group of formula: <IMAGE> thereby completing a benzene ring fused to the heterocyclic ring shown in formula (A), X is a -S-, -O-, imino, alkyl-imino or methylene group and m is 0 or 1 or R represents (ii) a group of formula: <IMAGE> (B), (iii) a 2-tetrahydrofuryl group, (iv) a group of formula -CH2-S-Z, Z representing a hydrogen atom, alkyl group or -CO- alkyl group or (v) a group of formula -CH2-O- alkyl, having from 1 to 8 carbon atoms, and their pharmaceutically acceptable acid addition salts are useful in therapy, especially for treatment of anxiety and depression.

Description

SPECIFICATION Phenylpiperazine derivatives The present invention relates to therapeutically useful phenylpiperazine derivatives.
The phenylpiperazine derivatives of the invention are compounds of the general formula (I)
in which n is 1, 2 or 3 and R represents (i) a group of formula:
(A) in which R, and R2 represent hydrogen atoms or together represent a group of formula:
thereby completing a benzene ring fused to the heterocyclic ring shown in formula (A), X is a thio, oxy, imino, alkylimino or methylene group and m is O or 1, or R represents (ii) a group of formula:
(iii) a 2-tetrahydrofuryl group, (iv) a group of formula -OH 2-Z, Z representing a hydrogen atom, alkyl group or -CO- alkyl group or (v) a group of formula -CH2-O- alkyl, the alkyl groups having from 1 to 8 carbon atoms, and their pharmaceutically acceptable acid addition salts.
The invention includes a process for the preparation of the compounds (I), which comprises reacting 1 -(m-trifluoromethylthiophenyl)piperazine (II)
with a compound (Ill) Y(CH2)nR (Ill) in which R and n have the meanings given above and Y represents an anion of an activated alcohol derivative, preferably a halide, mesylate, tosylate or halogenomethanesulphonate ion. Alternatively Y can be defined as a leaving atom or group reactive with a secondary amino group.
This reaction can be carried out conveniently at a temperature of 20 to 1 500C in a polar or nonpolar solvent, e.g. a benzene hydrocarbon, a hydroxylic or ketonic solvent, N,N-dimethylformamide (DMF) or hexamethylphosphorotriamide (HMPT).
In order to prepare the compound (I) in which n is 1 and R is a -CH2SH group, it is also possible to react the 1 -(m-trifluoromethylthiophenyl)piperazine (II) with ethylene sulphide.
It is also possible to prepare the compounds (i) in which R is
-CH2O-alkyl or -CH2S-alkyl (2-tetrahydrofuryl) by reacting m-(trifluoromethylthio)aniline (IV)
with a diethylamine derivative of formula (V)
in which R has the desired said particular meaning, n is 1, 2 or 3 and Hal represents a halogen atom.
The compounds (I) in which R is a -CH2-S-alkyl or-CH2-S-CO-alkyl group can also be obtained, according to the invention, from the compounds (I) in which R is a -CH2-SH group by reacting the latter with an alkyl halide or acyi(alkylcarbonyl)halide.
Pharmaceutically acceptable acid addition salts of compounds (I) can be prepared by converting the free base in a manner known per sa The compounds (III) are described in the iiterature.
The following Examples illustrate the preparation of the compounds (I) and their pharmaceutically acceptable salts. The analyses and the IR and NMR spectra confirm the structure of the compounds prepared.
Example 1.
1 -f 2-[4-(3-Trifluoromethylthio-phenyl)piperazin- 1 -yl]-ethyl }-pyrid-2-one and its hydrochloride.
A mixture of 18.36 g (0.07 mol) of 4-(3-trffluoromethylthio-phenyl)-piperazine 11.8 g (0.075 mol) of 1 -N-(P-chloroethyl)-pyrid-2-one, 58.8 ml of toluene, 17.25 g (0.1248 mol) of powdered potassium carbonate and 0.35 g of potassium iodide is heated to the reflux temperature under nitrogen.
After 1 6 hours, the mixture is filtered and the filtrate is then evaporated. The residue is taken up in ether and the mixture is extracted with 10% strength hydrochloric acid. The aqueous phase is made alkaline to pH 9-10 with sodium hydroxide solution.
The product is extracted with ether and the ether extract is then washed with water until the pH of the washings is 7-8.
The ether extract is dried and filtered and the filtrate is concentrated. This yields 24 g of an oil which is chromatographed on 600 g of silica (eluant MeOH 0.5/CHCl3 9.5). 18.8 g of a brown oil are recovered, this oil is dissolved in ether and 10.86 ml (0.0489 mol) of a 4.5 N solution of hydrogen chloride in ether are added. The mixture is filtered and the product is washed with ether and recrystallised from isopropanol. A white powder is obtained. The base is liberated using concentrated NH4OH, and the hydrochloride is obtained from the base using a 4.18 N solution of hydrogen chloride in ether. The mixture is filtered and the product is washed with ether and then dried in a heated desiccator in the presence of potassium hydroxide.
The resulting product melts at 21 7-21 80C.
Example 2.
1 -j2-[4-(3-Trifluoromethylthio-phenyl )-piperazin- 1 -yI]-ethyl j-3-methyl-benzimidazolidin-2-one
The following mixture: 10.5 g (0.04 mol) of 4-(3-trifluoromethylthio-phenyl)-piperazine, 12.16 g (0.088 mol) of powdered K2CO3, 40 ml of toluene, 9.48 g (0.045 mol) of 1 -(P-chloroethyl)-3-methyl- benzimidazolidin-2-one and 0.3 g of potassium iodide, is heated to the reflux temperature under nitrogen. After 1 6 hours, the reaction has virtually stopped. The mixture is filtered and the filtrate is evaporated. The crystalline product is taken up in ether and the mixture is filtered. The base is obtained.
Melting point= 12 5--1 27 OC.
The base is dissolved in 400 ml of acetone and 50 ml of CH2Cl2. 7 ml (0.0293 mol) of a 4.18 N solution of hydrogen chloride in ether are introduced thereto. The hydrochloride precipitates gradually.
The mixture is stirred for 1 hour and then filtered and the product is dried in a heated desiccator at 600C for 8 hours. A white powder is obtained.
Melting point = 260-2630C (decomposition).
Example 3.
1 -( m-Trifl uoromethylthio-phenyl).4-(tetrahydrofuryl-2-methyl)-piperazine and its hydrochloride.
A mixture of 13.5 g (0.05 mol) of (m-trifluoromethylthiophenyl)-piperazine, 13.5 g (0.054 mol) of tetrahydrofuryl-2-methyl tosylate and 13.5 ml of HMPT is heated at 1 200C for 2 hours. The mixture is cooled to 1 OOC and 100 ml of water are added. The oil is separated from the water and then washed 3 times with water in order to remove the HMPT. The oil is taken up in chloroform, the traces of water are separated off and the chloroform solution is dried over magnesium sulphate. A solution of hydrogen chloride in ether is added and the solvents are evaporated off. The evaporation residue is triturated with ether and the precipitate is filtered off. It is rendered alkaline with 2 N NaOH solution and the mixture is extracted with chloroform.The chloroform is evaporated off and the hydrochloride is prepared from the oil remaining after evaporation. The compound is recrystallised from a mixture of isopropanol and ether.
Melting point = C.
Example 4.
1 -(m-Trifluoromethylth io-phenyl)-4-(2-mercaptoethyl)-piperazine and its hydrochloride.
[n= 1, R = CH2SH] In an Erlenmeyer flask, 3.84 g (0.064 mol) of ethylene sulphide are added dropwise, at 200C, to a solution of 15 g (0.0557 mol) of (m-trifluoromethylthio-phenyl)-piperazine and 2 ml of methanol.
The mixture is heated gradually to 550C and this temperature is maintained for 1 hour 30 minutes. The solvent is evaporated off and the residue is rectified in a bulbed tube.
Boiling point = 2000C under a pressure of 0.1 mm Hg.
The hydrochloride is prepared by adding a solution of hydrogen chloride in ether to a solution of the base in ethyl acetate.
Melting point = 141 OC.
Example 5.
1 -( m-Trifluoromethylthio-phenyl)-4-(2-methylthioethyl)-piperazine and its hydrochloride.
[n = 1, R = CH3SCH2] 0.84 g (0.0175 mol) of a 50% strength dispersion of sodium hydride is added in portions to a solution, cooled to +50 C, of 4.8 g (0.015 mol) of 1 -(m-trifluoromethylthio-phenyl)-4-(2- mercaptoethyl)-piperazine in 40 ml of DMF. When the evolution of hydrogen has ceased, a solution of 2.16 g (0.0152 mol) of methyl iodide in 20 ml of DMF is added dropwise. The reactants are left in contact overnight. The mixture is poured onto ice and the resulting mixture is extracted twice with ether The ether solution is dried over magnesium sulphate and evaporated.
The hydrochloride is prepared in ethyl acetate by adding the theoretical amount ofa solution of hydrogen chloride in ethanol.
Melting point = 1 350 C.
The following table (I) shows the compounds (I) and salts which have been prepared by way of example.
TABLE
Ckaracteristics of the hydrochloride.
Compound n R ' Melting point ( C) 1 2P 188-190 (decomposition) I I 3 2 - 230 (decomposition) 4 2 ~3 178-180 (decomposition) 5 3 - 224-227 (decomposition) 6 3 $ 196-199 C out (Example 1) 8 2 P3 260-263 (decomposition) (Example 2) TABLE (Continued)
Characteristics of the hydrochloride.
Compound n R Melting point ("C) 9 3) 1 210 (Example 3) 10 1 -CH2SH 141 (Example 4) 11 1 -CH2SCH3 135 (Example 5) 12 1 -CH2OCH3 151 13 1 -CH2-8-COCH3 168 14 1 -CH2-O-C4H9 140 The compounds (I) and salts are active in therapy in the field of the central nervous system.
This activity has been demonstrated and measured by the 4 plate test (C. Aron, Thesis in Medicine, Paris 1970; J. R. Boissier, P. Simon and C. Aron, Une nouvelle method de détermination des tranquillisants chez la souris. ("A new method for testing tranquillisers in mice"), Eur. J. Pharmacol.
1968,4,145-151).
The compounds are administered orally in several doses (1, 3 and 10 mg/kg), 60 minutes before the test. The percentage disinhibition in-the mice is measured.
At a dose of 1 mg/kg, the percentage varies from 35 to 70; at a dose of 3 mg/kg, it varies from 80 to 1 50 and at a dose of 10 mg/kg, it varies from 120 to 300.
For the same doses, the higher the percentage, the greater is the activity of the compound.
The acute toxicity (LD50) is determined on mice either by intraperitoneal administration after 48 hours or by oral administration for 7 days. The LD50 for intraperitoneal administration varies from 75 to 230 mg/kg. The LD50 for oral administration varies from 250 to 1,000 mg/kg.
The compounds (I) and salts possess psychotropic properties which permit their use for the treatment of various states of anxiety and of depression.
They can be administered orally or parenterally with any suitable excipient in any suitable form of administration, namely sugar-coated pills, tablets, capsules, dragees, injectable solutions and the like.
The daily posology can range from 5 to 200 mg.

Claims (15)

1. Phenylpiperazine derivatives of the general formula (I)
in which n is 1, 2 or 3 and R represents (i) a group of formula:
in which R, and R2 represent hydrogen atoms or together represent a group of formula
thereby completing a benzene ring fused to the heterocyclic ring shown in formula (A), X is -0-, -S-or an imino, alkylimino or methylene group and m is 0 or 1, or R represents (ii) a group of formula::
(iii) a 2-tetrahydrofuryl group, (iv) a group of formula -CH2-S-Z, Z representing a hydrogen atom, alkyl group or --CO-alkyl group or (v) a group of formula -CH2-O-alkyl, the alkyl groups having from 1 to 8 carbon atoms, and their pharmaceutically acceptable acid addition salts.
2. Compounds according to claim 1, in which n is 1 and R is a -CH2SH, -CH 2S-alkyl, -CH2-0- alkyl or-CH2SC0-alkyl group.
3. Compounds according to claim 2, in which R is aCH2SCH3,CH2OCH3 or QH2SCOCH3 group.
4. Compounds according to claim 1 wherein n and R have the meanings set out in the Table hereinbefore and the pharmaceutically acceptable salts thereof.
5. Compounds according to any preceding claim in the form of hydrochloride salts.
6. A process for the preparation of compounds according to claim 1, which process comprises reacting 1 -(m-trifluoromethylth iophenyl)piperazine of formula
with a compound of formula R(CH2)nY (III) in which R and n have the meanings given in claim 1, 2 or 3 and Y represents an anion of an activated alcohol derivative, and if desired converting a free base thereby obtained into a pharmaceutically acceptable acid addition salt.
7. A process according to claim 6 wherein Y represents a halogen atom or a ptoluenesulphonyloxy, methanesulphonyloxy or halogenomethanesulphonyloxy group.
8. A process according to claim 6 or 7 in which the reaction between compounds II and Ill is effected at a temperature of 20 to 1 500C in an organic solvent.
9. A process for the preparation of compounds according to claim 1 in which n is 1 and R is a -CH2SH group, which process comprises reacting 1 -(rn-trifluornmethylthiophenyl)piperazine with ethylene sulphide, and if desired converting a free base thereby obtained into a pharmaceutically acceptable acid addition salt.
10. A process for the preparation of compounds according to claim 1 in which R is a 2tetrahydrofuryl, -CH2O-alkyl or -CH2S-alkyl group, which process comprises reacting m (trifluoromethylthio)aniline with a diethylamine derivative of formula
in which R is as defined above, n is 1, 2 or 3 and Hal represents a halogen atom, and if desired converting a free base thereby obtained into a pharmaceutically acceptable acid addition salt.
11. A process for the preparation of compounds according to claim 1 in which R is a -CH2-S- alkyl orH2-S-CO-aIkyl group, which process comprises reacting a compound according to claim 1 in which R is a -CH2-SH group with an alkyl halide or alkylcarbonyl halide in which the alkyl group has from 1 to 8 carbon atoms.
12. A process according to claim 6 substantially as described in Example 1,2 or 3.
1 3. A process according to claim 9 substantially as described in Example 4.
14. A process according to claim 11 substantially as described in Example 5.
15. Compounds according to claim 1 when prepared by a process claimed in any one of claims 6 to 14.
1 6. Pharmaceutical compositions comprising a compound claimed in any one of claims 1 to 5 or in claim 1 5 in association with a pharmaceutically acceptable excipient.
GB7921307A 1978-06-20 1979-06-19 1-substituted alkyl -4 -piperazines Expired GB2023594B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7818351A FR2429212A1 (en) 1978-06-20 1978-06-20 PHENYLPIPERAZINE DERIVATIVES AND THEIR THERAPEUTIC APPLICATION
FR7818352A FR2429216A1 (en) 1978-06-20 1978-06-20 CNS-active substd. alkyl-meta:tri:fluoro:methyl:thio:phenyl-piperazine - with psychotropic properties, useful in treatment of anxiety and depression

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GB2023594A true GB2023594A (en) 1980-01-03
GB2023594B GB2023594B (en) 1982-10-13

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ES (1) ES481632A1 (en)
FI (1) FI791926A (en)
GB (1) GB2023594B (en)
GR (1) GR67646B (en)
IL (1) IL57569A0 (en)
IT (1) IT1121588B (en)
LU (1) LU81396A1 (en)
NL (1) NL7904755A (en)
NO (1) NO792020L (en)
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SE (1) SE7905402L (en)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4361565A (en) * 1981-12-28 1982-11-30 Mead Johnson & Company 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyridines
US4367335A (en) * 1981-08-03 1983-01-04 Mead Johnson & Company Thiazolidinylalkylene piperazine derivatives
DE3228992A1 (en) * 1981-08-03 1983-02-17 Bristol-Myers Co., 10154 New York, N.Y. SPIROTHIAZOLIDINDION DERIVATIVES, PRODUCTION OF THESE COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
DE3248160A1 (en) * 1981-12-28 1983-07-07 Bristol-Myers Co., 10154 New York, N.Y. 2- (4 - ((4,4-DIALKYL-2,6-PIPERIDINDION-1-YL) -BUTYL) -1-PIPERAZINYL) PYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS
US4411901A (en) * 1981-12-23 1983-10-25 Mead Johnson & Company Benzisothiazole and benzisoxazole piperazine derivatives
US4452799A (en) * 1981-12-23 1984-06-05 Mead Johnson & Company Benzisothiazole and benzisoxazole piperazine derivatives
EP0183349A1 (en) * 1984-10-26 1986-06-04 H. Lundbeck A/S Indane derivatives and methods of preparation and treatment
US4668687A (en) * 1984-07-23 1987-05-26 Bristol-Myers Company Psychogeriatric 1-(2-pyrimidinyl)piperazinyl derivatives of 1-pyrrolidin-2-ones
US5098904A (en) * 1990-06-27 1992-03-24 Bristol-Myers Squibb Company Cerebral function enhancing pyrimidinyl derivatives
EP0482696A1 (en) * 1990-10-23 1992-04-29 Akzo Nobel N.V. 4-[4- or 6-(Trifluoromethyl-2-pyridinyl)]-1-piperazinyl-alkyl substituted lactams
EP0526434A1 (en) * 1991-07-30 1993-02-03 BOEHRINGER INGELHEIM ITALIA S.p.A. Benzimidazolone derivatives as 5-HT1A and 5-HT2 antagonists
US5656633A (en) * 1991-05-08 1997-08-12 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives and pharmaceutical compositions containing the same for use as a disturbance-of-consciousness improving agent, central nervous system stimulant or sigma receptor agonist
EP0911330A1 (en) * 1997-10-22 1999-04-28 Council of Scientific & Industrial Research 1-(4-Arylpiperazine-1-y1)-3-(2-oxopyrrolidin/piperidin-1-y1) propanes as therapeutic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders
EP0913397A1 (en) * 1997-10-22 1999-05-06 Council of Scientific and Industrial Research A proces for the synthesis of 1-(4-Arylpiperazine-1-y1)-3-(2-oxypyrrolidin/piperidin-1-y1) propanes as therapeutic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders
US7151103B2 (en) 2001-10-20 2006-12-19 Boehringer Ingelheim Pharma Kg Method of treating female hypoactive sexual desire disorder with flibanserin
US7183410B2 (en) 2001-08-02 2007-02-27 Bidachem S.P.A. Stable polymorph of flibanserin
US7923449B2 (en) 2005-10-29 2011-04-12 Boehringer Ingelheim International Gmbh Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders
WO2012037634A1 (en) 2010-09-24 2012-03-29 Aché Laboratórios Farmacêuticos S.A. Compounds and pharmaceutical compositions for treating disorders associated with the 5-ht1a and 5-ht2a receptors
US8227476B2 (en) 2005-08-03 2012-07-24 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
US8512748B2 (en) 2006-08-25 2013-08-20 Boehringer Ingelheim International Gmbh Controlled release system and method for manufacturing the same
US8545886B2 (en) 2006-08-14 2013-10-01 Boehringer Ingelheim International Gmbh Extended release tablet formulations of flibanserin and method for manufacturing the same
US8658207B2 (en) 2006-08-14 2014-02-25 Boehringer Ingelheim International Gmbh Extended release tablet formulations of flibanserin and method for manufacturing the same
US9546141B2 (en) 2008-12-15 2017-01-17 Sprout Pharmaceuticals, Inc. Salts
US9763936B2 (en) 2006-06-30 2017-09-19 Sprout Pharmaceuticals, Inc. Flibanserin for the treatment of urinary incontinence and related diseases
US10166230B2 (en) 2007-09-12 2019-01-01 Sprout Pharmaceuticals Inc. Treatment of vasomotor symptoms
US10675280B2 (en) 2001-10-20 2020-06-09 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4367335A (en) * 1981-08-03 1983-01-04 Mead Johnson & Company Thiazolidinylalkylene piperazine derivatives
DE3228992A1 (en) * 1981-08-03 1983-02-17 Bristol-Myers Co., 10154 New York, N.Y. SPIROTHIAZOLIDINDION DERIVATIVES, PRODUCTION OF THESE COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
DE3228990A1 (en) * 1981-08-03 1983-03-03 Bristol-Myers Co., 10154 New York, N.Y. THIAZOLIDINDION DERIVATIVES, PRODUCTION OF THESE COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
US4411901A (en) * 1981-12-23 1983-10-25 Mead Johnson & Company Benzisothiazole and benzisoxazole piperazine derivatives
US4452799A (en) * 1981-12-23 1984-06-05 Mead Johnson & Company Benzisothiazole and benzisoxazole piperazine derivatives
US4361565A (en) * 1981-12-28 1982-11-30 Mead Johnson & Company 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyridines
DE3248138A1 (en) * 1981-12-28 1983-07-07 Bristol-Myers Co., 10154 New York, N.Y. 2- (4- (4,4-DIALKYL-2,6-PIPERIDINDION-1-YL) BUTYL) -1-PIPERAZINYL) PYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS
DE3248160A1 (en) * 1981-12-28 1983-07-07 Bristol-Myers Co., 10154 New York, N.Y. 2- (4 - ((4,4-DIALKYL-2,6-PIPERIDINDION-1-YL) -BUTYL) -1-PIPERAZINYL) PYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS
US4668687A (en) * 1984-07-23 1987-05-26 Bristol-Myers Company Psychogeriatric 1-(2-pyrimidinyl)piperazinyl derivatives of 1-pyrrolidin-2-ones
EP0183349A1 (en) * 1984-10-26 1986-06-04 H. Lundbeck A/S Indane derivatives and methods of preparation and treatment
US5098904A (en) * 1990-06-27 1992-03-24 Bristol-Myers Squibb Company Cerebral function enhancing pyrimidinyl derivatives
EP0482696A1 (en) * 1990-10-23 1992-04-29 Akzo Nobel N.V. 4-[4- or 6-(Trifluoromethyl-2-pyridinyl)]-1-piperazinyl-alkyl substituted lactams
US5656633A (en) * 1991-05-08 1997-08-12 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives and pharmaceutical compositions containing the same for use as a disturbance-of-consciousness improving agent, central nervous system stimulant or sigma receptor agonist
EP0526434A1 (en) * 1991-07-30 1993-02-03 BOEHRINGER INGELHEIM ITALIA S.p.A. Benzimidazolone derivatives as 5-HT1A and 5-HT2 antagonists
WO1993003016A1 (en) * 1991-07-30 1993-02-18 Boehringer Ingelheim Italia S.P.A. Benzimidazolone derivatives as 5-ht1a and 5-ht2 antagonists
US5576318A (en) * 1991-07-30 1996-11-19 Boehringer Ingelheim Italia S.P.A. Benzimidazolone derivatives
EP0911330A1 (en) * 1997-10-22 1999-04-28 Council of Scientific & Industrial Research 1-(4-Arylpiperazine-1-y1)-3-(2-oxopyrrolidin/piperidin-1-y1) propanes as therapeutic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders
EP0913397A1 (en) * 1997-10-22 1999-05-06 Council of Scientific and Industrial Research A proces for the synthesis of 1-(4-Arylpiperazine-1-y1)-3-(2-oxypyrrolidin/piperidin-1-y1) propanes as therapeutic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders
US7420057B2 (en) 2001-08-02 2008-09-02 Boehringer Ingelheim Pharma Kg Stable polymorph of flibanserin
US7183410B2 (en) 2001-08-02 2007-02-27 Bidachem S.P.A. Stable polymorph of flibanserin
US7151103B2 (en) 2001-10-20 2006-12-19 Boehringer Ingelheim Pharma Kg Method of treating female hypoactive sexual desire disorder with flibanserin
US11058683B2 (en) 2001-10-20 2021-07-13 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US10675280B2 (en) 2001-10-20 2020-06-09 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US9468639B2 (en) 2001-10-20 2016-10-18 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US9782403B2 (en) 2001-10-20 2017-10-10 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US8227476B2 (en) 2005-08-03 2012-07-24 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
US10874668B2 (en) 2005-08-03 2020-12-29 Sprout Pharmaceuticals, Inc. Use of Flibanserin in the treatment of obesity
US10335407B2 (en) 2005-08-03 2019-07-02 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
US9730927B2 (en) 2005-08-03 2017-08-15 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
US7923449B2 (en) 2005-10-29 2011-04-12 Boehringer Ingelheim International Gmbh Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders
US10004731B2 (en) 2006-06-30 2018-06-26 Sprout Pharmaceuticals, Inc. Flibanserin for the treatment of urinary incontinence and related diseases
US9763936B2 (en) 2006-06-30 2017-09-19 Sprout Pharmaceuticals, Inc. Flibanserin for the treatment of urinary incontinence and related diseases
US8545886B2 (en) 2006-08-14 2013-10-01 Boehringer Ingelheim International Gmbh Extended release tablet formulations of flibanserin and method for manufacturing the same
US8658207B2 (en) 2006-08-14 2014-02-25 Boehringer Ingelheim International Gmbh Extended release tablet formulations of flibanserin and method for manufacturing the same
US8512748B2 (en) 2006-08-25 2013-08-20 Boehringer Ingelheim International Gmbh Controlled release system and method for manufacturing the same
US10166230B2 (en) 2007-09-12 2019-01-01 Sprout Pharmaceuticals Inc. Treatment of vasomotor symptoms
US9546141B2 (en) 2008-12-15 2017-01-17 Sprout Pharmaceuticals, Inc. Salts
WO2012037634A1 (en) 2010-09-24 2012-03-29 Aché Laboratórios Farmacêuticos S.A. Compounds and pharmaceutical compositions for treating disorders associated with the 5-ht1a and 5-ht2a receptors

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NZ190758A (en) 1980-10-24
IT7923695A0 (en) 1979-06-18
NL7904755A (en) 1979-12-27
LU81396A1 (en) 1981-02-03
ES481632A1 (en) 1980-02-16
IL57569A0 (en) 1979-10-31
AU4811279A (en) 1980-02-07
GB2023594B (en) 1982-10-13
SE7905402L (en) 1979-12-21
PT69775A (en) 1979-07-01
IT1121588B (en) 1986-04-02
DK251079A (en) 1979-12-21
DE2924681A1 (en) 1980-01-10
GR67646B (en) 1981-09-01
AU521110B2 (en) 1982-03-18
NO792020L (en) 1979-12-21

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