WO1988007528A1 - Bisphenylalkylpiperazine derivatives, a method of their preparation and a pharmaceutical preparation - Google Patents

Bisphenylalkylpiperazine derivatives, a method of their preparation and a pharmaceutical preparation Download PDF

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Publication number
WO1988007528A1
WO1988007528A1 PCT/SE1988/000144 SE8800144W WO8807528A1 WO 1988007528 A1 WO1988007528 A1 WO 1988007528A1 SE 8800144 W SE8800144 W SE 8800144W WO 8807528 A1 WO8807528 A1 WO 8807528A1
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hydrogen
lower alkyl
halogen
different
same
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PCT/SE1988/000144
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French (fr)
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Tomas Fex
Knut Gunnar Olsson
Aina Lisbeth Abramo
Erik Gunnar Christensson
Torbjörn Erik LUNDSTEDT
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Aktiebolaget Leo
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Priority to JP63503107A priority Critical patent/JPH0819104B2/en
Priority to HU882510A priority patent/HU201051B/en
Priority to AT88903427T priority patent/ATE85334T1/en
Priority to DE8888903427T priority patent/DE3878111T2/en
Publication of WO1988007528A1 publication Critical patent/WO1988007528A1/en
Priority to FI885560A priority patent/FI92320C/en
Priority to DK671588A priority patent/DK161313C/en
Priority to NO885386A priority patent/NO172640C/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/24—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
    • 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
    • C07D213/72—Nitrogen atoms
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Antipsychotic drugs in current use produce a range of troublesome extrapyramidal movement disorders (e.g. acute dystonic reactions and tardive dyskinesia) and are poor in ameliorating the negative symptoms (e.g. restricted or blunted emotional arousal) of schizophrenia.
  • the main disadvantage of the antidepressants is that they fail to alleviate depression in 30 to 40 % of patients.
  • Anxiolytics are commonly associated with addictive properties.
  • Azaperone a neuroleptic drug of the butyrophenone series
  • Buspirone is an anxiolytic. The anxiolytic effect is thought to be mediated via effects on the 5HT-receptors.
  • Pyridyl- and pyrimidyl-piperazines substituted in the 4-position of the piperazine ring with a highly lipophilic diphenyl-butyl group have unexpectedly been found to exhibit pharmacological properties superior to compounds known in the art.
  • R 1 and R 2 are the same or different and selcted from hydrogen and halogen; R 3 and R 4 are the same or different and selected from hydrogen and lower alkyl; n is 2 or 3; A is selected from the following pyrimidyl or pyridyl groups
  • R 5 is selected from hydrogen, lower alkyl or halogen
  • R 6 and R 7 are the same or different and selected from hydrogen, halogen, lower alkyl, electron donor groups such as lower alkoxy or hydroxy, electron acceptor groups such as cyano, nitro, trifluoromethyl, COOR 8 , COHR 9 R 10 or CO-B
  • R 8 is hydrogen or lower alkyl
  • R 9 and R 10 are the same or different and selected from hydrogen, lower alkyl and cycloalkyl
  • B is selected from
  • m 1, 2, 3 or 4.
  • R 11 is selected from hydrogen or lower alkyl, and the pharmacologically active salts thereof,
  • lower alkyl is meant to include straight and branched, saturated and unsaturated hydrocarbon groups having from 1 to 5 carbon atoms;
  • cycloalkyl is meant to include cyclic, saturated and unsaturated hydrocarbon groups having from 3 to 8 carbon atoms;
  • lower alkoxy is meant to include straight or branched, saturated or unsaturated alkoxy groups having from 1 to 5 carbon atoms;
  • halogen is meant to include fluoro, chloro and bromo. It is preferred that one of R 1 and R 2 is different from hydrogen and when one or both of R 1 and R 2 are halogen fluoro is preferred.
  • R 3 and R 4 hydrogen or methyl are preferred, especially hydrogen.
  • R 5 hydrogen, methyl, or halogen, especially fluoro, is preferred.
  • R 6 hydrogen, methyl, alkoxy, amide, nitro, trifluoromethyl, halogen or cyano is preferred.
  • R 7 is hydrogen, methyl, alkoxy, nitro, halogen, cyano or an amide group.
  • the compounds of formula (I) have basic properties and, consequently, they may be converted to their therapeutically active acid addition salts by treatment with appropriated acids ; e . g. inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid, or organic acids such as acetic, propanoic, glycolic, lactic, malonic, oxalic, succinic, fumaric, tartaric, citric and pamoic acid.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid
  • organic acids such as acetic, propanoic, glycolic, lactic, malonic, oxalic, succinic, fumaric, tartaric, citric and pamoic acid.
  • salt form can be converted into the free base form by treatment with alkali.
  • the compounds of formula (I) a.nd their pharmaceutically acceptable salts have valuable pharmacological properties, making them useful .for the treatment of mental disorders such as psychoses, depression and anxiety. Stress and anxiety in animals can also be treated. It has been assumed that the antipsychotic actions of neuroleptic drugs are inextricably linked to their ability to produce extrapyramidal side-effects, possibly by an action at a common site. This assumption is now being questioned since antipsychotic drugs nowadays exist with a reduced potential to produce these side-effects. Thus, it is thought that the two main actions of classical neuroleptic drugs, i.e. antipsychotic action and ability to produce extrapyramidal syndromes, are mediated by actions at different sites in the brain.
  • the neuroleptic drugs may produce their therapeutic antipsychotic effects by an action on the mesolimbic system.
  • this site in the brain is usually assumed to be the region where the neuroleptic drugs produce their extrapyramidal side-effects.
  • inhibition of amphetamine induced hypermotility in rodents measures the limbic effect whereas it is generally accepted that the ability of neuroleptics to induce catalepsy in rodents correlates well with the risk of extrapyramidal side-effects .
  • the compounds of the present invention show neuroleptic properties since they affect amphetamine-induced hypermotility, but show weak or no cataleptogenic activity. They show a high affinity for D 2 and 5-HT 2 receptors in the brain.
  • a high 5HT 2 -receptor binding affinity may indicate antidepressant properties, since many antidepressants (e.g. amitriptyline) are potent 5HT 2 -blockers.
  • a high 5HT 2 -receptor binding affinity also suggests anxiolytic properties.
  • Effective quantities of any of the foregoing pharmacologically active compounds of formula (I) may be administered to a human being or an animal for therapeutic purposes accoding to usual routes of administration and in usual forms, such as orally in solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutically acceptable carriers and parenterally in the for of sterile solutions.
  • the carrier of excipient may be a sterile, parenterally acceptable liquid, e.g. water, or a parenterally acceptable oil, e.g. arachidic oil.
  • unit dosages are usually from 2 milligrams upwards, preferably 10, 25 or 50 milligrams or even higher depending on the condition to be treated and the age and weight of the patients as well as the response to the medication.
  • the unit dose may be from 0.1 to 100 milligrams, preferably from 10 to 50 milligrams. Daily dosages should preferably range from 10 milligrams to 200 milligrams. The exact individual dosages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian. Methods of preparation
  • the compounds having the general formula (I) may be prepared by conventional methods.
  • a compound of formula (II), wherein R 1 and R 2 are as previously defined and Y is a suitable leaving group such as halogen and alkyl- or arylsulfonate is reacted with a compound of formula (III) wherein R 3 , R 4 , A and n are as defined previously.
  • the reactions may be carried out using standard N-alkylating procedures.
  • a compound of formula (IV), wherein R 1 , R 2 , R 3 , R 4 and n are as previously defined is reacted with a compound of formula (V), (VI), (VII) or (VIII), wherein R 5 , R 6 and R 7 are as previously defined and Z is a leaving group, e.g. halogen.
  • This example illustates the potency of compounds of formula (I) and their pharmaceutically active salts for treatment of mental disorders.
  • Test 1 Antagonism of amphetamine-induced hypermotility
  • mice Female NMRI-mice, weighing about 25 g are divided into groups of 4 animals and placed in macrolon cages. The cages are placed on recording arenas in nine sound attenuated boxes with constant light and ventilation . After a familiarization period of 90 minutes the mice are brought up from the cages and treated in the following way; one control group receives saline i.p., one control group receives d-amphetamine sulphate, 2 mg/kg i.p. and test animals are treated s.c. with. three different doses of the test compound and immediately thereafter with d-amphetamine 2 mg/kg i.p.
  • the ED 50 -value (mgAg) is calculated from the dose-response curve by means of linear regression.
  • the ED 50 -value represents a dose of test compound reducing the motility to the midpoint between amphetamine and saline controls.
  • the binding assay is carried out essentially as described by Leysen et al., (Mol. Pharmacol. 21, 301-14, 1982) using 3 H-spiroperidol as ligand.
  • the binding assay is carried out essentially as described by Leysen et al., (Mol. Pharmacol. 21, 301-14, 1982) using 3 H-ketanserine as ligand. TABLE 1. Antagonism of amphetamine induced hypermotility in mice
  • the amount of lactose used may be reduced.
  • Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to about 5% by weight.
  • These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.

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Abstract

The present invention concerns novel compounds of formula (I), wherein R1? and R2? are the same or different and selected from hydrogen and halogen; R3? and R4? are the same or different and selected from hydrogen and lower alkyl; n is 2 or 3; A is selected from the pyrimidyl or pyridyl groups (a), (b), (c), (d), wherein R5? is selected from hydrogen, lower alkyl or halogen; R6? and R7? are the same or different and selected from hydrogen, halogen, lower alkyl, electron donor groups such as lower alkoxy or hydroxy, electron acceptor groups such as cyano, nitro, trifluoromethyl, COOR8?, CONR9?R10? or CO-B; wherein R8? is hydrogen or lower alkyl; R9? and R10? are the same or different and selected from hydrogen, lower alkyl and cycloalkyl; B is selected from (e), (f), wherein m is 1, 2, 3 or 4. R11? is selected from hydrogen or lower alkyl, and the pharmacologically active salts thereof. The new compounds can be used for treating mental disorders.

Description

Bisphenylalkylpiperazine derivatives, a method of their prepation and a Title: pharmaceutical preparation. Background
There is an urgent need for novel drugs in the treatment of mental disorders which are more effective and which have fewer side effects than the drugs in clinical use today. Antipsychotic drugs in current use produce a range of troublesome extrapyramidal movement disorders (e.g. acute dystonic reactions and tardive dyskinesia) and are poor in ameliorating the negative symptoms (e.g. restricted or blunted emotional arousal) of schizophrenia. The main disadvantage of the antidepressants is that they fail to alleviate depression in 30 to 40 % of patients. Anxiolytics are commonly associated with addictive properties.
Prior art
Various pyridyl- and pyrimidyl-piperazine derivatives pharmacologically active in the central nervous system are known in the art. Some representative examples can be mentioned. Azaperone, a neuroleptic drug of the butyrophenone series, is a sedative for pigs. Buspirone is an anxiolytic. The anxiolytic effect is thought to be mediated via effects on the 5HT-receptors.
Figure imgf000003_0001
Description of the invention
Pyridyl- and pyrimidyl-piperazines substituted in the 4-position of the piperazine ring with a highly lipophilic diphenyl-butyl group have unexpectedly been found to exhibit pharmacological properties superior to compounds known in the art.
According to the invention there are provided novels compounds having the general formula (I).
Figure imgf000004_0001
wherein R1 and R2 are the same or different and selcted from hydrogen and halogen; R3 and R4 are the same or different and selected from hydrogen and lower alkyl; n is 2 or 3; A is selected from the following pyrimidyl or pyridyl groups
Figure imgf000004_0002
wherein R5 is selected from hydrogen, lower alkyl or halogen; R6 and R7 are the same or different and selected from hydrogen, halogen, lower alkyl, electron donor groups such as lower alkoxy or hydroxy, electron acceptor groups such as cyano, nitro, trifluoromethyl, COOR8, COHR9R10 or CO-B; wherein R8 is hydrogen or lower alkyl; R9 and R10 are the same or different and selected from hydrogen, lower alkyl and cycloalkyl; B is selected from
Figure imgf000005_0001
wherein m is 1, 2, 3 or 4.
R11 is selected from hydrogen or lower alkyl, and the pharmacologically active salts thereof,
and when used in the foregoing definitions the term lower alkyl is meant to include straight and branched, saturated and unsaturated hydrocarbon groups having from 1 to 5 carbon atoms;
the term cycloalkyl is meant to include cyclic, saturated and unsaturated hydrocarbon groups having from 3 to 8 carbon atoms;
the term lower alkoxy is meant to include straight or branched, saturated or unsaturated alkoxy groups having from 1 to 5 carbon atoms;
the term halogen is meant to include fluoro, chloro and bromo. It is preferred that one of R1 and R2 is different from hydrogen and when one or both of R1 and R2 are halogen fluoro is preferred.
As regards R3 and R4 hydrogen or methyl are preferred, especially hydrogen.
As regards R5 hydrogen, methyl, or halogen, especially fluoro, is preferred.
As regards R6 hydrogen, methyl, alkoxy, amide, nitro, trifluoromethyl, halogen or cyano is preferred.
It is preferred that R7 is hydrogen, methyl, alkoxy, nitro, halogen, cyano or an amide group.
Compounds wherein A is 2-substituted pyridyl are of special interest, especially those carrying an methoxy, amide, cyano or hydrogen substituent in the 3-position.
The compounds of formula (I) have basic properties and, consequently, they may be converted to their therapeutically active acid addition salts by treatment with appropriated acids ; e . g. inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid, or organic acids such as acetic, propanoic, glycolic, lactic, malonic, oxalic, succinic, fumaric, tartaric, citric and pamoic acid.
Conversely, the salt form can be converted into the free base form by treatment with alkali.
The compounds of formula (I) a.nd their pharmaceutically acceptable salts have valuable pharmacological properties, making them useful .for the treatment of mental disorders such as psychoses, depression and anxiety. Stress and anxiety in animals can also be treated. It has been assumed that the antipsychotic actions of neuroleptic drugs are inextricably linked to their ability to produce extrapyramidal side-effects, possibly by an action at a common site. This assumption is now being questioned since antipsychotic drugs nowadays exist with a reduced potential to produce these side-effects. Thus, it is thought that the two main actions of classical neuroleptic drugs, i.e. antipsychotic action and ability to produce extrapyramidal syndromes, are mediated by actions at different sites in the brain. The neuroleptic drugs may produce their therapeutic antipsychotic effects by an action on the mesolimbic system. On the other hand, since the main function of the nigrostriatal dopaminergic pathway is the control of motor performance, this site in the brain is usually assumed to be the region where the neuroleptic drugs produce their extrapyramidal side-effects. Experimentally, inhibition of amphetamine induced hypermotility in rodents measures the limbic effect whereas it is generally accepted that the ability of neuroleptics to induce catalepsy in rodents correlates well with the risk of extrapyramidal side-effects .
The compounds of the present invention show neuroleptic properties since they affect amphetamine-induced hypermotility, but show weak or no cataleptogenic activity. They show a high affinity for D2 and 5-HT2 receptors in the brain. A high 5HT2-receptor binding affinity may indicate antidepressant properties, since many antidepressants (e.g. amitriptyline) are potent 5HT2-blockers. A high 5HT2-receptor binding affinity also suggests anxiolytic properties. A novel anxiolytic, ritanserine, labels preferentially the 5-HT2 binding site. Effective quantities of any of the foregoing pharmacologically active compounds of formula (I) may be administered to a human being or an animal for therapeutic purposes accoding to usual routes of administration and in usual forms, such as orally in solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutically acceptable carriers and parenterally in the for of sterile solutions. For the parenteral administration of the active substance the carrier of excipient may be a sterile, parenterally acceptable liquid, e.g. water, or a parenterally acceptable oil, e.g. arachidic oil.
Although very small quantities of the active materials of the present invention are effective when minor therapy is involved or in the cases of administration to subjects having a relatively low body weight, unit dosages are usually from 2 milligrams upwards, preferably 10, 25 or 50 milligrams or even higher depending on the condition to be treated and the age and weight of the patients as well as the response to the medication.
The unit dose may be from 0.1 to 100 milligrams, preferably from 10 to 50 milligrams. Daily dosages should preferably range from 10 milligrams to 200 milligrams. The exact individual dosages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian. Methods of preparation
The compounds having the general formula (I) may be prepared by conventional methods.
Method 1
Figure imgf000009_0001
A compound of formula (II), wherein R1 and R2 are as previously defined and Y is a suitable leaving group such as halogen and alkyl- or arylsulfonate is reacted with a compound of formula (III) wherein R3, R4, A and n are as defined previously. The reactions may be carried out using standard N-alkylating procedures.
Method 2
Figure imgf000009_0002
A compound of formula (IV), wherein R1, R2, R3, R4 and n are as previously defined is reacted with a compound of formula (V), (VI), (VII) or (VIII), wherein R5, R6 and R7 are as previously defined and Z is a leaving group, e.g. halogen.
Examples
The following examples are intended to illustrate but not to limit the scope of the invention, although the compounds named are of particular interest for our intended purposes. These compounds have been designated by a number code, a:b, where a means the number of the example, wherein the preparation of the compound in question is described, and b refers to the order of the compounds prepared according to that example. Thus, compound 1:2 means the second compound prepared according to Example 1.
The structures of the compound are confirmed by NMR, massspectra and elementary analysis. When melting points are given, these are uncorrected.
Example 1
4-/4,4-bis(p-fluorophenyl)butyl/-1-(5-chloro-2-pyridyl)-pip razine dihydrochloride
19.8 g (0.06 mole) of 1-/4,4-bis (p-fluorophenyl)butyl/-piperazine and 2.96 g (0.02 mole) of 2,5-dic)ιloropyridine were heated together with 2 ml of toluene at 130°C (temperature of oil bath) for 20 h. After cooling the reaction mixture was partitioned between ligroin and MeOH/H2O (3:1). The MeOH/H2O phase was extracted an additional time with ligroin and the collected ligroin phases were dried with Na2SO4. Evaporation of the solvents yielded crude free base, which was dissolved in ether and the hydrochloride was precipitated with excess HCl in EtOH. Recrystallization. from EtOAc/EtOH yielded 4.3 g (42%) of the title compound (1:1), m.p. 173-6°.
Using essentially the same procedure the following compounds were prepared (isolated as the free bases or as the corresponding salts) from the corresponding starting materials.
1:2 4-/4,4-bis(p-fluorophenyl)butyl/-1-(6-methyl-2- pyridyl)-piperazine oxalate, m.p. 172-4°C 1:3
4-/4,4-bis(p-fluorophenyl)butyl/-1-(6-methoxy-2- pyridyl)-piperazine fumarate, m.p. 175-7°C
1:4 4-/4,4-bis(p-fluorophenyl)butyl/l-(3-trifluoro- methyl-2-pyridyl)-piperazine, monohydrochloride isopropanol, m.p. 94-95°C (sintered) 1:5 4-/4,4-bis(p-fluorophenyl)butyl/-1-(5-trifluoro- methyl-2-pyridyl)-piperazine monohydrochloride m.p. 197-9°C 1:6 4-/4,4-bis.(p-fluorophenyl)butyl/-1-(3-carbamoyl- 2-pyridyl)piperazine dihydrochloride, m.p. 208-10°C 1:7 4-/4,4-bis(p-fluorophenyl)butyl/-1-(5-carbamoyl-2- pyridyl)-piperazine dihydrochloride, m.p. 250°C 1:8 4-/4,4-bis(p-fluorophenyl)butyl/-1-/3-(N-methyl- carbamoyl)-2-pyridyl/-piperazine dihydrochloride d. 185°C 1:9 4-/4,4-bis(p-fluorophenyl)butyl/-1-/3-(N,N- dimethyl-carbamoyl)-2-pyridyl/-piperazine fumarate m.p, 182-3°C 1:10 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-morpholino- carbonyl-2-pyridyl)-piperazine oxalate m.p. 183-5°C
1:11 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-pyrrolidino- carbonyl-2-pyridyl)-piperazine fumarate m.p. 194-5°C
1:12 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-cyano-2- pyridyl)piperazine oxalate m.p. 180-1°C 1:13 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-nitro-2- pyridyl)-piperazine monohydrochloride, mp. 147-8°C 1:14 4-/4 ,4-bis(p-fluorophenyl)butyl/-1-(5-nitro-2- pyridyl)-piperazine hydrochloride m.p. 214-6°C 1:15 4-/4,4-bis(p-fluorophenyl)butyl/-1-(2-pyridyl)- (1,4-diaza-cycloheptane) x 2.5 oxalate m.p. 115-8°C 1:16 4-/4,4-bis(p-fluorophenyl)butyl/-1-(2-pyridyl)- trans-2,5-dimethylpiperazine oxalate m.p. 141-2°C
1:17 4-/4,4-bis(p-fluorophenyl)butyl/-1-/2-(methyl- pyridine-5-carboxylate)-yl/piperazine dihydrochloride ethanol m.p. 153 (sintered) 1:18 4-/4,4-bis(p-fluorophenyl\butyl/-1-(4-pyridyl)- piperazine difumarate m.p. 191-2°C
1:19 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-methyl-2- pyridyl piperazine dihydrochloride hemi-isopropanol m.p. 207-9°C 1:20 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-methoxy-2- pyridyl)-piperazine oxalate d. 187-8°C
1:21 4-/4,4-bis(p-fluorophenyl)butyl/-1-(6-chloro-2- pyridyl)-piperazine hydrochloride m.p. 172-3°C 1:22 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-chloro-2- pyridyl)-piperazine fumarate m.p. 145-6ºC 1 :23 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-carboxy-2- pyridyl)-piperazine dihydrochloride ethanol m.p. 185°C (sinters) m.p. 210°C
1:24 4-/4,4-bis(p-fluorophenyl)butyl/-1-/3-(4-methyl- piperidinocarbonyl)-2-pyridyl/-piperazine fumarate m.p. 191-2°C 1 : 25 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-carbamyl-2- pyridyl)-1,4-diazacycloheptane dihydrochloride hemihydrate m.p. 176-79°C (sintered) 1:26 4-[4,4- bis (p-fluorophenyl)butyl]-1-(3-trifluoromethyl)-6- chloro-2-pyridyl)-piperazine hydrochloride m.p. 141-2°C 1:27 4-/4,4-bis(3,4-difluorophenyl)butyl(-1-(2-pyridyl)- piperazine dihydrochloride, hydrate m.p. 169-70°C 1:28 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-hydroxy-2- pyridyl)-piperazine 1:29 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-pyridyl)- piperazine
1:30 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-carbamoyl-6- methyl-2-pyridyl)piperazine 1:31 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-carbamoyl-6- chloro-2-pyridyl)piperazine 1:32 4-/4,4-bis(p-fluorophenyl)butyl/-1-(4-methyl-2- pyridyl)-piperazine 1:33 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-ethoxy-2- pyridyl)-piperazine 1:34 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-propoxy-2- pyridyl)-piperazine
1:35 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-isopropoxy-2 pyridyl)-piperazine 1:36 4-/4,4-bis(p-fluorophenyl)butyl/-1-(3-cyclohexoxy- 2-pyridyl)-piperazine Example 2
4-/4,4-bis(p-fluorophenyl)butyl/-1-(2-pyrimidyl)-piperazinehydrochloride
8.3 g ( 0.025 mole) of 1-/4,4-bis(p-fluorophenyl)butyl/-piperazine and 3.1 g (0.027 mole) of 2-chloropyrimidin were heated in 5 ml DMF at 150°C until TLC showed the disappearance of the starting piperazine derivative. After cooling EtOAc (50 ml) and EtOH (enough to get a clear solution) were added. Ether was added, whereby the desired product crystallized. Recrystallization from EtOH, EtOAc + ether yielded 7.3 g (65%) of the title compound (2:1), m.p. 195-97°C.
Example 3
4-/4,4-bis(p-fluorophenyl)butyl/-1-(2-pyridyl)-piperazinedihydrochloride
3.3 g (0.01 mole) of 1-chloro-4,4-bis (p-fluorophenyl)butane, 3.3 g (0.02 mole) of 1-(2-pyridyl)-piperazine and 0.05 g of KI were refluxed in 15 ml of toluene for 48 h. After cooling and addition of ether (30 ml) 1-(2-pyridyl)-piperazine hydrochloride precipitated and was filtered off. After subsequent washing several times with H2O the organic layer was dried with K2CO3. Evaporation of the solvent yielded the crude base. This was dissolved in ether and HCl in EtOH was added to precipitate the hydrochloride. Recrystallization from EtOAc/EtOH yielded 3.2 g (67%) of the title compound (2:1), m.p. 224-27°C.
Using essentially the same procedure the following compounds are prepared (isolated as the free bases or as the corresponding salts) from the corresponding starting materials. 3:2 4-/4,4-bis(p-fluorophenyl)butyl/-1-(5-fluoro-2- pyrimidyl)-piperazine
Example 4
This example illustates the potency of compounds of formula (I) and their pharmaceutically active salts for treatment of mental disorders.
Test 1 - Antagonism of amphetamine-induced hypermotility
in mice
A low dose (2 mgAg) of d-amphetamine administered to mice induced pronounced locomotor activity.
Test procedure
Female NMRI-mice, weighing about 25 g are divided into groups of 4 animals and placed in macrolon cages. The cages are placed on recording arenas in nine sound attenuated boxes with constant light and ventilation . After a familiarization period of 90 minutes the mice are brought up from the cages and treated in the following way; one control group receives saline i.p., one control group receives d-amphetamine sulphate, 2 mg/kg i.p. and test animals are treated s.c. with. three different doses of the test compound and immediately thereafter with d-amphetamine 2 mg/kg i.p. Immediately after the administration the macrolon cages with the mice are put back into the test boxes and a computerized equipment records the locomotor activity in the cages for 90 minutes. For each test compound 4 cages are treated with saline, 4 cages with only d-amphetamine and 6 cages/dose test compoud + d-amphetamine. This is the total of three different experiments.
Data analysis
For each treatment group the mean number of counts during 90 minutes following the administration is calculated.
The ED50-value (mgAg) is calculated from the dose-response curve by means of linear regression. The ED50-value represents a dose of test compound reducing the motility to the midpoint between amphetamine and saline controls.
Test 2 - Affinity to D2-receptors
The binding assay is carried out essentially as described by Leysen et al., (Mol. Pharmacol. 21, 301-14, 1982) using 3H-spiroperidol as ligand.
Test 3 - Affinity to 5HT2-receptors
The binding assay is carried out essentially as described by Leysen et al., (Mol. Pharmacol. 21, 301-14, 1982) using 3H-ketanserine as ligand. TABLE 1. Antagonism of amphetamine induced hypermotility in mice
Compound ED50 mgAg s.c.
3:1 0.1
1:6 0.3
TABLE 2. Affinity to D2-receptors
Compound Ki (nM)
3:1 60 1:6 30 1:15 25
TABLE 3. Affinity to 5HT2-receptors
Compound Ki (nM)
3:1 5.8
1:6 2.1 1:15 1.3
The compounds listed in table 1, 2 and 3 are not given for the purpose of limiting the invention theretb but only to exemplify the useful pharmacological activities of compound within the scope of formula (I). Example 5
The following formulations are reprsentative for all of the pharmacologically active compounds of this invention. Example of a suitable capsule formulation:
Per capsule, mg
Active ingredient. as salt 10
Lactose 250
Starch 120
Magnesium stearate 5
Total 385
In case of higher amounts of active ingredient, the amount of lactose used may be reduced.
Example of a suitable tablet formulation:
Per tablet, mg
Active ingredient, as salt 10
Potato starch 90
Colloidal Silica 10
Talc 20
Magnesium stearate 2
5% aqueous solution of gelatin 25
Total 157
Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to about 5% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.

Claims

1. Novel compounds having the general formula (I)
Figure imgf000019_0001
wherein R1 och R2 are the same or different and selected from hydrogen and halogen; R3 and R4 are the same or different and selected from hydrogen and lower alkyl; n is 2 or 3;
A is selected from the following pyrimidyl or pyridyl groups :
Figure imgf000019_0002
wherein R5 is selected from hydrogen, lower alkyl or halogen; R6 and R7 are the same or different and selected from hydrogen, halogen, lower alkyl, electron donor groups such as lower alkoxy or hydroxy, electron acceptor groups such as cyano, nitro, trifluoromethyl, COOR8, CONR9R10 or CO-B; wherein R8 is hydrogen or lower alkyl; R9 and R10 are the same or different and selected from hydrogen, lower alkyl and cycloalkyl; B is selected from
Figure imgf000020_0001
wherein m is 1, 2, 3 or 4. R11 is selected from hydrogen or lower alkyl, and the pharmacologically active salts thereof.
2. Compounds according to claim 1 wherein one of R1 and R2 is halogen, preferably fluoro.
3. Compounds according to claim 1 or 2, wherein R3 and R4 are hydrogen or methyl, preferably hydrogen.
4. Compounds according to claim 1, 2 or 3, wherein A is
Figure imgf000020_0002
5. Compounds according to claim 4, wherein R6 is hydrogen, methyl, trifluoromethyl, alkoxy, amide, nitro or cyano and R7 is hydrogen, methyl, methoxy, nitro, halogen, cyano or an amide group.
6. Compounds according to claim 5, wherein R6 is hydrogen, methyl, or trifluoromethyl and R7 is alkoxy, nitro, halogen, cyano or an amide group and R7 is situated in the 3-position.
7. Compounds according to claim 6, wherein R6 is hydrogen and R7 is hydrogen, cyano, nitro, alkoxy or an amide substituent.
8. Compounds according to claim 7 wherein R7 is an amide, hydrogen, cyano or methoxy substituent.
9. A method of preparing compounds having the general formula (I)
Figure imgf000021_0001
wherein R1 and R2 are the same or different and selected from hydrogen and halogen; R3 and R4 are the same or different and selected from hydrogen and lower alkyl; n is 2 or 3; A is selected from the following pyrimidyl or pyridyl groups:
Figure imgf000022_0001
wherein R5 is selected from hydrogen, lower alkyl, or halogen; R6 and R7 are the same or different and selected from hydrogen, halogen, lower alkyl, electron donor groups such as lower alkoxy or hydroxy, electron acceptor groups such as cyano, nitro, trifluoromethyl, COOR8, CONR9R10 or CO-B; wherein R8 is hydrogen or lower alkyl; R9 and R10 are the same or different and selected from hydrogen, lower alkyl and cycloalkyl; B is selected from
Figure imgf000022_0002
wherein m is 1, 2, 3 or 4. R11 is selected from hydrogen or lower alkyl, and the pharmacologically active salts thereof, wherein a compound having the general formula (II)
Figure imgf000023_0001
wherein R1 and R2 are as defined above and X is a leaving group, is reacted with a compound having the general formula (III)
Figure imgf000023_0002
wherein R3, R4 n and A are as defined above
or wherein a compound having the general formula (IV)
Figure imgf000023_0003
wherein R1, R2, R3, R4 and n are as previously defined, is reacted with a compound having the formula (V), (VI), (VII) or (VIII):
Figure imgf000024_0001
R5, R6 and R7 are as previously defined and Z is a leaving group.
10. Pharmaceutical compositions containing as an active ingredient one or more of the compounds having the general formula (I), preferably together with a pharmaceutically acceptable carrier and, if desired, other pharmacologically active agents.
11. A method of treating a living body suffering from a mental disorder, which comprises the step of administering to said living animal body a compound having the general formula (I).
PCT/SE1988/000144 1987-04-02 1988-03-25 Bisphenylalkylpiperazine derivatives, a method of their preparation and a pharmaceutical preparation WO1988007528A1 (en)

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JP63503107A JPH0819104B2 (en) 1987-04-02 1988-03-25 Novel pyridyl and pyrimidyl derivatives
HU882510A HU201051B (en) 1987-04-02 1988-03-25 Bisphenylalkylpiperazine derivatives, a method of their preparation and a pharmaceutical preparation
AT88903427T ATE85334T1 (en) 1987-04-02 1988-03-25 BISPHENYLALKYLPIPERAZINE DERIVATIVES, METHOD OF MANUFACTURE AND DRUG PREPARATION.
DE8888903427T DE3878111T2 (en) 1987-04-02 1988-03-25 BISPHENYLALKYLPIPERAZINE DERIVATIVES, METHOD FOR THE PRODUCTION AND PREPARATION OF MEDICINAL PRODUCTS.
FI885560A FI92320C (en) 1987-04-02 1988-11-30 Process for the preparation of new therapeutically useful bisphenylalkylpiperazine derivatives
DK671588A DK161313C (en) 1987-04-02 1988-12-01 4- (BIS-FLUORPHENYL BUTYL) -1- (PYRIDYL OR PYRIMIDINYL) -PIPERAZINE OR -1,4-DIAZABICYCLOHEPTAN COMPOUNDS, PROCEDURES FOR THE PREPARATION OF DISPARED SUBSTANCES,
NO885386A NO172640C (en) 1987-04-02 1988-12-02 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERAZINE DERIVATIVES

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EP0385351A1 (en) * 1989-03-01 1990-09-05 Nisshin Flour Milling Co., Ltd. Nicotinic acid derivatives and pharmaceutical compositions comprising same
EP0400661A1 (en) * 1989-06-01 1990-12-05 Bristol-Myers Squibb Company Agents for treatment of brain ischemia
WO1993020821A1 (en) * 1992-04-21 1993-10-28 Kabi Pharmacia Ab Agents for treating substance abuse disorders
EP0580465A1 (en) * 1992-06-25 1994-01-26 Sanofi New therapeutic use of heterocyclic piperazines as 5-HT3 agonists and new derivatives
US5447931A (en) * 1992-06-25 1995-09-05 Sanofi New therapeutic use of heterocyclylpiperazines as 5-HT3 agonists and new compounds
EP1180514A1 (en) * 1999-04-09 2002-02-20 Meiji Seika Kaisha Ltd. Nitrogen-containing heterocyclic compounds and benamide compounds and drugs containing the same
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US6632823B1 (en) * 1997-12-22 2003-10-14 Merck & Co., Inc. Substituted pyridine compounds useful as modulators of acetylcholine receptors

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US4937245A (en) * 1987-04-02 1990-06-26 Tomas Fex Bisphenylalkylpiperazine derivatives, a method of their preparation and a pharmaceutical preparation
EP0385351A1 (en) * 1989-03-01 1990-09-05 Nisshin Flour Milling Co., Ltd. Nicotinic acid derivatives and pharmaceutical compositions comprising same
US5025012A (en) * 1989-03-01 1991-06-18 Nisshin Flour Milling Co., Ltd. Nicotinic acid derivatives and pharmaceutical compositions comprising same
EP0400661A1 (en) * 1989-06-01 1990-12-05 Bristol-Myers Squibb Company Agents for treatment of brain ischemia
WO1993020821A1 (en) * 1992-04-21 1993-10-28 Kabi Pharmacia Ab Agents for treating substance abuse disorders
EP0580465A1 (en) * 1992-06-25 1994-01-26 Sanofi New therapeutic use of heterocyclic piperazines as 5-HT3 agonists and new derivatives
US5447931A (en) * 1992-06-25 1995-09-05 Sanofi New therapeutic use of heterocyclylpiperazines as 5-HT3 agonists and new compounds
US6825189B1 (en) 1997-10-27 2004-11-30 Neurosearch A/S Certain heteroaryl diazacycloalkanes as cholinergic ligands at nicotinic acetylcholine receptors
US6897219B2 (en) 1997-10-27 2005-05-24 Neurosearch A/S Heteroaryl diazacycloalkanes, their preparation and use
EP1180514A1 (en) * 1999-04-09 2002-02-20 Meiji Seika Kaisha Ltd. Nitrogen-containing heterocyclic compounds and benamide compounds and drugs containing the same
EP1180514A4 (en) * 1999-04-09 2003-02-26 Meiji Seika Kaisha Nitrogen-containing heterocyclic compounds and benamide compounds and drugs containing the same
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