WO1992007832A2 - Substituted piperazines as central nervous system agents - Google Patents

Substituted piperazines as central nervous system agents Download PDF

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Publication number
WO1992007832A2
WO1992007832A2 PCT/US1991/008058 US9108058W WO9207832A2 WO 1992007832 A2 WO1992007832 A2 WO 1992007832A2 US 9108058 W US9108058 W US 9108058W WO 9207832 A2 WO9207832 A2 WO 9207832A2
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Prior art keywords
defined above
lower alkyl
amino
compound
nitro
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PCT/US1991/008058
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French (fr)
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WO1992007832A3 (en
Inventor
Shelly Glase
Juan Carlos Jaen
Sarah Jane Smith
Lawrence David Wise
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Warner-Lambert Company
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Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to EP92901210A priority Critical patent/EP0556329B1/en
Priority to JP4502239A priority patent/JP3064418B2/en
Priority to DE69116378T priority patent/DE69116378T2/en
Priority to CA002094703A priority patent/CA2094703C/en
Publication of WO1992007832A2 publication Critical patent/WO1992007832A2/en
Publication of WO1992007832A3 publication Critical patent/WO1992007832A3/en
Priority to GR960400878T priority patent/GR3019490T3/en

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    • 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
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel substituted piperazines and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment.
  • the novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention are dopaminergic agents.
  • R is hydrogen, halo, C ⁇ g —alkyloxy, hydroxy or phenyl; m is 2 or 3; R 1 , R 2 , R 3 , R 4 are each independently hydrogen or C ⁇ -al yl or where R 3 and R 4 are substituted on a different carbon atom, R 3 and R 4 taken together may form a bivalent radical -CH 2 -CH 2 -; R 5 is (aryl)C 2 _g- alkenyl, (aryl)C 2 _g-alkyny1, (aryl) (hydroxy)C ⁇ g -alkyl or (aryl) (oxo)C ⁇ g-alkyl; the n-oxide forms; and pharmaceutically acceptable acid addition salts and the possible stereochemically isomeric forms thereof having an itussive/analgesic properties.
  • GB 1055548 discloses compounds of formula A
  • R represents unsubstituted phenyl or phenyl substituted by methyl, halogen, nitro, amino, (lower alkanoyl)amino, or lower alkoxyl; and either A is alkyl of 1 to 4 carbon atoms and A' is alkyl of 1 to 4 carbon atoms, benzyl, chlorobenzyl, or dimethoxybenzyl; or A and A', together with the adjacent nitrogen atom, form one of the following heterocyclic rings: pyrrolidino, morpholino, thiomorpholino, 4-phenylpiperidino, 4-phenyl-4- hydroxypiperidino, N'—methylpiperazino, N'-benzylpiperazino, N'-phenylpiperazino,
  • o-am nophenyl, -N does not represent A' dimethylamino or diethylamino; and their acid addition salts, especially those containing physiologically innocuous anions having antiulcer activity.
  • Ar 1 -C «C-(CH 2 )a-N N-Ar 2
  • n is an integer of 2, 3, or 4;
  • Ar 1 and Ar 2 are each independently aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
  • R is aryl, lower alkyl, trifluoromethyl or a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from
  • R is as defined above, a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino r nitro,
  • R is as defined above, a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, or a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino lower alkyl amino, nitro, 0
  • Formula I are useful as antipsychotic agents for treating psychoses such as schizophrenia. They are also useful as antih pertensives and for the treatment of disorders which respond to dopaminergic activation.
  • other embodiments of the present invention include the treatment, by a compound of Formula I, of hyperprolactinaemia-related conditions, such as galactorrhea, amenorrhea, menstrual disorders and sexual dysfunction, and several central nervous system disorders such as Parkinson's disease, Huntingdon's chorea, and depression.
  • a still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a compound of Formula I in unit dosage form in the treatment methods mentioned above.
  • the present invention is directed to methods for production of a compound of Formula I.
  • lower alkyl means a straight or branched hydrocarbon radical having from one to six carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • aryl means an aromatic radical which is a phenyl group or phenyl group substituted by one to four substituents selected from halogen,lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy,
  • 5- or 6-membered heteroaromatic ring comprises but is not limited to: 2-, 3-, or
  • 8-, 9-, or 10—membered heteroaromatic bicyclic ring comprises but is not limited to: 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-(1,8)naphthyridinyl, unsubstituted or substituted by halogen, lower alkyl, hydroxy, lower acyloxy, lower 0
  • “Lower acyloxy” is -O-C-alkyl of from one to six carbon atoms as defined above for “lower alkyl”.
  • Halogen is fluorine, chlorine, bromine, or iodine.
  • Alkali metal is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like.
  • Alkaline-earth metal is a metal in Group IIA of the periodic table and includes, for example, calcium, barium, strontium, magnesium, and the like.
  • Noble metal is platinum, palladium, rhodium, ruthenium, and the like.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids, such as hydrochloric. nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • nontoxic inorganic acids such as hydrochloric. nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic s
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, S. M., et al, "Pharmaceutical Salts,” Journal of Pharmaceutical Science, Vol. 66, pages 1-19 (1977)).
  • the acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • a preferred compound of Formula I is one in which Ar 1 and Ar 2 are each independently aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino nitro, or 0
  • R is aryl, lower alkyl, trifluoromethyl, 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl,
  • R is as defined above, 10 -NH-S0 R, wherein R is as defined above, or -N-(S0 2 R) 2 , wherein R is as defined above, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 15 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl substituted by halogen, lower alkyl, lower alkoxy, 20 hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
  • Another preferred compound of Formula I is one in which n is 2 or 3 and Ar 1 and Ar 2 are each independently aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro, or
  • R is aryl, lower alkyl, trifluoromethyl
  • R is as defined above, — H-S0 2 -R, wherein R is as defined above, or -N-(S0 2 R) 2 , wherein R is as defined above, 2- or 3-indolyl, 2- or 3-indolyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino. lower alkyl amino, nitro, 0
  • Particularly preferred compounds are:
  • the compounds of Formula I are valuable dopaminergic agents.
  • the tests employed indicate that compounds of Formula I possess dopaminergic activity.
  • the compounds of Formula I were tested for their ability to inhibit locomotor activity in mice according to the assay described by J. R. McLean, et al, Pharmacology, Biochemistry and Behavior, Volume 8, pages 97-99 (1978) ; for their ability to inhibit [ 3 H]-spiroperidol binding in a receptor assay described by D. Grigoriadis and P.
  • IP 10 mg/kg IP
  • the present invention provides a process for the preparation of a compound of Formula I:
  • n is an integer of 2, 3, or 4;
  • Ar 1 and Ar 2 are each independently aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro, 0
  • R is aryl, lower alkyl, trifluoromethyl or a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0,
  • R is as defined above or -N-(S0 2 R) 2 , wherein R is as defined above, a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
  • -NH-S0 2 R wherein R is as defined above, or -N-(S0 2 R) , wherein R is as defined above, a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, or a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino lower alkyl amino, nitro, O
  • n is an integer of 2, 3, or 4 in a solvent, such as, for example, dichloromethane and the like, in the presence of an acid scavenger such as, for example, triethylamine and the like, and in the presence of a catalytically effective amount of bis(triarylphosphine)palladium(II)chloride ( [ (Ar 3 ) 3 P] 2 PdCl 2 ) , bis(triarylphosphine)palladium(II) acetate( [ (Ar 3 ) 3 P] 2 Pd(0 2 CCH 3 ) 2 ) , or triarylphosphine- palladium(II)acetate( (Ar 3 ) 3 P/Pd(0 2 CCH 3 ) 2 ) , wherein Ar 3 is phenyl or phenyl substituted by lower alkyl and cuprous iodide (Cul) to afford a compound of Formula IV
  • the reaction is carried out in a solvent such as, for example, dichloromethane and the like in the presence of triethylamine and bis(triphenyl- phosphine)palladium(II)chloride and cuprous iodide; b) reacting an alcohol of Formula IV with an alkyl- or aryl-sulfonyl halide such as, for example, methanesulfonyl chloride and the like, in a solvent such as, for example, dichloromethane and the like, and in the presence of an acid scavenger such as, for example, triethylamine, diisopropylethyla ine and the like, to afford a compound of Formula Va:
  • L a is alkyl- or aryl-sulfonyloxy and Ar 1 and n are as defined above.
  • the reaction is carried out with methanesulfonyl chloride in dichloromethane in the presence of triethylamine or alternatively, reacting an alcohol of Formula IV with a triarylphosphine such as, for example, triphenylphosphine and the like, combined with a tetrahalo ethane such as, for example, tetrabromomethane and the like, to afford a compound of Formula Vb
  • Ar l _C C-(CH 2 ) n -L b Vb
  • reaction is carried out with triphenylphosphine and tetrabromomethane; c) reacting a compound of Formula Va or Vb with a compound of Formula VI
  • Ar 2 is as defined above, in a solvent such as, for example, dimethylformamide and the like, in the presence of a base such as, for example, sodium bicarbonate and the like, to afford a compound of Formula I above.
  • a solvent such as, for example, dimethylformamide and the like
  • a base such as, for example, sodium bicarbonate and the like
  • the reaction is carried out in dimethylformamide in the presence of sodium bicarbonate.
  • the present invention provides another process for the preparation of a compound of Formula I above, which comprises: a) reacting a compound of Formula II
  • the reaction is carried out in a solvent such as, for example, dichloromethane and the like in the presence of triethylamine and bis(triphenylphosphine)palladium- (II)chloride and cuprous iodide; b) removing the trimethylsilyl group using a base such as, for example, potassium hydroxide and the like, and an alcohol such as, for example, ethanol and the like, to afford a compound of Formula IX
  • reaction is carried out in ethanol in the presence of potassium hydroxide; c) reacting a compound of Formula IX with an organolithium compound such as, for example, ri-but llithium and the like, at a temperature of about 0°C, and with a compound of Formula X
  • X 1 is Cl, Br, ' or I " and n and Ar 2 are as defined above in a solvent such as, for example, a mixture of tetrahydrofuran:hexamethylphosphoric triamide and the like, to afford a compound of Formula I.
  • a solvent such as, for example, a mixture of tetrahydrofuran:hexamethylphosphoric triamide and the like.
  • the reaction is carried out with n-butyllithium in a mixture of tetrahydrofuran- hexamethylphosphoric triamide.
  • n is an integer of 2, 3, or 4 and Ar la is aryl substituted by nitro, or
  • n is as defined above using the methodology used to prepare a compound of Formula IV from a compound of Formula II and a compound of Formula III to afford a compound of Formula la.
  • n is an integer of 2, 3, or 4 and Ar lb is aryl substituted by amino, or 2-, 3-, or 4-pyridinyl substituted by amino or a pharmaceutically acceptable acid addition salt thereof, comprises reacting a compound of Formula la with hydrogen in the presence of a catalyst such as, for example, platinum, palladium, rhodium, ruthenium, and the like, iron in the presence of an acid such as. for example, hydrochloric acid and the like in a solvent such as, for example, ethanol and the like at about 0°C to about the reflux temperature of the solvent to afford a compound of Formula lb.
  • a catalyst such as, for example, platinum, palladium, rhodium, ruthenium, and the like
  • iron in the presence of an acid such as. for example, hydrochloric acid and the like in a solvent such as, for example, ethanol and the like at about 0°C to about the reflux temperature of the solvent to afford a compound of Formula lb.
  • n is an integer of 2, 3, or 4 and Ar lc is aryl substituted by
  • R is aryl, lower alkyl, trifluoromethyl, or a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0,
  • R. is R-C- or (R-S0 2 ) 2 - and X is as defined above in the presence of a base such as, for example, triethylamine and the like and optionally a catalytic quantity of N,N-dimethylaminopyridine in a solvent such as, for example, dichloromethane and the like at about 0°C to about the reflux temperature of the solvent to afford a compound of Formula Ic.
  • a base such as, for example, triethylamine and the like and optionally a catalytic quantity of N,N-dimethylaminopyridine in a solvent such as, for example, dichloromethane and the like at about 0°C to about the reflux temperature of the solvent to afford a compound of Formula Ic.
  • a solvent such as, for example, dichloromethane and the like at about 0°C to about the reflux temperature of the solvent to afford a compound of Formula Ic.
  • the reaction is carried out in the presence of triethy
  • R is as defined above in the presence of a base such as, for example, triethylamine and the like in a solvent such as, for example, dichloromethane and the like at about -78°C to afford a compound of Formula Ic.
  • a base such as, for example, triethylamine and the like
  • a solvent such as, for example, dichloromethane and the like at about -78°C
  • the reaction is carried out in the presence of triethylamine in dichloromethane at about -78°C.
  • n is an integer of 2, 3, or 4 and Ar ld is aryl substituted by lower alkyl amino or 2-, 3-, or 4-pyridinyl substituted by lower alkyl amino or a pharmaceutically acceptable acid addition salt thereof, comprises reacting a compound of Formula lb with a compound of Formula XV
  • R is lower alkyl in the presence of a metal hydride such as, for example, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride and the like optionally in the presence of an acid such as, for example, acetic acid and the like in a solvent such as, for example, dichloroethane, dichloromethane and the like at about 0°C to about room temperature to afford a compound of Formula Id.
  • a metal hydride such as, for example, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride and the like
  • an acid such as, for example, acetic acid and the like in a solvent such as, for example, dichloroethane, dichloromethane and the like at about 0°C to about room temperature to afford a compound of Formula Id.
  • the reaction is carried out with sodium triacetoxyborohydride in the presence of acetic acid in dichloroethane at about room temperature.
  • the substituent group in Ar ld in a compound of Formula Id is methylamino it is prepared by reacting a compound of Formula lb with a mixture of acetic anhydride and formic acid in a solvent such as, for example, tetrahydrofuran and the like and subsequent reaction with a metal hydride reagent such as, for example, lithium aluminum hydride and the like to afford a compound of Formula Id.
  • a compound of Formula X is prepared from a compound of Formula VI and a compound of Formula XI
  • X 1 and n are as defined above in the presence of a solvent such as, for example, dichloromethane and the like, in the presence of an acid scavenger such as, for example, triethylamine and the like, to afford a compound of Formula X.
  • a solvent such as, for example, dichloromethane and the like
  • an acid scavenger such as, for example, triethylamine and the like
  • the reaction is carried out in dichloromethane in the presence of triethylamine.
  • a compound of Formula XII is prepared from a compound of Formula XVI
  • L is a halogen atom or an alkyl or arylsulfonyloxy and n is as defined above with the compound of Formula XVII VTI
  • a compound of Formula XVI is prepared from a compound of Formula III using the methodology used to prepare a compound of Formula Va and Vb from a compound of Formula IV.
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included.
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferable in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg, according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 1 mg to about 50 mg per kilogram daily.
  • a daily dose range of about 5 mg to about 25 mg per kilogram is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • the following nonlimiting examples illustrate the inventors' preferred compounds of the invention and methods for their preparation.
  • aqueous layer is extracted with 50 mL of ethyl acetate and the combined organic layers are dried (sodium sulfate) , and the solvent removed in vacuo.
  • the residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound containing 0.10 mol of water; mp 76.5-77.0°C.
  • EXAMPLE 2 1-(4-Fluorophenyl)-4-T4-(3-Pyridinyl)-3-butvnyll- piperazine; mp 97.0-97.2°C.
  • ⁇ XAMPL ⁇ 3 1-(2-Pyridinyl)-4-'4-(3-pyridinyl)-3-butynyll- piperazine, containing 0.3 mol of water; mp 105.5- 106.2°C.
  • Step b) Preparation of 1-T4-(5-Nitro-2-pyridinyl)- 3-butvnyl * -4-(2-pyridinyl)piperazine
  • the solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate.
  • the aqueous layer is extracted with 30 mL of dichloromethane and the combined organic layers are washed with water and dried (sodium sulfate) , and the solvent is removed in vacuo.
  • the residue is chromatographed (silica gel, 1% methanol/ 99% dichloromethane) to give the title compound as a brown solid; mp 126-126.5°C.
  • EXAMPLE 7 6- [4-"4-(2-Pyridinyl)-l-piperazinyll-l-butvnyll-3- pyridinamine
  • the hot solution is filtered through diatomaceous earth (Celite) and the filter cake is washed with 500 mL of hot ethanol.
  • the solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of water.
  • the aqueous layer is washed with 50 mL of dichloromethane and the combined organic layers are dried (sodium sulfate) , and the solvent is removed in vacuo.
  • the residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound as a tan solid; mp 140-141.5 ⁇ C.

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Abstract

Substituted piperazines and derivatives thereof are described, as well as methods for the preparation and pharmaceutical composition of the same, which are useful as central nervous system agents and are particularly useful as dopaminergic, antipsychotic, and antihypertensive agents as well as for treating hyperprolactinaemia-related conditions and central nervous system disorders.

Description

SUBSTI UTED PIPERAZINES AS CENTRAL NERVOUS SYSTEM AGENTS
BACKGROUND OF THE INVENTION
The present invention relates to novel substituted piperazines and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention are dopaminergic agents.
ΞP 0 211 457 A2 discloses compounds of formula:
Figure imgf000003_0001
wherein R is hydrogen, halo, C^g—alkyloxy, hydroxy or phenyl; m is 2 or 3; R1, R2, R3, R4 are each independently hydrogen or C^ -al yl or where R3 and R4 are substituted on a different carbon atom, R3 and R4 taken together may form a bivalent radical -CH2-CH2-; R5 is (aryl)C2_g- alkenyl, (aryl)C2_g-alkyny1, (aryl) (hydroxy)C^g-alkyl or (aryl) (oxo)C^g-alkyl; the n-oxide forms; and pharmaceutically acceptable acid addition salts and the possible stereochemically isomeric forms thereof having an itussive/analgesic properties.
GB 1055548 discloses compounds of formula A
R-C≡C-CH9-N
wherein R represents unsubstituted phenyl or phenyl substituted by methyl, halogen, nitro, amino, (lower alkanoyl)amino, or lower alkoxyl; and either A is alkyl of 1 to 4 carbon atoms and A' is alkyl of 1 to 4 carbon atoms, benzyl, chlorobenzyl, or dimethoxybenzyl; or A and A', together with the adjacent nitrogen atom, form one of the following heterocyclic rings: pyrrolidino, morpholino, thiomorpholino, 4-phenylpiperidino, 4-phenyl-4- hydroxypiperidino, N'—methylpiperazino, N'-benzylpiperazino, N'-phenylpiperazino,
N'-chlorophenylpiperazino, N'-tolylpiperazino, N'-methoxyphenylpiperazino, N'-(β—hydroxyethyl)- piperazino, N'-(β-acetoxyethyl)piperazino, '-(β-propionyloxyethyl)piperazino, N'-carbethoxypiperazino, hexa ethyleneimino, and heptamethyleneimino; provided that when R is phenyl, p—methoxyphenyl, o- or p-nitrophenyl, or
Figure imgf000004_0001
o-am nophenyl, -N does not represent A' dimethylamino or diethylamino; and their acid addition salts, especially those containing physiologically innocuous anions having antiulcer activity.
The aforementioned references do not teach nor suggest the combination of structural variations of the compounds of the present invention nor their use as dopaminergic agents described hereinafter. SUMMARY OF THE INVENTION
Accordingly, the present invention provides a compound of Formula I
Ar1-C«C-(CH2)a-N N-Ar2
wherein n is an integer of 2, 3, or 4;
Ar1 and Ar2 are each independently aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
0 fi
-NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl or a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from
N, S, and 0,
-NH-S02R, wherein R is as defined above or
-N-(S02R)2, wherein R is as defined above, a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl aminor nitro,
0 I
-NH-C-R, wherein R is as defined above,
-NH-S02R, wherein R is as defined above, or
-N-(S02R) , wherein R is as defined above, a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, or a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino lower alkyl amino, nitro, 0
I -NH-C-R, wherein R is as defined above,
-NH-S02R, wherein R is as defined above, or -N-(S02R) , wherein R is as defined above; or a pharmaceutically acceptable acid addition salt thereof, with the exclusion of a compound of Formula I wherein Ar2 is 3-pyridazinyl. As dopaminergic agents, the compounds of
Formula I are useful as antipsychotic agents for treating psychoses such as schizophrenia. They are also useful as antih pertensives and for the treatment of disorders which respond to dopaminergic activation. Thus, other embodiments of the present invention include the treatment, by a compound of Formula I, of hyperprolactinaemia-related conditions, such as galactorrhea, amenorrhea, menstrual disorders and sexual dysfunction, and several central nervous system disorders such as Parkinson's disease, Huntingdon's chorea, and depression.
A still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a compound of Formula I in unit dosage form in the treatment methods mentioned above.
Finally, the present invention is directed to methods for production of a compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
In the compounds of Formula I, the term "lower alkyl" means a straight or branched hydrocarbon radical having from one to six carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
The term "aryl" means an aromatic radical which is a phenyl group or phenyl group substituted by one to four substituents selected from halogen,lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy,
0 II amino, lower alkyl amino, nitro, -NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl or a 5- or
6-membered heteroaromatic ring as defined hereinafter,
-NH-S02R, wherein R is lower alkyl, trifluoromethyl, or a 5- or 6-membered heteroaromatic ring as defined hereinafter, or -N-(S02R) , wherein R is lower alkyl, trifluoromethyl, or a 5- or 6-membered heteroaromatic ring as defined hereinafter.
The term "5- or 6-membered heteroaromatic ring" comprises but is not limited to: 2-, 3-, or
4-pyridinyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, 2- or 3-furanyl, 2- or 3-thienyl, 2-, 4-, or 5-imidazolyl, 2-, 4-, or 5-thiazolyl, unsubstituted or substituted by halogen, lower alkyl, hydroxy, lower acyloxy, lower alkoxy, amino, lower alkyl amino,
0 I nitro, -NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl or a 5- or 6-membered heteroaromatic ring as defined herein for "5— or 6-membered heteroaromatic ring", -NH-S02R, wherein R is lower alkyl, trifluoromethyl, or a 5- or 6-membered heteroaromatic ring as defined herein for "5- or 6-membered heteroaromatic ring", or -N-(S0 R)2, wherein R is lower alkyl, trifluoromethyl, or a 5- or 6-membered heteroaromatic ring as defined herein for "5— or 6-membered heteroaromatic ring".
The term "8-, 9-, or 10—membered heteroaromatic bicyclic ring" comprises but is not limited to: 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-(1,8)naphthyridinyl, unsubstituted or substituted by halogen, lower alkyl, hydroxy, lower acyloxy, lower 0
II alkoxy, amino, lower alkyl amino, nitro, -NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl or a
5- or 6-membered heteroaromatic ring as defined herein for "5- or 6-membered heteroaromatic ring", -NH-S02R, wherein R is lower alkyl, trifluoromethyl, or a 5- or 6-membered heteroaromatic ring as defined herein for "5- or 6-membered heteroaromatic ring", or -N-(S02R)2f wherein R is lower alkyl, trifluoromethyl, or a 5- or 6-membered heteroaromatic ring as defined herein for
"5- or 6-membered heteroaromatic ring".
"Lower alkoxy" and "thioalkoxy" are O-alkyl or
S-alkyl of from one to six carbon atoms as defined above for "lower alkyl." 0
I
"Lower acyloxy" is -O-C-alkyl of from one to six carbon atoms as defined above for "lower alkyl".
"Halogen" is fluorine, chlorine, bromine, or iodine.
"Alkali metal" is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like.
"Alkaline-earth metal" is a metal in Group IIA of the periodic table and includes, for example, calcium, barium, strontium, magnesium, and the like.
"Noble metal" is platinum, palladium, rhodium, ruthenium, and the like.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids, such as hydrochloric. nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, S. M., et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, Vol. 66, pages 1-19 (1977)).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. A preferred compound of Formula I is one in which Ar1 and Ar2 are each independently aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino nitro, or 0
II
-NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl, 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl,
2- or 3-furanyl,
2- or 3-thienyl,
2-, 4-, or 5-imidazolyl, or
2-, 4-, or 5-thiazolyl, 2-, 3-, or 4-pyridinyl,
2-, 3-, or 4-pyridinyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy. amino, lower alkyl amino, nitro,
O 5 II
-NH-C-R, wherein R is as defined above,
—NH-S02R, wherein R is as defined above, or
10 -N-(S02R) , wherein R is as defined above,
2-, 4-, or 5-pyrimidinyl,
2-, 4-, or 5-pyrimidinyl substituted by halogen,
15 lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino,
20 lower alkyl amino, nitro,
0
II — H-C-R, wherein R is as defined
25 above,
—NH-S02R, wherein R is as defined above, or
-N-(S02R)2, wherein R is as defined above,
30 2-pyrazinyl,
2-pyrazinyl substituted by halogen, lower alkyl, lower alkoxy,
35 hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
0 5 II
-NH-C-R, wherein R is as defined above,
-NH-S02R, wherein R is as defined above, or
10 -N-(S02R)2Λ wherein R is as defined above,
2- or 3-furanyl,
2- or 3-furanyl substituted by halogen,
15 lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino,
20 lower alkyl amino, nitro,
O
I
-NH-C-R, wherein R is as defined 25 above,
-NH-S02R, wherein R is as defined above, or -N-(S02R)2 wherein R is as defined above, 30 2- or 3-thienyl,
2- or 3-thienyl substituted by halogen, lower alkyl, lower alkoxy, 35 hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
O 5 I
-NH-C-R wherein R is as defined above, -NH-S02R wherein R is as defined above, or 10 -N-(S02R)2, wherein R is as defined above, 2-, 4-, or 5-imidazolyl, 2-, 4-, or 5-imidazolyl substituted by halogen, 15 lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, 20 lower alkyl amino, nitro, 0
II -NH-C-R, wherein R is as defined
25 above,
—NH-S02R, wherein R is as defined above, or
—N-(S02R)2, wherein R is as defined above,
30 2-, 4-, or 5-thiazolyl,
2-, 4-, or 5-thiazolyl substituted by halogen, lower alkyl, lower alkoxy,
35 hydroxy, lower acyloxy. amino, lower alkyl amino, nitro,
O 5 I
-NH-C-R, wherein R is as defined above, -NH-S02R wherein R is as defined above, or 10 -N-(S02R)2 wherein R is as defined above, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl substituted by 15 halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, 20 amino, lower alkyl amino, nitro, O
I
25 -NH-C-R, wherein R is as defined above, -NH-S02R, wherein R is as defined above, or -N-(S02R) , wherein R is as 30 defined above,
2-, 3-, 4-, 5-, 6-, or 7-benzo[b] hienyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl substituted by halogen, 35 lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, 5 nitro,
O
II
-NH-C-R, wherein R is as defined above, 10 -NH-S0 R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 15 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl substituted by halogen, lower alkyl, lower alkoxy, 20 hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
25 O
II -NH-C— , wherein R is as defined above,
-NH-S02R, wherein R is as defined
30 above, or
-N—(S02R)2, wherein R is as defined above,
1-, 3-, 4-, 5-, 6—, 7-, or 8-isoquinolinyl,
1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl
35 substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, 5 amino, lower alkyl amino, nitro,
0
« 10 -NH-C-R, wherein R is as defined above,
-NH-S02R, wherein R is as defined above, or
-N-(S02R)2, wherein R is as
15 defined above,
2-, 3-, 4-, 5-, 6-, or 7-(l,8)naphthyri- dinyl, or
2-, 3-, 4-, 5-, 6-, or 7-(1,8)naphthyri- dinyl substituted by
20 halogen, lower alkyl, lower alkoxy,
' hydroxy, lower acyloxy,
25 amino, lower alkyl amino, nitro,
0
II
30 -NH-C-R, wherein R is as defined above, -NH-S02R, wherein R is as defined above, or -N-(S0 R)2 wherein R is as defined 35 above. Another preferred compound of Formula I is one in which n is 2 or 3 and Ar1 and Ar2 are each independently aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro, or
0
-NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl,
2-, 3-, or 4-pyridinyl, • 2-, 4-, or 5-pyrimidinyl,
2-pyrazinyl, 2- or 3-furanyl,
2- or 3-thienyl,
2-, 4-, or 5-imidazolyl, or
2-, 4-, or 5-thiazolyl, 2-, 3-, or 4-pyridinyl, 2-, 3-, or 4—pyridinyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino. lower alkyl amino, nitro, 0
I -NH-C-R, wherein R is as defined above, -NH-S02-R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above, -, 4-, or 5-pyrimidinyl, -, 4-, or 5-pyrimidinyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
0
-NH-C-R, wherein R is as defined above, -NH-S02-R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above, - or 3-thienyl, - or 3-thienyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino. lower alkyl amino, nitro,
0
I -NH-C-R, where R is as defined above, -NH-S02-R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above, - or 5-thiazolyl, - or 5-thiazolyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
0
I
-NH-C-R, wherein R is as defined above, — H-S02-R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above, 2- or 3-indolyl, 2- or 3-indolyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino. lower alkyl amino, nitro, 0
I! -NH-C-R, wherein R is as defined above, -NH-S02-R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above,
2-, 3-, or 4-quinolinyl, 2-, 3-, or 4-quinolinyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
O
I
-NH-C-R, wherein R is as defined above, -NH-S02-R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above 1-, 3-, or 4-isoquinolinyl, or 1-, 3-, or 4-isoquinolinyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino. lower alkyl amino, nitro,
0
« -NH-C-R, wherein R is as defined above,
-NH-S02-R, wherein R is as defined above, or
-N-(S02R)2, wherein R is as defined above.
Particularly preferred compounds are:
3-[4-[4-(2-Pyridinyl)-1-piperazinyl]-1-butynyl]- quinoline;
1-(4-Fluorophenyl)-4-[4-(3-pyridinyl)-3-butynyl]- piperazine;
1-(2-Pyridinyl)-4-[4-(3-pyridinyl)-3-butynyl]- piperazine;
2-[4-[4-(3-Pyridinyl)-3-butynyl]-1-piperazinyl]- pyrimidine; 1-[4-(5-Nitro-2-pyridinyl)-3-but nyl]-4-(2- pyridinyl)piperazine;
1-[4-(4-Nitroρhenyl)-3-butynyl]-4-(2- pyridinyl)piperazine;
6-[4-[4-(2-Pyridinyl)-1-piperazinyl]-1-butynyl]- 3-pyridinamine;
4-[4-[4-(2-Pyridinyl)-1-piperazinyl]-1-butynyl]- benzenamine;
5-[4-[4-(2-Pyridinyl)-1-piperazinyl]-1-butynyl]- 2-thiazo1amine; 5-[4-[4-(2-Pyridinyl)-1-piperazinyl]-1-butynyl]-
2-pyridinamine; and
3-[4-[4-(2-Pyridinyl)-1-piperazinyl]-1-butynyl]- lH-indole; or a pharmaceutically acceptable acid addition salt thereof. The compounds of Formula I are valuable dopaminergic agents. The tests employed indicate that compounds of Formula I possess dopaminergic activity. Thus, the compounds of Formula I were tested for their ability to inhibit locomotor activity in mice according to the assay described by J. R. McLean, et al, Pharmacology, Biochemistry and Behavior, Volume 8, pages 97-99 (1978) ; for their ability to inhibit [3H]-spiroperidol binding in a receptor assay described by D. Grigoriadis and P. Seeman, Journal of Neurochemistrv, Volume 44, pages 1925-1935 (1985) ; and for their ability to inhibit dopamine synthesis in rats according to the protocol described by J. R. Walters and R. H. Roth, Naunvn-Schmiedeberσ's Archives of Pharmacology, Volume 296, pages 5-14 (1976) . The above test methods are incorporated herein by reference. The data in the table show the dopaminergic activity of representative compounds of Formula I.
Biological Activity of Compounds of Formula I
Inhibition % Reversal of of Locomotor Brain ion of
Example Activity in Dopa ine Inhibit Number Compound Mice Synthesis in t3H]Spiroperidol
ED50, mg/kg, Rats at Binding IC50, nM
IP 10 mg/kg, IP
3-[4-[4-(2-Pyridinyl)-1- 1.5 177 piperazinyl]-1- butynyl]quinoline
1-(4-Fluorophenyl)-4-[4- 4.7 20 2,326 (3-pyridinyl)-3- butynyl]piperazine
1-(2-Pyridinyl)-4-[4-(3- 2.2 6,530 pyridinyl)-3-butynyl]- piperazine l-[4-(5-Nitro-2- 14.1 >10,000 pyridinyl)-3-butynyl]-4- (2-pyridiny1)piperazine;
1-[ -(4-Nitropheny1)-3- 7.7 2500 butynyl]-4-(2-pyridinyl)- piperazine;
10 6-[4-[4-(2-Pyridinyl)-1- 0.35 24 1900 piperazinyl]-1-butynyl]-3- pyridinamine;
4-[4-[4-(2-Pyridinyl)-1- 0.56 63 611 piperaziny1]-1-butyny1]— benzenamine;
Also, the present invention provides a process for the preparation of a compound of Formula I:
Ar1-C"C- (CH2)n-N N-Ar2
wherein n is an integer of 2, 3, or 4; Ar1 and Ar2 are each independently aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro, 0
II
-NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl or a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0,
-NH-S02R, wherein R is as defined above or -N-(S02R)2, wherein R is as defined above, a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
0
II -NH-C-R, wherein R is as defined above,
-NH-S02R, wherein R is as defined above, or -N-(S02R) , wherein R is as defined above, a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, or a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino lower alkyl amino, nitro, O
I
-NH-C-R, wherein R is as defined above, -NH-S02R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above; or a pharmaceutically acceptable acid addition salt thereof, with the exclusion of a compound of Formula I wherein Ar2 is 3-pyridazinyl, which comprises: a) reacting a compound of Formula II
Ar^X II
wherein X is Cl, Br, or I, and Ar1 is as defined above with a compound of Formula III
HC≡C-(CH2)n-0H III
wherein n is an integer of 2, 3, or 4 in a solvent, such as, for example, dichloromethane and the like, in the presence of an acid scavenger such as, for example, triethylamine and the like, and in the presence of a catalytically effective amount of bis(triarylphosphine)palladium(II)chloride ( [ (Ar3)3P]2PdCl2) , bis(triarylphosphine)palladium(II) acetate( [ (Ar3)3P]2 Pd(02CCH3)2) , or triarylphosphine- palladium(II)acetate( (Ar3)3P/Pd(02CCH3)2) , wherein Ar3 is phenyl or phenyl substituted by lower alkyl and cuprous iodide (Cul) to afford a compound of Formula IV
Ar^—C≡C-(CH2)n-OH IV
wherein Ar1 and n are as defined above. Preferably, the reaction is carried out in a solvent such as, for example, dichloromethane and the like in the presence of triethylamine and bis(triphenyl- phosphine)palladium(II)chloride and cuprous iodide; b) reacting an alcohol of Formula IV with an alkyl- or aryl-sulfonyl halide such as, for example, methanesulfonyl chloride and the like, in a solvent such as, for example, dichloromethane and the like, and in the presence of an acid scavenger such as, for example, triethylamine, diisopropylethyla ine and the like, to afford a compound of Formula Va:
Ar1-CsC-(CH2)n-La Va
wherein La is alkyl- or aryl-sulfonyloxy and Ar1 and n are as defined above. Preferably, the reaction is carried out with methanesulfonyl chloride in dichloromethane in the presence of triethylamine or alternatively, reacting an alcohol of Formula IV with a triarylphosphine such as, for example, triphenylphosphine and the like, combined with a tetrahalo ethane such as, for example, tetrabromomethane and the like, to afford a compound of Formula Vb
Ar l_C=C-(CH2)n-Lb Vb
wherein 1^ is a halogen atom and Ar1 and n are as defined above. Preferably, the reaction is carried out with triphenylphosphine and tetrabromomethane; c) reacting a compound of Formula Va or Vb with a compound of Formula VI
HN N-Ar2 VI
wherein Ar2 is as defined above, in a solvent such as, for example, dimethylformamide and the like, in the presence of a base such as, for example, sodium bicarbonate and the like, to afford a compound of Formula I above. Preferably the reaction is carried out in dimethylformamide in the presence of sodium bicarbonate.
The present invention provides another process for the preparation of a compound of Formula I above, which comprises: a) reacting a compound of Formula II
Ar1-X II
wherein X is Cl, Br or I and Ar1 is as defined above, with the compound of Formula VII
HC≤C-SiMe3 VII
in a solvent such as, for example, dichloromethane and the like, in the presence of an acid scavenger such as, for example, triethylamine and the like, and in the presence of a catalytically effective amount of bis(triarylphosphine)palladium(II)chloride ([ (Ar3)3P]2PdCl2) , bis (triarylphosphine)palladium(II) acetate([ (Ar3)3P]2 Pd(02CCH3)2) , or triarylphosphine- palladium(II)acetate( (Ar3)3P/Pd(02CCH3)2) r wherein Ar3 is phenyl or phenyl substituted by lower alkyl and cuprous iodide (Cul) to afford a compound of Formula VIII
Ar1-C≡C-SiMe3 VIII
wherein Ar1 is as defined above. Preferably, the reaction is carried out in a solvent such as, for example, dichloromethane and the like in the presence of triethylamine and bis(triphenylphosphine)palladium- (II)chloride and cuprous iodide; b) removing the trimethylsilyl group using a base such as, for example, potassium hydroxide and the like, and an alcohol such as, for example, ethanol and the like, to afford a compound of Formula IX
Ar1-CH=CH IX
wherein Ar1 is as defined above. Preferably, the reaction is carried out in ethanol in the presence of potassium hydroxide; c) reacting a compound of Formula IX with an organolithium compound such as, for example, ri-but llithium and the like, at a temperature of about 0°C, and with a compound of Formula X
Figure imgf000030_0001
wherein X1 is Cl, Br, ' or I"and n and Ar2 are as defined above in a solvent such as, for example, a mixture of tetrahydrofuran:hexamethylphosphoric triamide and the like, to afford a compound of Formula I. Preferably, the reaction is carried out with n-butyllithium in a mixture of tetrahydrofuran- hexamethylphosphoric triamide.
Preferably a compound of Formula la
Figure imgf000030_0002
la
wherein n is an integer of 2, 3, or 4 and Arla is aryl substituted by nitro, or
2-, 3-, or 4-pyridinyl substituted by nitro or a pharmaceutically acceptable acid addition salt thereof, comprises reacting a compound of Formula Ila Arla-X
Ila
wherein Arla and X are as defined above with a compound of Formula XII
Figure imgf000031_0001
XII
wherein n is as defined above using the methodology used to prepare a compound of Formula IV from a compound of Formula II and a compound of Formula III to afford a compound of Formula la.
Preferably, a compound of Formula lb
Figure imgf000031_0002
lb
wherein n is an integer of 2, 3, or 4 and Arlb is aryl substituted by amino, or 2-, 3-, or 4-pyridinyl substituted by amino or a pharmaceutically acceptable acid addition salt thereof, comprises reacting a compound of Formula la with hydrogen in the presence of a catalyst such as, for example, platinum, palladium, rhodium, ruthenium, and the like, iron in the presence of an acid such as. for example, hydrochloric acid and the like in a solvent such as, for example, ethanol and the like at about 0°C to about the reflux temperature of the solvent to afford a compound of Formula lb. Preferably, the reaction is carried out with iron and hydrochloric acid in ethanol at about 80°C. Preferably, a compound of Formula Ic
Figure imgf000032_0001
Ic
wherein n is an integer of 2, 3, or 4 and Arlc is aryl substituted by
0
1 -NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl, or a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0,
-NH-S02R, wherein R is as defined above, or
— -(S02R)2, wherein R is as defined above, or 2-, 3-, or 4-pyridinyl substituted by
0
I
-NH-C-R, wherein R is as defined above, —NH-S02R, wherein R is as defined above, or
—N-(S02R) , wherein R is as defined above, or a pharmaceutically acceptable acid addition salt thereof, comprises reacting a compound of Formula lb with a compound of Formula XIII
RX-X
XIII
0
I wherein R. is R-C- or (R-S02)2- and X is as defined above in the presence of a base such as, for example, triethylamine and the like and optionally a catalytic quantity of N,N-dimethylaminopyridine in a solvent such as, for example, dichloromethane and the like at about 0°C to about the reflux temperature of the solvent to afford a compound of Formula Ic. Preferably, the reaction is carried out in the presence of triethylamine in dichloromethane containing a catalytic amount of
N,N-dimethylaminopyridine at about room temperature. In the case wherein the substituent group in Arlc in a compound of Formula Ic is R-S02NH- it is prepared by reacting a compound of Formula lb with a compound of Formula XIV
(R-S02)20
XIV
wherein R is as defined above in the presence of a base such as, for example, triethylamine and the like in a solvent such as, for example, dichloromethane and the like at about -78°C to afford a compound of Formula Ic. Preferably, the reaction is carried out in the presence of triethylamine in dichloromethane at about -78°C.
Preferably, a compound of Formula Id
Figure imgf000034_0001
Id
wherein n is an integer of 2, 3, or 4 and Arld is aryl substituted by lower alkyl amino or 2-, 3-, or 4-pyridinyl substituted by lower alkyl amino or a pharmaceutically acceptable acid addition salt thereof, comprises reacting a compound of Formula lb with a compound of Formula XV
O
II
R2-CH
XV
wherein R is lower alkyl in the presence of a metal hydride such as, for example, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride and the like optionally in the presence of an acid such as, for example, acetic acid and the like in a solvent such as, for example, dichloroethane, dichloromethane and the like at about 0°C to about room temperature to afford a compound of Formula Id. Preferably, the reaction is carried out with sodium triacetoxyborohydride in the presence of acetic acid in dichloroethane at about room temperature. Alternatively, in the case wherein the substituent group in Arld in a compound of Formula Id is methylamino it is prepared by reacting a compound of Formula lb with a mixture of acetic anhydride and formic acid in a solvent such as, for example, tetrahydrofuran and the like and subsequent reaction with a metal hydride reagent such as, for example, lithium aluminum hydride and the like to afford a compound of Formula Id. A compound of Formula X is prepared from a compound of Formula VI and a compound of Formula XI
X1-(CH2)n-X1 XI
wherein X1 and n are as defined above in the presence of a solvent such as, for example, dichloromethane and the like, in the presence of an acid scavenger such as, for example, triethylamine and the like, to afford a compound of Formula X. Preferably, the reaction is carried out in dichloromethane in the presence of triethylamine.
A compound of Formula XII is prepared from a compound of Formula XVI
HC≤C-(CH2)n-L
XVI
wherein L is a halogen atom or an alkyl or arylsulfonyloxy and n is as defined above with the compound of Formula XVII
Figure imgf000036_0001
VTI
using the methodology used to prepare a compound of Formula I from a compound of Formula Va or Vb and VI. A compound of Formula XVI is prepared from a compound of Formula III using the methodology used to prepare a compound of Formula Va and Vb from a compound of Formula IV.
Compounds of Formula II, Ila, III, VI, VII, XI, XIII, XIV, XV, and XVII are either known or capable of being prepared by methods known in the art.
The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The pharmaceutical preparation is preferable in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as antipsychotic agents, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 1 mg to about 50 mg per kilogram daily. A daily dose range of about 5 mg to about 25 mg per kilogram is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. The following nonlimiting examples illustrate the inventors' preferred compounds of the invention and methods for their preparation.
EXAMPLE 1 3-'4-'4-(2-Pyridinyl)-l-piperazinyll-1-butynylT- cruinoline Step (a): Preparation of 4-(3-0uinolinyl)-3-butvn-l-ol
A solution of 3-bromoquinoline (13.57 mL, 0.10 mol) and 3-butyn-l-ol (9.0 mL, 0.12 mol) in 40 mL of triethylamine and 75 L of dichloromethane is degassed by bubbling in dry nitrogen for 15 minutes, and 0.7 g (0.001 mol) of bis (triphenyl¬ phosphine)palladium chloride and 0.013 g of cuprous iodide are added. The flask is flushed with nitrogen and the mixture is heated to reflux for 5 hours. The cooled mixture is diluted with dichloromethane and washed with water, dried (sodium sulfate) , and concentrated to give 27 g of an oil. The oil is triturated with diethyl ether to give 18.2 g of the title compound as a tan solid; mp 95.7-96.7°C.
Step (b) : Preparation of 3-r4-*4-(2-Pyridinyl)-1- piperazinyl]-1-butvnyllquinoline
A solution of the alcohol prepared in Step (a) (1.98 g, 0.01 mol), N,N-diisopropylethylamine (3.5 mL, 0.02 mol) and a catalytic amount of
4—dimethylaminopyridine in 100 mL of dichloromethane is cooled to 0°C, and methanesulfonyl chloride (0.8 mL, 0.0105 mol) is added dropwise. The solution is stirred at 0°C for 18 hours, and then concentrated under reduced pressure. The residue is taken up in dimethylformamide (20 mL) , and to this solution is added 1-(2-pyridinyl)piperazine (2.45 g, 0.015 mol) and sodium bicarbonate (3.4 g, 0.04 mol). The mixture is heated at 40°C for 5 hours and the solvent is removed under reduced pressure. The residue is partitioned between 50 mL of ethyl acetate and 50 mL of water. The aqueous layer is extracted with 50 mL of ethyl acetate and the combined organic layers are dried (sodium sulfate) , and the solvent removed in vacuo. The residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound containing 0.10 mol of water; mp 76.5-77.0°C.
Following the procedure of Example 1, the following compounds are prepared:
EXAMPLE 2 1-(4-Fluorophenyl)-4-T4-(3-Pyridinyl)-3-butvnyll- piperazine; mp 97.0-97.2°C. ΞXAMPLΞ 3 1-(2-Pyridinyl)-4-'4-(3-pyridinyl)-3-butynyll- piperazine, containing 0.3 mol of water; mp 105.5- 106.2°C.
EXAMPLE 4 2-f4-r4-(3-Pyridinyl)-3-butvnvπ-l-piperazinvn- pyrimidine, containing 0.4 mol of water; mp 96-97°C.
EXAMPLE 5
1-T4-(5-Nitro-2-pyridinyl)-3-butvnyll-4-(2-pyridinyl)- piperazine
Step (a): Preparation of 4-T (2-pyridyl)-1- piperazinyll—1-butvne A solution of 3-butynyl tosylate (25.0 g,
0.11 mol), 1-(2-pyridinyl)piperazine (12.1 g, 0.074 mol), and sodium bicarbonate (6.9 g, 0.082 mol) in 200 mL of dimethylformamide is heated at 80°C for 18 hours. The solvent is removed under reduced pressure, and the residue is partitioned between
200 mL of dichloromethane and 200 mL of water. The aqueous layer is extracted with 100 mL of dichloromethane and the combined organic layers are dried (sodium sulfate) , and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 25% ethyl acetate/75% hexane) to give the title compound as a white solid; mp 57-58°C.
Step b) : Preparation of 1-T4-(5-Nitro-2-pyridinyl)- 3-butvnyl*-4-(2-pyridinyl)piperazine
A solution of 2-bromo-5-nitropyridine (3.11 g, 0.015 mol) and the alkyne prepared in Step (a) (3.0 g, 0.014 mol) in 5.8 mL of triethylamine and 60 mL of acetonitrile is degassed by bubbling in dry nitrogen for 15 minutes, and 0.2 g (0.0003 mol) of bis(triphenylphosphine)palladium chloride and 0.05 g (0.0003 mol) of cuprous iodide are added. The flask is flushed with nitrogen and the mixture is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 30 mL of dichloromethane and the combined organic layers are washed with water and dried (sodium sulfate) , and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/ 99% dichloromethane) to give the title compound as a brown solid; mp 126-126.5°C.
Following the procedure of Example 5, the following compound is prepared:
EXAMPLE 6 1-T4-(4-Nitrophenyl)-3-butvnyll-4-(2-pyridinyl)- piperazine; mp 150-151°C.
EXAMPLE 7 6- [4-"4-(2-Pyridinyl)-l-piperazinyll-l-butvnyll-3- pyridinamine A solution of l-[4-(5-nitro-2—pyridinyl)-3- butynyl]—4-(2-pyridinyl)piperazine (Example 5) (3.5 g, 0.01 mol), reduced iron (4.0 g) , and concentrated hydrochloric acid (0.20 mL) in 60 mL of 90% ethanol and 10 mL of water is heated at 80°C with vigorous stirring for 30 minutes. The hot solution is filtered through diatomaceous earth (Celite) and the filter cake is washed with 500 mL of hot ethanol. The solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of water. The aqueous layer is washed with 50 mL of dichloromethane and the combined organic layers are dried (sodium sulfate) , and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound as a tan solid; mp 140-141.5βC.
Following the procedure of Example 7, the following compound is prepared:
EXAMPLE 8 4-*4-r4-(2-Pyridinyl)-l-piperazinyll-l-butynyl]- benzenamine; mp 119-120.3°C.

Claims

1. A compound of Formula I
Ar1-C"C—(CH2)„-N N-Ar2
wherein n is an integer of 2, 3, or 4; Ar1 and Ar2 are each independently aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
0
II -NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl or a 5- or
6-membered heteroaromatic ring comprising one or more heteroatoms selected from N,
S, and 0,
-NH-S02R, wherein R is as defined above or
-N-(S02R)2, wherein R is as defined above. a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, a 5- or 6-membered heteroaromatic ring 35 comprising one or more heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, 40 lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, 45 nitro,
0
II
-NH-C-R, wherein R is as defined above,
-NH-S02R, wherein R is as defined 50 above, or
—N-(S02R)2, wherein R is as defined above, , a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more 55 heteroatoms selected from N, S, and 0, or a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, 60 substituted by halogen, lower alkyl, lower alkoxy, hydroxy, 65 lower acyloxy, amino lower alkyl amino, nitro, 0
70
-NH-C-R, wherein R is as defined above, -NH-S0 R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined 75 above; or a pharmaceutically acceptable acid addition salt thereof, with the exclusion of a compound of Formula I wherein Ar2 is 3-pyridazinyl.
2. A compound according to Claim 1, in which Ar1 and Ar2 are each independently aryl, aryl substituted by one to four substituents 5 selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, 10 f hydroxy, lower acyloxy, amino, lower alkyl amino nitro, or
15 O
II -NH-C-R, wherein R is aryl, lower alkyl,
20 trifluoromethyl,
2-, 3-, or 4-pyridinyl,
2-, 4-, or 5-pyrimidinyl,
2-pyrazinyl, 2- or 3-furanyl, 25 2- or 3-thienyl,
2-, 4-, or 5-imidazolyl, or
2-, 4-, or 5-thiazolyl, 2-, 3-, or 4-pyridinyl, • 2-, 3-, or 4-pyridinyl substituted by 30 halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, 35 amino, lower alkyl amino, nitro, O
I
40 -NH-C-R, wherein R is as defined above, -NH-S02R, wherein R is as defined above, or -N-(S02R)2, wherein R is as 45 defined above,
2-, 4-, or 5-pyrimidinyl, 2-, 4-, or 5-pyrimidinyl substituted by halogen, lower alkyl, 50 lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, 55 nitro,
O
I
-NH-C-R, wherein R is as defined above. 60 -NH-S02R, wherein R is as defined above, or
-N-(S0 R)2, wherein R is as defined above,
2-pyrazinyl,
65 2-pyrazinyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy,
70 lower acyloxy, amino, lower alkyl amino, nitro,
0 75 8
-NH-C-R, wherein R is as defined above,
-NH-S02R, wherein R is as defined above, or
80 -N-(S02R)2, wherein R is as defined above,
2- or 3-furanyl,
2- or 3-furanyl substituted by halogen,
85 lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino,
90 lower alkyl amino, nitro,
0
B
—NH-C-R, wherein R is as defined 95 above, -NH-S02R, wherein R is as defined above, or -N-(S0 R) 2 wherein R is as defined above, 100 2- or 3-thienyl,
2- or 3-thienyl substituted by halogen, lower alkyl, lower alkoxy, 105 hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
110 0
II -NH-C-R wherein R is as defined above,
-NH-S0 R wherein R is as defined
115 above, or
-N-(S02R)2, wherein R is as defined above,
2-, 4-, or 5-imidazolyl,
2-, 4-, or 5-imidazolyl substituted by
120 halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy,
125 amino, lower alkyl amino, nitro,
O
I 130 -NH-C-R, wherein R is as defined above. -NH-S0R, wherein R is as defined above, or -N-(S02R)2, wherein R is as 135 defined above,
2-, 4-, or 5-thiazolyl, 2-, 4-, or 5-thiazolyl substituted by halogen, lower alkyl, 140 lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, 145 nitro,
0
II -NH—C-R, wherein R is as defined above,
150 — H-S02R wherein R is as defined above, or
-N—(S02R)2 wherein R is as defined above,
2-, 3-, 4-, 5-, 6-, or 7-indolyl,
155 2-, 3-, 4-, 5-, 6-, or 7-indolyl substituted by halogen, lower alkyl, lower alkoxy,
160 hydroxy, lower acyloxy, amino, lower alkyl amino, nitro,
165 O
II —NH-C—R, wherein R is as defined above, -NH-S02R, wherein R is as defined 170 above, or
-N-(S02R)2, wherein R is as defined above, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl 175 substituted by halogen, lower alkyl, lower alkoxy, hydroxy, 180 lower acyloxy, amino, lower alkyl amino, nitro,
0
185 I
-NH-C-R, wherein R is as defined above,
-NH-S02R, wherein R is as defined above, or
190 -N-(S02R)2, wherein R is as defined above,
2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,
2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl substituted by
195 halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy,
200 amino, lower alkyl amino, nitro, 0
I
205 -NH-C-R, wherein R is as defined above, -NH-S02R, wherein R is as defined above, or -N-(S02R)2, wherein R is as 210 defined above,
1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl substituted by halogen, 215 lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, 220 lower alkyl amino, nitro, 0
I
-NH-C-R, wherein R is as defined 225 above,
-NH-S02R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above, 230 2-, 3-, 4-, 5-, 6-, or 7-(1,8)naphthyri- dinyl, or 2-, 3-, 4-, 5-, 6-, or 7-(1,8)naphthyri- dinyl substituted by halogen, 235 lower alkyl, lower alkoxy, hydroxy, lower acyloxy. amino, 240 lower alkyl amino, nitro, 0
II
-NH-C-R, wherein R is as defined 245 above, or
-NH-S02R, wherein R is as defined above, -N-(S02R)2 wherein R is as defined above.
3. A compound according to Claim 2 in which n is 2 or 3 and
Ar1 and Ar2 are each independently aryl, 5 aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, 10 lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, 15 nitro, or
0
II
-NH-C-R, wherein R is aryl, 20 lower alkyl, trifluoromethyl,
2-, 3-, or 4-pyridinyl,
2-, 4-, or 5-pyrimidinyl,
2-pyrazinyl, 25 2- or 3-furanyl,
2- or 3-thienyl, 2-f 4-, or 5-imidazolyl, or 2-, 4-, or 5-thiazolyl, 2-, 3-, or 4-pyridinyl,
30 2-, 3-, or 4-pyridinyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy,
35 lower acyloxy, amino, lower alkyl amino, nitro,
0 40 8
-NH-C-R, wherein R is as defined above,
-NH-S02-R, wherein R is as defined above, or
45 -N-(S02R)2, wherein R is as defined above,
2-, 4-, or 5-pyrimidinyl,
2-, 4-, or 5-pyrimidinyl substituted by halogen,
50 lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino,
55 lower alkyl amino, nitro,
0
I
-NH-C-R, wherein R is as 60 defined above. -NH-S0 -R, wherein R is as defined above, or
-N-(S02R)2, wherein R is as defined above, 65 2- or 3-thienyl,
2- or 3-thienyl substituted by halogen, lower alkyl, lower alkoxy, 70 hydroxy, lower acyloxy, amino, lower alkyl amino, nitro, 75 0
8
-NH-C-R, where R is as defined above, -NH-S02-R, wherein R is as 80 defined above, or
—N-(S02R)2, wherein R is as defined above, 4- or 5-thiazolyl, 4- or 5-thiazolyl substituted by 85 halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, 90 amino, lower alkyl amino, nitro, O
1
95 -NH-C-R, wherein R is as defined above, -NH-S02-R, wherein R is as defined above, or -N-(S0R)2, wherein R is as 100 defined above,
2- or 3-indolyl, 2- or 3-indolyl substituted by halogen, lower alkyl, 105 lower alkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, 110 nitro,
0
I
-NH-C-R, wherein R is as defined above,
115 -NH-S02-R, wherein R is as defined above, or
-N-(S02R)2, wherein R is as defined above,
2-, 3-, or 4-quinolinyl,
120 2-, 3-, or 4-quinolinyl substituted by halogen, lower alkyl, lower alkoxy, hydroxy,
125 lower acyloxy, amino, lower alkyl amino, nitro,
O 130 8
-NH-C-R, wherein R is as defined above, -NH-S02-R, wherein R is as defined above, or 135 -N-(S02R)2, wherein R is as defined above 1-, 3-, or 4-isoquinolinyl, or 1-, 3-, or 4-isoquinolinyl substituted by 140 halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, 145 amino, lower alkyl amino, nitro, 0
I
150 -NH-C-R, wherein R is as defined above, -NH-S02-R, wherein R is as defined above, or -N-(S02R)2, wherein R is as 155 defined above.
. A compound according to Claim 3 selected from the group consisting of:
3-[4-[4-(2-Pyridinyl)-l-piperazinyl]-l- butynyl]quinoline; 5 1-(4-Fluorophenyl)-4-[4-(3-pyridinyl)-3- butynyl]piperazine;
1-(2-Pyridinyl)-4-[4-(3-pyridinyl)-3- butyny1]piperazine;
2-[4-[4-(3-Pyridinyl)-3-butynyl]-1- 10 piperazinyl]pyrimidine;
1-[4-(5-Nitro-2-pyridinyl)-3-butynyl]-4-(2- pyridinyl)piperazine; 1-[4-(4-Nitrophenyl)-3-butynyl]-4-(2- pyridinyl)piperazine; 6-[4-[4-(2-Pyridinyl)-1-piperazinyl]-1- butynyl]-3-pyridinamine;
4-[4-[4-(2-Pyridinyl)-1-piperazinyl]-1- butyny1]benzenamine.
5-[4-[4-(2-Pyridinyl)-1-piperazinyl]-1- butynyl]-2-thiazolamine;
5-[4-[4-(2-Pyridinyl)-l-piperazinyl]-l- butynyl]-2-pyridinamine; and
3-[4-[4-(2-Pyridinyl)-1-piperazinyl]-1- butynyl]-lH-indole;
5. A method of treating psychoses, depression, hypertension, galactorrhea, amenorrhea, menstrual disorders, sexual dysfunction, Parkinson's disease, or Huntingdon's chorea comprising administering to a host suffering therefrom a therapeutic effective amount of a compound according to Claim 1 in unit dosage form.
6. A method of treating schizophrenia comprising administering to a host suffering therefrom a therapeutic effective amount of a compound according to Claim 1 in unit dosage form.
7. A method of treating depression comprising administering to a host suffering therefrom a therapeutic effective amount of a compound according to Claim 1 in unit dosage form.
8. A pharmaceutical composition adapted for administration as a dopaminergic, antipsychotic, antihypertensive, or antidepressant agent comprising a therapeutic effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.
9. A method for the preparation of a compound of Formula I
Ar1-C"C-(CH2)n-N N-Ar2
wherein n is an integer of 2, 3, or 4; Ar1 and Ar2 are each independently . aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro, 0
I -NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl or a 5- or
6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, -NH-S02R, wherein R is as defined above or 30 -N-(S02R)2, wherein R is as defined above, a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, 35 a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and O, substituted by halogen, 40 lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, 45 lower alkyl amino, nitro, 0
1
-NH-C-R, wherein R is as defined above, 50 -NH-S02R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above, a 8-, 9-, or 10-membered heteroaromatic 55 bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, or a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more 60 heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino lower alkyl amino, nitro, O
I
-NH-C-R, wherein R is as defined above,
-NH-S02R, wherein R is as defined above, or -N-(S02R)2f wherein R is as defined above; or a pharmaceutically acceptable acid addition salt thereof, with the exclusion of a compound of Formula I wherein Ar2 is 3-pyridazinyl, which comprises: a) reacting a compound of Formula II
Ar^—X II
wherein X is Cl, Br, or I and Ar1 is as defined above with a compound of Formula III
HC≡C-(CH2)n-OH III
wherein n is an integer of 2, 3, or 4 in a solvent in the presence of an acid scavenger and in the presence of a catalyst to afford a compound of Formula IV
Ar1-C≡C-(CH2)n-OH IV
wherein Ar1 and n are as defined above; b) reacting an alcohol of Formula IV with an alkyl- or aryl-sulfonyl halide in a solvent and in the presence of an acid scavenger to
95 afford a compound of Formula Va
Ar1-CsC-(CH2)n-La Va
wherein La is alkyl- or aryl-sulfonyloxy and Ar1 and n are as defined above; or alternatively reacting an alcohol of Formula IV with a 100 triarylphosphine combined with a tetrahalomethane to afford a compound of Formula Vb
Ar1-C≡C-(CH2)n-Lb Vb
wherein Lj-, is a halogen atom and Ar1 and n are as defined above; 105 c) reacting a compound of Formula Va or Vb with a compound of Formula VI
Figure imgf000062_0001
wherein Ar2 is as defined above, in a solvent in the presence of a base to afford a compound of
110 Formula I above; and, if desired, converting the compound of Formula I to a corresponding pharmaceutically acceptable acid addition salt by conventional means and, if so desired', converting the corresponding pharmaceutically acceptable
115 acid addition salt to a compound of Formula I by conventional means.
10. A method for the preparation of a compound of Formula I / ^
Ar1~CβC - (CH2) a~N N-Ar2
N /
wherein n is an integer of 2, 3, or 4; Ar1 and Ar2 are each independently aryl, aryl substituted by one to four substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower thioalkoxy, hydroxy, lower acyloxy, amino, lower alkyl amino, nitro, 0
II -NH-C-R, wherein R is aryl, lower alkyl, trifluoromethyl or a 5- or
6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, -NH-S02R, wherein R is as defined above or -N-(S02R)2, wherein R is as defined above. a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, 35 a 5- or 6-membered heteroaromatic ring comprising one or more heteroatoms selected from N, S, and 0, substituted by halogen, 40 lower alkyl, lower alkoxy, hydroxy, lower acyloxy, amino, 45 lower alkyl amino, nitro, 0
II
-NH-C-R, wherein R is as defined above, 50 -NH-S02R, wherein R is as defined above, or -N-(S02R)2, wherein R is as defined above, ' a 8-, 9-, or 10-membered heteroaromatic
55 bicyclic ring comprising one or more heteroatoms selected from N, S, and 0, or a 8-, 9-, or 10-membered heteroaromatic bicyclic ring comprising one or more 60 heteroatoms selected from N, S, and 0, substituted by halogen, lower alkyl, lower alkoxy, 65 hydroxy, lower acyloxy, amino lower alkyl amino, nitro, 0
I
-NH-C-R, wherein R is as defined above, -NH-S02R, wherein R is as defined above, or -N-(S0R)2, wherein R is as defined above; or a pharmaceutically acceptable acid addition salt thereof, with the exclusion of a compound of Formula I wherein Ar2 is 3-pyridazinyl, which comprises; a) reacting a compound of Formula II
Ar1-X II
wherein X is Cl, Br, or I and Ar1 is as defined above with the compound of Formula VII
HC≡C-SiMe3 VII
in a solvent in the presence of an acid scavenger and a catalyst to afford a compound of Formula VIII
Ar1-C≡C-SiMe3 VIII
wherein Ar1 is as defined above; b) removing the trimethylsilyl group using a base and an alcohol to afford a compound of Formula IX
Ar1-C≡CH IX
wherein Ar1 is as defined above; 95 c) reacting a compound of Formula IX with an organolithium compound and with a compound of Formula X
Figure imgf000066_0001
wherein X1 is Cl, Br, or I, and n and Ar2 are as 100 defined above, in a solvent to afford a compound of Formula I above; and if desired, converting the compound of Formula I to a corresponding pharmaceutically acceptable acid addition salt by conventional means and, if so desired, converting 105 the corresponding pharmaceutically acceptable acid addition salt to a compound of Formula I by conventional means.
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