WO1993021179A1 - Novel amidoalkyl- and imidoalkyl-piperazines - Google Patents

Novel amidoalkyl- and imidoalkyl-piperazines Download PDF

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Publication number
WO1993021179A1
WO1993021179A1 PCT/SE1993/000295 SE9300295W WO9321179A1 WO 1993021179 A1 WO1993021179 A1 WO 1993021179A1 SE 9300295 W SE9300295 W SE 9300295W WO 9321179 A1 WO9321179 A1 WO 9321179A1
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group
compound
hydrogen atom
general formula
carbon atoms
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PCT/SE1993/000295
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English (en)
French (fr)
Inventor
Stefan Bengtsson
Lennart Florvall
Gerd Hallnemo
David Jackson
Svante Ross
Bo-Ragnar Tolf
Bengt Ulff
Lian Zhang
Christina ÅKESSON
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Aktiebolaget Astra
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Priority to EP93909109A priority Critical patent/EP0594813A1/en
Priority to CZ932701A priority patent/CZ270193A3/cs
Priority to JP5518225A priority patent/JPH06508378A/ja
Priority to AU39643/93A priority patent/AU665825B2/en
Priority to SK1389-93A priority patent/SK138993A3/sk
Publication of WO1993021179A1 publication Critical patent/WO1993021179A1/en
Priority to NO934426A priority patent/NO180794C/no
Priority to NO934426D priority patent/NO934426D0/no
Priority to FI935494A priority patent/FI935494A/fi
Priority to BG98281A priority patent/BG98281A/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
    • C07D209/66—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with oxygen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to novel, 1-aryl-4( ⁇ -amido-1-alkyl and ⁇ -imido-1-alkyl)piperazines, intermediates and processes for their preparation, pharmaceutical compositions containing the piperazines and to the use of said compounds in therapy.
  • the object of the present invention is to provide novel compounds that will be useful in the treatment of psychiatric disorders such as schizophrenia and other psychoses, anxiety, depression and manic-depressive psychosis.
  • R is a hydrogen atom or a phenyl group
  • m is an integer 3 to 8
  • R 4 is situated in the meta or para position of the ring and represents an NO 2 -group or a group NR 7 R 8 wherein R 7 and R 8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms,
  • R 5 is situated in the ortho, meta or para position and represents a hydrogen atom, a halogen atom, or CF 3 ,
  • R 6 is situated in the ortho, meta or para position and represents a halogen atom or CF 3
  • W is an optionally substituted aromatic ring(s), a heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group
  • A is a hydrogen atom, a hydroxy group, a halogen atom, CF 3 , an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group,
  • B is a hydrogen atom
  • a and B together constitute a carbonyl group, n 1 is 0 or 1, and n 2 is 0 or 1, in racemic or optically active form, or as a mixture of diastereomers, provided that 1) when W is an optionally substituted aromatic ring(s) then
  • R, m, R 4 , R 5 , and Rg are as defined above,
  • n 1 is 0 or 1
  • n 2 is 0 or 1
  • A is a hydrogen atom, a halogen atom, CF 3 , a hydroxy group, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, and
  • B is a hydrogen atom
  • R, m, R 4 , R 5 , and R 6 are as defined above,
  • n 1 is 0 or 1
  • n 2 is 0 or 1
  • a and B are hydrogen atoms or A and B together constitute a carbonyl group
  • R, m, R 4 , R 5 , and R 6 are as defined above,
  • n 1 and n 2 are 1 or
  • n 1 is 1 and n 2 is 0 or
  • An aromatic ring(s) in the definition above is preferably phenyl or naphthyl and is mono- or disubstituted, wherein the substituents are preferably chosen from the following: a hydrogen atom, a halogen atom, a hydroxy group, CF 3 , an alkyl group (s) having 1-3 carbon atoms, or an alkoxy group (s) having 1-3 carbon atoms.
  • Heterocyclic ring in the definition above is preferably furyl, thienyl, pyrrolyl, pyridyl, or indolyl.
  • a carbocyclic ring(s) in the definition above is preferably mono, bi, or polycyclic rings having 3-12 carbon atoms.
  • the substituents on the carbocyclic ring(s) in the definition above are preferably a hydrogen atom or an alkyl group having 1-3 carbon atoms.
  • the substituent on the methylene group in the definition above is preferably a hydrogen atom or an alkyl group having 1-4 carbon atoms.
  • Halogen in the definition above is preferably a chlorine, bromine, or fluorine atom.
  • R 1 is situated in the 3- or 4-position and represents a hydrogen atom, a halogen atom, CF 3 , an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, NO 2 , COCH 3 , or NR 2 R 3 wherein R 2 and R 3 are the same or different and each represents a hydrogen atom or an alkyl group having 1-6 carbon atoms, m is an integer 3 to 8,
  • R 4 is situated in the meta or para position of the ring and represents an NO 2 group or a group NR 7 R 8 wherein R 7 and R 8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms,
  • R 5 is situated in the ortho, meta, or para position of the ring and represents a hydrogen atom, a halogen atom, or CF 3
  • R 6 is situated in the ortho, meta, or para position of the ring and represents a halogen atom or CF 3
  • W is preferably chosen from the following groups : the substituents preferably being a halogen atom, a hydroxy group, or a methoxy group, mcst preferred are bromine, hydroxy, or methoxy in the ortho and/or meta positions.
  • m is preferably 4-6
  • R 4 is preferably NH 2 ,
  • R 4 is NH 2 in the meta or para positions
  • R 5 is preferably hydrogen or halogen
  • R 5 is hydrogen, chlorine, or bromine
  • R 5 are hydrogen or chlorine in the meta or para positions
  • R 6 is preferably CF 3 or halogen
  • R 6 is CF 3 or chlorine
  • R 6 are CF 3 or chlorine in the meta position.
  • R is preferably H.
  • n 1 is preferably 0 and n 2 is preferably 0 or 1, most preferred n 2 is 0,
  • A is preferably hydrogen, methoxy, or hydroxy in the ortho position.
  • n 1 is preferably 0.
  • n 1 is preferably 0,
  • A is preferably a hydrogen atom or an alkyl group with 1- 3 carbon atoms
  • W is viii, then
  • n 1 and n 2 are preferably 0 and
  • a and B preferably constitute a carbonyl group.
  • n 1 and n 2 are preferably 1 and
  • a and B preferably constitute a carbonyl group
  • n 1 and n 2 are preferably 0 and
  • a and B preferably constitute a carbonyl group
  • Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention.
  • Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, pamoic, ethanedisulfonic, sulfamic, succinic, propionic, glycollic, malic, mandelic acid, gluconic, pyruvic, phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic, naphthalenesulfonic, ascorbic, cyclohexyl
  • R is a hydrogen atom or a phenyl group
  • m is an integer 3 to 8
  • R 4 is situated in the meta or para position of the ring and represents an NC 2 -group or a group NR 7 R 8 wherein R 7 and R 8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms,
  • R 5 is situated in the ortho, meta or para position and represents a hydrogen atom, a halogen atom, or CF 3 ,
  • R 6 is situated in the ortho, meta or para position and represents a halogen atom, or CF 3 ,
  • W is an optionally substituted aromatic ring(s), a heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group,
  • A is a hydrogen atom, a hydroxy group, a halogen atom, CF 3 , an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group,
  • B is a hydrogen atom, or A and B together constitute a carbonyl group, n 1 is 0 or 1, and n 2 is 0 or 1, in racemic or optically active form, or as a mixture of diastereomers, provided that 1) when W is an optionally substituted aromatic ring(s) then
  • R, m, R 4 , R 5 , and R 6 are as defined above,
  • n 1 is 0 or 1
  • n 2 is 0 or 1
  • A is a hydrogen atom, a halogen atom, CF 3 , a hydroxy group, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group and
  • B is a hydrogen atom
  • R, m, R 4 , R 5 , and R 6 are as defined above,
  • n 1 is 0 or 1
  • n 2 is 0 or 1
  • a and B are hydrogen atoms or
  • a and B together constitute a carbonyl group, 3) when W is an optionally substituted methylene group then
  • R, m, R 4 , R 5 , and R 6 are as defined above, n 1 and n 2 are 1 or
  • n 1 is 1 and n 2 is 0 or
  • a and B together constitute a carbonyl group are prepared by any of the following alternative methods
  • R, m, W, A, B, n 1 and n 2 are as defined above and X is a suitable leaving group such as halogen, arylsulfonate or alkylsulfonate, with a compound of the general formula III
  • R 4 , R 5 and R 6 are as defined above in a suitable solvent, such as an alcohol, DMF, acetonitrile or DMSO in the presence of a base such as triethylamine, sodium hydroxide, or potassium carbonate and a catalytic amount of a sodium or potassium halide, such as KI at ambient or higher temperature for a prolonged time.
  • a suitable solvent such as an alcohol, DMF, acetonitrile or DMSO
  • a base such as triethylamine, sodium hydroxide, or potassium carbonate
  • a catalytic amount of a sodium or potassium halide such as KI at ambient or higher temperature for a prolonged time.
  • R, m, R 5 , R 6 , W, A, B, n 1 and n 2 are as defined above and Y is situated in the meta or para position and represents a group which can be transformed to a group R 4 , where R 4 is situated in the meta or para position of the ring and represents a group NR 7 R 8 , wherein R 7 and R 8 are as defined above, by a suitable hydrolytic, reductive, electrochemical or other known processes.
  • Compounds of the formula IV can be prepared according to Method A.
  • Such a group Y may be chosen from easily cleaved amides, carbamates, imines, benzylic amines or other suitably protected amino groups.
  • Such groups can be trifluoroacetamido, formamido, t-butoxycarbonylamino, or N-benzylamino .
  • Y can be a group such as nitro, azido, hydroxyamino, hydrazono, amido or imino, which can be transformed to R 4 1 by known reductive processes.
  • R, m, W, A, B, n 1 and n 2 are as defined above and Z is hydrogen, hydroxy, halogen, or alkoxy, with a compound of the general formula III
  • R 4 , R 5 and R 6 are as defined above in the presence of a suitable reducing agent such as sodium cyanoborohydride or lithium aluminium hydride in a direct or stepwise manner.
  • a suitable reducing agent such as sodium cyanoborohydride or lithium aluminium hydride in a direct or stepwise manner.
  • W, n 1 , n 2 , and A are as defined above, and T independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or heterocyclic acid or acid derivative, such as a halide, an ester, an imide, an anhydride, or other acid activating group, with a compound of the general formula VII
  • m, R 4 , R 5 and R 6 are as defined above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid, or tetrahydrofuran or neat at ambient or elevated temperature for a prolonged time.
  • a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid, or tetrahydrofuran or neat at ambient or elevated temperature for a prolonged time.
  • R, m, R 4 , W, A, B, n 1 and n 2 are as defined above and R 5 is H, halogen, or CF 3 with a suitable halogenating reagent such as sulfuryl chloride, or bromine in a suitable solvent such, as chloroform or dioxane.
  • a suitable halogenating reagent such as sulfuryl chloride, or bromine in a suitable solvent such, as chloroform or dioxane.
  • W, n 1 and n 2 are as defined above, A and B together represent a carbonyl group, and M represents a suitable alkali metal such as sodium or potassium, with a compound of the general formula X
  • X, R 4 , R 5 and R 6 are as defined above in a suitable solvent such as DMF, acetonitrile, or DMSO in the presence of a base such as triethylamine, sodium hydroxide, or potassium carbonate at ambient or higher temperature for a prolonged time.
  • a suitable solvent such as DMF, acetonitrile, or DMSO
  • a base such as triethylamine, sodium hydroxide, or potassium carbonate
  • a compound of the general formula II wherein R, m, W, A, B, n 1 , n 2 and X are as defined above, can be prepared by reacting a compound of the general formula VI
  • W, n 1 , n 2 , and A are as defined above, and T independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or heterocyclic acid or acid derivative, such as a halide, an ester, an imide, an anhydride, or other acid activating group, with a compound of the general formula XI
  • R, m, W, A, B, n 1 and n 2 are as defined above, with a suitable halogenating agent such as thionyl chloride, phosgene, oxalyl chloride, or phosphorous tribromide, or with a suitable sulfonating agent such as tosyl chloride or other arylsulfonyl chloride or alkylsulfonyl chloride.
  • a suitable halogenating agent such as thionyl chloride, phosgene, oxalyl chloride, or phosphorous tribromide
  • a suitable sulfonating agent such as tosyl chloride or other arylsulfonyl chloride or alkylsulfonyl chloride.
  • R 4 1 , R 5 and R 6 are as defined above can be prepared from a compound of the general formula XIII
  • R 5 and R 6 are as defined above and Y is NO 2 can be prepared by reacting a compound of the general formula XIV
  • R 5 and R 6 are as defined above, Y is NO 2 and U is a halogen, with piperazine or a suitably monosubstituted piperazine, where the substituent is easily removeable, such as a benzyl or an ethoxycarbonyl group,
  • X is as defined above and V is hydrogen or an easily removable group such as benzyl or ethoxycarbonyl.
  • the compounds of the formula I will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in association with a pharmaceutically acceptable dosage form.
  • the dosage form may be a solid, semisolid or liquid preparation.
  • the active substance will constitute between 0.1 and 99 % by weight of the preparation, more specifically between 0.5 and 20 % by weight for preparations intended for injection and between 0.2 and 50 % by weight for preparations suitable for oral administration.
  • the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • a concentrated sugar solution which may contain, e.g.
  • the tablet can be coated with a polymer well known in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents or in water. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compounds.
  • the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the active substance using either the above mentioned excipients for tablets e.g. saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.
  • Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from about 0.2 % to about 20 % by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol, and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharin and carboxymethylcellulose as a thickening agent or other excipients well known in the art .
  • Solutions for parenteral applications can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5 % to about 10 % by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules .
  • Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are 50 - 500 mg by oral administration and up to 100 mg via parenteral administration.
  • Example 4 1-(4-Amino-3-trifluoromethylphenyl) -4-[4-(4-chlorophthalimido)-1-butyl]piperazine dihydrochloride.
  • Example 18 1-(4-Amino-3-methylphenyl)-4-(4-phthalimido-1-butyl)-piperazine acetate.
  • Example 13 The product in Example 13 (1.0 g, 2 mmol) was dissolved in 20 ml dioxane and 5 ml methanol. Bromine (350 mg, 2.2 mmol) dissolved in 3 ml dioxane was added and the mixture stirred at ambient temperature for 5 hours, the solvent evaporated, the residue made alkaline with 2 M aqueous NaOH and extracted with methylene chloride. The solvent was removed and the residue dissolved in diisopropyl ether and a precipitate of the title compound was obtained with oxalic acid dissolved in ethanol.
  • the residual acid chloride was dissolved in 20 ml dichloromethane and added to a solution of 5-aminopentanol (1.8 g, 18 mmol) and triethylamine (4 ml, 28 mmol) in 30 ml dichloromethane at -35oC and the temperature allowed to rise to 0oC in 4 h.
  • the solution was washed with dilute HCl, the organic phase separated, and the solvent removed to yield 2.2 g of a crude oil.
  • This oil was dissolved in 20 ml dichloromethane, triethylamine (4 ml, 28 mmol) and tosylchloride (1.33 g, 7 mmol) were added, and the mixture was stirred at ambient temperature overnight.
  • compositions to be used in the method of the invention.
  • preparation of tablets the following compositions can be made.
  • compositions 1 000 tablets can be made, containing 50 mg and 100 mg of active substance, respectively. If desired, the obtained tablets can be film coated with e.g. hydroxypropyl methyl cellulose in an organic solvent or using water.
  • Tissue preparation The rats are decapitated and the striata dissected out on ice.
  • the tissue is homogenized at 0oC in 20 ml 0.05 M Tris-HCl buffer pH 7.7, using a Branson B30 sonifier.
  • the homogenate is centrifuged at 4oC for 10 minutes at 48000 g, in a Sorvall RC-5B Refrigerated Superspeed Centrifuge. The pellet is resuspended and recentrifuged.
  • the final pellet is resuspended in incubation buffer (0.05 M Tris-HCl pH 7.6 containing 0.1% ascorbic acid, 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 and 10 ⁇ M pargylin), to a final concentration of 2.5 mg wet weight/0.5 ml.
  • incubation buffer 0.05 M Tris-HCl pH 7.6 containing 0.1% ascorbic acid, 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 and 10 ⁇ M pargylin
  • Receptor binding assay Various concentrations of the test compound, the radioligand (InM H-Raclopride) and the homogenate are incubated for 60 min at room temperature. Non-specific binding is determined by the addition of 1 ⁇ M (+)-Butaclamol. The incubation is terminated by rapid filtration through glass fiber paper (Whatman GF/B) and subsequent washing with cold incubation buffer, using a cell harvester equipment. The radioactivity of the filters is measured in a Packard 2200CA liquid scintillation counter. Data is analyzed by non-linear regression using the LIGAND program, and presented as Ki values.
  • the incubation mixture (2 ml) contained 3 H-8-OH-DPAT (0.25 to 8 nM), 5 mg/ml tissue homogenate in 50 mM Tris-HCl buffer containing 4.0 mM CaCl 2 and 5.7 mM ascorbic acid, pH 7.5.
  • 6 different concentrations of 3 H-8-OH-DPAT were analyzed. Binding experiments were started by the addition of tissue homogenate and followed by incubation at 37oC for ten min.
  • the incubation mixtures were filtered through Whatman GF/B glass filters with a Brandel Cell Harvester (Gaithersburgh, MD, USA).
  • the filters were washed twice with 5 ml ice-cold 50 mM Tris-HCl buffer, pH 7.5, and counted with 5 ml Ultima GoldTM (Packard) in a Beckman LS 3801 scintillation counter. Non-specific binding was measured by the addition of 10 ⁇ M 5-HT to the reaction mixture.
  • the binding data were processed by non-linear least squares computer analysis (Munson and Rodbard, Anal. Biochem. 107, 220-239, (1980). Data were presented as K i values (nM).

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PCT/SE1993/000295 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl-piperazines WO1993021179A1 (en)

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EP93909109A EP0594813A1 (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl-piperazines
CZ932701A CZ270193A3 (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl piperazines
JP5518225A JPH06508378A (ja) 1992-04-09 1993-04-06 新規アミドアルキル−およびイミドアルキル−ピペラジン類
AU39643/93A AU665825B2 (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl-piperazines
SK1389-93A SK138993A3 (en) 1992-04-09 1993-04-06 Amidoalkyl - and imidoalkylpiperazines
NO934426A NO180794C (no) 1992-04-09 1993-12-06 Nye amidoalkyl- og imidoalkylpiperaziner samt farmasöytisk preparat inneholdende slike forbindelser
NO934426D NO934426D0 (no) 1992-04-09 1993-12-06 Nye amidoalkyl- og imidoalkylpipera-ziner
FI935494A FI935494A (fi) 1992-04-09 1993-12-08 Nya amidolakyl- och imidoalkylpiperaziner
BG98281A BG98281A (en) 1992-04-09 1993-12-08 Amidoalkyl- and imidoalkylpiperazines

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SE9201138A SE9201138D0 (sv) 1992-04-09 1992-04-09 Novel phthalimidoalkylpiperazines
SE9201138-6 1992-04-09
CN93118820A CN1099752A (zh) 1992-04-09 1993-08-31 新型酰氨烷基-和亚氨烷基-哌嗪

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Cited By (9)

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WO1995004049A1 (en) * 1993-07-30 1995-02-09 Recordati S.A., Chemical And Pharmaceutical Company PIPERAZINE DERIVATIVES AS α1A-ADRENERGIC RECEPTOR ANTAGONISTS
US5395835A (en) * 1994-03-24 1995-03-07 Warner-Lambert Company Naphthalamides as central nervous system agents
WO1995033743A1 (en) * 1994-06-03 1995-12-14 John Wyeth & Brother Limited Piperazine derivatives as 5ht1a antagonists
FR2742149A1 (fr) * 1995-12-11 1997-06-13 Inst Nat Sante Rech Med Nouveaux derives de 2-naphtamides et leurs applications therapeutiques
WO1997034884A1 (en) * 1996-03-21 1997-09-25 Neurogen Corporation Novel n-aminoalkyl-2-anthracenecarboxamides; new dopamine receptor subtype specific ligands
WO1997037983A1 (fr) * 1996-04-05 1997-10-16 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) ANTAGONISTES DU RECEPTEUR α1-ADRENERGIQUE
US6429312B2 (en) 1996-03-21 2002-08-06 Neurogen Corporation N-aminoalkyldibenzothiopencarboxamide receptor subtype specific ligands
WO2003028728A1 (en) * 2001-09-28 2003-04-10 Richter Gedeon Vegyészeti Gyár Rt. 4-(4-substituted piperazinyl-1yl)-butylcarboxamides as d3 dopamine subtype selective ligands
WO2003029233A1 (en) * 2001-09-28 2003-04-10 Richter Gedeon Vegyészeti Gyár Rt. New sulfonamide derivatives as d3-receptor agonists

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JP2005538974A (ja) * 2002-07-04 2005-12-22 シュバルツ　ファルマ　アクチェンゲゼルシャフト 中枢神経系の病気を治療するドーパミン−ｄ３リガンドとして使用するためのヘテロアレーンカルボキサミド
CN1948298B (zh) * 2006-11-09 2010-09-01 东南大学 一种多巴胺d3受体部分激动剂及其应用

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995004049A1 (en) * 1993-07-30 1995-02-09 Recordati S.A., Chemical And Pharmaceutical Company PIPERAZINE DERIVATIVES AS α1A-ADRENERGIC RECEPTOR ANTAGONISTS
US5395835A (en) * 1994-03-24 1995-03-07 Warner-Lambert Company Naphthalamides as central nervous system agents
WO1995025727A1 (en) * 1994-03-24 1995-09-28 Warner-Lambert Company Naphthylamides as central nervous system agents
US5723464A (en) * 1994-06-03 1998-03-03 American Home Products Corporation Piperazine derivatives
WO1995033743A1 (en) * 1994-06-03 1995-12-14 John Wyeth & Brother Limited Piperazine derivatives as 5ht1a antagonists
CN1093122C (zh) * 1994-06-03 2002-10-23 约翰韦恩兄弟有限公司 作为5－ht1a拮抗剂的哌嗪衍生物
CN1048985C (zh) * 1994-06-03 2000-02-02 约翰韦恩兄弟有限公司 作为5－ht1a拮抗剂的哌嗪衍生物
FR2742149A1 (fr) * 1995-12-11 1997-06-13 Inst Nat Sante Rech Med Nouveaux derives de 2-naphtamides et leurs applications therapeutiques
US5872119A (en) * 1995-12-11 1999-02-16 Institut National De La Sante et De La Recherche Medicale--INSERM 2-Naphthamide derivatives and their therapeutic applications
EP0779284A1 (fr) * 1995-12-11 1997-06-18 Institut National De La Sante Et De La Recherche Medicale (Inserm) Nouveaux dérivés de 2-naphthamides et leurs applications thérapeutiques comme agonistes des récepteurs D3
WO1997034884A1 (en) * 1996-03-21 1997-09-25 Neurogen Corporation Novel n-aminoalkyl-2-anthracenecarboxamides; new dopamine receptor subtype specific ligands
US6239179B1 (en) 1996-03-21 2001-05-29 Neurogen Corporation N-aminoalkyl-2-anthracenecarboxamides; new dopamine receptor subtype specific ligands
US6429312B2 (en) 1996-03-21 2002-08-06 Neurogen Corporation N-aminoalkyldibenzothiopencarboxamide receptor subtype specific ligands
WO1997037983A1 (fr) * 1996-04-05 1997-10-16 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) ANTAGONISTES DU RECEPTEUR α1-ADRENERGIQUE
WO2003028728A1 (en) * 2001-09-28 2003-04-10 Richter Gedeon Vegyészeti Gyár Rt. 4-(4-substituted piperazinyl-1yl)-butylcarboxamides as d3 dopamine subtype selective ligands
WO2003029233A1 (en) * 2001-09-28 2003-04-10 Richter Gedeon Vegyészeti Gyár Rt. New sulfonamide derivatives as d3-receptor agonists
US7473692B2 (en) 2001-09-28 2009-01-06 Richter Gedeon Vegyeszeti Gyar Rt. Sulfonamide derivatives as D3-receptor ligands

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BG98281A (en) 1994-09-30
CZ270193A3 (en) 1994-08-17
FI935494A0 (fi) 1993-12-08
NO934426D0 (no) 1993-12-06
NO180794C (no) 1997-06-25
EP0594813A1 (en) 1994-05-04
SE9201138D0 (sv) 1992-04-09
NO180794B (no) 1997-03-17
SK138993A3 (en) 1994-11-09
AU665825B2 (en) 1996-01-18
NO934426L (no) 1993-12-06
CA2109816A1 (en) 1993-10-28
SI9300191A (sl) 1993-12-31
HUT68891A (en) 1995-08-28
JPH06508378A (ja) 1994-09-22
AU3964393A (en) 1993-11-18
FI935494A (fi) 1993-12-08

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