GB1575904A - Phenyl piperazines - Google Patents

Phenyl piperazines Download PDF

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Publication number
GB1575904A
GB1575904A GB16526/76A GB1652676A GB1575904A GB 1575904 A GB1575904 A GB 1575904A GB 16526/76 A GB16526/76 A GB 16526/76A GB 1652676 A GB1652676 A GB 1652676A GB 1575904 A GB1575904 A GB 1575904A
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formula
piperazine
phenylpiperazine
ylmethyl
phenyl
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GB16526/76A
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Lilly Industries Ltd
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Lilly Industries Ltd
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Priority to GB16526/76A priority Critical patent/GB1575904A/en
Priority to NZ183715A priority patent/NZ183715A/en
Priority to ZA00771849A priority patent/ZA771849B/en
Priority to IE671/77A priority patent/IE44730B1/en
Priority to CA275,160A priority patent/CA1087617A/en
Priority to IL51787A priority patent/IL51787A/en
Priority to CH455777A priority patent/CH625802A5/en
Priority to CH525781A priority patent/CH633009A5/en
Priority to MX775629U priority patent/MX4596E/en
Priority to PH19656A priority patent/PH14124A/en
Priority to AU24386/77A priority patent/AU514822B2/en
Priority to PT66452A priority patent/PT66452B/en
Priority to FR7711669A priority patent/FR2348925A1/en
Priority to GR53236A priority patent/GR64084B/en
Priority to RO7790106A priority patent/RO72831A/en
Priority to BG7736062A priority patent/BG27746A3/en
Priority to DE19772717415 priority patent/DE2717415A1/en
Priority to ES457988A priority patent/ES457988A1/en
Priority to SE7704536A priority patent/SE7704536L/en
Priority to OA56149A priority patent/OA05643A/en
Priority to BG7737191A priority patent/BG28055A3/en
Priority to CS772668A priority patent/CS196360B2/en
Priority to YU01044/77A priority patent/YU104477A/en
Priority to DK176177A priority patent/DK176177A/en
Priority to LU77170A priority patent/LU77170A1/xx
Priority to NO771398A priority patent/NO146710C/en
Priority to BE6045977A priority patent/BE853899A/en
Priority to AR267310A priority patent/AR222003A1/en
Priority to FI771287A priority patent/FI63937C/en
Priority to AT285177A priority patent/AT355579B/en
Priority to PL1977197550A priority patent/PL117466B1/en
Priority to HU77LI311A priority patent/HU176820B/en
Priority to SU772474105A priority patent/SU664564A3/en
Priority to NL7704456A priority patent/NL7704456A/en
Priority to DD7700198558A priority patent/DD129790A5/en
Priority to JP4727677A priority patent/JPS52151183A/en
Priority to US05/813,912 priority patent/US4123529A/en
Priority to SU772558499A priority patent/SU727146A3/en
Priority to ES467948A priority patent/ES467948A1/en
Priority to AR271519A priority patent/AR222635A1/en
Publication of GB1575904A publication Critical patent/GB1575904A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07D307/38—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • 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
    • C07D307/38—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Furan Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Phenylpiperazine derivatives of formula (I) <IMAGE> as well as their pharmaceutically acceptable salts, are prepared. R<1> represents benzyl, C1-6 alkyl or an optionally substituted phenyl; R<2> represents an optionally substituted phenyl, R<3> represents hydrogen or C1-4 alkyl, Q represents furan, thiophene, oxazole or thiazole, m is an integer from 1 to 3 and n is 0 or 1. When m is 2 and n is 0, R<1> cannot represent a methyl group when Q is the thiazol-5-yl group. The preparation is carried out by condensation of a compound of formula (VII): R<1>-Q-(CH2)m-(CHR<3>)n-L (VII) in which L represents the split group, with a compound of formula (VIII): <IMAGE> The compounds of formula (I) and their pharmaceutically acceptable salts are useful in the prophylactic and therapeutic treatment of diseases of immediate hypersensitiveness, especially asthma in mammals. They have a low toxicity.

Description

(54) PHENYL PIPERAZINES (71) We, LILLY INDUSTRIES LIMITED, a British Company of Henrietta House, Henrietta Place, London, W.l., do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a novel class of phenylpiperazine derivatives which possess useful pharmacological activity. Furthermore, the invention inlcudes within its scope processes for preparing the novel compounds of the invention, pharmaceutical compositions containing the aforementioned pharmacologically active compounds.
According to the present invention there is provided a phenylpiperazine derivative of formula (I):
where R1 is benzyl, chlorobenzyl C1.6 alkyl or optionally substituted phenyl; R2 is optionally substituted phenyl; R3 is hydrogen or Cur 4 alkyl; Q is furan, thiophene, oxazole or thiazole; m is 1 to 3 and n is 0 or 1, provided that when m is 2 and n isO, R' cannot be methyl when Q is a thiazol-5-yl group; or a pharmaceuticallyacceptable salt thereof.
Preferably, R2, and R' when phenyl, is phenyl optionally substituted by one or two radicals selected from halogen, C1-4 alkyl, C1-4 haloalkyl, amino, C2-4 alkanoylamino, hydroxy, C1-4 alkoxy, nitro and C1-4 alkylsulphonamido.
The term "C1.4 alkyl" as used herein means a straight or branched chain alkyl group containing from 1 to 4 carbon atoms e.g. methyl, ethyl, iso-propyl, n-butyl, sbutyl, isobutyl and t-butyl. C 4 haloalkyl" signifies an aforementioned C14 alkyl group substituted by one or more fluorine, chlorine, bromine or iodine atoms, and includes groups such as trifluoromethyl or pentachloroethyl. Similarly, the term "C14 alkoxy" refers to the aforementioned C14 alkyl groups attached via an oxygen atom to the phenyl group.
Preferred classes of compounds of formula (I) are those having one or more of the following characteristics: (a) m is 1 and n is 0; (b) Q is thiazole; (c) Q is oxazole; (d) Q is thiophene; (e) Q is furan; (f) R' is C,, alkyl such as methyl or i-propyl; (g) R' is phenyl; (h) R' is benzyl; (i) R2 is phenyl substituted by one or two methyl radicals.
Particularly active classes of phenylpiperazine derivatives of formula (I) are furans of formula (II):
where R' is phenyl optionally substituted by one or two radicals selected from halogen, C, 4 alkyl, C, 4 alkoxy, and C1.4 haloalkyl; R2 is phenyl optionally substituted by C1-4 alkyl, amino, C1-4 alkylsulphonamido and C, 4 alkoxy and m is 1 or 3, with the exception of compounds in which R' is unsubstituted phenyl, m is 1 and R2 is unsubstituted phenyl; or where R' is methyl, m is 1 and R2 is phenyl optionally substituted by a single radical selected from halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl or is disubstituted by two C1-4 alkyl radicals; thiophenes of formula (III):
where R' is phenyl; R2 is phenyl, phenyl singly substituted by C, 4 alkyl or C1.4 haloalkyl or doubly substituted by two radicals selected from halogen, C14 haloalkyl and C14 alkyl, and where m is 1 or 2 and n=0; or where m is 1, n is I and R3 is ethyl; oxazoles of formula (IV):
where R' is phenyl optionally substituted by C, 4 alkoxy or halogen; R2 is phenyl optionally substituted by C, 4 alkyl, C1-4 haloalkyl, halogen, amino or C2.4 alkanoylamino and m is 1 or 2; thiazoles of formula (V):
where R' is benzyl, R2 is phenyl or p-halophenyl; or thiazoles of formula (VA):
where R1 is C1-4 alkyl or phenyl optionally substituted C1-4 alkyl, C1-4 alkoxy, nitro and C1-4 haloalkyl and R2 is phenyl optionally substituted by C1-4 haloalkyl; and their pharmaceutically-acceptable salts.
Preferably in the above derivatives, and where appropriate, m is 1.
Particularly preferred compounds of formula (I) are: 1 - [2 - (5 - Phenylthiophen - 2 - yl)ethyl] - 4 - phenylpiperazine; 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - (3 - chlorophenyl)piperazine; 1 - [5 - (4 - Methoxyphenyl) - furan - 2 - ylmethyl] - 4 - phenylpiperazine; 1 - [5 - (3,4 - Dimethylphenyl) - furan - 2 - ylmethyl] - 4 phenylpiperazine; 1 - {3 - [5 - (3,4 - dichlorophenyl) - furan - 2 - yl]prop - 1 - yl} - 4 - (4 methylphenyl)piperazine: 1 - [1 - (5 - Phenylthiophen - 2 - yl)but - 3 - yl] - 4 - phenylpiperazine; 1 - (5 - phenylthiophen - 2 - ylmethyl) - 4 - (3,4 - dimethylphenyl)piperazine; 1 - [3 - (5 - Phenylfuran - 2 - yl)prop - 1 - yl] - 4 - (4 methylphenyl)piperazine; 1 - [5 - (4 - Methoxyphenyl) - furan - 2 - ylmethyl] - 4 - (4 methylphenyl)piperazine; 1 - (5 - Phenyloxazol - 2 - ylmethyl) - 4 - (4 - methylphenyl) - piperazine; 1 - (2 - Benzylthiazol - 4 - ylmethyl) - 4 - phenylpiperazine; and their pharmaceutically acceptable acid-addition salts.
Other illustrative examples of novel compounds of the invention are: 1 - (5 - Phenylthiophen - 2 - ylmethyl) - 4 - (3 - chlorophenyl)piperazine; 1 - (5 - Phenylthiophen - 2 - ylmethyl) - 4 - (4 - methoxyphenyl)piperazine; 1 - [5 - (3 - Trifluoromethyl - 4 - chlorophenyl) - furan - 2 - ylmethyl] - 4 (4 - fluorophenyl)piperazine; 1 - [3 - (5 - Phenylfuran - 2 - yl)prop - 1 - yl] - 4 - (3 trifluoromethylphenyl)piperazine; 1 - (2 - Methylthiazol - 4 - ylmethyl) - 4 - (3 - chlorophenyl)piperazine; 1 - [2 - (4 - Phenylthiazol - 2 - yl)ethyl] - 4 - (4 - aminophenyl)piperazine; 1 - [2 - (4 - Phenylthiazol - 2 - yl)ethyl] - 4 - (4 - nitrophenyl)piperazine; 1 - (5 - Phenyloxazol - 2 - ylmethyl) - 4 - phenylpiperazine; 1 - [4 - (3 - Trifluoromethylphenyl) - thiazol - 2 - ylmethyl] - 4 phenylpiperazine; 1 - (4 - Phenylthiazol - 2 - ylmethyl) - 4 - phenylpiperazine; 1 - [2 - [5 - (4 - Chlorophenyl)oxazol - 2 - yl] - ethyl] - 4 phenylpiperazine; 1 -[2 -(5 - Phenyloxazol - 2 - yl)ethyl] - 4 - (4 - chlorophenyl) - piperazine; 1 - [2 - (5 - Phenyloxazol - 2 - yl)ethyl] - 4 - (4 - methoxyphenyl) piperazine; 1 - [1 - (5 - Phenyloxazol - 2 - yl)prop - 2 - yl] - 4 - (4 - methylphenyl) piperazine; 1 - [1 - (5 - Phenyloxazol - 2 - yl)ethyll - 4 - (4 - methylphenyl) piperazine; 1 - (5 - Phenyloxazol - 2 - ylmethyl) - 3 - methyl - 4 - (4 - methylphenyl) piperazine; 1 - (5 - Phenyloxazol - 2 - ylmethyl) - 2,3 - dimethyl - 4 - (4 methylphenyl) - piperazine; 1 - {2 - [4 - (Chlorophenyl) - thiazol - 2 - yl]ethyl} - 4 - phenylpiperazine; 1 - [2 - (4 - Phenylthiazol - 2 - yl)ethyl] - 4 - (4 - chlorophenyl) piperazine; 1 - [2 - (4 - Phenylthiazol - 2 - yl)ethyl] - 4 - (4 - methoxyphenyl) piperazine; 1 - [1 - (4 - Phenylthiazol - 2 - yl)prop - 2 - yl] - 4 - (4 - methylphenyl) piperazine; 1 - [1 - (4 - Phenylthiazol - 2 - yl)ethyl] - 4 - (4 - methylphenyl) piperazine; 1 - (4 - Phenylthiazol - 2 - ylmethyl) - 4 - (4 - methanesulphonamidophenyl) - piperazine; 1 - {2 - [5 - (4 - Chlorophenyl) - furan - 2 yl]ethyl} - 4 - phenylpiperazine; 1 - [2 - (5 - Phenylfuran - 2 - yl)ethyl] - 4 - (4 - chlorophenyl) - piperazine; 1 - [2 - (5 - Phenylfuran - 2 - yl)ethyl] - 4 - (4 - methoxyphenyl) piperazine; 1 - [1 - (5 - Phenylfuran - 2 - yl)prop - 2 - yl] - 4 - (4 - methylphenyl piperazine; 1 - [1 - (5 - Phenylfuran - 2 - yl)ethyl] - 4 - (4 - methylphenyl) - piperazine; 1 - (5 - Phenylfuran - 2 - ylmethyl) - 4 - (4 - methylphenyl) - piperazine; 1 - (5 - Phenylfuran - 2 - ylmethyl) - 4 - (4 methanesulphonamidophenyl) - piperazine; 1 - [4 - (4 - Phenylthiazol - 2 - yl)but - 1 - yl] - 4 - phenylpiperazine; 1 -(5 - Phenylthiophen - 2 - ylmethyl) - 4 - (4 - methylphenyl) - piperazine; - . (5 - Phenylthiophen - 2 - ylmethyl) - 4 - phenylpiperazine; - . (5 - Methyloxazol - 2 - ylmethyl) - 4 - phenylpiperazine; 1 - (4 - Methyloxazol - 2 - ylmethyl) - 4 - (4 - methylphenyl) - piperazine; 1 - [2 - (5 - Methyloxazol - 2 - yl)ethyl] - 4 - (4 - chlorophenyl) piperazine; 1 - [2 - (4 - Methyloxazol - 2 - ethyl] - 4 - (3 - methylphenyl) - piperazine; 1 - [3 - (5 - Methyloxazol - 2 - yl)prop - 1 - yl] - 4 - (2 chlorophenyl)piperazine; 1 - (5 - Benzyloxazol - 2 - ylmethyl) - 4 - (4 - nitrophenyl)piperazine; 1 - (4 - Benzyloxazol - 2 - ylmethyl) - 4 -(3 - acetylaminophenyl)piperazine; 1 - [2 - (5 - Benzyloxazol - 2 - yl)ethyl] - 4 - (4 - nitrophenyl)piperazine; 1 - [2 - (5 - Benzyloxazol - 2 - yl)ethyl] - 4 - (4 - ethylphenyl)piperazine; 1 - [3 - (5 - Benzyloxazol - 2 - yl)prop - 1 - yl] - 4 - (4 ethoxyphenyl)piperazine; 1 - (5 - Methylthiazol - 2 - ylmethyl) - 4 - phenylpiperazine; 1 - (4 - Methylthiazol - 2 - ylmethyl) - 4 - (4 - methylphenyl)piperazine; 1 - [2 - (5 - Methylthiazol - 2 - yl)ethyl] - 4 - (4 - chlorophenyl)piperazine; 1 - [2 - (4 - Methylthiazol - 2 - yl)ethyl] - 4 - (3 - methylphenyl)piperazine; 1 - [3 - (5 - Methylthiazol- 2- yl)prop - 1 - yl] - 4- (2 chlorophenyl)piperazine; 1 - (5 - Benzylthiazol - 2 - ylmethyl) - 4 - (4 - nitrophenyl) - piperazine; 1 - (4 - Benzylthiazol - 2 - ylmethyl) - 4 - (3 acetylaminophenyl)piperazine; 1 - [2 - (5 - Benzylthiazol - 2 - yl)ethyl] - 4 - (4 - aminophenyl)piperazine; 1 - [2 - (5 - Benzylthiazol - 2 - yl)ethyl] - 4 - (4 - ethylphenyl)piperazine; 1 - [3 - (5 - Benzylthiazol - 2 - yl)prop - 1 - yl] - 4 - (4 ethoxyphenyl)piperazine; - . (5 - Methylfuran - 2 - ylmethyl) - 4 - phenylpiperazine; 1 - (4 - Methylfuran - 2 - ylmethyl) - 4 - (4 - methylphenyl)piperazine; 1 - [2 - (5 - Methylfuran - 2 - yl)ethyl] - 4 -(4 - chlorophenyl) - piperazine; 1 - [2 - (4 - Methylfuran - 2 - yl)ethyl] - 4 -(3 - methylphenyl) - piperazine; - . [3 - (5 - Methylfuran - 2 - yl)prop - 1 - yl] - 4 - (2 - chlorophenyl)piperazine; - . (5 - Benzylfuran - 2 - ylmethyl) - 4 - (4 - nitrophenyl)piperazine; - . (4 - Benzylfuran - 2 - ylmethyl) - 4 - (3 - acetylaminophenyl)piperazine; 1 - [2 - (5 - Benzylfuran - 2 - yl)ethyl] - 4 - (4 - ethylphenyl)piperazine; 1 - [3 - (5 - Benzylfuran - 2 - yl)prop - 1 - yl] - 4 - (4 ethoxyphenyl)piperazine; 1 - (5 - Methylthiophen - 2 - ylmethyl) - 4 - phenylpiperazine; 1 - (4 - Methylthiophen - 2 - ylmethyl) - 4 - (4 - methylphenyl) - piperazine; 1 - [2 - (5 - Methylthiophen - 2 - yl)ethyl] - 4 - (4 chlorophenyl)piperazine; 1 - [2 - (4 - Methylthiophen - 2 - yl)ethyl] - 4 - (3 methylphenyl)piperazine; 1 - [3 - (5 - Methylthiophen - 2 - yl)prop - 1 - yl] - 4 - (2 - chlorophenyl)piperazine; 1 - (5 - Benzylthiophen - 2 - ylmethyl) - 4 - (4 - nitrophenyl)piperazine; 1 - (4 - Benzylthiophen - 2 - ylmethyl) - 4 - (3 - acetylaminophenyl)piperazine; 1 - [2 - (5 - Benzylthiophen - 2 - yl)ethyl] - 4 - (4 - nitrophenyl)piperazine; 1 - . [2 - (5 - Benzylthiophen - 2 - yl)ethyl] - 4 - (4 - ethylphenyl)piperazine; 1 - . [3 - (5 - Benzylthiophen - 2 - yl)prop - 1 - yl] - 4- (4 ethoxyphenyl)piperazine; and their pharmaceutically-acceptable acid-addition salts.
According to a further aspect of the present invention there is provided a method of preparing a piperazine derivative of formula (I), or an acid-addition salt thereof, which comprises: (A) condensing a compound of formula (Vl): R1-Q-(CH2)m-(CHR3)n-L (VI): where L represents a leaving group, with a compound of formula (VII):
(B) reducing a compound of formula:
to form a compound in which n is 0; or
to form a compound in which n is 1; or (C) cyclising a compound of formula (X):
where Z is a group cyclisable to Q to form a compound of formula (I) in which Q is oxazole.
The above condensation (A) is preferably carried out in the presence of a proton acceptor such as a base, for example, sodium bicarbonate. Polar solvents such as alkanols, e.g. ethanol, are suitable solvents for the reaction which is advantageously accomplished by heating under reflux. The leaving group L may be any radical known to be effective in such condensation reactions but it should be mentioned that halogen atoms, for instance chlorine, or methylsulphonyl or substituted benzene sulphonyl groups give good results in this reaction. The reaction is preferably effected in the temperature range from 20 to 1500C.
Compounds of formula (VI) are either known (see J.A.C.S. 56 47(l (1934) and 53 14703 (1931)) or can be prepared by known techniques.
Reduction of the amide of formula (VIII) can be effected using chemical reducing agents such as B2H or lithium aluminium hydride. Ethereal solvents such as tetrahydrofuran are of value in effecting the reaction which is preferably carried out at a temperature range from 0 to 800 C. The amides of formula (VIII) can be prepared by reaction of an acid chloride (prepared for instance from the corresponding acid by reaction with thionyl chloride) of formula:
with the phenylpiperazine of formula:
The reduction of compounds of formula (IX) can be carried out using the reaction conditions described in J.A.C.S. 93, 2897-2904 (1971) or in Synthesis 135-146 (1975). The reduction is preferably accomplished using sodium cyanoborohydride but other forms of reduction, for example, using catalytic hydrogenation or other suitable chemical reducing agents are possible. As before, the reduction is preferably accomplished in the temperature range of from 0 to 80"C.
Compounds of formula (X) are normally prepared by reaction of the corresponding carbonyl compound of formula:
with the appropriate phenyl base of formula
in the presence of a proton donor, such as acetic acid.
The nature of Z in the above cyclisation reaction (C) and the reaction conditions necessary to effect the desired ring-closure will be well-known to those skilled in the art. In case of doubt recourse may be had to standard treatises in the art such as Chemical Reviews, 75, 389437 (1975) and Advances in Heterocyclic Chemistry 17 (1974).
Preferably, Z is a group of formula: -Co-CH2-NH-Co- Thus, compounds of formula (XI)
can be cyclised to compounds of formula:
using dehydrating agents such as polyphosphoric acid, phosphorous oxychloride or concentrated sulphuric acid. The reaction is preferably accomplished at a temperature range of from 80 to 1800C.
Compounds of formula (XI) may be prepared by reacting the corresponding bromo derivative of formula: R1-CO-CH2-NH-CO-(CH2)m-(CHR3)n-Br (XII) with the corresponding base of formula
in the presence of an acid scavenger such as sodium carbonate.
The compounds of formula (XII) may themselves be prepared by reaction of the amine of formula: R1 COCH2NH2 with the corresponding acid chloride of formula ClCO(CH2)m(CH R3)nCl using dimethylformamide as solvent.
The compounds of formula (I) produced by the foregoing processes may be isolated per se or in acid-addition salt form.
The acid-addition salts are preferably the pharmaceutically acceptable, nontoxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, malic, tartaric, citric, salicylic, o-acetoxybenzoic, nicotinic or isonicotinic acid, or organic sulphonic acids for example methane sulphonic, ethane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic acid. Apart from pharmaceutically acceptable acidaddition salts, other salts are also included within the scope of acid-addition salts such as, for example, those with picric or oxalic acid; they may serve as intermediates in the purification of the compounds or in the preparation of other, for example, pharmaceutically acceptable, acid-addition salts, or are useful for identification, characterisation or purification of the bases.
A resulting acid-addition salt may be converted into the free compound according to known methods, for example, by treating it with a base, such as with a metal hydroxide or alkoxide, for example, an alkali metal or alkaline earth metal hydroxide, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; with a metal carbonate, such as an alkali metal or an alkaline earth metal carbonate or hydrogen carbonate; with ammonia; or with a hydroxyl ion exchange preparation, or with any other suitable reagent.
A resulting acid-addition salt may also be converted into another acid-addition salt according to known methods; for example, a salt with an inorganic acid may be treated with a metal salt, for example, a sodium, barium or silver salt, of an acid in a suitable diluent, in which a resulting inorganic salt is insoluble and is thus removed from the reaction medium. An acid addition salt may also be converted into another acid-addition salt by treatment with an anion exchange preparation.
According to a further aspect of the invention there is provided a pharmaceutical formulation which comprises a compound of formula (I), or a pharmaceutically-acceptable salt thereof, associated with a pharmaceuticallyacceptable carrier therefor.
Compounds of formula (I) and their pharmaceutically-acceptable salts have been shown to be useful in the prophylactic and therapeutic treatment of immediate hypersensitivity diseases including asthma in mammals. The compounds have low toxicity.
The compounds or compositions of the present invention may be administered by various routes and for this purpose may be formulated in a variety of forms.
Thus the compounds or compositions may be administered orally, rectally, topically or parenterally (e.g. by injection or by continuous or discontinuous intravenous infusion) in the form of, for example, tablets, lozenges, sub-lingual tablets, sachets, cachets, elixirs, suspensions, suppositories, aerosols, ointments (for example, containing from 1 to 100/, by weight of the active compound in a suitable base) soft and hard gelatin capsules, injection solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injection solutions.
Advantageously for this purpose, compositions may be provided in dosage unit form, preferably each dosage unit containing from 5 to 500 mg. (from 5.0 to 50 mg. in the case of parenteral administrations, from 5.0 to 50 mg. in the case of inhalation and from 25 to 500 mg. in the case of oral or rectal administration) of a compound of formula I. Dosages of from 0.5 to 300 mglkg per day, preferably 0.5 to 20 mg/kg of active ingredient may be administered although it will, of course, readily be understood that the amount of the compound or compounds of formula (I) actually to be administered will be determined by a physician, in the light of all the relevant circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way.
The formulations of the present invention normally will consist of at least one compound of formula I mixed with a carrier, diluted by a carrier, or enclosed or encapsulated by an- ingestible carrier in the form of a capsule, sachet, cachet, paper or other container or by a disposible container such as an ampoule. A carrier or diluent may be a solid, semi-solid or liquid material, which serves as a vehicle, excipient or medium for the active therapeutic substance.
Some examples of the diluents or carriers which may be employed in the pharmaceutical compositions of the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidine, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis oil, alginates, tragacanth, gelatin, syrup B.P., methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tabletting machine. For such purpose there may be employed for instance aluminium, magnesium or calcium stearates, talc or mineral oil.
The following Examples illustrate the invention.
EXAMPLE 1 (a) 2-Acetoxythioacetamide A stream of dry H2S gas was passed rapidly into a solution of 2acetoxyacetonitrile (150 g; 1.52 mole) and triethanolamine (20 ml) in dry ethanol (500 ml) with vigorous stirring. The internal temperature rose to ca. 550C. The gas flow was maintained for 3 hours whereupon G.L.C. indicated that the reaction was complete. Excess H2S gas was blown off with a stream of nitrogen and solvent EtOH evaporated to dryness. The remaining sticky crystalline mass was extracted with boiling ether, a small insoluble residue being discarded. The combined extracts were treated with decolourising charcoal, filtered and evaporated to approximately 400 ml volume. On cooling to OOC. there was obtained some 170 g. of somewhat sticky 2-acetoxythioacetamide. This was used for the next stage without further characterisation.
(b) 2 - Hydroxymethyl - 4 - phenylthiazole 2-Bromoacetophenone (39.9 g; 0.2 mole) and 2-acetoxythioacetamide (30 g; 0.225 mole) were dissolved in dioxan (150 ml). The mixture was stirred and heated on a steam bath for 15 minutes, yielding a mass of crystals. Aqueous 5 N HCI (40 ml) was added and the heating continued for a further 30 minutes. The dioxan was evaporated under vacuum and the residue neutralised with aqueous Na2CO3 solution. The solid was collected, washed with water and dried. After recrystallisation from benzene the product weighed 33.5 g (87 /n) and had a m.p. of 88--9"C.
(c) 2 - Chloromethyl - 4 - phenylthiazole Thionyl chloride (6.25 g, 0.052 mole) was added dropwise to a stirred solution of 2 - hydroxymethyl - 4 - phenylthiazole (9.55 g; 0.05 mole) and dry pyridine (4.0 g; 0.051 mole) in dry benzene (60 ml) held at room temperature. The mixture was stirred and heated to boiling for 1 hour. The cooled reaction mixture was then shaken with 2x 70 ml H2O and dried over anhydrous MgSO4. The solvent was removed under vacuum and the remaining red oil extracted with 40--60"C. petroleum ether (100 ml), discarding a small tarry residue. The extract was treated with decolourising charcoal, filtered and evaporated, leaving a yellow-red oil that crystallised on refrigeration.
Yield 9.9 g, 94.5.
No further purification was undertaken, and the material was used directly for the next stage.
(d) 1 - (4 - Phenyl - 2 - thiazolylmethyl) - 4 - phenylpiperazine A mixture of crude 2 - chloromethyl - 4 - phenylthiazole (4.19 g; 0.02 mole), N-phenylpiperazine (3.24 g, 0.02 mole) and finely-powdered, anhydrous sodium carbonate in absolute ethanol (60 ml) was stirred and boiled under reflux for 8 hours. The solvent was evaporated to dryness, solid residue suspended in water (100 ml) and then extracted with 2x 100 ml CH2Cl2. The extracts were washed with water and dried over anhydrous MgSO4. On evaporation of the solvent, and recrystallisation of the residue from benzene/60--80"C. petroleum ether mixture (with charcoal treatment) there was obtained the required product (5.03 g; 75%) having m.p. 142-30C.
EXAMPLES 2 to 19 Similarly, there were prepared: (2) 1 - (4 - Phenyl - 2 - thiazolylmethyl) - 4 - (3 - bromophenyl) - piperazine, m.p. 127.5-128.50C.
(3) 1 - (4 - Phenyl - 2 - thiazolylmethyl) - 4 - (3,4 - dichlorophenyl) piperazine, m.p. 144-6 C.
(4)1 - (4 - Phenyl - 2 - thiazolylmethyl) - 4 - (3 - trifluoromethylphenyl) piperazine, m.p. 112-3 C.
(5) 1 - (4 - Phenyl - 2 - thiazolylmethyl) - 4 - (4 - chloro - 3 trifluoromethylphenyl) - piperazine, m.p. 117-9 C.
(6) 1 - (4 - Phenyl - 2 - thiazolylmethyl) - 4 - (4 - methylphenyl) piperazine, m.p. 141-30C.
(7) 1 - (4 - Phenyl - 2 - thiazolylmethyl) - 4 - (4 - methoxyphenyl) piperazine, m.p. 148-90C.
(8)1 - [4 - (4 - Chlorophenyl) - 2 - thiazolylmethyl] - 4 - phenylpiperazine, m.p. 164-50C.
(9) 1 - [4 - (4 - Chlorophenyl)- 2- thiazolylmethyll - 4- (3 bromophenyl) - piperazine, m.p. 100-101 C.
(10)1 - [4 - (4 - Bromophenyl) - 2 - thiazolylmethyl] - 4 - phenylpiperazine, m.p. 166 C.
(11) 1 - [4 - (3 - Chlorophenyl) - 2 - thiazolylmethyl] - 4 - phenylpiperazine, m.p. 129-131 C.
(12) 1 - [4 - (2 - Chlorophenyl) - 2 - thiazolylmethyl] - 4 - phenylpiperazine, m. p. 100-101 C.
(13) 1 - [4 - (3,4 - Dichlorophenyl) - 2 - thiazolylmethyl] - 4 phenylpiperazine, m.p. 138-139.50C.
(14) 1 - [4 - (3 - Trifluoromethylphenyl) - 2 - thiazolylmethyl] - 4 phenylpiperazine m.p. 110-111 C.
(15) 1 - [4 - (4 - MethoxyphenyA) - 2- thiazolylmethyl] - 4phenylpiperazine. HC1 m.p. 2010C.
(16)1 - [4 - (4 - Methylphenyl) - 2 - thiazolylmethyl] - 4 - phenylpiperazine.
HC1 m.p. 175-1800C.
(17) 1 - [4 - (3 - Methylphenyl) - 2 - thiazolylmethyl] - 4 - phenylpiperazine, m.p. 113-113.5 C.
(18) 1 - [4 - (4 - Hydroxyphenyl) - 2 - thiazolylmethyl] - 4 phenylpiperazine, m.p. 228-230 C.
(19) 1 - [4 - (4 - Nitrophenyl) - 2 - thiazolylmethyl] - 4 - phenylpiperazine, m.p. 195-8 C.
EXAMPLE 20 (a) N-Phenacyl chloroacetamide Chloroacetyl chloride (25 g; 0.226 mole) was added slowly to a stirred solution of phenacylamine hydrochloride (25.9 g; 0.151 mole) in anhydrous dimethylformamide (DMF) (80 ml) at room temperature. The internal temperature rose to ca. 40 C. The mixture was stirred for 4 hours after the addition and the bulk of the DMF evaporated under vacuum. The residue was treated with water (200 ml) and the crystalline precipitate collected, washed with water and dried. Yield 24.75 g (77%). m.p. 118-1190C.
(b) 2 - Chloromethyl - 5 - phenyloxazole N-Phenacyl chloroacetamide (22.6 g; 0.107 mole) was mixed with polyphosphoric acid (200 g) and the mass heated with stirring for 30 minutes at 1500C. The hot liquid was then poured with vigorous stirring into water (800 ml).
The mixture so formed was extracted with 3x 100 ml chloroform, the extracts washed by shaking with water and dried over magnesium sulphate. The CHCl3 was evaporated off and the remaining oil extracted with 400 ml boiling 60-80 C. petroleum ether. The resultant solution was treated with decolourising charcoal to remove tarry matter and evaporated, giving a pale yellow oil which crystallized rapidly. Yield 18.8 g (91 /") m.p. 70-1 C.
(c) 1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - phenylpiperazine A solution of 2 - chloromethyl - 5 - phenyloxazole (3.87 g; 0.02 mole) and Nphenylpiperazine (3.25 g; 0.02 mole) in absolute ethanol (60 ml) was boiled and stirred with finely powdered anhydrous sodium carbonate (5 g) for 6 hours.
The solution was evaporated to dryness and treated with water (60 ml). The suspension thus obtained was extracted with 2x70 ml. dichloromethane. The extracts were dried over magnesium sulphate and evaporated to dryness. The solid residue was recrystallised from 80-100 C. petroleum ether with the use of decolourising charcoal.
Yield 4.67 g., m.p. 960C.
EXAMPLES 21-35 Similaryl, there were prepared: (21) 1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - (4 - methylphenyl) piperazine, m.p. 113-114 C.
(22) 1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - (3 - chlorophenyl) - piperazine, m.p. 730C.
(23) 1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - (4 - chlorophenyl) piperazine, m.p. 125-60C.
(24) 1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - (3 trifluoromethylphenyl) - piperazine, m.p. 69-70 C.
(25) 1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - (3,4 - dichlorophenyl) piperazine, m.p. 134-50C.
(26) 1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - (4 - methoxyphenyl) piperazine, m.p. 121-20C.
(27) 1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - (3 - methoxyphenyl) piperazine, m.p. 100 C.
(28) 1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - (2,4 - dimethoxyphenyl) piperazine, m.p. 89-91 C.
(29)1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - (3,4 - dimethoxyphenyl) piperazine, m.p. 93-50C.
(30) 1 - (5 - Phenyl - oxazol - 2 - ylmethyl) - 4 - (4 - ethoxyphenyl) piperazine, m.p. 980C.
(31) 1 - [5 - (4 - Fluorophenyl) - oxazol - 2 - ylmethyl] - 4 phenylpiperazine, m.p. 114-1 l60C.- (32) 1 - [5 - (4 - Fluorophenyl) - oxazol - 2 - ylmethyl] - 4 - (4 methoxyphenyl) - piperazine, m.p. 112 C.
(33) 1 - [5 - (4 - Methoxyphenyl)- oxazol- 2 - ylmethyl] - 4phenylpiperazine, m.p. 112-1 150C.
(34) 1 - [5 - (4 - Methoxyphenyl) - oxazol - 2 - ylmethyl] - 4 - (4 methoxyphenyl) - piperazine, m.p. 148-50 C.
(35)1 - (5 - Phenyloxazol - 2 - ylmethyl) - 4 - (4 - nitrophenyl) - piperazine, m.p. 1720C.
EXAMPLE 36 1 - (5 - Phenyloxazol - 2 - ylmethyl) - 4 - (4 - aminophenyl) - piperazine A solution of 1 - (5 - phenyloxazol - 2 - ylmethyl) - 4 - (4 - nitrophenyl) piperazine (7.28 g; 0.02 mole) in glacial acetic acid (50 ml) was hydrogenated over 5% Palladium-on-charcoal catalyst (100 mg) at atmospheric pressure and room temperature, until the uptake of hydrogen was complete. The solvent was evaporated off under vacuum and the residue treated with aqueous sodium bicarbonate solution, yielding a white crystalline solid. Weight after drying=6.54 g (98%), m.p. 1300C.
EXAMPLE 37 1 - (5 - Phenyloxazol - 2 - ylmethyl) - 4 - (4 - acetamidophenyl) - piperazine The 4-aminophenyl compound of Example 36 (3.0 g; 0.009 mole) was warmed on a steam bath with glacial acetic acid (5 ml) and acetic anhydride (10 ml) for 1 hour. The mixture was poured into water (200 ml), stirred well and the collected precipitate washed with water and dried. After recrystallisation from methanol the product weighed 2.45 g and melted at 196-7 C.
EXAMPLE 38 1 - (5 - Phenyloxazol - 2 - ylmethyl) 4 - (4 - hydroxyphenyl) - piperazine Propane-l-thiol (5.02 g; 0.066 mole) was added slowly to a stirred suspension of 50% sodium hydride/mineral oil mixture (3.17 g; 0.066 mole) in anhydrous dimethylformamide (140 ml). To the solution of sodium propan-l-thiolate thus formed was added 1 - (5 - phenyloxazol - 2- ylmethyl) - 4 - (4 methoxyphenyl) - piperazine (7.7 g; 0.022 mole). The solution was heated to reflux on an oil bath for 10 hours under an atmosphere of nitrogen. The mixture was then poured into water (600 ml) and extracted with 3x200 ml ethyl acetate. The extracts were shaken several times with water, dried and evaporated to a white solid. After recrystallisation frdm dioxan/60-80 C. petroleum ether, the product weighed 5.5 g (74.5%), m.p. 189-190 C.
EXAMPLE 39 1 - [2 - (5 - Phenyloxazol - 2 - yl) - ethyl] - 4 - phenylpiperazine (a) N - Phenacyl - 3 - bromopropanamide 3-Bromopropionyl chloride (25 g; 0.146 mole) was added slowly to a stirred suspension of phenacylamine hydrochloride (17.15 g; 0.1 mole) in dry dimethylformamide (50 ml) at room temperature. The internal temperature rose to ca. 40"C. The mixture was stirred for 2 hours and the DMF removed under vacuum. The residue was diluted with water (200 ml) and the crystalline solid collected, washed with water and dried. Weight of product=9.49 g (35%), m.p.
114"C.
(b) N - Phenacyl - 3 - (4 - phenylpiperazin - 1 - yl) - propanamide A solution of N - phenacyl - 3 - bromopropanamide (10.2 g; 0.038 mole) and N-phenylpiperazine (12.0 g; 0.074 mole) in dry DMF (100 ml) was stirred with anhydrous, finely-powdered sodium carbonate (15.0 g) for 18 hours at room temperature. The temperature was then increased to 800C and held for 12 hours to complete the reaction. The DMF was evaporated off under vacuum and the residue diluted with water (100 ml). The mixture was extracted with chloroform (3x 100 ml). The extracts were shaken with 2x 100 ml 2 N HC1 and the organic layer discarded. The aqueous layer was basified with NaOH solution to pH 9 and extracted with 3x75 ml CHCl2. The extracts were washed with water and dried.
After removal of the solvent the remaining viscous gum triturated with ether to give a buff-coloured solid. After recrystallisation from isopropanol the product weighed 6.0 g and melted at 1260C.
(c) 1 - [2 - (5 - Phenyloxazol - 2 - yl) - ethyl] - 4 - phenylpiperazine N - Phenacyl - 3 - (4 - phenylpiperazin - 1 - yl) - propanamide (4.03 g; 0.011 mole) was mixed with polyphosphoric acid (36 g) and stirred and heated at 1400C. for 30 minutes. The mixture was dissolved in water (100 ml), cooled, and extracted (2x30 ml chloroform). The extracts were discarded and the aqueous phase basified to pH 9 with 50% aqueous NaOH solution. The emulsion formed was extracted with 3x 100 ml chloroform, the extracts dried and evaporated. The crystalline residue was recrystallised from 6800C. petroleum ether. Yield 2.6 g, m.p. 84 5"C.
EXAMPLE 40 1 - [5 - (3 - Trifluoromethylphenyl) - furan - 2 - ylmethyl] - 4 - phenylpiperazine (a) 2 - Hydroxymethyl - 5 - (3 - trifluoromethylphenyl) - furan 2 - (3 - Trifluoromethylphenyl) - furan (J. Chem. Soc. (C) 1968, 2737 and Acta Chem. Scand 24, 2379 (1970)) (21.2 g; 0.1 mole) was stirred in tetrahydrofuran (100 ml), cooled at -40PC. and n-butyl lithium (0.1 mole, solution in hexane) was added dropwise. After stirring for 1 hour at -400C, paraformaldehyde (3.3 g; 0.11 mole) was added gradually. The mixture was stirred at --400C. for 30 minutes, then the temperature was allowed to rise. At 100C. an exothermic reaction set in and the temperature gradually rose to 400C. (over 10 minutes), then gradually fell back to 20"C. After stirring for further 1 hour the clear brown solution was poured onto ice/water, adjusted to pH ca 4 with dilute hydrochloric acid and extracted via ethyl acetate. The dried acetate extract (MgSO4) was evaporated to give a brownish yellow viscous oil which was distilled in vacuo to give 2 - hydroxymethyl - 5 - (3 trifluoromethylphenyl) - furan as a colourless liquid b.p. 1250C./0.5 mm., (16.2 g), which on standing gave crystals, m.p. 450C.
(b) 2 - Bromomethyl - 5 - (3 - trifluoromethylphenyl) - furan The hydroxymethyl compound (4.84 g; 0.02 mole) prepared in (a) above, was dissolved in dimethylformamide (30 ml) cooled to C50C. and thionyl bromide (1.7 ml; 0.02 mole) was added dropwise with stirring. After 2 hours the greenish-yellow solution was poured onto ice/water and extracted via diethyl ether. The ether extract was washed with NaCI (saturated solution) dried over molecular sieve 3A and evaporated to give a light brown oil which slowly crystallised (4.6 g).
(c) 1 - [5 - (3 - Trifluoromethylphenyl) - furan - 2 - ylmethyl] - 4 phenylpiperazine The bromomethyl product (0.015 mole) of (b) above was stirred in dioxan (50 ml) with N-phenylpiperazine (2.75 g; 0.017 mole) in the presence of anhydrous sodium carbonate (1.5 g) and the mixture heated under reflux for 7 hours, poured onto ice/water and extracted via chloroform. The chloroform extract was washed with water, then with saturated salt solution and finally evaporated to give an oil which on treatment with ethereal hydrochloric acid gave a cream coloured crystalline solid (2.1 g). This hydrochloride (2 g) was dissolved in chloroform (15 ml), stirred with water (15 ml) and a saturated solution of sodium carbonate added dropwise until alkaline. The phases were separated and the chloroform layer was evaporated to give a straw-coloured oil (1.7 g) which slowly crystallised and was recrystallised from petroleum ether (60/800 C. to give the title compound 1 - [5 (3 - trifluoromethylphenyl) - furan - 2 - ylmethyl] - 4 - phenylpiperazine, 1.2 g, m.p. 940C.
In a similar manner were prepared the following except that the intermediate hydroxymethyl compounds were converted to the chloromethyl compounds via thionyl chloride.
EXAMPLE 41 I - [5 - (4 Chlorophenyl) - furan - 2 - ylmethyl] - 4 - phenylpiperazine m.p. 1400C.
EXAMPLE 42 1 - [5 - (4 - Chlorophenyl) - furan - 2- ylmethyl] - 4- (3 trifluoromethylphenyl) - piperazine Monohydrochloride The free base was obtained as an intractable viscous oil and was converted to the monohydrochloride, m.p. 2200 C.
EXAMPLE 43 I - [5 - (4 - Chlorophenyl - furan - 2 - ylmethyl] - 4 - (3 - chlorophenyl) piperazine Monohydrochloride m.p. 2150C.
EXAMPLE 44 1 - [5 - (4 - Chlorophenyl) - furan - 2 - ylmethyl] - 4 - (3 - bromophenyl) piperazine Monohydrochloride 5 - (4 - Chlorophenyl) - 2 - furoic acid (Australian Journal of Chemistry, 26, 1147 (1973)) (6.67 g; 0.03 mole) was refluxed in benzene (100 ml) with thionyl chloride (4.5 ml) for 1.5 hours). After removal of the excess thionyl chloride, the remaining acid chloride in benzene was added dropwise with stirring and cooling to a mixture of N - (3 - bromophenyl)- piperazine (7.23 g; 0.03 mole) and triethylamine (4.5 ml, ca. 0.03 mole) in benzene (100 ml). After stirring for 1 hour at room temperature, the mixture was shaken with water (100 ml). The separated benzene phase was further washed with saturated salt solution, then evaporated to give an oil which readily crystallised. The product was recrystallised from ethyl acetate/60--80"C. petroleum ether (1/3 v/v) to yield 1 - [5 - (4 - chlorophenyl) 2 - furoyl] - 4 - (3 - bromophenyl) - piperazine (12.3 g) m.p. 1300C.
The above tertiary amide (4.45 g; 0.01 mole) was dissolved in dry tetrahydrofuran (30 ml) and added dropwise with stirring and cooling to OOC. to a solution of diborane in tetrahydrofuran (20 ml. 1 M solution) (N.B. the reaction was carried out under nitrogen). The temperature rose to ca. 80C. and the resultant hazy solution was refluxed for 1 hour. The clear pale yellow solution was cooled, then heated on a steam bath for 15 minutes with 5 N HCI (20 ml). After again cooling the solution was made alkaline (4 N NaOH) and extracted via diethyl ether.
The ether extract after drying over MgSO4 was evaporated to give an oil which was converted to its monohydrochloride to give the title compound. (2.8 g), m.p. 2170C.
In a similar manner were prepared the following: EXAMPLE 45 1 - [5 - (4 - Chlorophenyl) - furan - 2 - ylmethyl] - 4 - (3 - trifluoromethyl 4 - chlorophenyl) - piperazine m.p. 1040C.
EXAMPLE 46 1 - [5 - (4 - Methylphenyl) - furan - 2 - ylmethyll - 4 - phenylpiperazine m.p. 870C.
EXAMPLE 47 1 - [5 - (2 - Methylphenyl) - furan - 2 - ylmethyl] - 4 - phenylpiperazine m.p. 670C.
EXAMPLE 48 1 - [5 - (3,4 - Dichlorophenyl) - furan - 2 - ylmethyl] - 4 - phenylpiperazine m.p. 920C.
EXAMPLE 49 1 - [5 - (3 - Trifluoromethyl - - 4 - chlorophenyl) - furan - 2 - ylmethyl] 4 phenylpiperazine m.p. 1020C.
EXAMPLE 50 1 - [5 - (3 - Trifluoromethyl - 4 - chlorophenyl) - furan - 2 - ylmethyl] - 4 (3 - chlorophenyl) - piperazine Monohydrochloride m.p. 2160C.
EXAMPLE 51 1 - [5 - (3 - Trifluoromethyl - 4 - chlorophenyl) - furan - 2 - ylmethyl] - 4 (4 - methylphenyl) - piperazine m.p. 1260C.
EXAMPLE 52 1 - (5 - Phenylfuran - 2 - ylmethyl) - 4 - (3 - chlorophenyl) - piperazine Monohydrochloride m.p. 2080C.
In the following Examples 53 to 58 the final reduction step was carried out using the internal reduction method of K. M. Biswas and A. H. Jackson, Tetrahedron 24, 1145 (1967).
EXAMPLE 53 1 - (5 - Phenylfuran - 2 - ylmethyl) - 4 - (3 - trifluoromethylphenyl) - piperazine 1 - (5 - Phenyl - 2 - furoyl) - 4 - (3 - trifluoromethylphenyl) - piperazine (6.0 g, 0.015 mole) and sodium borohydride (1.28 g, 0.034 mole) were stirred in diglyme (25 ml), under nitrogen, and redistilled boron trifluoride etherate (6 ml. 0.045 mole) in diglyme (20 ml) added dropwise with continuous stirring. The resultant clear solution was stirred at room temperature for 3 hours and then evaporated to remove diglyme. The residue was carefully diluted with water (100 ml), followed by 5 NHCl (20 ml) and the mixture heated on a steam bath for 15 minutes. The mixture was cooled and made alkaline (4 N NaOH) and extracted via diethyl ether. The dried ether extract (MgSO4) was evaporated to give an oil which failed to crystallise. The product was converted to the hydrochloride and then reconverted to the free base as in Example 40. The base was obtained as a mobile oil which on very strong cooling crystallised, m.p. 560C.
Similarly prepared were the following: EXAMPLE 54 1 - (5 - Phenylfuran - 2 - ylmethyl)- - 4 - (3,4 - dichlorophenyl) - piperazine m.p. 1500C.
EXAMPLE 55 I - (5 - Phenylfuran - 2 - ylmethyl) - 4 - phenylpiperazine m.p. 1060C.
EXAMPLE 56 1 - (5 - Phenylfuran - 2 - ylmethyl) - 4 - (4 - methylphenyl) - piperazine m.p. 1140C.
EXAMPLE 57 I - [5 - (3,4 - Dimethylphenyl) - furan - 2 - ylmethyl] - 4 - (3 - trifluoromethyl - 4 - chlorophenyl) - piperazine m.p. 800C.
EXAMPLE 58 1 - [5 - (3,4 - Dimethylphenyl) - furan - 2 - ylmethyl] - 4 - (3 - methoxyphenyl) piperazine Monohydrochloride m.p. 2000C.
EXAMPLE 59 1 - [5 - (4 - Methoxyphenyl) - furan - 2 - ylmethyl] - 4 - (3 - trifluoromethyl 4 - chlorophenyl) - piperazine m.p. 100 C.
EXAMPLE 60 I - [5 - (4 - Methoxyphenyl)furan - 2 - ylmethyl] - 4 - phenylpiperazine m.p. 960C.
EXAMPLE 61 I - [5 - (4 - Methoxyphenyl)furan - 2 - ylmethyl] - 4 - (3 trifluoromethylphenyl)piperazine m.p. 740C.
EXAMPLE 62 I - (5 - Phenylthiophen - 2 - ylmethyl) - 4 - phenylpiperazine 5 - Phenyl - 2 - thiophene carboxylic acid (Khim Geterosikl Soedin, 1967, 1020 (Russ)) was reacted as in Example 44 to give the title compound (recrystallised from 60/800C petroleum ether containing a few drops of ethyl acetate). m.p. 880C.
EXAMPLE 63 I - (5 - Phenylthiophen - 2 - ylmethyl) - 4 - (3 - chlorophenyl)piperazine 5 - Phenyl - 2 - thiophenecarboxylic acid was reacted as in Example 44 to the amide which was then reduced to the title compound as in Example 53. m.p. 1 150C.
Similarly prepared were the following: EXAMPLE 64 - . (5 - Phenylthiophen - 2 - ylmethyl) - 4 - (4 - methoxyphenyl)piperazine m.p. 1360C.
EXAMPLE 65 I - (5 - Phenyl - thiophen - 2 - ylmethyl) - 4 - (3 - trifluoromethyl 4 - chlorophenyl)piperazine m.p. 1140C.
EXAMPLE 66 1 - (5 - Phenylthiophen - 2 - ylmethyl) - 4 - (4 - methylphenyl)piperazine m.p. 1350C.
EXAMPLE 67 1 - (5 - Phenylthiophep - 2 - ylmethyl) - 4 - (3 trifluoromethylphenyl)piperazine m.p. 940C.
EXAMPLE 68 1 - (5 - Phenylthiophen - 2 - ylmethyl) - 4 - (4 - fluorophenyl)piperazine m.p. 1280C.
EXAMPLE 69 1 . (5 - Phenylthiophen - 2 - ylmethyl) - 4 - (3,4 - dimethylphenyl)piperazine m.p. 130 C.
EXAMPLE 70 - . [5 - (3,4 - Dimethylphenyl) - furan - 2 - ylmethyl) - 4 - phenylpiperazine 5 - (3,4 - Dimethylphenyl) - furan - 2 - carboxaldehyde (4.0 g; 0.02 mole), prepared by the method of C. S. Davis and G. S. Lougheed J. Het. Chem. 4,153, (1967), was added rapidly to a stirred solution of N-phenylpiperazine (3.2 g; 0.02 mole) in methanol (30 ml) adjusted to pH 7 (using MeOH/HCI). After 30 minutes a solution of sodium cyanoborohydride (0.48 g; 0.0075 mole) in methanol (10 ml) was added dropwise and the mixture stirred at room,temperature for 2 hours. After removal of the methanol by evaporation, the resultant solid was purified by silica gel chromatography. The fractions containing the desired compound were combined, evaporated and the crystalline solid which formed was recrystallised from 60/80"C petroleum ether to give the title compound, m.p. 1100C.
Similarly prepared were the following: EXAMPLE 71 1 - [5 - (3 - Trifluoromethyl - 4 - chlorophenyl) - furan - 2 - ylmethyl] 4 - (4 - fluorophenyl)piperazine m.p. 94 C.
EXAMPLE 72 -[5 - (4 - Chlorophenyl) - furan - 2 - ylmethyl] - 4 - (4 nitrophenyl)piperazine m.p. 1490C.
EXAMPLE 73 1 - [5 - (4 - Methoxyphenyl)furan - 2 - ylmethyl] - 4 - (4 methylphenyl)piperazine m.p. 138 C.
EXAMPLE 74 1 - [5 - (3,4 - Dichlorophenyl)furan - 2 - ylmethyl] - 4 - (3 trifluoromethylphenyl)piperazine Monohydrochloride m.p. 210 C.
EXAMPLE 75 1 - (5 - Phenylthiophen - 2 - ylmethyl) - 4 - (3,4 - dichlorophenyl)piperazine m.p. 140 C.
EXAMPLE 76 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - (3 - chlorophenyl)piperazine 5 - Methyl - 2 - furoic acid prepared by the method of D. J. Chadwick et al.
J.C.S. Perkin 1, 1766 (1973) was reacted as in Example 44 to give the title compound. b.p. 1450C/0.01 mm (Kugelrohr).
EXAMPLE 77 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - phenylpiperazine 5 - Methyl - 2 - furoic acid was converted as in Example 44 to the amide which was reduced to the title compound as in Example 53. b.p. 1150C/0.01 mm (Kugelrohr).
Similarly prepared were the following: EXAMPLE 78 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - (4 - methylphenyl)piperazine m.p. 520C.
EXAMPLE 79 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - (4 - methoxyphenyl)piperazine m.p. 86 C.
EXAMPLE 80 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - (4 - chlorophenyl)piperazine m.p. 78 C.
EXAMPLE 81 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - (3 - trifluoromethyl 4 - chlorophenyl)piperazine Pale yellow oil, which partially decomposed on distillation.
EXAMPLE 82 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - (3 - trifluoromethylphenyl)piperazine b.p. 105 C/0.02 mm (Kugelrohr).
EXAMPLE 83(a) 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - (4 - fluorophenyl)piperazine m.p. 50 C.
EXAMPLE 83(b) 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - (3,4 - dimethylphenyl)piperazine m.p. 47 C...
EXAMPLE 84 1 - (5 - tert.Butylfuran - 2 - ylmethyl) - 4 - phenyl Piperazine 5 - tert - Butyl - 2 - furoic acid, Bull. Soc. Chim. France 1166 (1962), was reacted as in Example 77 to give the title compound. m.p. 480C.
Similarly prepared were the following: EXAMPLE 85 1 - (5 - tert - Butylfuran - 2 - ylmethyl) - 4 - (4 - methylphenyl)piperazine m.p. 620C.
EXAMPLE 86 1 - (5 - tert.Butylfuran - 2 - ylmethyl) - 4 - (3 - chlorophenyl)piperazine b.p. 1400C/0.01 mm (Kugelrohr).
EXAMPLE 87 1 - (5 - tert.Butylfuran - 2 - ylmethyl) - 4 - (4 - methoxyphenyl)piperazine m.p. 700C.
EXAMPLE 88 I - (5 - tert.Butylfuran - 2 - ylmethyl) - 4 - (3 - trifluoromethyl 4 - chlorophenyl)piperazine b.p. 130 C/0.01 mm (Kugelrohr).
EXAMPLE 89 1 - (5 - tert.Butylfuran - 2 - ylmethyl) - 4 - (3 - trifluoromethylphenyl)piperazine Pale yellow oil.
EXAMPLE 90 1 - (5 - tert - Butylfuran - 2 - ylmethyl) - 4 - (4 - fluorophenyl)piperazine Pale yellow oil.
EXAMPLE 91 1 - (5 - tert.Butylfuran - 2 - ylmethyl) - 4 - (3,4 - dimethylphenyl)piperazine m.p. 70 C.
EXAMPLE 92 1 - [3 - (5 - Phenylfuran - 2 - yl)prop - I - yl] - 4 - phenylpiperazine 5 - Phenyl - 2 - furanpropionic acid, J. Heterocyc. Chem 6, 713, (1969) was reacted as Example 77 to give the title compound m.p. 950C.
Similarly prepared were the following: EXAMPLE 93 I - [3 - (5 - Phenylfuran - 2 - ylprop - 1 - yl] - 4 - (4 - methylphenyl)piperazine m.p. 920C.
EXAMPLE 94 1 - [3 - (5 - Phenylfuran - 2 - yl)prop - I - yl] - 4 - (3 trifluoromethylphenyl)piperazine m.p. 560 C.
EXAMPLE 95 1 - [3 - (5 - (4 - Chlorophenyl)furan - 2 - yllprop - t - yl] - 4 - (4 - methylphenyl)piperazine m.p. 1300C.
EXAMPLE 96 1 - [3 - (5 - (3,4 - Dichlorophenyl)furan - 2 - yliprop - 1 - yl] - 4 - (4 methylphenyl)piperazine m.p. 1000C.
EXAMPLE 97 1 - [3 - (5 - Phenylthiophen - 2 - yl)prop - 1 - yl] - 4 - (4 methylphenyl)piperazine m.p. 920C.
EXAMPLE 98 (a) 5 - Phenyl - 2 - (2 - hydroxyethyl)thiophene 2-Phenylthiophene (16.0 g; 0.1 mole) was reacted in a similar manner to Example 40 but using ethylene oxide (10 ml; 0.2 mole) instead of paraformaldehyde. The title compound was obtained as a pale yellow crystalline solid, m.p. 74 C.
(b) 1 - [2 - (5 - Phenylthiophen - 2 - yl)ethyl] - 4 - phenylpiperazine The hydroxyethyl compound (6.13 g; 0.03 mole) from (a) above was reacted as in Example 40(b), but using thionyl chloride instead of thionyl bromide. The chloroethyl compound was obtained as a straw coloured oil (6.2 g) which crystallised on standing, m.p. 400 C. This product was stirred in dioxane (50 ml) with N-phenylpiperazine (4.8 g; 0.03 mole) in the presence of anhydrous sodium carbonate (3.0 g) and the mixture heated under refluxed for 24 hours. The mixture was filtered from sodium carbonate and the filtrate evaporated to give a pale yellow oil which was taken up in hot 40/600C petroleum ether and percolated through a column of silica gel using benzene/ethyl acetate 4:1 v/v as developing solvent. The initial fast moving band contained unreacted chloroethyl compound (3.5 g). The slower moving band contained the title compound which after recrystallisation from ethyl acetate had m.p. 1240C.
Similarly prepared was: EXAMPLE 99 I - [2 - (5 - Phenylthiophen - 2 - yl)ethyl] - 4 - (4 - methylphenyl)piperazine m.p. 1580C.
EXAMPLE 100 (a) 1 - (5 - Phenylfuran - 2 - ylmethyl) - 4 - (4 - nitrophenyl)piperazine 5 - Phenyl - 2 - furancarboxylic acid was reacted as in Example 44 to the amide which was reduced to the title compound as in Example 53. m.p. 1700C.
(b) I - (5 - Phenylfuran - 2 - ylmethyl) - 4 - (4 - aminophenyl)piperazine The product from (a) was hydrogenated and worked up as in Example 36. m.p. 1020C.
(c) 1 - (5 - Phenylfuran - 2 - ylmethyl) - 4 - (4 - methanesulphonamido - phenyl)piperazine The product from (b) (2.9 g; 0.009 mole) was stirred in anhydrous ether (50 ml) at room temperature and reacted with methanesulphonyl chloride (0.68 ml) in the presence of triethylamine (1.2 ml). The mixture was stirred overnight, then the ether was evaporated to give a solid which was partitioned between water/chloroform. The chloroform extract was washed with saturated sodium chloride solution and evaporated to give the desired compound as a highly crystalline solid which was recrystallised from ethyl acetate, m.p. 1780C.
Similarly prepared was: EXAMPLE 101 1 - (5 - Phenylthiophen - 2 - ylmethyl) - 4 - (4 - methanesulphonamidophenyl) piperazine m.p. 1880C.
EXAMPLE 102 (a) 5 - Phenyl - 2 - (2 - hydroxypropyl)furan 2-Phenylfuran (14.4 g, 0.1 mole) was reacted in a similar manner to Example 40 but using propylene oxide (9 ml, 0.13 mole). The title compound was obtained as a straw coloured oil (16.0 g) b.p. 145"C/0.05 mm with decomposition.
(b) 1 - [1 - (5 - Phenylfuran - 2 - yl)prop - 2 - yl] - 4 - phenylpiperazine Monohydrochloride The hydroxypropyl compound (8.0 g; 0.04 mole) was oxidised to the corresponding ketone by the method of S. L. Huang et al J.O.C. 41, 3329 (1976).
The ketone was obtained as a brown oil (4.0 g) which was reacted with Nphenylpiperazine and sodium cyanoborohydride as in Example 70, but for 3 days.
After purification by column chromatography the title compound was obtained as a straw coloured oil which failed to crystallise and was converted to its monohydrochloride (ethyl acetate-hydrogen chloride) (1.3 g) m.p. 2060C.
Similarly prepared were the following: EXAMPLE 103 I - [1 - (5 - Phenylthiophen - 2 - yl)prop - 2 - yl] - 4 - phenylpiperazine m.p. 980C.
EXAMPLE 104 1 - [1 - (5 - Phenylthiophen - 2 - yl)but - 3 - yl] - 4 - phenylpiperazine Monohydrochloride m.p. 2000C.
EXAMPLE 105 1 - (2 - Methylthiazol - 4 - ylmethyl) - 4 - (3 - bromophenyl)piperazine A mixture of 4 - chloromethyl - 2 - methylthiazole (7.4 g; 0.05 mole), 1 - (3 bromophenyl)piperazine (12.05 g; 0.05 mole) and anhydrous sodium carbonate (10 g) was suspended in absolute ethanol (150 ml). The mixture was stirred and boiled under reflux for 8 hours. The solvent was then evaporated to dryness and water added (100 ml). The emulsion thus formed was extracted with dichloromethane, the organic extracts being dried over magnesium sulphate and evaporated to an oil.
This was dissolved in hot benzene, treated with decolourising charcoal and filtered.
The filtrate was evaporated to give the title compound as an oil which crystallised completely, m.p. 820C (ether).
Similarly prepared were the following: EXAMPLE 106 1 - (2 - Methylthiazol - 4 - ylmethyl) - 4 - (3 - trifluoromethylphenyl)piperazine Dihydrochloride m.p. 176-8 C.
EXAMPLE 107 1 - (2 - Methylthiazol - 4 - ylmethyl) - 4 - (3 - chlorophenyl)piperazine m.p. 71-20C.
EXAMPLE 108 - . (2 - Methylthiazol - 4 - ylmethyl) - 4 - (3 - methoxyphenyl)piperazine m.p. 71.5-72.50C.
EXAMPLE 109 1 - (2 - Methylthiazol - 4 - ylmethyl) - 4 - (4 - bromophenyl)piperazine m.p. 114-1l50C.
EXAMPLE
EXAMPLE 117 1 - (2 - Methylthiazol - 4 - ylmethyl) - 4 - (4 - methoxyphenyl)piperazine Hydrochloride m.p. 134-50C.
EXAMPLE 118 (a) 2 - n - Propyl - 4 - chloromethylthiazole To a solution of thiabutanamide (30.96 g, 0.3 mole) in absolute ethanol (200 ml) was slowly added a solution of 1,3-dichloroacetone (38.1 g; 0.3 mole) in ethanol (100 ml). The mixture was boiled under reflux for I hour and the solvent evaporated. The residue was treated with excess saturated sodium bicarbonate solution and extracted with ether. The extracts were dried and evaporated to a brown oil which was distilled in vacuo to give a pale yellow oil, b.p. 50 C/0.06 mm Hg. This was converted to the title compound (hydrochloride salt) using ethereal hydrogen chloride m.p. 600C dec.
Similarly prepared were: (b) 2 - Benzyl - 4 - chloromethylthiazole b.p. 116-118 C/0.09 mm Hg.
(c) 2 - isoPropyl - 4 - chloromethylthiazole hydrochloride m.p. 580C (dec).
EXAMPLE 119 1 - (2 - n - Propylthiazol - 4 - ylmethyl) - 4 - phenylpiperazine A mixture of 2 - n - propyl - 4 - chloromethylthiazole hydrochloride (3.18 g; 0.015 mole), 1-phenylpiperazine (2.43 g; 0.015 mole) and sodium carbonate (anhydrous, 10 g) in absolute ethanol (60 ml) was stirred and boiled under reflux for 6 hours. The suspension was filtered and the filtrate evaporated to a yellow oil. This was dissolved in boiling benzene and treated with decolourising charcoal. After filtration, the benzene was removed giving a yellow oil which crystallised 4.27 g.
This solid was recrystallised from petroleum ether (b.p. 60--800C) at 0 C to give a white crystalline solid (m.p. 38-39 C).
Similarly prepared were: EXAMPLE 120 1 - (2 - n - Propylthiazol - 4 - ylmethyl) - 4 - (4 - chlorophenyl)piperazine m.p. 51--540C.
EXAMPLE 121 1 - (2 - n - Propylthiazol - 4 - ylmethyl) - 4 - (4 - methylphenyl)piperazine m.p. 41-440C.
EXAMPLE 122 1 - (2 - n - Propylthiazol - 4 - ylmethyl) - 4 - (4 - methoxyphenyl)piperazine m.p. 46--470C.
EXAMPLE 123 1 - (2 - n - Propylthiazol - 4 - ylmethyl) - 4 - (3 - trifluoromethylphenyl) piperazine Hydrochloride m.p. 162-60C.
EXAMPLE 124 1 - (2 - n - Propylthiazol - 4 - ylmethyl) - 4 - (3,4 - dichlorophenyl) piperazine Dihydrochloride m.p. 158-1600C.
EXAMPLE 125 I . (2 - n - Propylthiazol- 4- ylmethyl) - 4- (4 - chloro - 3 - trifluoromethylphenyl) - piperazine Dihydrochloride m.p. 174--80C.
EXAMPLE 126 - - (2 - Benzylthiazol - 4 - ylmethyl) - 4 - phenylpiperazine m.p. 6O620C.
EXAMPLE 127 1 - (2 - Benzylthiazol - 4 - ylmethyl) - 4 - (4 - chlorophenyl)piperazine m.p. 740C.
EXAMPLE 128 - . (2 - Benzylthiazol - 4 - ylmethyl) - 4 - (4 - methoxyphenyl)piperazine m.p. 650C.
EXAMPLE 129 I - (2 - Benzylthiazol - 4 - ylmethyl) - 4 - (3 - bromophenyl)piperazine m.p. 690 C.
EXAMPLE 130 I - (2 - Benzylthiazol - 4 - ylmethyl) -4 - (4 - chloro - 3 - trifluormethylphenyl) piperazine Colourless oil.
EXAMPLE 131 1 - [2 - (4 - chlorobenzyl)thiazol - 4 - ylmethyl] - 4 - phenyl Piperazine Dihydrochloride m.p. 1500C (Dec).
EXAMPLE 132 1 - (2 - isoPropylthiazol - 4 - ylmethyl) - 4 - (4 - chlorophenyl)piperazine m.p. 54 C.
EXAMPLE 133 1 - (2 - isoPropylthiazol - 4 - ylmethyl) - 4 - phenylpiperazine m.p. 420C.
EXAMPLE 134 1 - (2 - isoPropylthiazol - 4 - ylmethyl) - 4 - (3 - methoxyphenyl)piperazine m.p. 650C.
EXAMPLE 135 1 - (2 - isoPropylthiazol - 4 - ylmethyl) - 4 - (3 - bromophenyl)piperazine Colourless oil.
EXAMPLE 136 1 - (2 - isoPropylthiazol - 4 - ylmethyl) - 4 - (4 - chloro - 3 trifluoromethylphenyl Piperazine Colourless oil.
The following further Examples illustrate the preparation of pharmaceutical formulations containing compounds of the invention. The active compound utilised was 1 - (2 - benzylthiazol - 4 - ylmethyl) - 4 - phenylpiperazine, although it will be appreciated by those skilled in the art that other active solid compounds of the invention could equally well be used.
EXAMPLE 137 Hard gelatin capsules were prepared using the following ingredients: Quantity (mg/capsule) Active compound 250 Starch dried 200 Magnesium stearate 10 The above ingredients were mixed and filled into hard gelatin capsules.
EXAMPLE 138 The above procedure was repeated except that microcrystalline cellulose was used in place of starch.
EXAMPLE 139 Tablets were prepared using the following components: Quantity (mg/tablet) Active compound 500 Starch 100 Magnesium stearate 7 Amberlite XE88 (Trade Mark) 5 The starch and active compound were mixed together and sufficient water added for a uniform dispersion to be attained. The mixture was then wet screened and dried. After drying the material was screened again, and the magnesium stearate and amberlite resin then added. Finally the mixture was compressed into tablets.
EXAMPLE 140 An alternative tablet formula was prepared using the ingredients below: Quantity (mg/tablet) Active compound 250 Cellulose microcrystalline 400 Silicon dioxide fumed 10 Stearic acid 5 The components were blended and compressed to form tablets.
* EXAMPLE 141 An aerosol solution was prepared containing the following components: Weight /n Active ingredient 0.25 Ethanol 29.75 Propellant 22 70 (Chlorodifluoromethane) The active compound was mixed with ethanol and the mixture added to the propellant 22, cooled to -300C and transferred to a filling device. the required amount was then fed to a stainless steel container and diluted further with a metered amount of propellant. The valve units were then fitted to the container.
EXAMPLE 142 A suppository forumula was prepared containing 200 mg of the compound using the following ingredients: Active compound 200 mg Polyethylene glycol 1000 750 mg Polyethylene glycol 4000 250 mg The active compound was mixed in the molten glycol bases and then the mixture was poured into appropriate suppository moulds, to give the active fill weight.
EXAMPLE 143 An ointment was made to the following formula: Active compound 1% by weight White soft paraffin q.s. to 100% The active compound was added to the molten paraffin and then the mixture was allowed to cool.
EXAMPLE 144 A topical cream was prepared having the following ingredients: grams Active compound 0.5 Cetomacrogol 1000 2.8 Cetostearyl alcohol 11.2 Liquid paraffin 8.0 Water q.s. to 100 The active principle was suspended in liquid paraffin. The cetostearyl alcohol was added and the mixture heated to 700C with stirring. The cetomacrogol 1000 was dissolved in 60 g. of water and heated to 700 C. The two solutions were then mixed with stirring, and stirring continued until the temperature fell to ambient.
The cream was then made up to weight with water and passed through a stainless steel colloid mill set at a gap of 15/1000 inch.

Claims (36)

WHAT WE CLAIM IS:
1. A process for preparing a phenylpiperazine derivative of formula (I):
where R' is benzyl, chlorobenzyl C,, alkyl or optionally substituted phenyl; RZ is optionally substituted phenyl; R3 is hydrogen or C14 alkyl; Q is furan, thiophene, oxazole or thiazole; m is 1 to 3 and n is 0 or 1, provided that when m is 2 and n is 0, R' cannot be methyl when Q is a thiazol - 5 - yl group; or a pharmaceuticallyacceptable salt thereof; which process comprises: (A) condensing a compound of formula (VI): R1-Q-(CH2)m-(CHR2)n-L (VI) where L represents a leaving group, with a compound of formula (VII):
(B) reducing a compound of formula:
to form a compound in which n is 0; or
to form a compound in which n is 1; or (C) cyclising a compound of formula (X):
where Z is a group cyclisable to Q to form a compound of formula (I) in which Q is oxazole.
2. A process according to Claim I, wherein R' and R2 independently represent phenyl optionally substituted by one or two radicals selected from halogen, C1-4 alkyl, C1-4 haloalkyl, amino, C24 alkanoylamino, hydroxy, C1-4 alkoxy, nitro and C, 4 alkylsulphonamido
3. A process according to Claim I for preparing a thiazole of formula (V):
where R' is benzyl, and R2 is phenyl or p-halophenyl.
4. A process according to Claim I for preparing a thiazole of formula:
where R' is C, 4 alkyl or phenyl optionally substituted by C14 alkyl, C14 alkoxy, nitro and C, 4 haloalkyl and R2 is phenyl optionally substituted by C14 haloalkyl.
5. A process according to Claim 1 for preparing a furan of formula (II):
where R' is phenyl optionally substituted by one or two radicals selected from halogen, C1-4 alkyl, C1-4 alkoxy, and C, 4 haloalkyl; R2 is phenyl optionally substituted by C, 4 alkyl, amino, C1-4 alkylsulphonamido and C, 4 alkoxy and m is 1 or 3, with the exception of compounds in which R1 is unsubstituted phenyl, m is I and R2 is unsubstituted phenyl; or where R' is methyl, m is 1 and R2 is phenyl optionally substituted by a single radical selected from halogen, C1-4 alkyl, C1-4 alkoxy, C14 haloalkyl or is disubstituted by two C1-4 alkyl radicals.
6. A process according to Claim 1 for preparing an oxazole of formula (IV):
where R1 is phenyl optionally substituted by C14 alkoxy or halogen; R2 is phenyl optionally substituted by C1-4 alkyl, C14 haloalkyl, halogen, amino or C2.4 alkanoylamino and m is I or 2.
7. A process according to Claim I for preparing a thiophene of formula XIII:
where R' is phenyl; R2 is phenyl, phenyl singly substituted by C1-4 alkyl or C, 4 haloalkyl or doubly substituted by two radicals selected from halogen, C1-4 haloalkyl and 1 C1-4 alkyl and m is I or 2.
8. A process according to Claim 3 for preparing 1 - (2 - benzylthiazol - 4 ylmethyl) - 4 - phenylpiperazine.
9. A phenylpiperazine whenever prepared by a process according to any one of Claims 1 to 8.
10. A phenylpiperazine derivative of formula (I) as defined in Claim 1 or a pharmaceutically-acceptable salt thereof.
11. A phenylpiperazine of formula (I) as defined in Claim 2.
12. A phenylpiperazine of formula (II) as defined in Claim 5.
13. A phenylpiperazine of formula (I) according to Claim 10 which is a thiophene of formula (III):
where R' is phenyl; R2 is phenyl, phenyl singly substituted by C, 4 alkyl or C14 haloalkyl or doubly substituted by two radicals selected from halogen, C,4 haloalkyl and C1-4 alkyl, and where m is I or 2 and n=0, or where m is 1, n is 1 and R3 is ethyl.
14. A phenylpiperazine of formula (IV) as defined in Claim 6.
15. A phenylpiperazine of formula (V) as defined in Claim 3.
16. A phenylpiperazine of formula (VA) as defined in Claim 4.
17. 1 - [2 - (5 - Phenylthiophen - 2 - yl)ethyl] - 4 - phenylpiperazine.
18. 1 - (5 - Methylfuran - 2 - ylmethyl) - 4 - (3 - chlorophenyl)piperazine.
19. 1 - [5 - (4 - Methoxyphenyl) - furan - 2- ylmethyl] - 4phenylpiperazine.
20. 1 - [5 - (3,4 - Dimethylphenyl)- furan - 2 - ylmethyl] - 4phenylpiperazine.
21. 1 - 3 - [5 - (3,4 - Dichlorophenyl) - furan - 2 - yl]prop - 1 - yl - 4 - (4 methylphenyl)piperazine.
22. 1 - [1 - (5 - Phenylthiophen - 2 - yl)but - 3 - yl] - 4 - phenylpiperazine.
23. 1 - (5 - Phenylthiophen - 2 - ylmethyl) - 4 - (3,4 dimethylphenyl)piperazine.
24. 1 - [3 - (5 - Phenylfuran - 2 - yl)prop - 1 - yl] - 4 - (4 - methylphenyl)piperazine.
25. 1 - [5 - (4 - Methoxyphenyl)- furan - 2 - ylmethyl] - 4 - (4 - methylphenyl)piperazine.
26. 1 - (5 - Phenyloxazol - 2 - ylmethyl) - 4 - (4 - methylphenyl) - piperazine.
27. 1 - (2 - Benzylthiazol - 4 - ylmethyl) - 4 - phenylpiperazine.
28. A pharmaceutically-acceptable salt of a phenylpiperazine as claimed in any one of Claims 10 to 27.
29. A pharmaceutical formulation which comprises a phenylpiperazine derivative of formula (I) as defined in Claim 1, or a pharmaceutically-acceptable salt thereof; associated with a pharmaceutically-acceptable carrier therefor.
30. A pharmaceutical formulation according to Claim 29 in which the derivative of formula (I) is as defined in Claim 2.
31. A process for preparing a pharmaceutical formulation which comprises admixing a phenylpiperazine of formula (I) as defined in Claim 1, or a pharmaceutically-acceptable salt thereof, with a pharmaceutically-acceptable carrier therefor.
32. A process according to Claim 31, wherein the phenylpiperazine is the derivative of formula (I) as defined in Claim 2.
33. A process according to Claim 1 substantially as hereinbefore described with reference to any one of Examples 1 to 117 and 119 to 136.
34. A phenylpiperazine of formula (I) as claimed in Claim 10 substantially as hereinbefore described with reference to any one of the foregoing Examples 1 to 117 and 119 to 136.
35. A pharmaceutical formulation as claimed in Claim 29 substantially as hereinbefore described with reference to any one of Examples 137 to 144.
36. A process according to Claim 31 substantially as hereinbefore described with reference to any one of the foregoing Examples 137 to 144.
GB16526/76A 1976-04-23 1976-04-23 Phenyl piperazines Expired GB1575904A (en)

Priority Applications (40)

Application Number Priority Date Filing Date Title
GB16526/76A GB1575904A (en) 1976-04-23 1976-04-23 Phenyl piperazines
NZ183715A NZ183715A (en) 1976-04-23 1977-03-28 Phenylpiperazine derivatives
ZA00771849A ZA771849B (en) 1976-04-23 1977-03-28 Phenyl piperazines
IE671/77A IE44730B1 (en) 1976-04-23 1977-03-30 Phenyl piperazines
CA275,160A CA1087617A (en) 1976-04-23 1977-03-30 Phenyl piperazines
IL51787A IL51787A (en) 1976-04-23 1977-03-30 1 heterocyclylalkyl 4 phenyl piperazine derivatives their preparation and pharmaceutical compositions containing them
CH455777A CH625802A5 (en) 1976-04-23 1977-04-13 Process for the preparation of phenylpiperazine derivatives
CH525781A CH633009A5 (en) 1976-04-23 1977-04-13 Process for the preparation of new phenylpiperazine derivatives
MX775629U MX4596E (en) 1976-04-23 1977-04-13 PROCEDURE TO PREPARE A PHENYLPIPERAZINE DERIVATIVE
PH19656A PH14124A (en) 1976-04-23 1977-04-14 Phenyl piperazines
AU24386/77A AU514822B2 (en) 1976-04-23 1977-04-18 Phenyl diperazines derivatives
PT66452A PT66452B (en) 1976-04-23 1977-04-18 Process for preparing a phenylpiperazine
FR7711669A FR2348925A1 (en) 1976-04-23 1977-04-19 PHENYLPIPERAZINE DERIVATIVES
GR53236A GR64084B (en) 1976-04-23 1977-04-19 Method for the preparation of phenyl piperazines
RO7790106A RO72831A (en) 1976-04-23 1977-04-20 PROCESS FOR THE PREPARATION OF FENILPYPERAZINES
BG7736062A BG27746A3 (en) 1976-04-23 1977-04-20 Method of obtaining of phenylpiperazine derivatives
DE19772717415 DE2717415A1 (en) 1976-04-23 1977-04-20 PROCESS FOR MANUFACTURING PHENYLPIPERAZINE DERIVATIVES, PHENYLPIPERAZINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE
ES457988A ES457988A1 (en) 1976-04-23 1977-04-20 Phenyl piperazines
SE7704536A SE7704536L (en) 1976-04-23 1977-04-20 PROCEDURE FOR THE PREPARATION OF PHENYL PIPERAZINE DERIVATIVES
OA56149A OA05643A (en) 1976-04-23 1977-04-20 Phenylpiperazine derivatives.
BG7737191A BG28055A3 (en) 1976-04-23 1977-04-20 Method of obtaining of phenylperazine derivatives
CS772668A CS196360B2 (en) 1976-04-23 1977-04-21 Process for preparing derivatives of phenylpiperazine
YU01044/77A YU104477A (en) 1976-04-23 1977-04-21 Process for obtaining phenyl piperazine derivatives
DK176177A DK176177A (en) 1976-04-23 1977-04-21 PROCEDURE FOR THE PREPARATION OF PHENYL PIPERAZINES
LU77170A LU77170A1 (en) 1976-04-23 1977-04-21
NO771398A NO146710C (en) 1976-04-23 1977-04-22 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENYL PIPERAZINE DERIVATIVES
BE6045977A BE853899A (en) 1976-04-23 1977-04-22 PHENYLPIPERAZINE DERIVATIVES
AR267310A AR222003A1 (en) 1976-04-23 1977-04-22 PROCEDURE FOR THE PREPARATION OF PHENYLPIPERAZINE DERIVATIVES
FI771287A FI63937C (en) 1976-04-23 1977-04-22 FREQUENCY REQUIREMENT FOR THERAPEUTIC USE OF THERAPEUTIC TREATMENT
AT285177A AT355579B (en) 1976-04-23 1977-04-22 METHOD FOR PRODUCING NEW PHENYL PIPERAZINE DERIVATIVES AND THEIR SALTS
PL1977197550A PL117466B1 (en) 1976-04-23 1977-04-22 Process for preparing novel derivatives of phenylopiperazine
HU77LI311A HU176820B (en) 1976-04-23 1977-04-22 Process for preparing phenyl-piperazine derivatives
SU772474105A SU664564A3 (en) 1976-04-23 1977-04-22 Method of obtaining phenylpiperazine derivatives or salts thereof
NL7704456A NL7704456A (en) 1976-04-23 1977-04-22 PROCESS FOR THE PREPARATION OF PHARMACEUTICALLY ACTIVE PHENYLPIPERAZINS, PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION AND PREPARATION, OBTAINED BY THIS PROCESS.
DD7700198558A DD129790A5 (en) 1976-04-23 1977-04-22 PROCESS FOR THE PREPARATION OF PHENYLPIPERAZINE DERIVATIVES
JP4727677A JPS52151183A (en) 1976-04-23 1977-04-23 Phenylpyperazine
US05/813,912 US4123529A (en) 1976-04-23 1977-07-08 Phenylpiperazine derivatives
SU772558499A SU727146A3 (en) 1976-04-23 1977-12-28 Method of preparing phenylpiperazine derivatives or their salts
ES467948A ES467948A1 (en) 1976-04-23 1978-03-16 Phenyl piperazines
AR271519A AR222635A1 (en) 1976-04-23 1978-03-22 PROCEDURE FOR THE PREPARATION OF PHENYLPIPERAZINE DERIVATIVES

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB16526/76A GB1575904A (en) 1976-04-23 1976-04-23 Phenyl piperazines

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GB1575904A true GB1575904A (en) 1980-10-01

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JP (1) JPS52151183A (en)
AR (2) AR222003A1 (en)
AT (1) AT355579B (en)
AU (1) AU514822B2 (en)
BE (1) BE853899A (en)
BG (2) BG28055A3 (en)
CA (1) CA1087617A (en)
CH (2) CH633009A5 (en)
CS (1) CS196360B2 (en)
DD (1) DD129790A5 (en)
DE (1) DE2717415A1 (en)
DK (1) DK176177A (en)
ES (2) ES457988A1 (en)
FI (1) FI63937C (en)
FR (1) FR2348925A1 (en)
GB (1) GB1575904A (en)
GR (1) GR64084B (en)
HU (1) HU176820B (en)
IE (1) IE44730B1 (en)
IL (1) IL51787A (en)
LU (1) LU77170A1 (en)
MX (1) MX4596E (en)
NL (1) NL7704456A (en)
NO (1) NO146710C (en)
NZ (1) NZ183715A (en)
OA (1) OA05643A (en)
PH (1) PH14124A (en)
PL (1) PL117466B1 (en)
PT (1) PT66452B (en)
RO (1) RO72831A (en)
SE (1) SE7704536L (en)
SU (2) SU664564A3 (en)
YU (1) YU104477A (en)
ZA (1) ZA771849B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007100852A1 (en) * 2006-02-28 2007-09-07 Helicon Therapeutics, Inc. Therapeutic piperazines as pde4 inhibitors
US8927546B2 (en) 2006-02-28 2015-01-06 Dart Neuroscience (Cayman) Ltd. Therapeutic piperazines

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1601310A (en) * 1978-05-23 1981-10-28 Lilly Industries Ltd Aryl hydantoins
DE3142608A1 (en) * 1981-10-28 1983-05-05 Basf Ag, 6700 Ludwigshafen POLYAZO DYES
JPH07157477A (en) * 1993-12-02 1995-06-20 Asahi Kagaku Kogyo Kk Production of thiazole derivative
EP0749966A4 (en) * 1994-03-11 1997-07-02 Yamanouchi Pharma Co Ltd 5-ht 3 receptor agonist, novel thiazole derivative, and intermediate therefor
GB9517381D0 (en) * 1995-08-24 1995-10-25 Pharmacia Spa Aryl and heteroaryl piperazine derivatives

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007100852A1 (en) * 2006-02-28 2007-09-07 Helicon Therapeutics, Inc. Therapeutic piperazines as pde4 inhibitors
US7829713B2 (en) 2006-02-28 2010-11-09 Helicon Therapeutics, Inc. Therapeutic piperazines
US8338405B2 (en) 2006-02-28 2012-12-25 Dart Neuroscience Llc Therapeutic piperazines
AU2007221021B2 (en) * 2006-02-28 2013-01-17 Dart Neuroscience (Cayman) Ltd Therapeutic piperazines as PDE4 inhibitors
US8501745B2 (en) 2006-02-28 2013-08-06 Dart Neuroscience (Cayman) Ltd. Piperazine PDE4 inhibitors and uses thereof
US8927546B2 (en) 2006-02-28 2015-01-06 Dart Neuroscience (Cayman) Ltd. Therapeutic piperazines
US9624200B2 (en) 2006-02-28 2017-04-18 Dart Neuroscience (Cayman) Ltd. Therapeutic piperazines

Also Published As

Publication number Publication date
BE853899A (en) 1977-10-24
NL7704456A (en) 1977-10-25
FI63937B (en) 1983-05-31
IE44730B1 (en) 1982-03-10
NZ183715A (en) 1980-04-28
SU727146A3 (en) 1980-04-05
AU514822B2 (en) 1981-02-26
CS196360B2 (en) 1980-03-31
YU104477A (en) 1983-01-21
AR222635A1 (en) 1981-06-15
PL197550A1 (en) 1979-05-21
AT355579B (en) 1980-03-10
OA05643A (en) 1981-04-30
AU2438677A (en) 1978-10-26
JPS52151183A (en) 1977-12-15
PL117466B1 (en) 1981-08-31
FR2348925A1 (en) 1977-11-18
MX4596E (en) 1982-06-25
FI63937C (en) 1983-09-12
SE7704536L (en) 1977-10-24
SU664564A3 (en) 1979-05-25
RO72831B (en) 1983-07-30
ES457988A1 (en) 1978-07-16
IL51787A (en) 1980-02-29
FI771287A (en) 1977-10-24
BG28055A3 (en) 1980-02-25
PH14124A (en) 1981-02-26
RO72831A (en) 1983-08-03
CH625802A5 (en) 1981-10-15
DK176177A (en) 1977-10-24
IL51787A0 (en) 1977-05-31
NO146710C (en) 1982-11-24
ES467948A1 (en) 1978-11-01
LU77170A1 (en) 1979-01-18
GR64084B (en) 1980-01-21
HU176820B (en) 1981-05-28
IE44730L (en) 1977-10-23
PT66452B (en) 1979-03-09
DD129790A5 (en) 1978-02-08
NO146710B (en) 1982-08-16
AR222003A1 (en) 1981-04-15
NO771398L (en) 1977-10-25
CH633009A5 (en) 1982-11-15
ATA285177A (en) 1979-08-15
CA1087617A (en) 1980-10-14
PT66452A (en) 1977-05-01
FR2348925B1 (en) 1980-04-11
BG27746A3 (en) 1979-12-12
ZA771849B (en) 1978-11-29
DE2717415A1 (en) 1977-11-10

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PS Patent sealed [section 19, patents act 1949]
PCNP Patent ceased through non-payment of renewal fee