CA1087617A - Phenyl piperazines - Google Patents
Phenyl piperazinesInfo
- Publication number
- CA1087617A CA1087617A CA275,160A CA275160A CA1087617A CA 1087617 A CA1087617 A CA 1087617A CA 275160 A CA275160 A CA 275160A CA 1087617 A CA1087617 A CA 1087617A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- piperazine
- compound
- phenyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—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
Abstract
A B S T R A C T
Phenylpiperazine derivatives of formula (I):
Phenylpiperazine derivatives of formula (I):
Description
10~76~7 This invention relates to a novel class of phenylpip-erazine derivatives which possess useful pharmacological acti-vity. Furthermore, the invention includes within its scope pro-cesses for preparing the novel compounds of the invention, pharmaceutical compositions containing the aforementioned pharmacologically active compounds as well as a method of treating animals, including humans, which comprises administer-ing thereto a chemotherapeutically effective amount of a pharmacologically active compound or composition of the invention.
According to the present invention there is provided a phenylpiperazine derivative of formula tI):
1 3 ~ 2 R -Q-(CH2)m-(CHR )n~N ~ N - R (I) where Rl is benzyl, chlorobenzyl, Cl 6 alkyl or a phenyl group optionally substituted by one or two radicals selected from halogen, Cl ~ alkyl, Cl 4 haloalkyl, amino, C2 4alkanoylamino, hydroxy, Cl 4 alkoxy, nitro and Cl 4 alkylsulphonamido; R2 is a phenyl group optionally substituted by one or two radicals selected from halogen, Cl 4 alkyl, Cl 4 haloalkyl, amino, C2 4 alkanoylamino, hydroxy, Cl 4 alkoxy, nitro and Cl 4 alkylsulphon-amido, R3 is hydrogen or Cl 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 is 0, Rl cannot be methyl when Q is a thiazol-5-yl group; or a pharmaceutically-acceptable salt thereof.
Preferably, R2, and Rl when phenyl, is phenyl option-ally substituted by one or two radicals selected from halogen, -Cl 4 alkyl, Cl 4 haloalkyl, amino, C2 4 alkanoylamino, hydroxy, Cl 4 alkoxy, nitro and Cl 4 alkylsulphonamido.
The term "Cl 4alkyl" as used herein means a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, e.g, methyl, ethyl, lso-propyl, n-butyl, S-butyl, iso-butyl and t-butyl. "Cl 4haloalkyl" signifies an aforementioned Cl 4alkyl -
According to the present invention there is provided a phenylpiperazine derivative of formula tI):
1 3 ~ 2 R -Q-(CH2)m-(CHR )n~N ~ N - R (I) where Rl is benzyl, chlorobenzyl, Cl 6 alkyl or a phenyl group optionally substituted by one or two radicals selected from halogen, Cl ~ alkyl, Cl 4 haloalkyl, amino, C2 4alkanoylamino, hydroxy, Cl 4 alkoxy, nitro and Cl 4 alkylsulphonamido; R2 is a phenyl group optionally substituted by one or two radicals selected from halogen, Cl 4 alkyl, Cl 4 haloalkyl, amino, C2 4 alkanoylamino, hydroxy, Cl 4 alkoxy, nitro and Cl 4 alkylsulphon-amido, R3 is hydrogen or Cl 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 is 0, Rl cannot be methyl when Q is a thiazol-5-yl group; or a pharmaceutically-acceptable salt thereof.
Preferably, R2, and Rl when phenyl, is phenyl option-ally substituted by one or two radicals selected from halogen, -Cl 4 alkyl, Cl 4 haloalkyl, amino, C2 4 alkanoylamino, hydroxy, Cl 4 alkoxy, nitro and Cl 4 alkylsulphonamido.
The term "Cl 4alkyl" as used herein means a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, e.g, methyl, ethyl, lso-propyl, n-butyl, S-butyl, iso-butyl and t-butyl. "Cl 4haloalkyl" signifies an aforementioned Cl 4alkyl -
- 2 - ~
. . , ~ .
1~7~1~7 group substituted by one or more fluorine, chlorine, bromine or iodine atoms, and includes groups such as trifluoromethyl or pentachloroethyl. Similarly, the term "Cl 4alkoxy" refers to the aforementioned Cl 4alkyl groups attached vla an oxygen atom to the phenyl group.
preferred classes of compounds of formula (I) are those - having one or more of the following characteristics:
- 2a -:
, 1(387~17 (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) Rl is Cl 3alkyl such as methyl or l-propyl;
(g) Rl 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):
Rl ~ ~ (CH2~m N N - R2 (II) where Rl is phenyl optionally substituted by one or two radi-cals selected from halogen, Cl 4alkyl, Cl 4alkoxy, and Cl 4 haloalkyl; R2 is phenyl optionally substituted by Cl 4alkyl, amino, Cl 4alkylsulphonamido and Cl 4alkoxy and m is 1 or 3, with the exception of compounds in which Rl is unsubstituted phenyl, m is 1 and R2 is unsubstituted phenyl; or where Rl is methyl, m is 1 and R2 is ph`enyl optionally substituted by a single radical selected from halogen, Cl 4alkyl, Cl 4alkoxy, Cl 4haloalkyl or is disubstituted by two Cl 4alkyl radicals;
thiophenes of formula (III):
Rl S ~C~2~m (C~R ~n 3 - R2 (III~
1()87617 where Rl is phenyl; R2 is phenyl, phenyl singly substituted by Cl 4 alkyl or Cl 4 haloalkyl or doubly substituted by two radi-cals selected from the group comprising halogen, Cl 4 haloalkyl and Cl 4 alkyl, and where m is 1 or 2 and n = 0; or where m is 1, n is 1 and R3 is ethyl; oxazoles of formula (IV):
1 ~ ~ ICH2)m - N N- R2 (IV) where Rl is phenyl optionally substituted by Cl 4alkoxy or halo-gen; R2 is phenyl optionally substituted by Cl 4alkyl, Cl 4 haloalkyl, halogen, amino or C2 4 alkanoylamino and m is 1 or 2;
thiazoles of formula (V):
2 : :
Rl where Rl is benzyl, R2 is phenyl or p-halophenyl;
: or thiazoles of formula:
Rl ~ ::
~ ~5 ~ C~2 ~ N - R2 :
where Rl is Cl 4alkyl or phenyl optionally substituted by ~`
C1 4alkyl, C1 4alkoxy, nitro or Cl 4haloalkyl and R2 is phenyl :
optionally substituted by Cl 4haloalkyl;
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-y~ -4-(4-methylphenyl)piperazine;
1-[2-(5-Phenylthiophen-2-yl)but-1-yl~-4-phenylpiperazine;
1-(5-phenylthiophen-2-ylmethyl)-4-t3~4-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 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-Plenylthiazol-2-yl)e.hyl]-4-~4-aminophenyl)piperazine;
'I : , 1, ' 1 -4a- ~
1~ .
il, .
' ' : ' , ' : , .: , ' : , 1~37617 1-[2-(4-Phenylthiazol-2-yl)ethyl]-4-(4-nitrophenyl)piperazine;
l-(S-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-yl3-ethyl~-4-phenylpiperazine;
1-[2-(S-Phenyloxazol-2-yl)ethyl~-4-~4-chlorophenyl)-piperazine;
1-[2-(S-Phenyloxazol-2-yl)ethyl~-4-(4-methoxyphenyl)-piperazine;
l-[l-(S-Phenyloxazol-2-yl)prop-2-yl~-4-(4-methylphenyl)-piperazine;
1-[1-(5-Phenyloxazol-2-yl)ethyl]-4-(4-methylphenyl)-piperazine;
1-(5-Phenyloxazol-2-ylmethyl)-3-methyl-4-~ methylphenyl)-piperazine;
1-(5-Phenyloxazol-2-ylmethyl)-2~3-dimethyl-4-(4-methylphenyl)-piperazine;
~ 2-[4-(Chlorophenyl)-thiazol-2-yl~ethyl~-4-phenylpiperazine;
: 1 1-[2-(4-Phenylthiazol-2-yl)ethyl~-4-(4-chlorophenyl)-pîperazine;
1-[2-(4-Phenylthiazol-2-yl)ethyl~-4-(4-methoxyphenyl)-piperazine;
`: 15 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~ethyl3-4-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;
¦l 1-(5-Phenylfuran-2-ylmethyl)-4-(4-methylphenyl)-piperazine;
¦~ 1-(5-Phenylfuran-2-ylmethyl)-4-(4-methanesulphonamidophenyl)-piperazine;
¦1 1-[4-(4-Phenylthiazol-2-yl)but-1-yl~-4-phenylpiperazine;
¦¦ 1-(5-Phenylthiophen-2-ylmethyl)-4-(4-methylphenyl)-piperazine;
i ~ ~ 5 .
' ' ., 1-(5-Phenylthiophen-~-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;
I 1-[2-(4-Methyloxazol-2-yl)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-Ben2yloxazol-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; ~ :
.5 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;
:0 ¦l 1-[3-(5-Benzylthiazol-2-yl)prop-1-yl]-4-(4-ethoxyphenyl)piperazine;
¦ 1-(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;
!l l-[2-(4-Methylfuran-2-yl)ethyl]-4-(3-methylphenyl)-piperazine;
1~¦ 1-[3-(5-Methylfuran-2-yl)prop-1-yl~-4-(2-chlorophenyl)piperazine;
1-(5-Benzylfuran-2-ylmethyl)-4-(4-nitrophenyl)piperazine;
1-(4-Benzylfuran-2-ylmethyl)-4-(3-acetylaminophenyl)piperazine;
1 1-[2-(5-Benzylfuran-2-yl)ethyl~-4-(4-ethylphenyl)piperazine;
1-[3-(5-Benzylfuran-2-yl)prop-1-yl~-4-(4-ethoxyphenyl)piperazine;
~0 , 1-(5~Methylthiopher-2-ylmethyl)-4-phenylpiperazine;
(4 ~ thylthiophen-2-ylmethyl)-4-(4-methylphenyl)-piperazine; ¦
A
~ 108761~7 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-vl)-4-(2-chlorophenyl)piper-azine; l-(5-Benzylthiophen-2-ylmethyl)-4-(4-nitrophenyl)piper-azine; l-(4-Benzylthiophen-2-ylmethyl)-4-(3-acetylaminophenyl)-- piperazine; 1-[2-(5-senzylthiophen-2-yl)ethyl]-4-(4-nitrophenyl)-piperazine; l-[2-(5-Benzylthiophen-2-yl)ethyl]-4-(4-ethylphenyl)- Z
piperazine; l-[3-(5-Benzylthiophen-2-yl)prop-1-yl]-4-(4-ethoxy-phenyl)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), as previously defined, or an acid-addition salt thereof, which comprises:
(A) condensing a compound of formula (VI):
R -Q-~CH2)m-(CHR )n~L (VI):
where L represents a leaving group, with a compound of formula (VII):
~ 2 HN N-R (VII) 20 (B) reducing a compound of formula:
(i) R ~Q~(CH2)m 1 - C - N N R2 (VIII) to form a compound in which n is 0; or (ii) Rl - Q - (CH2)m-CR3 = (+)N N - R2 ~IX) , . . ., , :
.... ..
761 ~
to form a compound in which n is l; or (C) cyclising a compound of formula (X):
1 3 N ~ 2 R - Z- (CH2)m - (CHR )n ~ N - R (X) where Z is a group cyclisable to Q to form a compound of formula (I) in which Q is oxazole; and where desired, forming an acid addition salt of said compound of formula (I). In the above formulas, Rl, R2, R3 Q, _ and n are as previously defined in page 2.
The above condensation (A) is preferably carried out ---; in the presence of a proton acceptor such as a base, for example, ; sodium carbonate. Polar solvents such as alkanols, e.g.
ethanol, are suitable solvents for the reaction which is ad- -vantageously accomplished by heating under reflux. The leaving group L may be any radical known to be effective in such conden-sation 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 150C. Compounds of formula (VI~ are either known (see J.A.C.S. 56 470-1(1934) and 53 1470-3(1931)) or can be prepared by known techniques.
Reduction of the amide of formula ~VIII) can be -effected using chemical reducing agents such as B2H6 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 80C. The amides of formula (VIII) can be prepared by reaction of an acid chlor-ide (prepared for instance from the corresponding acid by reaction with thionyl chloride) of formula:
- . , .. ~ .
lQ876~7 R -Q-(CH2)m 1 - C - Cl with the phenylpiperazine of formula:
H~ NR
,, ,, . -.
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 cyanoboro-hydride 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 80C.
Compounds of formula (X) are normally prepared by ' reaction of the corresponding carbonyl compound of formula:
, Q (CH2)m-1 f ::
, R3 .. - - .
' 20 with the appropriate phenyl base of formula . .
~ - . . .
NH ~ N - R
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 Che~ical Reviewsr 75, 389-437 U975) and Advance's in Heterocyc'li'c Chemi's'try' 17 (1974~. ' ' , '. ' '.
- 9 - - , .
: :: , . . . , - .. . . . .
1~)876:17 Preferably, z is a group of formula:
Thus, compounds of formula (XI) 1 CO 3 ~ 2 CH2 NH - CO - (CH2)m-(CHR ) - N N- R
(XI) can by cyclised to compounds of formula:
R ~ ~ (C~2)m - (C~R3)n - N N - R2 using dehydrating agents such as polyphosphoric acid, phosphorus oxychloride or concentrated sulphuric acid. The reaction is preferably accomplished at a temperature range of from 80 to 180C.
Compounds of formula (XI) may be prepared by reacting the corresponding bromo derivative of formula:
.1 Rl _ CO - CH2 - NH - CO - (CH2)m - (CHR )n ~ Br (XII) with the corresponding base of formula / ' in the presence of an acid scanvenger such as sodum carbonate.
The compounds of formula (XII~ may themselves be pre-pared by reaction of the amine of formula:
with the corresponding acid chloride of formula -- 10 -- : -l~B7617 ClCO(CH2)m - (CHR )nC1 using dimethylformamide as solvent.
The compounds of formula (I) produced by the fore-going processes may be isolated per se or in acid-addition salt form.
The acid-addition salts are preferably the pharmaceuti-cally acceptable, non-toxic 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-_-sulfonic, or naphthalene-2-sulphonic acid. Apart from pharmaceutically acceptable acid-addition 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 identifica-tion, 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 hydro-xide, 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 ~on 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 com-pound of formula (I), or a pharmaceutically-acceptable salt thereof, associated with a pharmaceutically-acceptable 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 dis-continuous 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 10~ by weight of the active com-pound in a suitable base~ soft and hard gelatin capsules, in- ~-jection 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 con-- lla -' ', ~
.:
--- 10~37617 taining from 5 to 500 mg. (from 5.0 to 50 mg. in the case of parenteral administration, 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 mg/kg - llb ~ -- . .
lOB7617 per day, prcferably 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 oE 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, or 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 disposable container such as an ampoule. A carrier or diluent may be a solid, semi-solid or liquid material, which serves as a vehicle, excipi~nt 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~ ~aolin, 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 Il powdered ingredients in the dies and on the punch of the tabletting machine.
¦I For such purpose there may be employed for instance aluminium, magnesium or ~ calcium stearates, talc or mineral oil.
I The following Examples illustrate the invention.
, ~: , .
. . I
~ -12- 1 1,, I
76~7 (a) 2-Acetoxythioacetamide A stream of dry H2S gas was passed rapidly into a solution of 2-acetoxy-acetonitrile (150 g; 1.52 mole) and triethanolamine (20 ml) in dry ethanol ~ (500 ml) with vigorous stirring. The internal temperature rose to sa. 55C.
The gas flow was maintained for 3 hours whereupon G.L.C. indicated that the _~
I reaction was complete. Excess H2S gas was blown off with a stream of nitrogen -I~ and solvent EtOH evaporated to dryness. The remaining sticky crystalline mass ~l was extracted with boiling ether, a small insoluble residue being discarded.
¦I The cornbined extracts were treated with decolourising charcoal, filtered and I evaporated to approximately 400 ml volume. On cooling to O C. there was ¦ obtained some 170 g. of somewhat sticky 2-acetoxythioacetamide. This was used for the next stage without further characterisation.
¦ I (b) 2-Hydroxymethyl-4-phenylthiazole 2-Bromoacetophenone (39.9 g5 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 5N HCl (40 ml) was added and the heating continued for a further 20 ¦ 30 minutes. The dioxan was evaporated under vacuum and the residue neutral- ;
ised with aqueous Na2C03 solution. The solid was collected, washed with ~, water and dried. After recrystallisation from benzene the product weighed 33.5 g (87%) and had a m.p. of 88-9C.
1 (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.
~IThemixture wasstirred and heated to boiling for 1 hour. ~he cooled reaction 30 ~ mixture was then shaken with 2 x 70 ml H20 and dried over anhydrous MgS04.
.''' 1' - .
~ -13-. ~
''. . .. :
The solvent was removed under vacuum and the remaining red oil extracted with ¦
40-60C. petroleum ether ~100 ml), discarding a small tarry residue. The extract w~s treated with decolourising charcoal, filtered and evaporated, I leaving a yellow-red oil that crystallised on refrigeration.
~ Yield 9.9 g 94.5%
i No further purification was undertaken, and the material was used ~
¦ directly for the next stage. ¦
(d) 1-(4-Phenyl-2-thiazolylmethyl)-4-phenylpiperazine l 10 l ~1 A mixture of crude 2-chloromethyl-4-phenylthiazole (4.19g; 0.02 mole), I N-phenylpiperazine (3.24 g; 0.02 mole) and finely-powdered~ anhydrous sodium ¦I carbonate in absolute ethanol (60 ml) was stirred and boiled under reflux I for 8 hours. The solvent was evaporated to dryness, solid residue suspended ¦l in water (100 ml) and then extracted with 2 x 100 ml CH2C12. The extracts were washed with water and dried over anhydrous MgS04. On evaporation of the solvent, and recrystallisation of the residue from benzene/60-80C.
petroleum ether mixture (with charcoal treatment) there was obtained the required product (5.03 g; 75~/O) having m.p. 142-3C.
` ";
!I EXAMPLES 2 to 19 ?
¦I Similarly, there were prepared :
¦! (2) 1-(4-Phenyl-2-thiazolylmethyl)-4-(3-bromophenyl)-piperazine~ m.p.
1~ 127.5 - 128.5C.
251' 1.
. . , ~ .
1~7~1~7 group substituted by one or more fluorine, chlorine, bromine or iodine atoms, and includes groups such as trifluoromethyl or pentachloroethyl. Similarly, the term "Cl 4alkoxy" refers to the aforementioned Cl 4alkyl groups attached vla an oxygen atom to the phenyl group.
preferred classes of compounds of formula (I) are those - having one or more of the following characteristics:
- 2a -:
, 1(387~17 (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) Rl is Cl 3alkyl such as methyl or l-propyl;
(g) Rl 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):
Rl ~ ~ (CH2~m N N - R2 (II) where Rl is phenyl optionally substituted by one or two radi-cals selected from halogen, Cl 4alkyl, Cl 4alkoxy, and Cl 4 haloalkyl; R2 is phenyl optionally substituted by Cl 4alkyl, amino, Cl 4alkylsulphonamido and Cl 4alkoxy and m is 1 or 3, with the exception of compounds in which Rl is unsubstituted phenyl, m is 1 and R2 is unsubstituted phenyl; or where Rl is methyl, m is 1 and R2 is ph`enyl optionally substituted by a single radical selected from halogen, Cl 4alkyl, Cl 4alkoxy, Cl 4haloalkyl or is disubstituted by two Cl 4alkyl radicals;
thiophenes of formula (III):
Rl S ~C~2~m (C~R ~n 3 - R2 (III~
1()87617 where Rl is phenyl; R2 is phenyl, phenyl singly substituted by Cl 4 alkyl or Cl 4 haloalkyl or doubly substituted by two radi-cals selected from the group comprising halogen, Cl 4 haloalkyl and Cl 4 alkyl, and where m is 1 or 2 and n = 0; or where m is 1, n is 1 and R3 is ethyl; oxazoles of formula (IV):
1 ~ ~ ICH2)m - N N- R2 (IV) where Rl is phenyl optionally substituted by Cl 4alkoxy or halo-gen; R2 is phenyl optionally substituted by Cl 4alkyl, Cl 4 haloalkyl, halogen, amino or C2 4 alkanoylamino and m is 1 or 2;
thiazoles of formula (V):
2 : :
Rl where Rl is benzyl, R2 is phenyl or p-halophenyl;
: or thiazoles of formula:
Rl ~ ::
~ ~5 ~ C~2 ~ N - R2 :
where Rl is Cl 4alkyl or phenyl optionally substituted by ~`
C1 4alkyl, C1 4alkoxy, nitro or Cl 4haloalkyl and R2 is phenyl :
optionally substituted by Cl 4haloalkyl;
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-y~ -4-(4-methylphenyl)piperazine;
1-[2-(5-Phenylthiophen-2-yl)but-1-yl~-4-phenylpiperazine;
1-(5-phenylthiophen-2-ylmethyl)-4-t3~4-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 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-Plenylthiazol-2-yl)e.hyl]-4-~4-aminophenyl)piperazine;
'I : , 1, ' 1 -4a- ~
1~ .
il, .
' ' : ' , ' : , .: , ' : , 1~37617 1-[2-(4-Phenylthiazol-2-yl)ethyl]-4-(4-nitrophenyl)piperazine;
l-(S-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-yl3-ethyl~-4-phenylpiperazine;
1-[2-(S-Phenyloxazol-2-yl)ethyl~-4-~4-chlorophenyl)-piperazine;
1-[2-(S-Phenyloxazol-2-yl)ethyl~-4-(4-methoxyphenyl)-piperazine;
l-[l-(S-Phenyloxazol-2-yl)prop-2-yl~-4-(4-methylphenyl)-piperazine;
1-[1-(5-Phenyloxazol-2-yl)ethyl]-4-(4-methylphenyl)-piperazine;
1-(5-Phenyloxazol-2-ylmethyl)-3-methyl-4-~ methylphenyl)-piperazine;
1-(5-Phenyloxazol-2-ylmethyl)-2~3-dimethyl-4-(4-methylphenyl)-piperazine;
~ 2-[4-(Chlorophenyl)-thiazol-2-yl~ethyl~-4-phenylpiperazine;
: 1 1-[2-(4-Phenylthiazol-2-yl)ethyl~-4-(4-chlorophenyl)-pîperazine;
1-[2-(4-Phenylthiazol-2-yl)ethyl~-4-(4-methoxyphenyl)-piperazine;
`: 15 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~ethyl3-4-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;
¦l 1-(5-Phenylfuran-2-ylmethyl)-4-(4-methylphenyl)-piperazine;
¦~ 1-(5-Phenylfuran-2-ylmethyl)-4-(4-methanesulphonamidophenyl)-piperazine;
¦1 1-[4-(4-Phenylthiazol-2-yl)but-1-yl~-4-phenylpiperazine;
¦¦ 1-(5-Phenylthiophen-2-ylmethyl)-4-(4-methylphenyl)-piperazine;
i ~ ~ 5 .
' ' ., 1-(5-Phenylthiophen-~-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;
I 1-[2-(4-Methyloxazol-2-yl)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-Ben2yloxazol-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; ~ :
.5 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;
:0 ¦l 1-[3-(5-Benzylthiazol-2-yl)prop-1-yl]-4-(4-ethoxyphenyl)piperazine;
¦ 1-(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;
!l l-[2-(4-Methylfuran-2-yl)ethyl]-4-(3-methylphenyl)-piperazine;
1~¦ 1-[3-(5-Methylfuran-2-yl)prop-1-yl~-4-(2-chlorophenyl)piperazine;
1-(5-Benzylfuran-2-ylmethyl)-4-(4-nitrophenyl)piperazine;
1-(4-Benzylfuran-2-ylmethyl)-4-(3-acetylaminophenyl)piperazine;
1 1-[2-(5-Benzylfuran-2-yl)ethyl~-4-(4-ethylphenyl)piperazine;
1-[3-(5-Benzylfuran-2-yl)prop-1-yl~-4-(4-ethoxyphenyl)piperazine;
~0 , 1-(5~Methylthiopher-2-ylmethyl)-4-phenylpiperazine;
(4 ~ thylthiophen-2-ylmethyl)-4-(4-methylphenyl)-piperazine; ¦
A
~ 108761~7 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-vl)-4-(2-chlorophenyl)piper-azine; l-(5-Benzylthiophen-2-ylmethyl)-4-(4-nitrophenyl)piper-azine; l-(4-Benzylthiophen-2-ylmethyl)-4-(3-acetylaminophenyl)-- piperazine; 1-[2-(5-senzylthiophen-2-yl)ethyl]-4-(4-nitrophenyl)-piperazine; l-[2-(5-Benzylthiophen-2-yl)ethyl]-4-(4-ethylphenyl)- Z
piperazine; l-[3-(5-Benzylthiophen-2-yl)prop-1-yl]-4-(4-ethoxy-phenyl)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), as previously defined, or an acid-addition salt thereof, which comprises:
(A) condensing a compound of formula (VI):
R -Q-~CH2)m-(CHR )n~L (VI):
where L represents a leaving group, with a compound of formula (VII):
~ 2 HN N-R (VII) 20 (B) reducing a compound of formula:
(i) R ~Q~(CH2)m 1 - C - N N R2 (VIII) to form a compound in which n is 0; or (ii) Rl - Q - (CH2)m-CR3 = (+)N N - R2 ~IX) , . . ., , :
.... ..
761 ~
to form a compound in which n is l; or (C) cyclising a compound of formula (X):
1 3 N ~ 2 R - Z- (CH2)m - (CHR )n ~ N - R (X) where Z is a group cyclisable to Q to form a compound of formula (I) in which Q is oxazole; and where desired, forming an acid addition salt of said compound of formula (I). In the above formulas, Rl, R2, R3 Q, _ and n are as previously defined in page 2.
The above condensation (A) is preferably carried out ---; in the presence of a proton acceptor such as a base, for example, ; sodium carbonate. Polar solvents such as alkanols, e.g.
ethanol, are suitable solvents for the reaction which is ad- -vantageously accomplished by heating under reflux. The leaving group L may be any radical known to be effective in such conden-sation 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 150C. Compounds of formula (VI~ are either known (see J.A.C.S. 56 470-1(1934) and 53 1470-3(1931)) or can be prepared by known techniques.
Reduction of the amide of formula ~VIII) can be -effected using chemical reducing agents such as B2H6 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 80C. The amides of formula (VIII) can be prepared by reaction of an acid chlor-ide (prepared for instance from the corresponding acid by reaction with thionyl chloride) of formula:
- . , .. ~ .
lQ876~7 R -Q-(CH2)m 1 - C - Cl with the phenylpiperazine of formula:
H~ NR
,, ,, . -.
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 cyanoboro-hydride 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 80C.
Compounds of formula (X) are normally prepared by ' reaction of the corresponding carbonyl compound of formula:
, Q (CH2)m-1 f ::
, R3 .. - - .
' 20 with the appropriate phenyl base of formula . .
~ - . . .
NH ~ N - R
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 Che~ical Reviewsr 75, 389-437 U975) and Advance's in Heterocyc'li'c Chemi's'try' 17 (1974~. ' ' , '. ' '.
- 9 - - , .
: :: , . . . , - .. . . . .
1~)876:17 Preferably, z is a group of formula:
Thus, compounds of formula (XI) 1 CO 3 ~ 2 CH2 NH - CO - (CH2)m-(CHR ) - N N- R
(XI) can by cyclised to compounds of formula:
R ~ ~ (C~2)m - (C~R3)n - N N - R2 using dehydrating agents such as polyphosphoric acid, phosphorus oxychloride or concentrated sulphuric acid. The reaction is preferably accomplished at a temperature range of from 80 to 180C.
Compounds of formula (XI) may be prepared by reacting the corresponding bromo derivative of formula:
.1 Rl _ CO - CH2 - NH - CO - (CH2)m - (CHR )n ~ Br (XII) with the corresponding base of formula / ' in the presence of an acid scanvenger such as sodum carbonate.
The compounds of formula (XII~ may themselves be pre-pared by reaction of the amine of formula:
with the corresponding acid chloride of formula -- 10 -- : -l~B7617 ClCO(CH2)m - (CHR )nC1 using dimethylformamide as solvent.
The compounds of formula (I) produced by the fore-going processes may be isolated per se or in acid-addition salt form.
The acid-addition salts are preferably the pharmaceuti-cally acceptable, non-toxic 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-_-sulfonic, or naphthalene-2-sulphonic acid. Apart from pharmaceutically acceptable acid-addition 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 identifica-tion, 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 hydro-xide, 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 ~on 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 com-pound of formula (I), or a pharmaceutically-acceptable salt thereof, associated with a pharmaceutically-acceptable 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 dis-continuous 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 10~ by weight of the active com-pound in a suitable base~ soft and hard gelatin capsules, in- ~-jection 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 con-- lla -' ', ~
.:
--- 10~37617 taining from 5 to 500 mg. (from 5.0 to 50 mg. in the case of parenteral administration, 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 mg/kg - llb ~ -- . .
lOB7617 per day, prcferably 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 oE 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, or 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 disposable container such as an ampoule. A carrier or diluent may be a solid, semi-solid or liquid material, which serves as a vehicle, excipi~nt 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~ ~aolin, 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 Il powdered ingredients in the dies and on the punch of the tabletting machine.
¦I For such purpose there may be employed for instance aluminium, magnesium or ~ calcium stearates, talc or mineral oil.
I The following Examples illustrate the invention.
, ~: , .
. . I
~ -12- 1 1,, I
76~7 (a) 2-Acetoxythioacetamide A stream of dry H2S gas was passed rapidly into a solution of 2-acetoxy-acetonitrile (150 g; 1.52 mole) and triethanolamine (20 ml) in dry ethanol ~ (500 ml) with vigorous stirring. The internal temperature rose to sa. 55C.
The gas flow was maintained for 3 hours whereupon G.L.C. indicated that the _~
I reaction was complete. Excess H2S gas was blown off with a stream of nitrogen -I~ and solvent EtOH evaporated to dryness. The remaining sticky crystalline mass ~l was extracted with boiling ether, a small insoluble residue being discarded.
¦I The cornbined extracts were treated with decolourising charcoal, filtered and I evaporated to approximately 400 ml volume. On cooling to O C. there was ¦ obtained some 170 g. of somewhat sticky 2-acetoxythioacetamide. This was used for the next stage without further characterisation.
¦ I (b) 2-Hydroxymethyl-4-phenylthiazole 2-Bromoacetophenone (39.9 g5 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 5N HCl (40 ml) was added and the heating continued for a further 20 ¦ 30 minutes. The dioxan was evaporated under vacuum and the residue neutral- ;
ised with aqueous Na2C03 solution. The solid was collected, washed with ~, water and dried. After recrystallisation from benzene the product weighed 33.5 g (87%) and had a m.p. of 88-9C.
1 (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.
~IThemixture wasstirred and heated to boiling for 1 hour. ~he cooled reaction 30 ~ mixture was then shaken with 2 x 70 ml H20 and dried over anhydrous MgS04.
.''' 1' - .
~ -13-. ~
''. . .. :
The solvent was removed under vacuum and the remaining red oil extracted with ¦
40-60C. petroleum ether ~100 ml), discarding a small tarry residue. The extract w~s treated with decolourising charcoal, filtered and evaporated, I leaving a yellow-red oil that crystallised on refrigeration.
~ Yield 9.9 g 94.5%
i No further purification was undertaken, and the material was used ~
¦ directly for the next stage. ¦
(d) 1-(4-Phenyl-2-thiazolylmethyl)-4-phenylpiperazine l 10 l ~1 A mixture of crude 2-chloromethyl-4-phenylthiazole (4.19g; 0.02 mole), I N-phenylpiperazine (3.24 g; 0.02 mole) and finely-powdered~ anhydrous sodium ¦I carbonate in absolute ethanol (60 ml) was stirred and boiled under reflux I for 8 hours. The solvent was evaporated to dryness, solid residue suspended ¦l in water (100 ml) and then extracted with 2 x 100 ml CH2C12. The extracts were washed with water and dried over anhydrous MgS04. On evaporation of the solvent, and recrystallisation of the residue from benzene/60-80C.
petroleum ether mixture (with charcoal treatment) there was obtained the required product (5.03 g; 75~/O) having m.p. 142-3C.
` ";
!I EXAMPLES 2 to 19 ?
¦I Similarly, there were prepared :
¦! (2) 1-(4-Phenyl-2-thiazolylmethyl)-4-(3-bromophenyl)-piperazine~ m.p.
1~ 127.5 - 128.5C.
251' 1.
(3) 1~(4-Phenyl-2~thiazolylmethyl)-4-(3,4-dichlorophenyl)-piperazine, ¦
m.p. 144-6C. ~
~.
, ~ (4) 1-(4-Phenyl-2-thiazoLylmethyl)-4-(3-trifluoromethylphenyl)-piperazine, m.p. 112-3C.
.
,: . . :
.. . . . .
3761q (5) 1-(4-Phenyl-2-thiazolylmethyl)-4-(4~chloro-3-triflUoro~ethylphenyl)-piper _ azine, m.p. 117-9C.
(6) 1-(4-Phenyl-2-thiazolylmethyl)-4-(4-methylphenyl)-piperazine, m.p. 141-3C.
(7) 1_(4_Phenyl-2-thi~zolylmethvl)-4-(4-methoxyphenyl)-piperazine, m.p.
(8) 1-~4-(4-Chlorophenyl)-2-thiazolylmethyl~-4-phenylpiperazine, m.p. L
164-5C.
(9) 1-[4-(4-Chlorophenyl)-2-thiazolylmethyl]-4-(3-bromophenyl)-piperazine, m.p. 100-101C.
(10) X4-(4-Bromophenyl)-2-thiazolylmethyl]-4-phenylpiperazine~ m.p.
, ~11) 1-[4-(3-Chlorophenyl)-2-thiazolylmethyl~-4-phenylpiperazine, m.p.
129-131C. ' O
(12) 1-C4-(2-Chlorophenyl)-2-thiazolylmethyl~-4-phenylpiperazine, m.p.
100-101C.
¦ (13) 1-~4-(3,4-~ichlorophenyl)-2-thiazolylmethyl~-4-phenylpiperazine, m.p.
138-139.5C.
` (14) 1-[4-(3-Trifluoromethylphenyl)-2-thiazolylmethyl~-4-phenylpiperazine ~_ m.p. 110-111C.
. , .
.' .
!
.
~t376~7 1 (15) 1-[4-(4-Methoxyphenyl)-2-thiazolylmethyl~-4-phenylpipera~ine. HCl m.p. 201C.
(16) 1-[4-(4-Methylphenyl)-2-thia~olylmethyl~-4-phenylpiperazine. HCl ' m.p. 175-180C.
(17) 1-[4-(3-Methylphenyl)-2-thiazolylmethyl~-4-phenylpiperazine, m.p.
j 113-113.5C.
' 11 (18) 1-[4-(4-Hydroxyphenyl)-2-thiazolylmethyl~-4-phenylpiperazine~ m.p. ~
228-230C.
I (19) 1-[4-(4-~itrophenyl)-2-thiazolylmethyl]-4-phenylpiperazine~ m.p.
195-8C.
. I
(a) N-Phenacyl chloroacetamide Chloroacetyl chloride (25 g; 0.226 mole) was added slowly to a I
stirred solution of phenacylamine hydrochloride (25.9 g; 0.151 mole) in I ' ;
anhydrous dimethylformamide (DMF) (80 ml) at room temperature. The I *
internal temperature rose to ca. 40C. 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 coll-¦ ected~ washed with water and dried. Yield 24.75 g (77%). m.p. 118-119C. ~
(b) 2-Chloromethyl-5-phenyloxazole a N-Phenacyl chloroacetamide (22.6 g; 0.107 mole) was mixed with poly-¦ phosphoric acid (200 g) and the mass heated with stirring for 30 minutes ; 30 ~ at 150C. The hot liquid was then poured with vigorous stirring into water .
,1 - .
~ -16-- . . . . ..
- . . ' ,,'. : ' ~ . : .
1~8761~7 1 I(800 ml). The mixture so formed was extracted with 3 x 100 ml chloroformJthe extracts washed by shaking with water and dried over magnesium sulphate~
The CHC13 was evaporated off and the remaining oil extracted with 400 ml boil-ing 60-80C, 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. 70-1C.
. ~
(c) 1-(5-Phenyl-oxazol-2-ylmethylj-4-phenylpiperazi_e A solution of 2-chloromethyl-5-phenyloxazole (3.87 g; 0.02 mole) and N-phenylpiperazine (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 2 x 70 ml. dichloromethane.
The extracts were dried over magnesium sulphate and evaporated to dryness.
The solid residue was recrystallised from 80-100C. petroleum ether with the use of decolourising charcoal, Yield 4.67 g. m.p. 96C.
Similarly, there were prepared :
(21) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(4-methylphenyl)-piperazine, m.p.
113-114C.
(22) 1;(5-Phenyl-oxazol-2-ylmethyl)-4-(3-chlorophenyl)-piperazine~ m.p, -I
(23) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(4-chlorophenyl)-piperazine~ m.p, 1~5 6C.
17- ' ! 1 1~87617 1 1 (24) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(3-trifluoromethylphenyl)-piperazine~
¦ m,p. 69-70C.
(25) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(3,4-dichlorophenyl)-piperazine, j m.p. 134-5C.
(26) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(4-methoxyphenyl)-piperazine, m p.
121-2C.
(27) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(3-methoxyphenyl)-piperazine~ m.p.
100C.
~28) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(2,4-dimethoxyphenyl) piperazine~
m.p. 89-91C.
(29) 1-(5-Phenyl-oxaæol-2-ylmethyl)-4-(3,4-dimethoxyphenyl)-piperazine, m.p. 93-5C.
(30) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(4-ethoxyphenyl)-piperazine, m.p.
1 98C. ~ ;
1l . "~
(31) 1-[5-(4-Fluorophenyl)-oxazol-2-ylmethyl~-4-phenylpiperazine~ m.p.
114-116C.
~' ~32) 1-[5-(4-Fluorophenyl)-oxazol-2-ylmethyl~-4-(4-methoxyphenyl)-piperazine~ ¦
m.p. 112C. ¦
l l (33) 1-[5-(4-~thoxyphenyl)-oxazol-2-ylmethyl~-4-phenylpiperazine, m.p.
112- 15C.
I 1, ~ -18-.
- . .
.. ,. . . , . .. . . .
3761`7 1 (34) 1-[5-(4-Methoxyphenyl)-oxazol-2-ylmethyl]-4-(4-methoxyphenyl)-piperazine ' m.p. 148-50C.
1, l (35) 1-(5-Phenyloxazol-2-ylmethyl)-4-(4-nitrophenyl)-piperazine, m.p.
170-2C.
1-(5-Phenyloxazol-2-ylmethyl)-4-(4-aminophenyl)-piperazine I A solution of 1-(5-phenyloxazol-2-ylmethyl)-4-(4-nitrophenyl)-piperazine L
(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 complet:e. 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. 130C.
, I
i ' I
¦ EXAMPLE 37 ¦ 1-(5-Phenyloxazol-2-ylmethyl)-4-(4-acetamidophenyl)-piperazm e The 4-aminophenyl compound of Example 36 (3.0 g; 0.009 mole) was warmed O
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 recrystallisa-1 tion from methanol the product weighed 2.45 g and melted at 196-7C.
1~
I . . 1 ` ¦ EXAMPLE 38 1-(5-Phenyloxazol-2-ylmethyl)-4-(4-hydroxyphenyl)-piperazine I
Pro~ me-l-thiol (5.02 g; 0.066 mole~ was ~dded slowly to a stirred . .
.
I
! .
~71617 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 3 x 200 ml ethyl acetate. The extracts were shaken several t~es with water, dried and evaporated to a white solid. After recrystallisation from dioxan/60-80C. petroleum ether, the product weighed 5.5 g (74.5%), m.p. 189-190C.
1- L2-(5-Phenyloxazol-2-yl)-ethy~ -4-phenylpiperazine (a) N-Phenacyl-3-bromopropanamide -~
3-Bromopropionyl chloride (25 g; 0.146 mole) was added slowly to a stirred suspension of phenacylamine hydro-chloride (17.15 g; 0.1 mole) in dry dimethylformamide (50 ml) at room temperature. The internal temperature rose to ca.
40C. 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. 114C.
(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 tem-perature was then increased to 80C 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 (3 x 100 ml). The extracts were shaken with 2 x 100 ml .
1~76~7 1 >N ~ICl and the organic layer discarded. The aqueous layer was basified with! ¦
NaOH solution to pH 9 and extracted with 3 x 75 ml CHC13. 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 l at 126C. I lI
l i (c) 1-[2-(5-Phenyloxazol-2-yl)-ethyll-4-phenylpiperazine N-Phenacyl-3-(4-phenylpiperazin-1-yl)-proponamide (4.03 g9 0.011 mole) 1 10 was mixed with polyphosphoric acid (36 g) and stirred and heated at 140C.
for 30 minutes. The mixture was dissolved in water (100 ml), cooled, and extracted (2 x 30 ml chloroform). The extracts were discarded and the aqueous phase basified to pH 9 with 50% aqueous ~aOH solution. The emulsion formed was extracted with 3 x 100 ml chloroform~the extracts dried and evaporated. The crystalline residue was recrystallised from 60-ôOC.
petroleum ether. Yield 2.6 g m.p. 84-5C.
. ' .
1-[5-(3-Trifluoromethylphenyl)-furan-2-ylmethyl~-4-phenylpiperazine , (a) 2-HYdroxyme~Y1-5- ~ henyl)-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 tetra-hydrofuran (100 ml), cooled to -40C. and n-butyl lithium (0.1 mole, solution in hexane) was added dropwise. After stirring for 1 hour at -40C, para-~ formaldehyde (3.3 g; 0.11 mole) was added gradually. The mixture was ¦ stirred at -40 C. for 30 minutes, then the temperature was allowed to rise.
¦ At 10C. an exothermic reaction set in and the temperature gradually rose r~
! to 40C. (over 10 minutes)~ then gradually fell back to 20C. After stirring for further 1 hour the clear brown solution was poured onto ice/water, .
~ -21-1~761 ~ ¦
1 adjusted to pll ca 4 with dilute hydrochloric acid and extracted via ethyl acetate. The dried acetate extract (MgS04) was evaporated to give a brownish yellow viscous oil which was distilled in vacuo to give 2-hydroxymethyl-5-l (3-trifluoromethylphenyl)-furan as a colourless liquid b.p. 125 C./0.5 mm., (16.2 g), which on standing gave crystals, m.p. 45C.
(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 0-5 C. 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 NaCl (saturated solution) dried over molecular sieve 3A and evaporated to give a light brown oil which slowly crystallised (4.6 g).
tc) 1-[5-(3-Trifluoromethylphenyl)-furan-2-ylmethyll-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 chioroform extract was washed with water, then with saturated salt solution and finally evaporated to give an bil 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 saturat 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 60/80C. to give the title compound 1-[5-(3-trifluoromethyl- _ 1 phenyl iuran-2-ylmethyl~-4-phenylpiper~zine~ 1.2 g, m,p. 94C.
1~
1!
76~7 1 In a similar manner were prepared the following except that the intermediate hydroxymethyl compounds were converted to the chloromethyl Il compounds via thionyl chloride.
EXAMPLE 41 ~
1-[5-(4-Chlorophenyl?-furan-2-ylmethyll-4-phenylpiperazine `¦
m.p. 140 C.
10 . ~
1' ~
l-r5-(4-Chlorophenyl)-furan-2-ylmethyll-4-(3-trifluoromethylphenyl)-piperazine monohydrochloride The free base was obtained as an intractable viscous oil and was converted to the monohydrochloride, m.p. 220 C.
; , 1-[5-(4-Chlorophenyl-furan-2-ylmethyll-4-(3-chlorophenyl)-piperazine monohydrochloride m.p. 215C.
1-[5-(4-Chlorophenyl)-furan-2-ylmethyll-4-(3-bromophenyl)-piperazine monohydrochloride l 5-(4-Chlorophenyl)-2-furoic acid (Australian Journal of Chemistry, 26, r_ 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 1~
~ ~ -23-il, !l 1~37617 1 l 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 P~
crystallised. The product was recrystallised from ethyl acetate / 60 - 80C.
petroleum ether (1/3 /v) to yield 1-[5-(4-chlorophenyl)-2-furoyl]-4-(3-bromophenyl)-piperazine (12.3 g) m.p. 130C.
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 0C.
to a solution of diborane in tetrahydrofuran (20 ml, lM solution) (N.B. the reaction was carried out under nitrogen). The temperature rose to ca. 8C.
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 5N HCl (20 ml). After again cooling the solution was made al~aline (4N NaOH) and extracted via diethyl ether. The ether extract a ter drying over MgS04 was evaporated to give an oil which was converted to its monohydro-chloride to give the title compound. (2.8 g) m.p. 217C.
' In a similar manner were prepared the following : ¦
EXAMPLE 45 ¦
1-[5-(4-Chlorophenyl)-furan-2-ylmethyll-4-(3-trifluoromethyl-4-chlorophenyl)- 31 ~iperazine. _ m.p. 104C.
. . : : . . .: . : - . . . .
.
761.7 ¦l 1~[5-(4-Met_ylphenyl)-furan-2-ylmethyll-4-phenylpiperazine l;
m.p. 87C.
-C5-(2-Methylphenyl)-furan-2-ylmethyll-4-phenylpiperazine o ~1 m.p. 67 C. l 1-C5-(3,4-Dichlorophenyl)-furan-2-ylmethyll-4-phenylpiperazine m.p. 92C.
EXA~IPLE 49 1-[5-53-Trifluoromethyl-4-chlorophenyl)-furan-2 ylmethy;~-4-phenylpiperazine m.p. 102C.
. .
' 1-[5-(3-Trifluoromethyl-4-chlorophenyl)-furan-2-ylmethyll-4-(3-chlorophenyl)-piper-zine monohydrochloride m.p. 216C.
. 11 EXAMPLE 51 ¦¦
1-[5-(3-Trifluoromethvl-4-chlorophenyl)-furan-2-ylmethyll-4-(4-methylPhenyl)- ' ,_, piperazine m.p. 126C.
ll 1,, . ' .1. 1 -.... .. . . . .
.: ' - - :.. :
~9B7617 ,, ~
1-(5-Phenylfuran-2-ylmethyl)-4-(3-chlorop~nyl)-piperazine monohydrochloride m.p. 208C.
In the following Examples 53 to 58 the final reduc-~on step was carried out using the internal reduction method - of K.M. Biswas and A.H. Jackson, Tetrahedron 24, 1145 (1967).
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 nitro- - --gen, and redistilled boron trifluoride etherate (6 ml, 0.045 mole) in diglyme (20 ml) added dropwise with continuous stirr-ing. The resultant clear solution was stirred at room temper-ature for 3 hours and then evaporated to remove diglyme. The residue was carefully diluted with water (100 ml), followed by 5NHC1 (20 ml) and the mixture heated on a steam bath for 15 minutes. The mixture was cooled and made alkaline (4N 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. 56C. -Similarly prepared were the following:
"
.
: .
~87617 1-~5-Phenylfuran-2-ylmethyl)-4-(3~4-dichlorophenyl)-piperazine m.p. 150C.
EXAMPLE 55 .
1-(5-Phenylfuran-2-ylmethyl)-4-phenylpiperazine m.p. 106C.
, '''10 . ~
1-(5-Phenylfuran-2-ylmethyl)-4-(4-methylphenyl~-piperazine m.p. 114C.
~15 l-r5-(3.4-Dimethylphenyl)-furan-2-ylmethyll-4-(3-trifluoromethyl-4-chloro-phenyl)-piperazine m.p. 80Co , l-r5-(3.4-Dimethylphenyl)-furan-2-ylmethyll-4-(3-methoxyphenyl)-piperazine monohydrochloride m.p. 200C.
I -27- ' . 11 ., ' .
1~t37617 1-~5-(4-methoxyphenyl)-fura:n-2-y]methyl]-4-(3-trifluoromethyl-
m.p. 144-6C. ~
~.
, ~ (4) 1-(4-Phenyl-2-thiazoLylmethyl)-4-(3-trifluoromethylphenyl)-piperazine, m.p. 112-3C.
.
,: . . :
.. . . . .
3761q (5) 1-(4-Phenyl-2-thiazolylmethyl)-4-(4~chloro-3-triflUoro~ethylphenyl)-piper _ azine, m.p. 117-9C.
(6) 1-(4-Phenyl-2-thiazolylmethyl)-4-(4-methylphenyl)-piperazine, m.p. 141-3C.
(7) 1_(4_Phenyl-2-thi~zolylmethvl)-4-(4-methoxyphenyl)-piperazine, m.p.
(8) 1-~4-(4-Chlorophenyl)-2-thiazolylmethyl~-4-phenylpiperazine, m.p. L
164-5C.
(9) 1-[4-(4-Chlorophenyl)-2-thiazolylmethyl]-4-(3-bromophenyl)-piperazine, m.p. 100-101C.
(10) X4-(4-Bromophenyl)-2-thiazolylmethyl]-4-phenylpiperazine~ m.p.
, ~11) 1-[4-(3-Chlorophenyl)-2-thiazolylmethyl~-4-phenylpiperazine, m.p.
129-131C. ' O
(12) 1-C4-(2-Chlorophenyl)-2-thiazolylmethyl~-4-phenylpiperazine, m.p.
100-101C.
¦ (13) 1-~4-(3,4-~ichlorophenyl)-2-thiazolylmethyl~-4-phenylpiperazine, m.p.
138-139.5C.
` (14) 1-[4-(3-Trifluoromethylphenyl)-2-thiazolylmethyl~-4-phenylpiperazine ~_ m.p. 110-111C.
. , .
.' .
!
.
~t376~7 1 (15) 1-[4-(4-Methoxyphenyl)-2-thiazolylmethyl~-4-phenylpipera~ine. HCl m.p. 201C.
(16) 1-[4-(4-Methylphenyl)-2-thia~olylmethyl~-4-phenylpiperazine. HCl ' m.p. 175-180C.
(17) 1-[4-(3-Methylphenyl)-2-thiazolylmethyl~-4-phenylpiperazine, m.p.
j 113-113.5C.
' 11 (18) 1-[4-(4-Hydroxyphenyl)-2-thiazolylmethyl~-4-phenylpiperazine~ m.p. ~
228-230C.
I (19) 1-[4-(4-~itrophenyl)-2-thiazolylmethyl]-4-phenylpiperazine~ m.p.
195-8C.
. I
(a) N-Phenacyl chloroacetamide Chloroacetyl chloride (25 g; 0.226 mole) was added slowly to a I
stirred solution of phenacylamine hydrochloride (25.9 g; 0.151 mole) in I ' ;
anhydrous dimethylformamide (DMF) (80 ml) at room temperature. The I *
internal temperature rose to ca. 40C. 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 coll-¦ ected~ washed with water and dried. Yield 24.75 g (77%). m.p. 118-119C. ~
(b) 2-Chloromethyl-5-phenyloxazole a N-Phenacyl chloroacetamide (22.6 g; 0.107 mole) was mixed with poly-¦ phosphoric acid (200 g) and the mass heated with stirring for 30 minutes ; 30 ~ at 150C. The hot liquid was then poured with vigorous stirring into water .
,1 - .
~ -16-- . . . . ..
- . . ' ,,'. : ' ~ . : .
1~8761~7 1 I(800 ml). The mixture so formed was extracted with 3 x 100 ml chloroformJthe extracts washed by shaking with water and dried over magnesium sulphate~
The CHC13 was evaporated off and the remaining oil extracted with 400 ml boil-ing 60-80C, 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. 70-1C.
. ~
(c) 1-(5-Phenyl-oxazol-2-ylmethylj-4-phenylpiperazi_e A solution of 2-chloromethyl-5-phenyloxazole (3.87 g; 0.02 mole) and N-phenylpiperazine (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 2 x 70 ml. dichloromethane.
The extracts were dried over magnesium sulphate and evaporated to dryness.
The solid residue was recrystallised from 80-100C. petroleum ether with the use of decolourising charcoal, Yield 4.67 g. m.p. 96C.
Similarly, there were prepared :
(21) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(4-methylphenyl)-piperazine, m.p.
113-114C.
(22) 1;(5-Phenyl-oxazol-2-ylmethyl)-4-(3-chlorophenyl)-piperazine~ m.p, -I
(23) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(4-chlorophenyl)-piperazine~ m.p, 1~5 6C.
17- ' ! 1 1~87617 1 1 (24) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(3-trifluoromethylphenyl)-piperazine~
¦ m,p. 69-70C.
(25) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(3,4-dichlorophenyl)-piperazine, j m.p. 134-5C.
(26) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(4-methoxyphenyl)-piperazine, m p.
121-2C.
(27) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(3-methoxyphenyl)-piperazine~ m.p.
100C.
~28) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(2,4-dimethoxyphenyl) piperazine~
m.p. 89-91C.
(29) 1-(5-Phenyl-oxaæol-2-ylmethyl)-4-(3,4-dimethoxyphenyl)-piperazine, m.p. 93-5C.
(30) 1-(5-Phenyl-oxazol-2-ylmethyl)-4-(4-ethoxyphenyl)-piperazine, m.p.
1 98C. ~ ;
1l . "~
(31) 1-[5-(4-Fluorophenyl)-oxazol-2-ylmethyl~-4-phenylpiperazine~ m.p.
114-116C.
~' ~32) 1-[5-(4-Fluorophenyl)-oxazol-2-ylmethyl~-4-(4-methoxyphenyl)-piperazine~ ¦
m.p. 112C. ¦
l l (33) 1-[5-(4-~thoxyphenyl)-oxazol-2-ylmethyl~-4-phenylpiperazine, m.p.
112- 15C.
I 1, ~ -18-.
- . .
.. ,. . . , . .. . . .
3761`7 1 (34) 1-[5-(4-Methoxyphenyl)-oxazol-2-ylmethyl]-4-(4-methoxyphenyl)-piperazine ' m.p. 148-50C.
1, l (35) 1-(5-Phenyloxazol-2-ylmethyl)-4-(4-nitrophenyl)-piperazine, m.p.
170-2C.
1-(5-Phenyloxazol-2-ylmethyl)-4-(4-aminophenyl)-piperazine I A solution of 1-(5-phenyloxazol-2-ylmethyl)-4-(4-nitrophenyl)-piperazine L
(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 complet:e. 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. 130C.
, I
i ' I
¦ EXAMPLE 37 ¦ 1-(5-Phenyloxazol-2-ylmethyl)-4-(4-acetamidophenyl)-piperazm e The 4-aminophenyl compound of Example 36 (3.0 g; 0.009 mole) was warmed O
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 recrystallisa-1 tion from methanol the product weighed 2.45 g and melted at 196-7C.
1~
I . . 1 ` ¦ EXAMPLE 38 1-(5-Phenyloxazol-2-ylmethyl)-4-(4-hydroxyphenyl)-piperazine I
Pro~ me-l-thiol (5.02 g; 0.066 mole~ was ~dded slowly to a stirred . .
.
I
! .
~71617 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 3 x 200 ml ethyl acetate. The extracts were shaken several t~es with water, dried and evaporated to a white solid. After recrystallisation from dioxan/60-80C. petroleum ether, the product weighed 5.5 g (74.5%), m.p. 189-190C.
1- L2-(5-Phenyloxazol-2-yl)-ethy~ -4-phenylpiperazine (a) N-Phenacyl-3-bromopropanamide -~
3-Bromopropionyl chloride (25 g; 0.146 mole) was added slowly to a stirred suspension of phenacylamine hydro-chloride (17.15 g; 0.1 mole) in dry dimethylformamide (50 ml) at room temperature. The internal temperature rose to ca.
40C. 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. 114C.
(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 tem-perature was then increased to 80C 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 (3 x 100 ml). The extracts were shaken with 2 x 100 ml .
1~76~7 1 >N ~ICl and the organic layer discarded. The aqueous layer was basified with! ¦
NaOH solution to pH 9 and extracted with 3 x 75 ml CHC13. 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 l at 126C. I lI
l i (c) 1-[2-(5-Phenyloxazol-2-yl)-ethyll-4-phenylpiperazine N-Phenacyl-3-(4-phenylpiperazin-1-yl)-proponamide (4.03 g9 0.011 mole) 1 10 was mixed with polyphosphoric acid (36 g) and stirred and heated at 140C.
for 30 minutes. The mixture was dissolved in water (100 ml), cooled, and extracted (2 x 30 ml chloroform). The extracts were discarded and the aqueous phase basified to pH 9 with 50% aqueous ~aOH solution. The emulsion formed was extracted with 3 x 100 ml chloroform~the extracts dried and evaporated. The crystalline residue was recrystallised from 60-ôOC.
petroleum ether. Yield 2.6 g m.p. 84-5C.
. ' .
1-[5-(3-Trifluoromethylphenyl)-furan-2-ylmethyl~-4-phenylpiperazine , (a) 2-HYdroxyme~Y1-5- ~ henyl)-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 tetra-hydrofuran (100 ml), cooled to -40C. and n-butyl lithium (0.1 mole, solution in hexane) was added dropwise. After stirring for 1 hour at -40C, para-~ formaldehyde (3.3 g; 0.11 mole) was added gradually. The mixture was ¦ stirred at -40 C. for 30 minutes, then the temperature was allowed to rise.
¦ At 10C. an exothermic reaction set in and the temperature gradually rose r~
! to 40C. (over 10 minutes)~ then gradually fell back to 20C. After stirring for further 1 hour the clear brown solution was poured onto ice/water, .
~ -21-1~761 ~ ¦
1 adjusted to pll ca 4 with dilute hydrochloric acid and extracted via ethyl acetate. The dried acetate extract (MgS04) was evaporated to give a brownish yellow viscous oil which was distilled in vacuo to give 2-hydroxymethyl-5-l (3-trifluoromethylphenyl)-furan as a colourless liquid b.p. 125 C./0.5 mm., (16.2 g), which on standing gave crystals, m.p. 45C.
(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 0-5 C. 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 NaCl (saturated solution) dried over molecular sieve 3A and evaporated to give a light brown oil which slowly crystallised (4.6 g).
tc) 1-[5-(3-Trifluoromethylphenyl)-furan-2-ylmethyll-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 chioroform extract was washed with water, then with saturated salt solution and finally evaporated to give an bil 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 saturat 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 60/80C. to give the title compound 1-[5-(3-trifluoromethyl- _ 1 phenyl iuran-2-ylmethyl~-4-phenylpiper~zine~ 1.2 g, m,p. 94C.
1~
1!
76~7 1 In a similar manner were prepared the following except that the intermediate hydroxymethyl compounds were converted to the chloromethyl Il compounds via thionyl chloride.
EXAMPLE 41 ~
1-[5-(4-Chlorophenyl?-furan-2-ylmethyll-4-phenylpiperazine `¦
m.p. 140 C.
10 . ~
1' ~
l-r5-(4-Chlorophenyl)-furan-2-ylmethyll-4-(3-trifluoromethylphenyl)-piperazine monohydrochloride The free base was obtained as an intractable viscous oil and was converted to the monohydrochloride, m.p. 220 C.
; , 1-[5-(4-Chlorophenyl-furan-2-ylmethyll-4-(3-chlorophenyl)-piperazine monohydrochloride m.p. 215C.
1-[5-(4-Chlorophenyl)-furan-2-ylmethyll-4-(3-bromophenyl)-piperazine monohydrochloride l 5-(4-Chlorophenyl)-2-furoic acid (Australian Journal of Chemistry, 26, r_ 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 1~
~ ~ -23-il, !l 1~37617 1 l 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 P~
crystallised. The product was recrystallised from ethyl acetate / 60 - 80C.
petroleum ether (1/3 /v) to yield 1-[5-(4-chlorophenyl)-2-furoyl]-4-(3-bromophenyl)-piperazine (12.3 g) m.p. 130C.
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 0C.
to a solution of diborane in tetrahydrofuran (20 ml, lM solution) (N.B. the reaction was carried out under nitrogen). The temperature rose to ca. 8C.
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 5N HCl (20 ml). After again cooling the solution was made al~aline (4N NaOH) and extracted via diethyl ether. The ether extract a ter drying over MgS04 was evaporated to give an oil which was converted to its monohydro-chloride to give the title compound. (2.8 g) m.p. 217C.
' In a similar manner were prepared the following : ¦
EXAMPLE 45 ¦
1-[5-(4-Chlorophenyl)-furan-2-ylmethyll-4-(3-trifluoromethyl-4-chlorophenyl)- 31 ~iperazine. _ m.p. 104C.
. . : : . . .: . : - . . . .
.
761.7 ¦l 1~[5-(4-Met_ylphenyl)-furan-2-ylmethyll-4-phenylpiperazine l;
m.p. 87C.
-C5-(2-Methylphenyl)-furan-2-ylmethyll-4-phenylpiperazine o ~1 m.p. 67 C. l 1-C5-(3,4-Dichlorophenyl)-furan-2-ylmethyll-4-phenylpiperazine m.p. 92C.
EXA~IPLE 49 1-[5-53-Trifluoromethyl-4-chlorophenyl)-furan-2 ylmethy;~-4-phenylpiperazine m.p. 102C.
. .
' 1-[5-(3-Trifluoromethyl-4-chlorophenyl)-furan-2-ylmethyll-4-(3-chlorophenyl)-piper-zine monohydrochloride m.p. 216C.
. 11 EXAMPLE 51 ¦¦
1-[5-(3-Trifluoromethvl-4-chlorophenyl)-furan-2-ylmethyll-4-(4-methylPhenyl)- ' ,_, piperazine m.p. 126C.
ll 1,, . ' .1. 1 -.... .. . . . .
.: ' - - :.. :
~9B7617 ,, ~
1-(5-Phenylfuran-2-ylmethyl)-4-(3-chlorop~nyl)-piperazine monohydrochloride m.p. 208C.
In the following Examples 53 to 58 the final reduc-~on step was carried out using the internal reduction method - of K.M. Biswas and A.H. Jackson, Tetrahedron 24, 1145 (1967).
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 nitro- - --gen, and redistilled boron trifluoride etherate (6 ml, 0.045 mole) in diglyme (20 ml) added dropwise with continuous stirr-ing. The resultant clear solution was stirred at room temper-ature for 3 hours and then evaporated to remove diglyme. The residue was carefully diluted with water (100 ml), followed by 5NHC1 (20 ml) and the mixture heated on a steam bath for 15 minutes. The mixture was cooled and made alkaline (4N 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. 56C. -Similarly prepared were the following:
"
.
: .
~87617 1-~5-Phenylfuran-2-ylmethyl)-4-(3~4-dichlorophenyl)-piperazine m.p. 150C.
EXAMPLE 55 .
1-(5-Phenylfuran-2-ylmethyl)-4-phenylpiperazine m.p. 106C.
, '''10 . ~
1-(5-Phenylfuran-2-ylmethyl)-4-(4-methylphenyl~-piperazine m.p. 114C.
~15 l-r5-(3.4-Dimethylphenyl)-furan-2-ylmethyll-4-(3-trifluoromethyl-4-chloro-phenyl)-piperazine m.p. 80Co , l-r5-(3.4-Dimethylphenyl)-furan-2-ylmethyll-4-(3-methoxyphenyl)-piperazine monohydrochloride m.p. 200C.
I -27- ' . 11 ., ' .
1~t37617 1-~5-(4-methoxyphenyl)-fura:n-2-y]methyl]-4-(3-trifluoromethyl-
4-chlorophenyl)piperazine m.p. 100C
1-c5-(4-methoxyphenyl)furan-2-ylmethyl]-4-phenylplperazine m.p. 96C
1-[5-(4-methoxyphenyl)furan-2-ylmethy~ -4-(3-trifluoromethyl-phenyl)piperazine m.p. 74C
1-(5-Phenylthiophen-2-ylmethyl)-4-phenylpiperazine
1-c5-(4-methoxyphenyl)furan-2-ylmethyl]-4-phenylplperazine m.p. 96C
1-[5-(4-methoxyphenyl)furan-2-ylmethy~ -4-(3-trifluoromethyl-phenyl)piperazine m.p. 74C
1-(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 60/80C petroleum ether containing a few drops of ethyl acetate).
m.p. 88C
1-(5-Phenylthiophen-2-ylmethyl)-4-(3-chlorophenyl)piperazine 5-Phenyl-2-thiophenecarboxylic acid was reacted as i in Example 44 to the amide which was then reduced to the title compound as in Example 53.
m.p. 115C
Similarly prepared were the following: ~
.
1-(5-Phenylthiophen-2-ylmethyl)-4-(4-methoxyphenyl)piperazine m.p. 136C
1-(5-Phenyl-thiophen-2-ylmethyl)-4-(3-trifluoromethyl-4-chloro- ~5 phenyl) piperazine m.p. 114C
. ~ . .
1C)~761~
EX~MPLE 66 (5-Phenylthiophen-2-ylmethyl)-4-(4-methylphenyl~PiPeraZine m.p. 135C
1-(5-Phenylthiophen-2-ylmethyl)-4-(3-trifluoromethylphenyl)piperazine m.p. 94C
1-(5-l'henylthiophen-2-ylmethyl)-4-(4-fluorophenyl)piperazine m.p. 128C
1-(5-Phenylthiophen-2-ylmethyl)-4-(3,4-dimethylphenyl) piperazine m.p. 130C
1-[5-(3~4-Dimethylphenyl~-furan-2-ylmethyl)-4-phenylpiperazine 5-(3,4-Dimethylphenyl)-furan-2-carboxaldehyde (4.0g;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 (3.2g;
0.02 moie) in methanol (30ml) adjusted to pH 7 (using Meo~l/HCl). After 30 minutes a solution of sodium cyanoborohydride (0.48g; 0.0075 mole) in methanol (lOml) 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 60/805: petroleum ether to give the - title compound, m.p. 110C.
l Similarly prepared were the following:-1-[5-(3-trifluoromethyl-4-chlorophenyl)-furan-2-YlmethYll-4-(4-fluorophenyl) piperazine m.p. 94C
,~
' ' ~ -2~-lOB7617 EXAMPLE_72 1-[5-(4-Chlorophenyl)-furan-2-ylmethyll-4-(4-nitrophenyl)piperazine m.p. 149C
1-[5-(4-Methoxyphenyl)furan-2-ylmethyll-4-(4-methylphenyl)piperazine m.p. 138C
1-[5-(3.4 Dichlorophenyl)furan 2-ylmethyl~-4-(3-trifluoromethylphenyl) piperazine monohydrochloride m.p. 210C
1-(5-Phenylthiophen-2-ylmethyl)-4-(3,4-dichlorophenyl)piperazine m.p. 140C
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 I, 1766 (1973) was reacted as in Example 44 to gi~e the title compound.
; b.p. 145C/O.Ol mm (Kugelrohr) 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. 115C/O.Olmm (Kugelrohr) Similarly prepared were the followi~
1-(5-Methylfuran-2-ylmethyl)-4-(4-methylphenyl)piperazine m.p. 52 C
i 1-(5-Methylfuran-2-ylmethyl)-4-(4-methoxyphenyl) piperazine m.p. 86C .
1, Il -30-,, . ~
t ~7617 l-(5-Methylfuran-2-ylmethyl)-4-(4-chlorophenyl)piperaæine ¦ m.p. 78C
j EXAMPLE 81 1-(5-Methylfuran-2-ylmethyl)-4-(3-trifluoromethyl-4-chlorophenyl)pipera-zine Pale yellow oil, which partially decomposed on distillation~
1-(5-Methylfuran-2-ylmethyl)-4-(3-trifluoromethylphenyl)piperazine b.p. 105C/0.02mm(Kugelrohr) EXAMPLE 83(a) 1-(5-Methylfuran-2-yl-methyl)-4-(4-fluorophenyl)piperazine m.p. 50C
EXAMPLE 83(b) 1-(5-Methy_f ran-2-ylmethyl)-4-(3~4-dimethylphenyl) piperazine m.p. 47C
I 1-(5-tert.Butylfuran-2ylmethyl)-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. 48C
Similarly prepared were the following:
j 1-(5-tert-Butylfuran-2-yl-methyl)-4-(4-methylphenyl)piperazine m.p. 62C
¦ EXAMPLE 86 1 1-(5-tert.Butylfuran-2-ylmethyl)-4-(3-chlorophenyl)piPerazine b.p. 140C/O.Olmm (Kugelrohr) 1-(5-tert.Butylfuran-2-ylmethyl)-4-(4-methoxyphenyl)piperazine m.p. 70C
.' .
., .: ~ , ,: - - - ' - .
10~7617 1-(5-tert.Butylfuran-2-ylmethyl)-4-(3-trifluoromethyl-4-chlorophenyl) ¦ piperazine b.p. 130 C/O.Olmm (Kugelrohr) 1-(5-tert.Butylfuran-2-ylmethyl)-4-(3-trifluoromethvlphenyl) piperazine Pale yellow oil.
1-(5-tert-Butylfuran-2-ylmethyl)- 4-(4-fluorophenyl)piperazine Pale yellow oil. -1-(5-tert.Butylfuran-2-ylmethyl)-4-(3~4-dimethylphenyl) piperazine m.p. 70C
1-[3-(5-Phenylfuran-2-yl)prop-1-yll-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. 95C.
Similarly prepared were the following:-l-C3-(5-Phenylfuran-2-yl)prop-l-yll-4-(4-methylphenyl)piperazine m.p. 92C
1-[3-(5 Phenylfuran-2-yl)prop-l-yll-4-(3-trifluoromethylphenyl) piperazine m.p. 56C.
1-[3~ 5-(4-Chlorophenyl)furan-2-y~ prop-1-yl~-4-(4-methylphenyl) piperazine m.p. 130C
¦l l-C3-~5-(3~4-Dichlorophenyl)furan-2-yl~prop-l-yll-4-(4-methylphenyl) piperazine m.p. 100C
i ' .
i 1-[3-(5-Phenylthiophen-2-yl)prop-l-yll-4-(4-methYlP-henyl) piperazine , m.p. 92C .
7~i~7 (a) 5-Phenyl-2-(2-hydroxyethyl)thiophene I
2-Phenylthiophene(16.0g;0.1 mole) was reacted in a similar manner to Example 40 but using ethylene oxide (lOml; 0.2 mole) instead of para-formaldehyde. The title compound was obtained as a pale yellow crystalline solid, m.p. 74C.
(b) 1-[2-(5-Phenylthiophen-2-yl)ethyll-4-phenylPiperazine The hydroxyethyl compound (6.13g; 0.03 mole) from (a) a~ove 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 (6.2g) which crystallised on standing~ m.p. 40C. This product was stirred in dioxane (50ml) with N-phenylpiperazine (4.8g;0.03 mole) in the presence of anhydrous sodi~m carbonate (3.0g) and the mixture heated under reflux 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 40/60C
petroleum ether and percolated through a column of silica gel using benzeneJ
ethyl acetate 4:1 /v as developing solvent. The initial fast moving band contained unreacted chloroethyl compound (3.5g). The slower moving band contained the title compound which after recrystallisation from ethyl acetate had m.p. 124C.
Similarly prepared was:-1-[2-(5~Phenylthiophen-2-yl)ethyll-4-(4-methylphenyl) piperazine m.p. 158C.
(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. 170C
(b) 1_(5_Phenylfuran-2ylmethyl)-4-(4-aminophenyl) piperazine ¦, The product from (a) was hydrogenated and worked up as in Example 36.
¦I m.p. 102C. .
I
: ,, ~ l -33-: . . , -. ~ - .
~187617 (c) 1-(5-Phenylfuran-2-ylmethyl~-4-(4-methanesulphonamido-phenyl) piperazine The product from (b) (2.9g; 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 tri-ethylamine (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. 178C.
Similarly prepared was:-l-t5-Phenylthiophen-2-ylmethyl)-4-(4-methanesulphonamidophenyl) ;
piperazine m.p. 188C.
(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 col-oured oil (16.0g) b.p. 145C/0.05 mm with decomposition.
(b) 1-[2-(5-Phenylfuran-2-yl)prop-1-yJ -4-phenylpiperazine monohydrochloride The hydroxypropyl compound (8.0g; 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 (4.0g) which was reacted with N-phenylpiperazine ~
and sodium cycnoborohydride 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 crystal-lise and was converted to its monohydrochloride (ethyl acetate-hydrogen chloride) (1.3g) m.p. 206C.
Similarly prepared were the following:
1-~2-(5-Phenylthiophcn-2-yl)prop-1-yl~-4-phenylpiperazine m.p. 98C.
EX~MPLE 104 1-[2-(5-Phenylthiophen-2-yl)but-1-yll-4-phenylpiperazine monohydrochloride m.p. 200C.
1-(2-Methylthiazol-4-ylmethyl)-4-(3-bromophenyl)piperazine A mixture of 4-chloromethyl-2-methylthiazole (7.4g; 0.05 mole)~ 1-(3-bromophenyl)piperazine (12.05g; 0.05 mole) and anhydrous sodium carbonate (lOg) 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. 82 C
(ether).
Similarly prepared were the following:-EX~MPLE 106 1-(2-Methylthiazol-4-ylmethyl)-4-(3-trifluoromethylPhenyl)piperazine~
dihydrochloride m.p. 176-8C.
¦ 1-(2-Methylthiazol-4-ylmethyl)-4-(3-chlorophenyl)piperazine ¦ m.p. 71-2C.
1-(2-Methylthiazol-4-ylmethyl)-4-(3-methoxyphenvl)piperazine m.p. 71.5-72.5C.
30 l, EXAMPLE 109 1 1-(2-Methylthiazol-4-ylmethyl)-4-(4-bromophenyl)piperazine m.p. 114-115C.
,. 1, 1 .
- . . .
.
.: ' . , :.
- . . . . .
l()B7617 ¦ EXA~IPLE llO
1-(2-Methylthiazol-4-ylmethyl)=4-(2-bromophenyl)piperazine m.p. 85-86.5C.
1-(2-Methylthiazol-4-ylmethyl)-_-_ ,4-dichlorophenyl?p;perazine dihydrochloride m.p. 175-176C.
1-(2-Meth~ylthiazol-4-ylmethxl-)-4-(3-nitrophenyl)piperazine hydrochloride m.p~ 218-222C.
1-(2-Meth~ylthiazol-4-ylmethyl)-4-(4-methylphenyl)piperazine hydrochloride I m.p. 190-2C.
1-~2-Meth~lthiazol-4-ylmethyl~-4---(3-methylphenyl)piperazine hvdrochloride_ m.p. 158-160C.
1-(2-Methylthiazol-4-ylmethyl)-4-(4-chlorophenyl~piperazine m.p. 98C. ~
1-(2-Methylthiazol-4-ylmethyl)-4-(4-chloro-3-trifluoromethylPhenyl) E~E~ drochloride m.p. 185-7C.
EXhMPLE 117 1-(2-Methylthiazol-4-ylmethyl)-4-(4-methoxyphenyl)piperazine hydrochloride m.p. 134-5C.
l~B7617 (a) 2-n-~ropyl-4-chloromethylthiazole To a solution oE thiabutanamide (30.96g, 0.3 mole) in absolute ethanol (200m1) was slowly added a solution of 1,3-dichloroacetone (38.1g;
0.3 mole) in ethanol (lOOml). The mixture was boiled under reflux for 1 hour and the solvent evaporated. The residue was treated with excess saturated sodium bicarbonate solution and extracted with ether. The extrac~
were dried and evaporated to a brown oil which was distilled in vacuo to give a pale yellow oil, b.p. 50C/0.06mm Hg. This was converted to the title compound (hydrochloride salt) using ethereal hydrogen chloride m.p. 60C dec.
Similarly prepared were:-(b) 2-Benzyl-4-chloromethylthiazole b.p. 116-118C/0.09mm Hg.
(c) 2- _ Propyl-4-chloromethylthiazole hydrochloride m.p. 58C (dec.) ¦ 1-(2-n-Propylthiazol-4-ylmethyl)-4-ph_nylpiperazine A mixture of 2-n-propyl-4-chloromethylthiazole hydrochloride (3.18g;
0.015 mole)~ l-phenylpiperazine (2.43g; 0.015 mole) and sodium carbonate (anhydrous,lOg) in absolute ethanol (60ml) 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 I yellow oil which crystallised 4.27g. This solid was recrystallised from petroleum ether (b.p. 60-80C) at 0C to give a white crystalline solid (m.p. 38-39C) Similarly prepared were:-.-.
.
lOE~7617 EX~MPLE 120 (2-n.-propylthi~azo~L-4-ylmethyl)-4-t4-chlorophenyl)piperazine m,p. 51-54C.
1-(2-n-Propylthiaæol-4-ylmethyl)-4-(4-methylphenyl) piperazine m.p. 41-44C, 1-(2-n-Propylthiazol-4-ylmethyi)-4-(4-methoxyphenyl)piperazine m.p. 46-47C.
1-(2-n-Propylthiazol-4-ylmethyl)-4-~3-trifluoromethylphenyl)piperazine hydrochloride m.p. 162-6C.
1-(2-n-Propylthiazol-4-ylmethyl)-4-(3,4-dichlorophenyl) piperazine dihydrochloride m.p. 158-160C
1-(2-n-Propylthiazol-4-ylmethyl)-4-(4-chloro-3-trifluoromethylphenyl) piperazine dihydrochloride m.p. 174-8C.
1-(2-Benzylthiazol-4-ylmethyl)-4-phenylpiperazine m.p. 60-62C.
1-(2-Benzylthiazol-4-ylmethyl~-4-(4-chlorophenyl~piperazine m.p. 74C.
1-(2-Benzylthiazol-4-ylmethyl~-4-(4-methoxyphenyl~piperazine m.p. 65C.
i 1-(2-Benzylthiazol-4-ylmethyl)-4-(3-bromoPhenyl)piperazine m.p. 69C.
~, .
1~il76~7 1-(2-Benzylthiazol-4-ylmethyl)-4-(4-chloro-3-trifluoromethyl-_enyl piperazine colourless oil.
1- ~-(4-chlorobenzyl)-thiazol-4-ylmethy~ -4-phenyl piperazine dihydrochloride m.p. 150C (Dec.) 1-(2-1 Propylthiazol-4-ylmethyl)-4-(4-chlorophenyl)piperazine ~ .
m.p. 54C.
1-(2-isoPropylthiazol-4-ylmethyl)-4-phenylpiperazine -m.p. 42C.
1-(2-i Propylthiazol-4-ylmethyl)-4-(3-methoxyphenyl)piperazine m.p. 65C.
.' EXAMPLE_135 1-(2-1 Propylthiazol-4-ylmethyl)-4-(3-bromophenyl)piperazine ::
colourless oil.
1-(2-1 Propylthiazol-4-ylmethyl)-4-(4-chloro-3-trifluoro- --methylphenyl piperazine colourless oil.
The following further Examples illustrate the pre-paration of pharmaceutical formulations containing compounds of the invention. The active compound utilised was 1-(2-benzylthiazol-4-ylmethyl)-4-phenylpiperazine, although it w~ll be appreciated by those skilled in the art that other active solid compounds of the invention could equally well be used.
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Hard gelatin capsules were prepared using the following ingred-ients:
Quantity (mg/capsule) Active compound 250 Starch dried 200 - Magnesium stearate 10 The above ingredients were mixed and filled into hard gelatin capsules.
The above procedure was repeated except that microcrystalline cellulose was used in place of starch.
Tablets were prepared using the following components:
~uantity (mg/tablet) Active compound 500 Starch 100 Magnesium stearate 7 "Amberlite XE88"* 5 The starch and active compound were mixed together and suffi-cient water added for a uniform dispersion to be attained. The mixture was then wet screened and dried. After drying the ma-terial was screened again, and the magnesium stearate and "Amberlite"* resin then added. Finally the mixture was com-pressed into tablets.
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 * Trademark for an ion exchange resin.
- .. . .. ' ~ ;', . , . ~. :
The components were blended and compressed to form tablets.
An aerosol solution was prepared containing the following com-ponents:
Weight Active ingredient 0.25 Ethanol 29.75 "Propellant 22" (trademark) 70 (Chlorodifluoromethane) The active compound was mixed with ethanol and the mixture added to the "Propellane 22", cooled to -30C and transferred 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.
A suppository formula was prepared containing 200 mg of the ~ompound 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 ulds, to give the active fill weight.
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.
A topical cream was prepared having the following ingredients:
. . ' .
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. .
.. . . . . . . .
~37617 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 70C
with stirring. The "Cetomacrogol lOOO"**was dissolved in 60g.
of water and heated to 70C. The two solutions were then mixed with stirring, and stirring continued until the tempera-ture fell to ambient. The cream was then made up to weight with water a~d passed through a stainless steel colloid mill se' at a gap of 15/1000 inch.
*Trademark. "Cetomacrogol 1000" is polyethylene glycol mono-cetyl ether having 20-24 oxyethylene groups in the polyoxy-ethylene chain.
** Trademark ' ~
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:
m.p. 88C
1-(5-Phenylthiophen-2-ylmethyl)-4-(3-chlorophenyl)piperazine 5-Phenyl-2-thiophenecarboxylic acid was reacted as i in Example 44 to the amide which was then reduced to the title compound as in Example 53.
m.p. 115C
Similarly prepared were the following: ~
.
1-(5-Phenylthiophen-2-ylmethyl)-4-(4-methoxyphenyl)piperazine m.p. 136C
1-(5-Phenyl-thiophen-2-ylmethyl)-4-(3-trifluoromethyl-4-chloro- ~5 phenyl) piperazine m.p. 114C
. ~ . .
1C)~761~
EX~MPLE 66 (5-Phenylthiophen-2-ylmethyl)-4-(4-methylphenyl~PiPeraZine m.p. 135C
1-(5-Phenylthiophen-2-ylmethyl)-4-(3-trifluoromethylphenyl)piperazine m.p. 94C
1-(5-l'henylthiophen-2-ylmethyl)-4-(4-fluorophenyl)piperazine m.p. 128C
1-(5-Phenylthiophen-2-ylmethyl)-4-(3,4-dimethylphenyl) piperazine m.p. 130C
1-[5-(3~4-Dimethylphenyl~-furan-2-ylmethyl)-4-phenylpiperazine 5-(3,4-Dimethylphenyl)-furan-2-carboxaldehyde (4.0g;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 (3.2g;
0.02 moie) in methanol (30ml) adjusted to pH 7 (using Meo~l/HCl). After 30 minutes a solution of sodium cyanoborohydride (0.48g; 0.0075 mole) in methanol (lOml) 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 60/805: petroleum ether to give the - title compound, m.p. 110C.
l Similarly prepared were the following:-1-[5-(3-trifluoromethyl-4-chlorophenyl)-furan-2-YlmethYll-4-(4-fluorophenyl) piperazine m.p. 94C
,~
' ' ~ -2~-lOB7617 EXAMPLE_72 1-[5-(4-Chlorophenyl)-furan-2-ylmethyll-4-(4-nitrophenyl)piperazine m.p. 149C
1-[5-(4-Methoxyphenyl)furan-2-ylmethyll-4-(4-methylphenyl)piperazine m.p. 138C
1-[5-(3.4 Dichlorophenyl)furan 2-ylmethyl~-4-(3-trifluoromethylphenyl) piperazine monohydrochloride m.p. 210C
1-(5-Phenylthiophen-2-ylmethyl)-4-(3,4-dichlorophenyl)piperazine m.p. 140C
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 I, 1766 (1973) was reacted as in Example 44 to gi~e the title compound.
; b.p. 145C/O.Ol mm (Kugelrohr) 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. 115C/O.Olmm (Kugelrohr) Similarly prepared were the followi~
1-(5-Methylfuran-2-ylmethyl)-4-(4-methylphenyl)piperazine m.p. 52 C
i 1-(5-Methylfuran-2-ylmethyl)-4-(4-methoxyphenyl) piperazine m.p. 86C .
1, Il -30-,, . ~
t ~7617 l-(5-Methylfuran-2-ylmethyl)-4-(4-chlorophenyl)piperaæine ¦ m.p. 78C
j EXAMPLE 81 1-(5-Methylfuran-2-ylmethyl)-4-(3-trifluoromethyl-4-chlorophenyl)pipera-zine Pale yellow oil, which partially decomposed on distillation~
1-(5-Methylfuran-2-ylmethyl)-4-(3-trifluoromethylphenyl)piperazine b.p. 105C/0.02mm(Kugelrohr) EXAMPLE 83(a) 1-(5-Methylfuran-2-yl-methyl)-4-(4-fluorophenyl)piperazine m.p. 50C
EXAMPLE 83(b) 1-(5-Methy_f ran-2-ylmethyl)-4-(3~4-dimethylphenyl) piperazine m.p. 47C
I 1-(5-tert.Butylfuran-2ylmethyl)-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. 48C
Similarly prepared were the following:
j 1-(5-tert-Butylfuran-2-yl-methyl)-4-(4-methylphenyl)piperazine m.p. 62C
¦ EXAMPLE 86 1 1-(5-tert.Butylfuran-2-ylmethyl)-4-(3-chlorophenyl)piPerazine b.p. 140C/O.Olmm (Kugelrohr) 1-(5-tert.Butylfuran-2-ylmethyl)-4-(4-methoxyphenyl)piperazine m.p. 70C
.' .
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10~7617 1-(5-tert.Butylfuran-2-ylmethyl)-4-(3-trifluoromethyl-4-chlorophenyl) ¦ piperazine b.p. 130 C/O.Olmm (Kugelrohr) 1-(5-tert.Butylfuran-2-ylmethyl)-4-(3-trifluoromethvlphenyl) piperazine Pale yellow oil.
1-(5-tert-Butylfuran-2-ylmethyl)- 4-(4-fluorophenyl)piperazine Pale yellow oil. -1-(5-tert.Butylfuran-2-ylmethyl)-4-(3~4-dimethylphenyl) piperazine m.p. 70C
1-[3-(5-Phenylfuran-2-yl)prop-1-yll-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. 95C.
Similarly prepared were the following:-l-C3-(5-Phenylfuran-2-yl)prop-l-yll-4-(4-methylphenyl)piperazine m.p. 92C
1-[3-(5 Phenylfuran-2-yl)prop-l-yll-4-(3-trifluoromethylphenyl) piperazine m.p. 56C.
1-[3~ 5-(4-Chlorophenyl)furan-2-y~ prop-1-yl~-4-(4-methylphenyl) piperazine m.p. 130C
¦l l-C3-~5-(3~4-Dichlorophenyl)furan-2-yl~prop-l-yll-4-(4-methylphenyl) piperazine m.p. 100C
i ' .
i 1-[3-(5-Phenylthiophen-2-yl)prop-l-yll-4-(4-methYlP-henyl) piperazine , m.p. 92C .
7~i~7 (a) 5-Phenyl-2-(2-hydroxyethyl)thiophene I
2-Phenylthiophene(16.0g;0.1 mole) was reacted in a similar manner to Example 40 but using ethylene oxide (lOml; 0.2 mole) instead of para-formaldehyde. The title compound was obtained as a pale yellow crystalline solid, m.p. 74C.
(b) 1-[2-(5-Phenylthiophen-2-yl)ethyll-4-phenylPiperazine The hydroxyethyl compound (6.13g; 0.03 mole) from (a) a~ove 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 (6.2g) which crystallised on standing~ m.p. 40C. This product was stirred in dioxane (50ml) with N-phenylpiperazine (4.8g;0.03 mole) in the presence of anhydrous sodi~m carbonate (3.0g) and the mixture heated under reflux 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 40/60C
petroleum ether and percolated through a column of silica gel using benzeneJ
ethyl acetate 4:1 /v as developing solvent. The initial fast moving band contained unreacted chloroethyl compound (3.5g). The slower moving band contained the title compound which after recrystallisation from ethyl acetate had m.p. 124C.
Similarly prepared was:-1-[2-(5~Phenylthiophen-2-yl)ethyll-4-(4-methylphenyl) piperazine m.p. 158C.
(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. 170C
(b) 1_(5_Phenylfuran-2ylmethyl)-4-(4-aminophenyl) piperazine ¦, The product from (a) was hydrogenated and worked up as in Example 36.
¦I m.p. 102C. .
I
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~187617 (c) 1-(5-Phenylfuran-2-ylmethyl~-4-(4-methanesulphonamido-phenyl) piperazine The product from (b) (2.9g; 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 tri-ethylamine (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. 178C.
Similarly prepared was:-l-t5-Phenylthiophen-2-ylmethyl)-4-(4-methanesulphonamidophenyl) ;
piperazine m.p. 188C.
(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 col-oured oil (16.0g) b.p. 145C/0.05 mm with decomposition.
(b) 1-[2-(5-Phenylfuran-2-yl)prop-1-yJ -4-phenylpiperazine monohydrochloride The hydroxypropyl compound (8.0g; 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 (4.0g) which was reacted with N-phenylpiperazine ~
and sodium cycnoborohydride 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 crystal-lise and was converted to its monohydrochloride (ethyl acetate-hydrogen chloride) (1.3g) m.p. 206C.
Similarly prepared were the following:
1-~2-(5-Phenylthiophcn-2-yl)prop-1-yl~-4-phenylpiperazine m.p. 98C.
EX~MPLE 104 1-[2-(5-Phenylthiophen-2-yl)but-1-yll-4-phenylpiperazine monohydrochloride m.p. 200C.
1-(2-Methylthiazol-4-ylmethyl)-4-(3-bromophenyl)piperazine A mixture of 4-chloromethyl-2-methylthiazole (7.4g; 0.05 mole)~ 1-(3-bromophenyl)piperazine (12.05g; 0.05 mole) and anhydrous sodium carbonate (lOg) 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. 82 C
(ether).
Similarly prepared were the following:-EX~MPLE 106 1-(2-Methylthiazol-4-ylmethyl)-4-(3-trifluoromethylPhenyl)piperazine~
dihydrochloride m.p. 176-8C.
¦ 1-(2-Methylthiazol-4-ylmethyl)-4-(3-chlorophenyl)piperazine ¦ m.p. 71-2C.
1-(2-Methylthiazol-4-ylmethyl)-4-(3-methoxyphenvl)piperazine m.p. 71.5-72.5C.
30 l, EXAMPLE 109 1 1-(2-Methylthiazol-4-ylmethyl)-4-(4-bromophenyl)piperazine m.p. 114-115C.
,. 1, 1 .
- . . .
.
.: ' . , :.
- . . . . .
l()B7617 ¦ EXA~IPLE llO
1-(2-Methylthiazol-4-ylmethyl)=4-(2-bromophenyl)piperazine m.p. 85-86.5C.
1-(2-Methylthiazol-4-ylmethyl)-_-_ ,4-dichlorophenyl?p;perazine dihydrochloride m.p. 175-176C.
1-(2-Meth~ylthiazol-4-ylmethxl-)-4-(3-nitrophenyl)piperazine hydrochloride m.p~ 218-222C.
1-(2-Meth~ylthiazol-4-ylmethyl)-4-(4-methylphenyl)piperazine hydrochloride I m.p. 190-2C.
1-~2-Meth~lthiazol-4-ylmethyl~-4---(3-methylphenyl)piperazine hvdrochloride_ m.p. 158-160C.
1-(2-Methylthiazol-4-ylmethyl)-4-(4-chlorophenyl~piperazine m.p. 98C. ~
1-(2-Methylthiazol-4-ylmethyl)-4-(4-chloro-3-trifluoromethylPhenyl) E~E~ drochloride m.p. 185-7C.
EXhMPLE 117 1-(2-Methylthiazol-4-ylmethyl)-4-(4-methoxyphenyl)piperazine hydrochloride m.p. 134-5C.
l~B7617 (a) 2-n-~ropyl-4-chloromethylthiazole To a solution oE thiabutanamide (30.96g, 0.3 mole) in absolute ethanol (200m1) was slowly added a solution of 1,3-dichloroacetone (38.1g;
0.3 mole) in ethanol (lOOml). The mixture was boiled under reflux for 1 hour and the solvent evaporated. The residue was treated with excess saturated sodium bicarbonate solution and extracted with ether. The extrac~
were dried and evaporated to a brown oil which was distilled in vacuo to give a pale yellow oil, b.p. 50C/0.06mm Hg. This was converted to the title compound (hydrochloride salt) using ethereal hydrogen chloride m.p. 60C dec.
Similarly prepared were:-(b) 2-Benzyl-4-chloromethylthiazole b.p. 116-118C/0.09mm Hg.
(c) 2- _ Propyl-4-chloromethylthiazole hydrochloride m.p. 58C (dec.) ¦ 1-(2-n-Propylthiazol-4-ylmethyl)-4-ph_nylpiperazine A mixture of 2-n-propyl-4-chloromethylthiazole hydrochloride (3.18g;
0.015 mole)~ l-phenylpiperazine (2.43g; 0.015 mole) and sodium carbonate (anhydrous,lOg) in absolute ethanol (60ml) 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 I yellow oil which crystallised 4.27g. This solid was recrystallised from petroleum ether (b.p. 60-80C) at 0C to give a white crystalline solid (m.p. 38-39C) Similarly prepared were:-.-.
.
lOE~7617 EX~MPLE 120 (2-n.-propylthi~azo~L-4-ylmethyl)-4-t4-chlorophenyl)piperazine m,p. 51-54C.
1-(2-n-Propylthiaæol-4-ylmethyl)-4-(4-methylphenyl) piperazine m.p. 41-44C, 1-(2-n-Propylthiazol-4-ylmethyi)-4-(4-methoxyphenyl)piperazine m.p. 46-47C.
1-(2-n-Propylthiazol-4-ylmethyl)-4-~3-trifluoromethylphenyl)piperazine hydrochloride m.p. 162-6C.
1-(2-n-Propylthiazol-4-ylmethyl)-4-(3,4-dichlorophenyl) piperazine dihydrochloride m.p. 158-160C
1-(2-n-Propylthiazol-4-ylmethyl)-4-(4-chloro-3-trifluoromethylphenyl) piperazine dihydrochloride m.p. 174-8C.
1-(2-Benzylthiazol-4-ylmethyl)-4-phenylpiperazine m.p. 60-62C.
1-(2-Benzylthiazol-4-ylmethyl~-4-(4-chlorophenyl~piperazine m.p. 74C.
1-(2-Benzylthiazol-4-ylmethyl~-4-(4-methoxyphenyl~piperazine m.p. 65C.
i 1-(2-Benzylthiazol-4-ylmethyl)-4-(3-bromoPhenyl)piperazine m.p. 69C.
~, .
1~il76~7 1-(2-Benzylthiazol-4-ylmethyl)-4-(4-chloro-3-trifluoromethyl-_enyl piperazine colourless oil.
1- ~-(4-chlorobenzyl)-thiazol-4-ylmethy~ -4-phenyl piperazine dihydrochloride m.p. 150C (Dec.) 1-(2-1 Propylthiazol-4-ylmethyl)-4-(4-chlorophenyl)piperazine ~ .
m.p. 54C.
1-(2-isoPropylthiazol-4-ylmethyl)-4-phenylpiperazine -m.p. 42C.
1-(2-i Propylthiazol-4-ylmethyl)-4-(3-methoxyphenyl)piperazine m.p. 65C.
.' EXAMPLE_135 1-(2-1 Propylthiazol-4-ylmethyl)-4-(3-bromophenyl)piperazine ::
colourless oil.
1-(2-1 Propylthiazol-4-ylmethyl)-4-(4-chloro-3-trifluoro- --methylphenyl piperazine colourless oil.
The following further Examples illustrate the pre-paration of pharmaceutical formulations containing compounds of the invention. The active compound utilised was 1-(2-benzylthiazol-4-ylmethyl)-4-phenylpiperazine, although it w~ll be appreciated by those skilled in the art that other active solid compounds of the invention could equally well be used.
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Hard gelatin capsules were prepared using the following ingred-ients:
Quantity (mg/capsule) Active compound 250 Starch dried 200 - Magnesium stearate 10 The above ingredients were mixed and filled into hard gelatin capsules.
The above procedure was repeated except that microcrystalline cellulose was used in place of starch.
Tablets were prepared using the following components:
~uantity (mg/tablet) Active compound 500 Starch 100 Magnesium stearate 7 "Amberlite XE88"* 5 The starch and active compound were mixed together and suffi-cient water added for a uniform dispersion to be attained. The mixture was then wet screened and dried. After drying the ma-terial was screened again, and the magnesium stearate and "Amberlite"* resin then added. Finally the mixture was com-pressed into tablets.
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 * Trademark for an ion exchange resin.
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The components were blended and compressed to form tablets.
An aerosol solution was prepared containing the following com-ponents:
Weight Active ingredient 0.25 Ethanol 29.75 "Propellant 22" (trademark) 70 (Chlorodifluoromethane) The active compound was mixed with ethanol and the mixture added to the "Propellane 22", cooled to -30C and transferred 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.
A suppository formula was prepared containing 200 mg of the ~ompound 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 ulds, to give the active fill weight.
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.
A topical cream was prepared having the following ingredients:
. . ' .
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. .
.. . . . . . . .
~37617 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 70C
with stirring. The "Cetomacrogol lOOO"**was dissolved in 60g.
of water and heated to 70C. The two solutions were then mixed with stirring, and stirring continued until the tempera-ture fell to ambient. The cream was then made up to weight with water a~d passed through a stainless steel colloid mill se' at a gap of 15/1000 inch.
*Trademark. "Cetomacrogol 1000" is polyethylene glycol mono-cetyl ether having 20-24 oxyethylene groups in the polyoxy-ethylene chain.
** Trademark ' ~
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:
Claims (14)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a phenylpiperazine derivative of formula (I):
(I) where R1 is benzyl, chlorobenzyl, C1-6 alkyl or a phenyl group 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; R2 is a phenyl group 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 alkyl-sulphonamido; R3 is hydrogen or C1-4 alkyl; Q is furan, thiophene, oxazole or thiazole; m is 1 to 3 andn is 0 or 1; provided that when m is 2 and n is 0, R1 cannot be methyl when Q is a thiazol-5-yl group; or a pharmaceutically-acceptable salt thereof;
which process comprises:
(A) condensing a compound of formula (VI):
R1-Q-(CH2)m-(CH3)n - L (VI) where L represents a leaving group, and R1, Q and R3 are as defined above, with a compound of formula (VII):
(VII) (B) reducing a compound of formula:
where R2 is as defined above, (i) (VIII) where R1, Q and R2 are as previously defined, to form a com-pound in which n is 0; or (ii) (IX) to form a compound in which n is 1; or (C) cyclising a compound of formula (X):
(X) where Z is a group of formula -CO-CH2-NH-CO-, in which Q is oxazole; and R1, R2 and R3 are as previously defined; and where desired, forming a pharmaceutically acceptable acid addition salt of said compound of formula (I).
(I) where R1 is benzyl, chlorobenzyl, C1-6 alkyl or a phenyl group 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; R2 is a phenyl group 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 alkyl-sulphonamido; R3 is hydrogen or C1-4 alkyl; Q is furan, thiophene, oxazole or thiazole; m is 1 to 3 andn is 0 or 1; provided that when m is 2 and n is 0, R1 cannot be methyl when Q is a thiazol-5-yl group; or a pharmaceutically-acceptable salt thereof;
which process comprises:
(A) condensing a compound of formula (VI):
R1-Q-(CH2)m-(CH3)n - L (VI) where L represents a leaving group, and R1, Q and R3 are as defined above, with a compound of formula (VII):
(VII) (B) reducing a compound of formula:
where R2 is as defined above, (i) (VIII) where R1, Q and R2 are as previously defined, to form a com-pound in which n is 0; or (ii) (IX) to form a compound in which n is 1; or (C) cyclising a compound of formula (X):
(X) where Z is a group of formula -CO-CH2-NH-CO-, in which Q is oxazole; and R1, R2 and R3 are as previously defined; and where desired, forming a pharmaceutically acceptable acid addition salt of said compound of formula (I).
2. A process for preparing a thiazole of formula (V):
(V) where R1 is benzyl, and R2 is phenyl or p-halophenyl, which comprises condensing a compound of formula , where L is a leaving group, and R1 is benzyl, with a compound of the formula where R2 is as defined above.
(V) where R1 is benzyl, and R2 is phenyl or p-halophenyl, which comprises condensing a compound of formula , where L is a leaving group, and R1 is benzyl, with a compound of the formula where R2 is as defined above.
3. A process for preparing a thiazole of formula where R1 is C1-4 alkyl or phenyl optionally substituted by C1-4 alkyl, C1-4 alkoxy, nitro or C1-4 haloalkyl, and R2 is phenyl optionally substituted by C1-4 haloalkyl, which comprises condensing a compound of formula where L is a leaving group, and R1 is as defined above, with a compound of the formula where R2 is as defined above.
4. A process for preparing a furan of formula (II):
(II) where R1 is phenyl optionally substituted by one or two radicals selected from halogen, C1-4 alkyl, C1-4 alkoxy, and C1-4 halo-alkyl; R2 is phenyl optionally substituted by C1-4 alkyl, amino, C1-4 alkylsulphonamido and C1-4 alkoxy and m is 1 or 2, with the exception of compounds in which R1 is unsubstituted phenyl, m is 1 and R2 is unsubstituted phenyl [or dihalophenyl];
or where R1 is methyl, m is 1 and R2 is phenyl optionally sub-stituted 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, which comprises condensing a compound of the formula where L is a leaving group and R1 and m are as defined above, with a compound of the formula where R2 is as defined above.
(II) where R1 is phenyl optionally substituted by one or two radicals selected from halogen, C1-4 alkyl, C1-4 alkoxy, and C1-4 halo-alkyl; R2 is phenyl optionally substituted by C1-4 alkyl, amino, C1-4 alkylsulphonamido and C1-4 alkoxy and m is 1 or 2, with the exception of compounds in which R1 is unsubstituted phenyl, m is 1 and R2 is unsubstituted phenyl [or dihalophenyl];
or where R1 is methyl, m is 1 and R2 is phenyl optionally sub-stituted 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, which comprises condensing a compound of the formula where L is a leaving group and R1 and m are as defined above, with a compound of the formula where R2 is as defined above.
5. A process for preparing an oxazole of formula (IV):
(IV) where R1 is a phenyl group optionally substituted by C1-4 alkoxyl or halogen; R2 is a phenyl group optionally substituted by C1-4 alkyl, C1-4 haloalkyl, halogen, amino or C2-4 alkanoyl amino, and m is 1 or 2, which comprises condensing a compound of the formula where L is a leaving group and R1 and m are as defined above, with a compound of the formula where R2 is as defined above.
(IV) where R1 is a phenyl group optionally substituted by C1-4 alkoxyl or halogen; R2 is a phenyl group optionally substituted by C1-4 alkyl, C1-4 haloalkyl, halogen, amino or C2-4 alkanoyl amino, and m is 1 or 2, which comprises condensing a compound of the formula where L is a leaving group and R1 and m are as defined above, with a compound of the formula where R2 is as defined above.
6. A process for preparing a thiophene of formula (VI):
(VI) where R1 is phenyl; R2 is phenyl, phenyl singly substituted by C1-4 alkyl or C1-4 haloalkyl or doubly substituted by two radicals selected from halogen, C1-4 haloalkyl and C1-4 alkyl;
and m is 1 or 2, which comprises condensing a compound of formula , where L is a leaving group and m and R1 are as defined above, with a compound of the formula where R2 is as defined above.
(VI) where R1 is phenyl; R2 is phenyl, phenyl singly substituted by C1-4 alkyl or C1-4 haloalkyl or doubly substituted by two radicals selected from halogen, C1-4 haloalkyl and C1-4 alkyl;
and m is 1 or 2, which comprises condensing a compound of formula , where L is a leaving group and m and R1 are as defined above, with a compound of the formula where R2 is as defined above.
7. A process according to claim 2 for preparing 1 - (2-benzylthiazol-4-yl-methyl) -4-phenylpiperazine which comprises condensing 2-benzyl 4-chloromethylthiazole hydro-chloride with 1-phenylpiperazine in the presence of a base.
8. A phenylpiperazine derivative of formula (I) as defined in claim 1, whenever prepared by a process according to claim 1 or by an obvious chemical equivalent thereof.
9. A phenylpiperazine derivative of formula (V) as defined in claim 2, whenever prepared by a process according to claim 2 or an obvious chemical equivalent thereof.
10. A phenylpiperazine derivative having the formula defined in claim 3, whenever prepared by a process according to claim 3 or an obvious chemical equivalent thereof.
11. A phenylpiperazine derivative of formula (II) as defined in claim 4, whenever prepared by a process accord-ing to claim 4 or an obvious chemical equivalent thereof.
12. A phenylpiperazine derivative of formula (IV) as defined in claim 5, whenever prepared by a process according to claim 5 or an obvious chemical equivalent thereof.
13. A phenylpiperazine derivative of formula (VI) as defined in claim 6, whenever prepared by a process according to claim 6 or an obvious chemical equivalent thereof.
14. 1-(2-benzylthiazol-4-ylmethyl)-4-phenylpiper-azine, whenever prepared by a process according to claim 7 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB16526/76 | 1976-04-23 | ||
| GB16526/76A GB1575904A (en) | 1976-04-23 | 1976-04-23 | Phenyl piperazines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1087617A true CA1087617A (en) | 1980-10-14 |
Family
ID=10078930
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA275,160A Expired CA1087617A (en) | 1976-04-23 | 1977-03-30 | Phenyl piperazines |
Country Status (34)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (7)
| 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 |
| KR970701705A (en) * | 1994-03-11 | 1997-04-12 | 오노다 마사요시 | 5-HT₃ receptor agonists, novel thiazole derivatives, and intermediates thereof |
| GB9517381D0 (en) * | 1995-08-24 | 1995-10-25 | Pharmacia Spa | Aryl and heteroaryl piperazine derivatives |
| AU2007221021B2 (en) * | 2006-02-28 | 2013-01-17 | Dart Neuroscience (Cayman) Ltd | Therapeutic piperazines as PDE4 inhibitors |
| US8927546B2 (en) | 2006-02-28 | 2015-01-06 | Dart Neuroscience (Cayman) Ltd. | Therapeutic piperazines |
-
1976
- 1976-04-23 GB GB16526/76A patent/GB1575904A/en not_active Expired
-
1977
- 1977-03-28 NZ NZ183715A patent/NZ183715A/en unknown
- 1977-03-28 ZA ZA00771849A patent/ZA771849B/en unknown
- 1977-03-30 IL IL51787A patent/IL51787A/en unknown
- 1977-03-30 IE IE671/77A patent/IE44730B1/en unknown
- 1977-03-30 CA CA275,160A patent/CA1087617A/en not_active Expired
- 1977-04-13 CH CH525781A patent/CH633009A5/en not_active IP Right Cessation
- 1977-04-13 CH CH455777A patent/CH625802A5/en not_active IP Right Cessation
- 1977-04-13 MX MX775629U patent/MX4596E/en unknown
- 1977-04-14 PH PH19656A patent/PH14124A/en unknown
- 1977-04-18 PT PT66452A patent/PT66452B/en unknown
- 1977-04-18 AU AU24386/77A patent/AU514822B2/en not_active Expired
- 1977-04-19 FR FR7711669A patent/FR2348925A1/en active Granted
- 1977-04-19 GR GR53236A patent/GR64084B/en unknown
- 1977-04-20 BG BG7737191A patent/BG28055A3/en unknown
- 1977-04-20 ES ES457988A patent/ES457988A1/en not_active Expired
- 1977-04-20 RO RO7790106A patent/RO72831A/en unknown
- 1977-04-20 OA OA56149A patent/OA05643A/en unknown
- 1977-04-20 DE DE19772717415 patent/DE2717415A1/en not_active Withdrawn
- 1977-04-20 SE SE7704536A patent/SE7704536L/en not_active Application Discontinuation
- 1977-04-20 BG BG7736062A patent/BG27746A3/en unknown
- 1977-04-21 YU YU01044/77A patent/YU104477A/en unknown
- 1977-04-21 CS CS772668A patent/CS196360B2/en unknown
- 1977-04-21 DK DK176177A patent/DK176177A/en not_active Application Discontinuation
- 1977-04-21 LU LU77170A patent/LU77170A1/xx unknown
- 1977-04-22 AT AT285177A patent/AT355579B/en not_active IP Right Cessation
- 1977-04-22 SU SU772474105A patent/SU664564A3/en active
- 1977-04-22 HU HU77LI311A patent/HU176820B/en unknown
- 1977-04-22 FI FI771287A patent/FI63937C/en not_active IP Right Cessation
- 1977-04-22 BE BE6045977A patent/BE853899A/en not_active IP Right Cessation
- 1977-04-22 PL PL1977197550A patent/PL117466B1/en unknown
- 1977-04-22 DD DD7700198558A patent/DD129790A5/en unknown
- 1977-04-22 NO NO771398A patent/NO146710C/en unknown
- 1977-04-22 AR AR267310A patent/AR222003A1/en active
- 1977-04-22 NL NL7704456A patent/NL7704456A/en not_active Application Discontinuation
- 1977-04-23 JP JP4727677A patent/JPS52151183A/en active Pending
- 1977-12-28 SU SU772558499A patent/SU727146A3/en active
-
1978
- 1978-03-16 ES ES467948A patent/ES467948A1/en not_active Expired
- 1978-03-22 AR AR271519A patent/AR222635A1/en active
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