IP Library › Patent Application 12223444

Patent Application

App. No. 12/223,444

Piperazine Derivatives

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Patent No.: US None
App. No.: 12/223,444

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Abstract

Compounds of general formula (I) in which R 1 , A 1 , A 2 and R 2 have any of the meanings given in the specification, have affinity for sigma receptors and are useful in the treatment of disorders of the central nervous system.

Claims (210)

1 - 15 . (canceled)

16 . A compound of general formula (I)

in which: —

R 1 represents a phenyl group that is substituted by one or two fluorine atoms;

A 1 represents (CH 2 ) m or (CH 2 ) m-1 C(═O);

m is 2, 3, 4 or 5;

A 2 represents (CH 2 ) n or C(═O)(CH 2 ) n-1 ;

n is 2, 3, 4 or 5; and

R 2 represents a phenyl group that is unsubstituted or substituted by one, two or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a cyano group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group, a (1-4C)alkoxy(1-4C)alkoxy group, a hydroxy(1-4C)alkoxy group, a (1-4C)alkylsulfanyl group, a (1-4C)alkylsulfonyl group, a halo(1-4C)alkoxy group, and a halo(1-4C)alkylsulfonyl group;

or a pharmaceutically acceptable salt thereof,

or a stereoisomeric form or a polymorphic form of said compound or of said salt;

provided that when A 1 and A 2 each represents (CH 2 ) 2 , then R 1 and R 2 do not both represent 4-fluorophenyl.

17 . A compound as claimed in claim 16 , in R 1 represents a 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, or 2,4-difluorophenyl group.

18 . A compound as claimed in claim 16 or claim 17 in which m is 2.

19 . A compound as claimed in claim 16 or claim 17 in which m is 3.

20 . A compound as claimed in any one of claims 16 and 17 in which A 1 represents (CH 2 ) m .

21 . A compound as claimed in any one of claims 16 and 17 in which n is 2.

22 . A compound as claimed in any one of claims 16 and 17 in which n is 3.

23 . A compound as claimed in any one of claims 16 and 17 in which A represents (CH 2 ) n .

24 . A compound of general formula (I)

in which: —

R 1 represents a phenyl group that is substituted by one or two fluorine atoms;

A 1 represents (CH 2 ) m or (CH 2 ) m-1 C(═O);

m is 2, 3, 4 or 5;

A represents (CH 2 ) n or C(═O)(CH 2 ) n-1 ;

n is 2, 3, 4 or 5; and

R 2 represents a phenyl group that is substituted by one or two substituents selected independently from a fluorine atom, a cyano group, a fluoro(1-4C) alkyl group, a (1-4C)alkylsulfonyl group, a fluoro(1-4C)alkoxy group and a fluoro(1-4C)alkylsulfonyl group;

or a pharmaceutically acceptable salt thereof,

or a stereoisomeric form or a polymorphic form of said compound or of said salt;

provided that when A 1 and A 2 each represents (CH 2 ) 2 , then R 1 and R 2 do not both represent 4-fluorophenyl.

25 . A compound as claimed in claim 17 , in which R 2 represents a substituent selected from the group consisting of 2-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-trifluoromethylsulfonylphenyl, and 4-trifluoromethylsulfonylphenyl.

26 . A compound as claimed in claim 25 in which R 2 represents 2-fluorophenyl.

27 . A compound as claimed in claim 25 in which R 2 represents 4-fluorophenyl.

28 . A compound selected from the group consisting of:

1,4-Bis-[2-(2-fluorophenoxy)ethyl]piperazine dihydrochloride,

1,4-Bis-[3-(4-fluorophenoxy)propyl]piperazine,

1,4-Bis-[3-(2-fluorophenoxy)propyl]piperazine dihydrochloride,

1-[2-(4-Fluorophenoxy)ethyl]-4-[3-(4-fluorophenoxy)propyl]piperazine dihydrochloride,

and 2-(4-Fluorophenoxy)-1-{4-[2-(4-fluorophenoxy)acetyl]piperazin-1-yl}-ethanone,

or a pharmaceutically acceptable salt of the selected compound, including a stereoisomeric form or a polymorphic form of said compound or of said salt.

29 . A compound selected from the group consisting of:

4-(2-{4-[2-(4-Fluorophenoxy)ethyl]piperazin-1-yl}ethoxy)benzonitrile,

4-(2-{4-[2-(2-Fluorophenoxy)ethyl]piperazin-1-yl}ethoxy)benzonitrile,

4-(2-{4-[2-(2,4-Difluorophenoxy)ethyl]piperazin-1-yl}ethoxy)benzonitrile,

3-(2-{4-[2-(4-Fluorophenoxy)ethyl]piperazin-1-yl}ethoxy)benzonitrile,

3-(2-{4-[2-(2-Fluorophenoxy)ethyl]piperazin-1-yl}ethoxy)benzonitrile,

3-(2-{4-[2-(2,4-Difluorophenoxy)ethyl]piperazin-1-yl}ethoxy)benzonitrile,

1-[2-(4-Fluorophenoxy)ethyl]-4-[2-(3-trifluoromethylphenoxy)ethyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[2-(3-trifluoromethylphenoxy)ethyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[2-(3-trifluoromethylphenoxy)ethyl]piperazine,

1-[2-(4-Fluorophenoxy)ethyl]-4-[2-(4-trifluoromethylphenoxy)ethyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[2-(4-trifluoromethylphenoxy)ethyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[2-(4-trifluoromethylphenoxy)ethyl]piperazine,

1-[2-(4-Fluorophenoxy)ethyl]-4-[2-(4-methanesulfonylphenoxy)ethyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[2-(4-methanesulfonylphenoxy)ethyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[2-(4-methanesulfonylphenoxy)ethyl]piperazine,

1-[2-(4-Fluorophenoxy)ethyl]-4-[2-(3-methanesulfonylphenoxy)ethyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[2-(3-methanesulfonylphenoxy)ethyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[2-(3-methanesulfonylphenoxy)ethyl]piperazine,

1-[2-(4-Fluorophenoxy)ethyl]-4-[2-(4-trifluoromethanesulfonylphenoxy)ethyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[2-(4-trifluoromethanesulfonylphenoxy)ethyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[2-(4-trifluoromethanesulfonylphenoxy)ethyl]piperazine,

1-[2-(4-Fluorophenoxy)ethyl]-4-[2-(3-trifluoromethanesulfonylphenoxy)ethyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[2-(3-trifluoromethanesulfonylphenoxy)ethyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[2-(3-trifluoromethanesulfonylphenoxy)ethyl]piperazine,

4-(3-{4-[2-(4-Fluorophenoxy)ethyl]piperazin-1-yl}propoxy)benzonitrile,

4-(3-{4-[2-(2-Fluorophenoxy)ethyl]piperazin-1-yl}propoxy)benzonitrile,

4-(3-{4-[2-(2,4-Difluorophenoxy)ethyl]piperazin-1-yl}propoxy)benzonitrile,

3-(3-{4-[2-(4-Fluorophenoxy)ethyl]piperazin-1-yl}propoxy)benzonitrile,

3-(3-{4-[2-(2-Fluorophenoxy)ethyl]piperazin-1-yl}propoxy)benzonitrile,

3-(3-{4-[2-(2,4-Difluorophenoxy)ethyl]piperazin-1-yl}propoxy)benzonitrile,

1-[2-(4-Fluorophenoxy)ethyl]-4-[3-(4-trifluoromethylphenoxy)propyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[3-(4-trifluoromethylphenoxy)propyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[3-(4-trifluoromethylphenoxy)propyl]piperazine,

1-[2-(4-Fluorophenoxy)ethyl]-4-[3-(3-trifluoromethylphenoxy)propyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[3-(3-trifluoromethylphenoxy)propyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[3-(3-trifluoromethylphenoxy)propyl]piperazine,

1-[2-(4-Fluorophenoxy)ethyl]-4-[3-(4-methanesulfonylphenoxy)propyl]piperazine,

1-[2-(2-Difluorophenoxy)ethyl]-4-[3-(4-methanesulfonylphenoxy)propyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[3-(4-methanesulfonylphenoxy)propyl]piperazine,

1-[2-(4-Fluorophenoxy)ethyl]-4-[3-(3-methanesulfonylphenoxy)propyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[3-(3-methanesulfonylphenoxy)propyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[3-(3-trifluoromethanesulfonylphenoxy)propyl]piperazine,

1-[2-(4-Fluorophenoxy)ethyl]-4-[3-(4-trifluoromethanesulfonylphenoxy)propyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[3-(4-trifluoromethanesulfonylphenoxy)propyl]piperazine,

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[3-(4-trifluoromethanesulfonylphenoxy)propyl]piperazine,

1-[2-(4-Fluorophenoxy)ethyl]-4-[3-(3-trifluoromethanesulfonylphenoxy)propyl]piperazine,

1-[2-(2-Fluorophenoxy)ethyl]-4-[3-(3-trifluoromethanesulfonylphenoxy)propyl]piperazine, and

1-[2-(2,4-Difluorophenoxy)ethyl]-4-[3-(3-trifluoromethanesulfonylphenoxy)propyl]piperazine,

or a pharmaceutically acceptable salt of the selected compound, or a stereoisomeric form or a polymorphic form of said compound or of said salt.

30 . A process for preparing a compound of the general formula (I)

in which: —

R 1 represents a phenyl group that is substituted by one or two fluorine atoms;

A 1 represents (CH 2 ) m or (CH 2 ) m-1 C(═O);

m is 2, 3, 4 or 5;

A represents (CH 2 ) n or C(═O)(CH 2 ) n-1 ;

n is 2, 3, 4 or 5; and

R 1 represents a phenyl group that is unsubstituted or substituted by one, two or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a cyano group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group, a (1-4C)alkoxy(1-4C)alkoxy group, a hydroxy(1-4C)alkoxy group, a (1-4C)alkylsulfanyl group, a (1-4C)alkylsulfonyl group, a halo(1-4C)alkoxy group, and a halo(1-4C)alkylsulfonyl group;

or a pharmaceutically acceptable salt thereof,

or a stereoisomeric form or a polymorphic form of said compound or of said salt;

provided that when A 1 and A 2 each represents (CH 2 ) 2 , then R 1 and R 2 do not both represent 4-fluorophenyl,

comprising a process selected from the group consisting of:

a) reacting a compound of general formula (II)

in which each of Z 1 and Z 2 independently represents a leaving atom or group, or a corresponding compound in which one or more substituents on R 2 are protected, with a compound of general formula (III)

R 1 —O-A 1 -NH 2 (III);

b) reacting a compound of general formula (IV)

in which each of Z 3 and Z 4 independently represents a leaving atom or group, with a compound of general formula (V)

H 2 N-A 2 -O—R 2 (V)

or a corresponding compound in which one or more substituents on R 2 are protected;

c) reacting a compound of general formula (VI)

with a compound of general formula (VII)

Z 5 -A 2 -O—R 2 VII)

in which Z 5 represents a leaving atom or group;

d) reacting a compound of formula (VIII)

with a compound of general formula (IX)

R 1 —O-A 1 -Z 6 (IX)

in which Z 6 represents a leaving atom or group; and

e) for a compound of formula (I) in which A 1 represents (CH 2 ) m and A 2 represents (CH 2 ) n , reducing a corresponding compound of formula (I) in which A 1 represents (CH 2 ) m-1 C(═O) and/or A 2 represents C(═O)(CH 2 ) n-1 ;

the selected process followed by removing any protecting group, and, optionally, forming a pharmaceutically acceptable salt.

31 . A pharmaceutical composition, which comprises a compound as claimed in any one of claims 16 , 17 , 24 , 28 , or 29 and a pharmaceutically acceptable diluent or carrier.

32 . A method of treating a condition responsive to a modulator of sigma receptor function in a patient requiring treatment, which comprises administering to said patient an effective amount of a compound of general formula (I)

in which: —

R 1 represents a phenyl group that is substituted by one or two fluorine atoms;

A 1 represents (CH 2 ) m or (CH 2 ) m-1 C(═O);

m is 2, 3, 4 or 5;

A represents (CH 2 ) n or C(═O)(CH 2 ) n-1 ;

n is 2, 3, 4 or 5; and

or a pharmaceutically acceptable salt thereof, or a stereoisomeric form or a polymorphic form of said compound or of said salt,

provided that when A 1 and A 2 each represents (CH 2 ) 2 , then R 1 and R 2 do not both represent 4-fluorophenyl.

33 . The method according to claim 32 which comprises administering to said patient an effective amount of a compound of the general formula (I) in which R 1 represents a 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, or 2,4-difluorophenyl group.

34 . A method of treating a condition as in any one of claims 32 and 33 , wherein m is 2 in the compound of general formula (I).

35 . A method of treating a condition as in any one of claims 32 and 33 , wherein m is 3 in the compound of general formula (I).

36 . A method of treating a condition as in any one of claims 32 and 33 , wherein A 1 represents (CH 2 ) m in the compound of general formula (I).

37 . A method of treating a condition as in any one of claims 32 and 33 , wherein n is 2 in the compound of general formula (I).

38 . A method of treating a condition as in any one of claims 32 and 33 , wherein n is 3 in the compound of general formula (I).

39 . A method of treating a condition as in any one of claims 32 and 33 , wherein A 2 represents (CH 2 ) n in the compound of general formula (I).

40 . A method of treating a condition responsive to a modulator of sigma receptor function in a patient requiring treatment, which comprises administering to said patient an effective amount of a compound of general formula (I)

in which: —

R 1 represents a phenyl group that is substituted by one or two fluorine atoms;

A 1 represents (CH 2 ) m or (CH 2 ) m-1 C(═O);

m is 2, 3, 4 or 5;

A represents (CH 2 ) n or C(═O)(CH 2 ) n-1 ;

n is 2, 3, 4 or 5; and

or a pharmaceutically acceptable salt thereof,

or a stereoisomeric form or a polymorphic form of said compound or of said salt;

provided that when A 1 and A 2 each represents (CH 2 ) 2 , then R 1 and R 2 do not both represent 4-fluorophenyl.

41 . A method of treating a condition as claimed in claim 40 , in which R 2 of the compound represents a substituent selected from the group of 2-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-trifluoromethylsulfonylphenyl, and 4-trifluoromethylsulfonylphenyl.

42 . A compound as claimed in claim 41 , in which R 2 of the compound represents 2-fluorophenyl.

43 . A compound as claimed in claim 41 , in which R 2 of the compound represents 4-fluorophenyl.

44 . A method of treating a condition responsive to a modulator of sigma receptor function in a patient requiring treatment, which comprises administering to said patient an effective amount of a compound selected from the group consisting of:

1,4-Bis-[2-(2-fluorophenoxy)ethyl]piperazine dihydrochloride,

1,4-Bis-[3-(4-fluorophenoxy)propyl]piperazine,

1,4-Bis-[3-(2-fluorophenoxy)propyl]piperazine dihydrochloride,

1-[2-(4-Fluorophenoxy)ethyl]-4-[3-(4-fluorophenoxy)propyl]piperazine dihydrochloride,

and 2-(4-Fluorophenoxy)-1-{4-[2-(4-fluorophenoxy)acetyl]piperazin-1-yl}-ethanone,

or a pharmaceutically acceptable salt of the selected compound,

or a stereoisomeric form or a polymorphic form of said compound or of said salt.

45 . A method of treating a condition responsive to a modulator of sigma receptor function in a patient requiring treatment, which comprises administering to said patient an effective amount of a compound selected from the group consisting of:

4-(2-{4-[2-(4-Fluorophenoxy)ethyl]-piperazin-1-yl}ethoxy)benzonitrile,