GB2435827A

GB2435827A - Use of substituted piperazine compounds for the treatment of food related disorders

Info

Publication number: GB2435827A
Application number: GB0604780A
Authority: GB
Inventors: Helmut Heinrich Buschmann; Jordi-Ramon Quintana Ruiz; Ramon Merce Vidal; Xavier Codony Soler
Original assignee: Laboratorios del Dr Esteve SA
Current assignee: Esteve Pharmaceuticals SA
Priority date: 2006-03-09
Filing date: 2006-03-09
Publication date: 2007-09-12
Also published as: GB0604780D0

Abstract

Use of substituted piperazine compounds of general formula I, as defined herein; <EMI ID=1.1 HE=32 WI=64 LX=759 LY=579 TI=CF> <PC>for the prophylaxis and/or treatment of disorders or diseases that are at least partially mediated via 5-HT6 receptors, in particular food related disorders such as obesity.

Description

Use of substituted piperazine compounds tor me trealmeul. u. iw.a

related disorders The present invention relates to the use of substituted piperazine compounds of general formula I, /___\/ _ G-N N-±CH2 1 E \J\ In I, for the prophylaxis and/or treatment of disorders or diseases that are at least partially mediated via 5-HT6 receptors. * a S

The superfamily of serotonin receptors (5-HT) includes 7 classes (5-HT1 -5-HT7) . encompassing 14 human subclasses [D. Hoyer, et al., Neuropharmacology, 1997, 36, 419]. The 5-HT6 receptor is the latest serotonin receptor identified by molecular cloning both in rats [F.J. Monsma et al., Mol. Pharmacol., 1993, 43, 320; M. Ruat et *.*.

al., Biochem. Biophys. Res. Commun., 1993, 193, 2681 and in humans [R. Kohen, et al., J. Neurochem., 1996, 66, 47]. * S S S. S

Recently, it has been shown that the 5-HT6 receptor plays a role in food ingestion [Neuropharmacology, 41, 2001, 210-219].

Food ingestion disorders, particularly obesity, are a serious, fast growing threat to the health of humans of all age groups, since they increase the risk of developing other serious, even life-threatening diseases such as diabetes or coronary diseases as well.

Therefore an object of the present invention was to provide compounds that can be used for the prophylaxis and/or treatment of disorders or diseases related to 5-HT6 receptors such as food intake related disorders.

Surprisingly, it has been found that the substituted piperazine compounds of general formula I given below show good to excellent affinity to 5-HT6-receptors. These compounds are therefore particularly suitable for the prophylaxis and/or treatment of

I

disorders or diseases related to 5-HT6-receptors such as food intake related disorders like obesity.

Thus, in one of its aspects the present invention relates to the use of at least one substituted piperazine compound of general formula I, /____\/ _ G-N N CH2 E \J\ In I, wherein S.. S S * *5 n isl2,3,4,5or6; G represents R2.5*SS.

R3...T,._LJ.,R1 wherein R', R2, R3 and R4, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, -C1-5-alkyl, -C2-5-alkenyl, -0- C1-5-alkyl, -S-C1-5-alkyl, -C(=O)-OH, -C(=O)-Ci-5-alkyl, -C1..5-alkylene-C(=O)-OH, -C(=O)-O-C1-5-alkyl, -0-C(=O)-C1-5-alkyl, F, Cl, Br, I, -CN, -CF3, -OCF3, -SCF3, -OH, - SH, -NH2, -NH(C1-5-alkyl), -N(Ci-5-alkyl)2, -NH(C2-5-alkenyl), -N(C2-5-alkenyl)2, -NO2, - CHO, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-N H(C1-5-alkyl), -C(=O)-N(Ci-5-alkyl)2, -S(=O)2-Ci-5-alkyl, -S(=O)2-phenyl, -S(=O)2-OH, -NH-C(=O)-C1-5-alkyl, -NH-C(=O)- phenyl, -NH-S(=O)2-phenyl, -NH-S(=O)2-Ci-5-alkyl, -S(=O)2-NH-phenyl, -S(=O)2-NH-Ci-5-alkyl and -S(=O)2-N(C1 -5-alkyl)2; or G represents N=( wherein R6 represents a radical selected from the group consisting of hydrogen, -Ci- 5-alkyl, -C(=O)-C1 -5-alkyl and -C(=O)-O-C1-5-alkyl; E represents \AB * * * S * *. ** wherein the dotted line represents an optional chemical bond, a... * *SSS *5SS

A represents C-R7 and B represents N * , : or A represents N and B represents C-R1 or A represents N and B represents N or A represents C-R7 and B represents C-R' and D represents N or C-R9; or E represents

AB

wherein A represents NR6 and B represents N or A represents NR6 and B represents C-R1 and D represents N or C-R9; or E represents R7, R8, R9 and R10, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, -C1-5-alkyl, -C2.5-alkenyl, -0-Ci-5-alkyl, -S-C1-5-alkyl, -C(=O)-OH, -C(=O)-Ci-5-alkyl, -C-1.5-alkylene-C(=O)-OH, oxo (=0), thioxo (=S), -C(=O)-O-C1-5-alkyl, -O-C(=O)-C1.5-alkyl, F, Cl, Br, I, -CN, -CF3, - OCF3, -SCF3, -OH, -SH, -NH2, -NH(C1-5-alkyl), -N(C1-5-alkyl)2, -NH(C2-5-alkenyl), -N(C2-5-alkenyl)2, -NO2, -CHO, -CF2H, -CFH2, -C(O)-NH2, -C(0)-NH(Ci-5-alkyl), - C(=O)-N(C1..5-alkyl)2, -S(=O)2-Ci.5-alkyl, -S(=O)2-phenyl, -S(=O)2-OH, -NH-C(=O)-Ci- 5-alkyl, -NH-C(=O)-phenyl, -NH-S(=O)2-phenyl, -NH-S(=O)2-Ci-5-alkyl, -S(=O)2-NH-phenyl, -S(=0)2-NH-C1.. 5-alkyl, -S(=0)2-N(C,-5-alkyl)2, phenyl, pyrrolyl, pyridinyl, ** ; phenoxy and benzyl; whereby said cyclic substituents pyrrolyl, pyridinyl, -S(=O)2-phenyl, -NHC(=0)-phenyl, -NH-S(=0)2-phenyl, -S(=O)2-NH-phenyl, phenyl, phenoxy and benzyl may be unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, tert-butyl, methoxy, ethoxy, F, Cl, Br, -CN, -CF3, -OCF3, -SCF3, -OH, -SH, -NH2 and NO2; or optionally R8 and R1 together form a -(CH2)m-group, wherein m is 3 or 4, or a -CH=CH-CH=CH-group; or optionally R8 and R9 together form a -(CH2)k-group, wherein k is 3 or 4, or a -CH=CH-CH=CH-group or a -CH=C(CH3)-C(CH3)=CH-group or a -N=CHCH=CH-group; or optionally R7 and R1 together form a -CH=CH-CH=CH-group; R11 and R12, independently of one another, in each case represent -C1-5-alkyl; or R11 and R12 together form a -(CH2)q-group, wherein q is 3 or 4; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof; for the manufacture of a medicament for the prophylaxis and/or treatment of a disorder or disease related to food intake.

C15-alkyl denotes a linear or branched alkyl radical consisting of I to 5 carbon atoms in the chain. Preferably C1.5-alkyl denotes a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and n-pentyl.

C2.5-alkenyl denotes a linear or branched alkenyl radical consisting of 2 to 5 carbon * .* . atoms in the chain. Preferably C2.5-alkenyl denotes a radical selected from the group consisting of ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-* pentenyl and 2-methyl-I -propenyl. . ::: : C15-alkylene denotes a linear or branched alkyl radical consisting of I to 5 carbon atoms in the chain that is substituted at two ends. Preferably C1..5-alkylene denotes a radical selected from the group consisting of-CH2-, -CH2-CH2-, -CH2-CH2-CH2-, - CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-, -CH(CH3)-CH2-, -CH(CH3)-and -CH(CH3)-CH(CH3)-.

Preferred is the use of at least one substituted piperazine compound of general formula I given above, wherein n isl,2,3,4,5or6; G represents R2 R1

S-N

wherein R1, R2, R3 and R4, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, -C(=O)-NH2, -C(0)- NH-CH3, -C(=O)-N(CH3)2, -C(=O)-NH-C2H5, -C(=O)-N(C2H5)2, -O-CH3, -O-C2H5, -0- CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, -C(=0)-OH, -C(=O)-O-CH3, -C(=0)-O- C2H5, -C(=O)-O-CH2-CH2-CH3, -C(=O)-O-CH(CH3)2, -C(=O)-O-C(CH3)3, F, CI, Br, I, -CN, -NH2, -NH-CH3, -NH-C2H5, -NH-CH2-CH2-CH3, -NH-CH(CH3)2, -NH-C(CH3)3, -NH-CH(CH3)(C2H5), -N(CH3)2, -N(C2H5)2 and -NO2; N=< S...

orG represents,,R6:;:; wherein R6 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, - C(=O)-O-CH3, -C(=O)-O-C2H5, -C(=O)-O-CH2-CH2-CH3, -C(=O)-O-CH(CH3)2, -C(=O)- O-C(CH3)3, -C(0)-CH3, -C(0)-C2H5, -C(0)-CH2-CH2-CH3, -C(=O)-CH(CH3)2 and -C(=O)-C(CH3)3; R8 E represents A wherein the dotted line represents an optional chemical bond, A represents C-R7 and B represents N or A represents N and B represents C-R1 or A represents N and B represents N or A represents C-R7 and B represents C-R1 and 0 represents N or C-R9; or E represents 0 0 0 or -N R7, R8, R9 and R10, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, vinyl, allyl, -CF3, -C(0)-NH2, -C(0)-e.

NH-CH3, -C(=O)-N(CH3)2, -C(=O)-NH-C2H5, -C(=O)-N(C2H5)2, -O-CH3, -O-C2H5, -0- CH2-CH2-CH3, -O--CH(CH3)2, -O-C(CH3)3, -C(=O)-OH, -C(=O)-O-CH3, -C(=0)-O-C2H5, -C(0)-O-CH2-CH2-CH3, -C(0)-O-CH(CH3)2, -C(0)-O-C(CH3)3, F, Cl, Br, I, oxo (=0), thioxo (=S), -CN, -NH2, -NH-CH3, -NH-C2H5, -NH-CH2-CH2-CH3, -NH- CH(CH3)2, -NH-C(CH3)3, -NHCH(CH3)(C2H5), -N(CH3)2, -N(C2H5)2, -NO2, -NH-S(=O)2- phenyl, -NH-S(=O)2-CH3, -NH-S(=O)2-C2H5, -NH-S(=O)2-CH2-CH2-CH3, -NH--S(=O)2- CH2-CH2-CH2-CH3, -NH-C(=O)-phenyl, -NH-C(=O)-CH3, -NH-C(=O)-C2H5, -S(=O)2-OH, -S(=O)2-N(CH3)2, pyrrolyl and phenyl; or optionally R8 and R9 together form a -(CH2)k-group, wherein k is 3 or 4, or a - CH=CH-CH=CH-group or a -CH=C(CH3)-C(CH3)=CH-group or a -N=CH-CH=CH-group; or optionally R7 and R1 together form a -CH=CH-CH=CH-group;

L -

or optionally R8 and R1 together form a -(CH2)m-group, wherein m is 3 or 4, or a -CH=CH-CH=CH-group; R11 and R12, independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl and n-pentyl; or R11 and R12 together form a (CH2)qgroup, wherein q is 3 or4; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

S * S * **

Particularly preferred is the use of at least one substituted piperazine compound of general formula I given above, wherein n is4; *:.*. *5** S...

G represents R2 R1

S--N

wherein R1, R2, R3 and R4, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, -O-CH3, -O-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br and I; or G represents N=< cNR6 wherein R6 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl and n-pentyl; E represents

HN

wherein the dotted line represents an optional chemical bond, A represents C-R7 and B represents N rr A represents N and B represents C-R1 or A represents N and B represents N or A represents C-R7 and B represents C-R1 and D represents N or C-R9; or E represents or R7 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pent-yl, F, Cl, Br and I; R8 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CE3, F, Cl, Br and I; R9 represents a radical selected from the group consisting of hydrogen, -CE3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Brand I; R1 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, -.: pentyl, F, Cl, Brand I; or optionally R8 and R9 together form a -(CH2)k-group, wherein k is 3 or 4, or a -* * . CH=CH-CH=CH-group or a -CH=C(CH3)-C(CH3)=CH-group or a -NCHCHCH-S...

group;

S S S * S. S

or optionally R7 and R1 together form a -CH=CH-CH=CH-group; or optionally R8 and R1 together form a -(CH2)m-group, wherein m is 3 or 4, or a -CH=CH-CH=CH-group; R11 and R12, independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-bulyl, isobutyl and n-pentyl; or R11 and R12 together form a (CH2)qgroup, wherein q is 3 or4; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

More particularly preferred is the use of at least one substituted piperazine compound of general formula Ia, wherein Ia, wherein R1 a, R2 a R3 a and R 4a, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-:. *.

propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, -O-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-C(CH3)3, F, Cl, Br and I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof. S...

S S S.

More particularly preferred is the use of at least one substituted piperazine compound of general formula lb, wherein R7b R2b R3b Rib R4b NN Nb Ib, wherein Rfl', R2b, R3b and R4b, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CE3, -O-CH3, -O-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br and I; and R7b represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

More particularly preferred is the use of at least one substituted piperazine compound of general formula Ic, wherein 9c R2C R\ R8C R4cC\N Rb0c:; Ic, wherein R, R2C, R3C and R4C, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, -O-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -0-C(CH3)3, F, Cl, Br and I; R8C represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, F,Cl, Brand I; R9C represents a radical selected from the group consisting of hydrogen, -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyt, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; and RlOC represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Brand I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof. *

More particularly preferred is the use of at least one substituted piperazine compound of general formula Id, wherein S

S S 9d s

R2d R R8d " R4dCyN:; Id, wherein Rd, R2d, R3d and R, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, -O-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br and I; R7d represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; R&d represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CE3, F, Cl, Br and I; and R9d represents a radical selected from the group consisting of hydrogen, -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Brand I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof. p.

More particularly preferred is the use of at least one substituted piperazine:* : : compound of general formula le, wherein

S S

R2. .5 N(R8e N: :: -. le,

wherein R1, R, R and R4, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, -O-CH3, -O-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br and I; R7 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobulyl, n-pentyl, F, Cl, Brandl; and R8 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CE3, F, Cl, Brand I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

More particularly preferred is the use of at least one substituted piperazine compound of general formula If, wherein R91 \ R8 R10 D6f I e p 0 a.. If,

wherein R6 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl and n-pentyl; R8 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CE3, F, Cl, Br and I; Rrepresents a radical selected from the group consisting of hydrogen, -CE3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; and R10 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

Even more particularly preferred is the use of at least one substituted piperazine compound of general formula I selected from the group consisting of [1] 8-[4-(4-benzo[d]isoth iazol-3-yl-piperazin-I -yl)butyl]-8-azaspiro[4.5]decane-7,9-dione, * * * t [21 3-(4-(4-(1 H-benzo[d]imidazole-1 -yl)butyl)piperazin-1 -yI)benzo[d]isothiazole, * * [3] 3-(4-(4-(4-chloro-I H-pyrazol-I -yl)butyl)piperazin-1 -yI)benzo[djisothiazole, [4] 3-(4-(4-(4, 5-dichloro-2-methyl-I H-imidazol-1 -yl)butyl)piperazin-1 -yI)benzo[djisothiazole hydrochloride, *: : : [5] 3-(4-(4-( I H-1,2,4-triazol-I -yl)butyl)piperazin-I -yl)benzo[d]isothiazole [6] 1 -(4-( 1 H-pyrazol-I -yI)butyl)-4-( 1-methyl-I H-imidazol-2-yl)piperazine [7] 3-(4-(4-( 1 H-benzo[d]imidazole-I -yl)butyl)piperazin-1 -yl)benzo[d]isothiazole hydrochloride and [8] 3-(4-(4-(4-chloro-1 H-pyrazol-I -yl)butyl)piperazin-I -yl)benzo[d]isothiazole hydrochlonde; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

In another aspect the present invention relates to the use of at least one substituted piperazine compound of general formula I, Ia, Ib, Ic, Id, le or If given above, in the following text referred to as compound of general formula I, optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the manufacture of a medicament suitable for 5-HT6-receptor regulation, preferably for the prophylaxis and/or treatment of a disorder or a disease that is least partially mediated via 5-HT6-receptors.

In another aspect the present invention relates to the use of at least one substituted piperazine compound of general formula I given above, optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the manufacture of a medicament for the regulation of appetite; for the maintenance, increase or reduction of body weight; for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), for the prophylaxis and/or treatment of stroke; seizures; migraine; head trauma; epilepsy; irritable colon syndrome; irritable bowel syndrome; bipolar disorders; neurodegenerative disorders, preferably selected from the group.* . consisting of Morbus Alzheimer, Morbus Parkinson, Morbus Huntington and Multiple Sclerosis; schizophrenia; convulsions; or hyperactivity disorder (ADHD, attention S...

deficit/hyperactivity disorder). : More preferred is the use of at least one substituted piperazine compound of general formula I as defined above, optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the preparation of a medicament for the regulation of appetite; for the maintenance, increase or reduction of body weight; or for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus).

Most preferred is the use of at least one substituted piperazine compound of general formula I as defined above, optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof, for the preparation of a medicament for the prophylaxis and/or treatment of obesity.

The inventively obtained medicament may be in any form suitable for the application to patients and can be produced by standard procedures known to those skilled in the art. The composition of the medicament may vary depending on the route of administration.

Such medicaments may be produced according to standard procedures known to those skilled in the art, e.g. from the tables of contents from Pharmaceutics: the Science of Dosage Forms", Second Edition, Aulton, M.E. (Ed.) Churchill Livingstone, Edinburgh (2002); ,, Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, J. and Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); Modern Pharmaceutics", Fourth Edition, Banker G.S. and Rhodes C.T. (Eds.) Marcel Dekker, Inc. New York 2002 and,,The Theory and Practice of Industrial Pharmacy", Lachman L., Lieberman H. and Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The respective descriptions are incorporated by reference and form part of the present:

disclosure.

The medicament obtained according to the present invention may, for example, be administered parentally in combination with conventional injectable liquid carriers, * .. . such as water or suitable alcohols. Conventional pharmaceutical excipients for S...

injection, such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions. These medicaments may for example be injected intramuscularly, intraperitoneally, or intravenously. The med icament obtained according to the present invention may also be administered topically, e.g. by means of a transdermal therapeutic system (US), or via a suppository.

In a preferred embodiment of the present invention, the med icament is suitable for oral administration.

Suitable oral administration forms include tablets, dragees, capsules, syrups, gels, juices (oil-or water-based), chewing gums, sprays, aqueous or oily suspensions, or dry powdered forms, preferably in a sachet, suitable for reconstitution with water or other suitable liquid medium before use.

Other suitable oral administration forms are multiparticulate formulations, preferably microtablets, microparticles, nanoparticles, pellets or granules, optionally compressed into a tablet, filled into a capsule or suspended in a suitable liquid.

Suitable liquids are known to those skilled in the art.

The inventively obtained medicament may also comprise at least one substituted piperazine compound of general formula I given above at least partially in sustained-release form. By incorporating one or more of the substituted piperazine compounds of general formula I given above at least partially or completely into a sustained-release form it is possible to extend the duration of their effect, allowing for the beneficial effects of such a sustained release form, e.g. the maintenance of optimal therapeutical plasma or tissue concentrations.

Suitable sustained-release forms as well as materials and methods for their preparation are known to those skilled in the art, e.g. from the tables of contents from *.

Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. and:. . : Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); Handbook of Pharmaceutical Controlled Release Technology", Wise, D.L. (Ed.), Marcel Dekker, Inc. New York, (2000);"Controlled Drug Delivery", Vol. I, Basic Concepts, Bruck, S.D. * (Ed.), CRC Press Inc., Boca Raton (1983) and from Takada, K. and Yoshikawa, H.,

S

Oral Drug delivery", Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), " p...

John Wiley & Sons, Inc., New York (1999), Vol. 2,728-742; Fix, J., Oral drug: delivery, small intestine and colon", Encylopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respective descriptions are incorporated by reference and are part of the present

disclosure.

If the medicament obtained according to the present invention comprises at least one of the substituted piperazine compounds of general formula I at least partially in a sustained-release form, said sustained release may preferably be achieved by the application of at least one coating or provision of a matrix comprising at least one sustained- release material.

The sustained-release material is preferably based on an optionally modified, water-insoluble, natural, semisynthetic or synthetic polymer, or a natural, semisynthetic or synthetic wax or fat or fatty alcohol or fatty acid, or on a mixture of at least two of these afore mentioned components.

The water-insoluble polymers used to produce a sustained-release material are preferably based on an acrylic resin, which is preferably selected from the group of poly(meth)acrylates, particularly preferably poly(Ci 4alkyl (meth)acrylates, poly(C,4dialkylamino(C14alkyl (meth)acrylates and/or copolymers or mixtures thereof, and very particularly preferably copolymers of ethyl acrylate and methyl methacrylate with a monomer molar ratio of 2:1 (Eudragit NE3OD ), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate-chloride with a monomer molar ratio of 1:2:0.1 (Eudragit RS ), copolymers of ethyl acrytate, methyl methacrylate and trimethylammonium ethyl methacrylate-chloride with a monomer molar ratio of 1:2:0.2 (Eudragit RL ), or a mixture of at least two of:. . the above-mentioned copolymers. These coating materials are commercially available as 30 wt.% aqueous latex dispersions, i.e. as Eudragit RS300 , Eudragit NE3OD or Eudragit RL3OD , and may also be used as such for coating purposes.

In another embodiment, the sustained-release material is based on water-insoluble cellulose derivatives, preferably alkyl celluloses, particularly preferably ethyl cellulose, or cellulose esters, e.g. cellulose acetate. Aqueous ethyl cellulose dispersions are commercially available, for example, under the trademarks Aquacoat or Surelease .

As natural, semisynthetic or synthetic waxes, fats or fatty alcohols, the sustained-release material may be based on carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate, glycerol ditripalmitostearate, microcrystalline wax, cetyl alcohol, cetylstearyl alcohol or a mixture of at least two of these components.

The afore mentioned polymers of the sustained-release material may also comprise a conventional, physiologically acceptable plasticizer in amounts known to those skilled in the art.

Examples of suitable plasticizers are lipophilic diesters of a C6-C40 aliphatic or aromatic dicarboxylic acid and a C1-C8 aliphatic alcohol, e.g. dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, hydrophilic or lipophilic citric acid esters, e.g. triethyl citrate, tributyl citrate, acetyltributyl citrate or acetyltriethyl citrate, polyethylene glycols, propylene glycol, glycerol esters, e.g. triacetin, Myvacet (acetylated mono-and diglycerides, C23HO5 to C25H4704, medium-chain triglycerides (Miglyol ), oleic acid or mixtures of at least two of said plasticizers.

Aqueous dispersions of Eudragit RS and optionally Eudragit RL preferably contain triethyl citrate. The sustained-release material may comprise one or more plasticisers in amounts of, for example, 5 to 50 wt. % based on the amount of polymer(s) used.

The sustained-release material may also contain other conventional auxiliary substances known to those skilled in the art, e.g. lubricants,coloured pigments or surfactants.

S * S S

The medicament obtained according to the present invention may also have at least:* one enteric coating which dissolves as a function of pH. Because of this coating, the medicament can pass through the stomach undissolved and the compounds of general formula I are only released in the intestinal tract. The enteric coating **.

preferably dissolves at a pH of between 5 and 7.5. S...

* S* S The enteric coating may be based on any enteric material known to those skilled in * the art, e.g. on methacrylic acid/methyl methacrylate copolymers with a monomer molar ratio of 1:1 (Eudragit L ), methacrylic acid/methyl methacrylate copolymers with a monomer molar ratio of 1:2 (Eudragit S ), methacrylic acid/ethyl acrylate copolymers with a monomer molar ratio of 1:1 (Eudragit L3OD-55 ), methacrylic acid/methyl acrylate/methyl methacrylate copolymers with a monomer molar ratio of 7:3:1 (Eudragit FS ), shellac, hydroxypropyl methyl cellulose acetate-succinates, cellulose acetate-phthalates or a mixture of at least two of these components, which can optionally also be used in combination with the above-mentioned water-insoluble poly(meth)acrylates, preferably in combination with Eudragit NE3OD and/or Eudragit RL and/or Eudragit RS .

The coatings of the medicament of the present invention may be applied by the conventional processes known to those skilled in the art, e.g. from Johnson, J.L., Pharmaceutical tablet coating", Coatings Technology Handbook (Second Edition), Satas, D. and Tracton, A.A. (Eds), Marcel Dekker, Inc. New York, (2001), 863-866; Carstensen, 1., ,,Coating Tablets in Advanced Pharmaceutical Solids", Swarbrick, J. (Ed.), Marcel Dekker, Inc. New York (2001), 455-468; Leopold, C.S., Coated dosage forms for colon-specific drug delivery", Pharmaceutical Science & Technology Today, 2(5), 197-204 (1999), Rhodes, C.T. and Porter, S.C., Coatings, in Encyclopedia of Controlled Drug Delivery. Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 1, 299-311. The respective descriptions are incorporated by reference

and are part of the disclosure.

In another embodiment, the medicament obtained according to the present invention may contain one or more of the substituted piperazine compounds of general formula I not only in sustained-release form, but also in non-retarded form. By combination with the immediately released form, a high initial dose can be achieved for the rapid *.

onset of the beneficial effect. The slow release from the sustained release form then:. : prevents the beneficial effect from diminishing.

Preferred is the administration of the piperazine compound at a dosage of 0.1 -50 * mg/kglday, more preferred 0.15 -10 mg/kg/day, even more preferred 0.2-5 mg/kg/day:;:; Preferably the medicament is designed for once daily, twice daily, or three times daily administration. More preferably the medicament is designed for once daily or twice daily administration, most preferably for once daily administration.

The inventively used substituted piperazine compounds can be prepared as outlined in Merce-Vidal, R.; Frigola-Constansa, J; Pares-Corominas, J. EP 502 786; Merce-Vidal, R.; Frigola-Constansa, J; Pares-Corominas, J. EP 497 659; and the references cited therein. The respective description is hereby incorporated by

reference and forms part of the disclosure.

The inventively used substituted piperazine compounds may, for example, be obtained by the following process, according to which at least one compound of general formula II, [ G-N N Xe II, wherein G has the meaning given above and X represents chlorine, bromine, iodine, mesyloxy and tosyloxy, is reacted with at least one compound of general formula Ill, H-N"T" R8

B Ill,

wherein A, B, D and R8 have the meaning given above, in at least one reaction medium, preferably in a reaction medium selected from the group consisting of dimethylsulfoxide, dimethylformamide, ethanol, n-propanol, isopropanot, n-butanol, n-hexane, n-heptane, toluene, ether and diphenylether, in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of sodium carbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, cesium hydroxide, pyridine, triethylamine, e.

diisopropylethylamine and potassium tert-butoxide, to yield a substituted piperazine compound of general formula I, *:::: /__\I HN N-fCH2±E /n I, R8 wherein G has the meaning given above, n is 4 and E represents A whereby A, B, D and R8 have the meaning given above, which is optionally isolated and/or optionally purified.

The compounds of general formula II may be prepared as described in J. P. Yevich et al. Journal of Medicinal Chemistry 1986, Vol. 29, 359. The respective description is hereby incorporated by reference and forms part of the disclosure.

The inventively used substituted amine compounds may also be obtained by the following process, according to which at least one compound of general formula IV, G-N N+CH2±X /n IV, wherein G and n have the meaning given above and X represents a leaving group, preferably a leaving group selected from the group consisting of chlorine, bromine, mesyloxy and tosyloxy, is reacted with at least one compound of general formula Ill, H-N'1 R8

B S. Ill,

wherein A, B, D and R8 have the meaning given above, in at least one reaction medium, preferably in a reaction medium selected from the group consisting of dimethylsulfoxide, dimethylformamide, ethanol, n-propanol, isopropanol, n-butanol, n-: ** hexane, n-heptane, toluene, ether and diphenylether, in the presence of at least one e.

base, preferably in the presence of at least one base selected from the group.. . consisting of sodium carbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, cesium hydroxide, to yield a substituted piperazine compound of general formula I, G-N N-±CH2±E /n I,

R

wherein 0 and n have the meaning given above and E represents A whereby A, B, 0 and R8 have the meaning given above, which is optionally isolated and/or optionally purified.

The inventively used substituted amine compounds may also be obtained by the following process, according to which at least one compound of general formula V, XCH2-E wherein E, n and p have the meaning given above and X represents a leaving group, preferably a leaving group selected from the group consisting of chlorine, bromine, mesyloxy and tosyloxy, is reacted with at least one compound of general formula VI,

G-N NH \I VI,

wherein G has the meaning given above, in at least one reaction medium, preferably in a reaction medium selected from the group consisting of dimethylsulfoxide, dimethylformamide, ethanol, n-propanol, isopropanol, n-butanol, n-hexane, n-heptane, toluene, ether and diphenylether, in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of sodium carbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, cesium hydroxide, to yield a compound of general formula I, G-N N-±CH2+E \J\ In I, wherein G, E and n have the meaning given above, which is optionally isolated and/or optionally purified.

The inventively used substituted amine compounds may also be obtained by the following process, according to which at least one compound of general formula VII, HN N+CH2I E \J\ /n VII, wherein E and n have the meaning given above, is reacted with at least one compound of general formula G-X, wherein G has the meaning given above and X represents a leaving group, preferably a leaving group selected from the group consisting of chlorine, bromine, mesyloxy and tosyloxy, in at least one reaction medium, preferably in a reaction medium selected from the group consisting of dimethylsulfoxide, dimethylformamide, ethanol, n-propanol, isopropanol, n-butanol, n-hexane, n-heptane, toluene, ether and diphenylether, in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of sodium carbonate, sodium hydroxide, potassium hydroxide, potassium *: carbonate, cesium carbonate, cesium hydroxide, to yield a compound of general formula I,

I

G-N N-fCH2) E \J\ In I, wherein D, E, n and p have the meaning given above, which is optionally isolated and/or optionally purified.

During the processes described above the protection of sensitive groups or of reagents may be necessary and/or desirable. The introduction of conventional protective groups as well as their removal may be performed by methods well-known to those skilled in the art.

Salts of the inventively used piperazine compounds of general formula I, may be obtained by a process, wherein at least one compound of general formula I having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presence of a suitable reaction medium. Suitable reaction media include, for example, any of the ones given above. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are e. g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.

Salts of the inventively used substituted piperazine compounds of general formula I may also be prepared by a method, wherein at least one compound of general formula I having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. Suitable bases are e. g.

hydroxides, carbonates or alkoxides, which include suitable cations, derived e. g.

from alkaline metals, alkaline earth metals or organic cations, e. g.

wherein n is 0, 1, 2, 3 or 4 and R represents a branched or unbranched C14-alkyl-radical. Suitable reaction media are, for example, any of the ones given above.

The term "solvate" according to this invention is to be understood as meaning any form of the substituted piperazine compounds of general formula I in which they have *: .*.

attached to it via non-covalent binding another molecule (most likely a polar solvent) S...

especially including hydrates and alcoholats, e.g. methanolat. I S * *

S

Solvates, preferably hydrates, of the inventively used substituted piperazine compounds of general formula I, or of corresponding salts thereof may also be obtained by standard procedures known to those skilled in the art.

Those skilled in the art understand that the term substituted piperazine compounds as used herein is to be understood as encompassing derivatives such as ethers, esters and complexes of these compounds as well. The term "derivatives" as used in this application is defined here as meaning a chemical compound having undergone a chemical derivation starting from an acting (active) compound to change (ameliorate for pharmaceutical use) any of its physicochemical properties, especially a so-called prodrug, e. g. their esters and ethers. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e. g. in Krogsgaard-Larsen et al., Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002). The respective description is hereby incorporated by reference and forms part of the disclosure.

The purification and isolation of the inventively used substituted piperazine compounds of general formula (I), of a corresponding salt, or solvate or any intermediate thereof may, if required, be carried out by conventional methods known to those skilled in the art, e. g. chromatographic methods or recrystallization. * . * S * S. I.. * * S S. * S * 5 5 *5 *S **** * S US.. *USb S 5 S. S

Pharmacological Methods: I) BINDING TO SEROTONIN RECEPTOR 5-HT6 Cell membranes of HEK-293 cells expressing the 5HT6-human recombinant receptor were supplied by Receptor Biology. In said membranes the receptor concentration is 2.18 pmol/mg protein and the protein concentration is 9.17 mg/mI. The experimental protocol follows the method of B. L. Roth et al. [B. L. Roth, S. C. Craigo, M. S. Choudhary, A. Uluer, F. J. Monsma, Y. Shen, H. Y. Meltzer, D. R. Sibley: Binding of Typical and Atypical Antipsychotic Agents to 5-Hydroxytryptamine-6 and Hydroxytryptamine-7 Receptors. The Journal of Pharmacology and Experimental Therapeutics, 1994, 268, 1403] with the following slight changes. The respective part of the literature description is hereby incorporated by reference and forms part of the *

disclosure. 4** * p *

The commercial membrane is diluted (1:40 dilution) with the binding buffer: 50 mM Tris-HCI, 10 mM MgCl2, 0.5 mM EDTA (pH 7.4). The radioligand used is [3H1-LSD at..

a concentration of 2.7 nM with a final volume of 200 p1. Incubation is initiated by adding 100 p1 of membrane suspension, ( 22.9 pg membrane protein), and is . prolonged for 60 minutes at a temperature of 37 C. The incubation is ended by fast filtration in a Brandel Cell Harvester through fiber glass filters made by Schleicher & Schuell GF 3362 pretreated with a solution of polyethylenimine at 0.5 %. The filters are washed three times with three milliliters of buffer Tris-HCI 50 mM pH 7.4. The filters are transferred to flasks and 5 ml of Ecoscint H liquid scintillation cocktail are added to each flask. The flasks are allowed to reach equilibrium for several hours before counting with a Wallac Winspectral 1414 scintillation counter. Non-specific binding is determined in the presence of 100 pM of serotonin. Tests were made in triplicate. The inhibition constants (Ki, nM) were calculated by non-linear regression analysis using the program EBDNLIGAND described in Munson and Rodbard, Analytical Biochemistry, 1980, 107, 220, the respective part of which is hereby incorporated by reference and forms part of the disclosure.

II.) FOOD INTAKE MEASUREMENT (BEHAVIOURAL MODEL): Male W rats (200-270 g) obtained from Harlan, S.A. are used. The animals are acclimatized to the animal facility for at least 5 days before they are subjected to any treatment. During this period the animals are housed (in groups of five) in translucid cages and provided with food and water ad libitum. At least 24 hours before the treatment starts, the animals are adapted to single-housing conditions.

The acute effect of the substituted piperazine compounds according to the present invention in fasted rats is then determined as follows: The rats were fasted for 23 hours in their single homecages. After this period, the rats are orally or intraperitoneally dosed with a composition comprising a substituted piperazine compound or a corresponding composition (vehicle) without said substituted piperazine compound. Immediately afterwards, the rat is left with preweighed food and cumulative food intake is measured after 1, 2, 4 and 6 hours.

SI

Said method of measuring food intake is also described in the literature publications S I. of Kask et a!., European Journal of Pharmacology 414 (2001), 215-224 and Turnbull et al., Diabetes, Vol. 51, August 2002. The respective parts of the descriptions are hereby incorporated by reference and form part of the disclosure.

The present invention is illustrated below with the aid of examples. These illustrations are given solely by way of example and do not limit the general spirit of the present invention.

Examples

Example 1: 8-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1 -yl)butyl]-8-azaspiro(4.5ldecane-7,9-dione, Example 2: 3-(4-(4-(1 H-benzo(d]imidazole-1 -yl)butyl)piperazin-1 -yl)benzo(d]isoth iazole 1H-NMR (CDCI3, 100 MHz) 6 1.56 (m, 2H); 1.96 (m, 2H); 2.42 (t, J = 7.1 Hz, 2H); 2.61 (m, 4H); 3.53 (m, 4H); 4.19 (t, J = 7.0 Hz, 2H); 7.10-7.50 (m, 5H); 7.70-7.90 (m, 4H) JR (film): 2944, 2828, 1495, 1459, 1422, 1285, 746 cm1 * * * . S a.

Example3:

3-(4-(4-(4-chloro-1 H-pyrazol-1 -yl)butyl)piperazi n-I -yl)benzo[d]-isothiazole A mixture of 67 g (0.19 mol) 8-(1,2-benzisothiazole-3-yl)-8-aza-5-azaspiro[4.5]decan bromide, 20.5 g (0.2 mol) 4-chioropyrazole and 41 g (0.3 mol) potassium carbonate a:s are heated to 140 C for 18 hours in 300 mL dimethylformamide. The solvent is I..' evaporated and chloroform is added. The organic phase is washed with water and dried over sodium sulfate. After evaporation of the solvent the title compound (60 g, %) is obtained as a liquid oil.

1H-NMR (CDCI3, 100 MHz) 6 1.50 (m, 2H); 1.85 (m, 2H); 2.45 (t, J = 7.2 HZ, 2H); 2.60 (t, J = 4.7 Hz, 4H); 3.53 (t, J = 5.0 Hz, 4H); 4.07 (t, J = 7.0 Hz; 2H); 7.35 (m, 4H); 7.85 (m, 2H) JR (film): 2943, 2815, 1493, 1451, 1423, 1383, 1307, 1261, 970, 739, 613 cm1 Example 4: 3-(4-(4-(4,5-dichloro-2-methyl-1 H-imidazol-I -yl)butyl)piperazin-I -yl)benzo(d]isoth jazole 1H-NMR (CDCI3, 100 MHz) 6 1.55-1.85 (m, 4H); 2.34-2.49 (m, 5H); 2.62 (t, J = 4.7 Hz, 4H); 3.53 (t, J = 5.0 Hz, 4H); 3.84 (t, J = 7.0 Hz, 2H); 7.37 (m, 2H); 7.83 (m, 2H) IR (film): 2944, 2816, 1533, 1493, 1422, 1380, 1280, 1246, 1139, 1017, 754, 665 cm Example 5: 3-(4-(4-(I H-I,2,4-triazol-I -yl)butyl)piperazin-1 -yl)benzo[d]isothiazole 1H-NMR (CDCI3, 100 MHz) 1.55 (m, 2H); 1.97 (m, 2H); 2.45 (t, J = 7.3 Hz, 2H); 2.64 (m, 4H); 3.55 (m, 4H); 4.22 (t, J = 6.9 Hz, 2H); 7.35 (m, IH); 7.46 (m, IH); 7.80 (d, J = 8Hz, IH); 7.90 (d, J = 8 Hz, IH); 7.95 (s, IH); 8.08 (s, IH) lR (film): 2943, 2809, 1493, 1426, 1275, 1152, 1007, 738, 678 cm1 Example 6: 1 -(4-(I H-pyrazol-I -yl)butyl)-4-(1 -methyl-I H-imidazol-2-yl)piperazine 1H-NMR (COd3, 100 MHz) 1.52 (m, 2H); 1.85 (m, 2H); 2.45 (t, J = 7.2 Hz, 2H); 2.60 (t, J = 4.7 Hz, 4H); 3.53 (t, J = 5.0 Hz, 4H); 4.07 (t, J = 7.0 Hz, 2H); 7.35 (m, 4H); 7.85 (m, 2H) IR(film): 2943, 2812, 1525, 1509, 1469, 1455, 1282, 1137, 751 cm1 Example 7: 3-(4-(4-(I H-benzo(d]imidazole-I -yl)butyl)piperazin-1 -: yl)benzo(d]isothiazole hydrochloride Example 8: 3-(4-(4-(4-chloro-1 H-pyrazol-I -yl)butyl)piperazin-1 -yl)benzo(d]isothiazole hydrochloride *S.. * * **1* * * * S. S

Pharmacological data: The binding of the substituted piperazine compounds of general formula Ito the 5-HT6 receptor was determined as described above.

The binding results for some of these compounds are given in the following table: Compound according Compound number Binding to 5-HT6 to example receptor r/o] I E-5261 55.7 2 E-5323 81.1 3 E-4890 50 4 E-6406 43.4 7 E-5529 76.7:. . * ** 8 E-6383 51.7 * S * S S S. 55 55*S * * * S.. SSS* * S S S. *

Claims

Claims: Use of at least one substituted piperazine compound of general

formula I, /_\/ _ G-N N CH21 E /n I, wherein n is 1,2,3,4,5 or6; G represents ID2. * I-. a a R3..L<R1 ii I *.*ss

S-N

wherein R1, R2, R3 and R4, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, -C1-5-alkyl, -C2-5-alkenyl, -O-Ci-5-alkyl, -S-C1-5-alkyl, -C(0)-OH, -C(=O)-C1-5-alkyl, -C1..5-alkylene-C(=O)-OH, -C(=O)-O-C1-5-alkyl, -O-C(=O)-C1-5-alkyl, F, Cl, Br, I, -CN, -CE3, -OCF3, -SCF3, -OH, -SH, -NH2, -NH(C1-5-alkyl), -N(C1-5-alkyl)2, -NH(C2-5- alkenyl), -N(C2-5-alkenyl)2, -NO2, -CHO, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH(C1-5-alkyl), -C(=O)-N(C1-5-alkyl)2, -S(=O)2-C1-5-alkyl, -S(=O)2-phenyl, - S(=O)2-OH, -NH-C(=O)-Ci-5-alkyl, -NH-C(=O)-phenyl, -NH-S(=O)2-phenyl, -N H-S(=O)2-C1-5-alkyl, -S(=O)2-NH-phenyl, -S(=O)2-NH-Ci-5-alkyl and -S(=O)2-N(Ci -5-alkyl)2; or G represents N-( wherein R6 represents a radical selected from the group consisting of hydrogen, -C1-5-alkyl, -C(=O)-C1 -5-alkyl and -C(=O)-O-C1-5-alkyl; E represents R8 * * * S S *S 55 wherein the dotted line represents an optional chemical bond, 5S** A represents C-R7 and B represents N * ** : or A represents N and B represents C-R1 or A represents N and B represents N or A represents C-R7 and B represents C-R1 and D represents N or C-R9; or E represents E-<T R8;

-

wherein A represents NR6 and B represents N or A represents NR6 and B represents C-R1 and D represents N or C-R9; or E represents or R7, R8, R9 and R10, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, -C1-5-alkyl, -C2.5-alkenyl, -O-C1-5-alkyl, -S-C1-5-alkyl, -C(=O)-OH, -C(=O)-C1-5-alkyl, -C-1..5- alkylene-C(=O)-OH, oxo (=0), thioxo (=S), -C(=0)-O-C1-5-alkyl, -0-C(=O)-C1.5- alkyl, F, Cl, Br, I, -CN, -CF3, -OCF3, -SCF3, -OH, -SH, -NH2, -NH(C1-5-alkyl), - N(Ci-5-alkyl)2, -NH(C2-5-alkenyl), -N(C2-5-alkenyl)2, -NO2, -CHO, -CF2H, - CFH2, -C(=O)-NH2, -C(=O)-NH(C1-5-alkyl), -C(=O)-N(C1..5-alkyl)2, -S(=O)2-C1..5- alkyl, -S(=O)2-phenyl, -S(=O)2-OH, -NH-C(=O)-C1-5-alkyl, -NH-C(=O)-phenyl, -S...

NH-S(=O)2-phenyl, -NH-S(=O)2-Ci-5-alkyl, -S(=O)2-NH-phenyl, -S(=O)2-NH-C1.. S..

5-alkyl, -S(=0)2-N(Ci-5-alkyl)2, phenyl, pyrrolyl, pyridinyl, phenoxy and benzyl; whereby said cyclic substituents pyrrolyl, pyridinyl, -S(=0)2-phenyl, -NHC(0)-phenyl, -NH-S(=0)2-phenyl, -S(=0)2-NH-phenyl, phenyl, phenoxy and benzyl may be unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, F, Cl, Br, -CN, -CF3, -OCF3, -SCF3, -OH, -SH, -NH2 and NO2; or optionally R8 and R' together form a (CH2)m910UP, wherein m is 3 014, or a -CH=CH-CH=CH-group; or optionally R8 and R9 together form a -(CH2)k-group, wherein k is 3 or 4, or a -CH=CH-CH=CH-group or a -CH=C(CH3)-C(CH3)CH-group or a -N=CHCH=CH-group; or optionally R7 and R1 together form a -CH=CH-CH=CH-group; R11 and R12, independently of one another, in each case represent -C1-5-alkyl; or R11 and R12 together form a -(CH2)q-group, wherein q is 3 or 4; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof; for the manufacture of a medicament for the prophylaxis and/or treatment of a disorder or disease related to food intake.

2. Use of a compound according to claim 1, characterized in that n isl,2,3,4,5or6; * S Grepresents * S..

R2 *....S :.

R3y-1Rl

S-N

wherein R1, R2, R3 and R4, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, - C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-N(CH3)2, -C(=O)-NH-C2H5, -C(=O)- N(C2H5)2, -O-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, - C(=O)-OH, -C(=O)-O-CH3, -C(=O)-O-C2H5, -C(=O)-O-CH2-CH2-CH3, -C(=O)-O- CH(CH3)2, -C(=O)-O-C(CH3)3, F, Cl, Br, I, -CN, -NH2, -NH-CH3, -NH-C2H5, - NH-CH2-CH2-CH3, -NH-CH(CH3)2, -NH-C(CH3)3, -NH-CH(CH3)(C2H5), -N(CH3)2, -N(C2H5)2 and -NO2; N==(.

or G represents wherein R6 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -C(=O)-O-C H3, -C(=O)-O-C2H5, -C(0)-O-CH2-CH2-CH3, - C(=O)-O-CH(CH3)2, -C(=O)-O-C(CH3)3, -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-CH2-CH2-CH3, -C(=O)-CH(CH3)2 and -C(=O)-C(CH3)3; R8 E represents A *. . wherein the dotted line represents an optional chemical bond, A represents C-R7 and B represents N rr * * S S A represents N and B represents C-R1 S... * S or

A represents N and B represents N.. : or A represents C-R7 and B represents C-R1 and 0 represents N or C-R9; or E represents F_TJLJ or R7, R8, R9 and R10, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, vinyl, allyl, -CF3, - C(=O)-NH2, -C(=0)-NH-CH3, -C(=O)-N(CH3)2, -C(=O)-NH-C2H5, -C(=O)- N(C2H5)2, -O-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -0-C(CH3)3, - C(=O)-OH, -C(=O)-O-CH3, -C(=O)-O-C2H5, -C(=O)-O-CH2-CH2-CH3, -C(=O)-O- CH(CH3)2, -C(=O)-O-C(CH3)3, F, Cl, Br, I, oxo (=0), thioxo (=S), -CN, -NH2, - NH-CH3, -NH-C2H5, -NH-CH2-CH2-CH3, -NH-CH(CH3)2, -NH-C(CH3)3, -NH- CH(CH3)(C2H5), -N(CH3)2, -N(C2H5)2, -NO2, -NH-S(=O)2-phenyl, -NH-S(0)2- CH3, -NH-S(=O)2-C2H5, -NH-S(=O)2-CH2-CH2-CH3, -NH-S(=O)2-CH2-CH2-CH2- CH3, -NH-C(=O)-phenyl, -NH-C(=O)-CH3, -NH-C(0)-C2H5, -S(0)2-OH, -S(=O)2-N(CH3)2, pyrrolyl and phenyl; or optionally R8 and R9 together form a -(CH2)k--group, wherein k is 3 or 4, or a -CH=CH-CH=CH-group or a -CH=C(CH3)-C(CH3)=CH-group or a -N=CH-CH=CH-group; or optionally R7 and R1 together form a -CH=CH-CH=CH-group; *: .

S S

or optionally R8 and R1 together form a <CH2)mgrOup, wherein m 1s3 or 4, or.:.

a -CH=CH-CH=CH-group; R11 and R12, independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl and n-pentyl; or R11 and R12 together form a -(CH2)q-group, wherein q is 3 or 4; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

3. Use of a compound according to claim 1, characterized in that n is4; G represents R2 R1

S--N

wherein R1, R2, R3 and R4, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CE3, -O-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Brand I; i".' q. * * or G represents * * * * * .* I111_..*. N='( :

wherein R6 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl and n-pentyl; E represents R8 wherein the dotted line represents an optional chemical bond, A represents C-R7 and B represents N or A represents N and B represents C-R1 or A represents N and B represents N or A represents C-R7 and B represents C-R1 and D represents N or C-R9; or E represents or *%,4

S S ISa'

R7 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; R8 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, F, Cl, Br and I; R9 represents a radical selected from the group consisting of hydrogen, -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; R1 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; or optionally R8 and R9 together form a -(CH2)k-group, wherein k is 3 or 4, or a -CH=CH-CH=CH-group or a -CH=C(CH3)-C(CH3)CH-group or a -NCH-C H=CH-group; or optionally R7 and R1 together form a -CH=CH-CH=CH-group; or optionally R8 and R1 together form a -(CH2)m-group, wherein m is 3 or 4, or a -CH=CH-CH=CH-group; R11 and R12, independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl and n-pentyl; or R11 and R12 together form a {CH2)qgrOUp, wherein q is 3 cr4; I,,"; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof. *:. .: I IS.

4. Use of a compound of general formula Ia according to one or more of claims I to 3, p Ia, wherein R1 a R2 a R3 a and R 4a, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, -O-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Brand I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

5. Use of a compound of general formula lb according to one or more of claims Ito 3, R7b R2" R3J Rib R4b NN Nb *. :* S.N Ib, wherein R, R2b R3b and R4b, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, *.

-O-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br and I; and R7b represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Brand I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

6. Use of a compound of general formula Ic according to one or more of claims Ito 3, 9c R2C R R8C R4C N Ri Oc Ic, wherein R, R2C, Rand R4C, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, -O-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Brand I; RSC represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, F, Cl, Br and I; R represents a radical selected from the group consisting of hydrogen, -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; and RbOC represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Brand I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

7. Use of a compound of general formula Id according to one or more of claims I to 3, 9d R2c1 R8d Id, wherein R, R2d, Rsd and R, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, * ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, -O-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br and I; Rld represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Brand I; :;:: RBd represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -C F3, F, Cl, Br and I; and R9d represents a radical selected from the group consisting of hydrogen, -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

8. Use of a compound of general formula le according to one or more of claims 1 to 3, R2 R4etN R8e le, wherein R, R2, R and R, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, -O-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br and I; R7 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, :*.

n-pentyl, F, Cl, Br and I; 0 S S...

and.. : R8 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CE3, F, Cl, Br and I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

9. Use of a compound of general formula If according to one or more of claims I to 3,

R \ R8 N3

_-NciiN N R10 R6 If, wherein R6 represents a radical selected from the group consisting of *.

hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl and n-pentyl; R8 represents a radical selected from the group consisting of hydrogen, * methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, -CF3, F, Cl, Br and I; S.. I...

S

S

R represents a radical selected from the group consisting of hydrogen, -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; and R10 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br and I; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

10. Use of a compound according to one or more of claims I to 9 selected from the group consisting of [1] 8-[4-(4-benzo[d]isoth iazol-3-yl-piperazin-I -yl)butyl]-8-azaspiro[4.5]decane-7,9-dione, [2] 3-(4-(4-(1 H-benzo[d]imidazole-1 -yl)butyl)piperazin-1 -yl)benzo[d]isothiazole, [3] 3-(4-(4-(4-chloro-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)benzo[d]isothiazole, [4] 3-(4-(4-(4, 5-dichloro-2-methyl-1 H-imidazol-I -yl)butyl)piperazin-1 -yl)benzo[d]isothiazole hydrochloride, * * a.

[5] 3-(4-(4-(1 H-i,2,4-triazol-i -yl)butyl)piperazin-1 -yI)benzo[dlisothiazole [6] 1 -(4-(1 H-pyrazol-1 -yI)butyl)-4-(1 -methylI H-imidazol-2-yl)piperazine.*. *.. * a a...

[7] 3-(4-(4-(I H-benzo[d]imidazole-I -yI)butyl)piperazin-1 -*: : : yI)benzo[d]isoth iazole hydrochloride and [8] 3-(4-(4-(4-chloro-1 H-pyrazol-1 -yl)butyl)piperazin-I -yl)benzo[d]isothiazole hydrochloride; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

II. Use of at least one substituted piperazine compound of general formula I, Ia, Ib, Ic, Id, le or If according to one or more of claims ito 10 for the manufacture of a med icament for the regulation of appetite; for the maintenance, increase or reduction of body weight; or for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), more preferably for the prophylaxis and/or treatment of obesity.

12. Use of at least one substituted piperazine compound of general formula I, Ia, Ib, Ic, Id, le or If according to one or more of claims Ito 10 for the manufacture of a medicament for the prophylaxis and/or treatment of stroke; seizures; migraine; head trauma; epilepsy; irritable colon syndrome; irritable bowel syndrome; bipolar disorders; neurodegenerative disorders, preferably selected from the group consisting of Morbus Alzheimer, Morbus Parkinson, Morbus Huntington and Multiple Sclerosis; schizophrenia; convulsions; or hyperactivity disorder (ADHD, attention deficit/hyperactivity disorder). * S & S

I S.-* I... I * 5 e S