GB2435829A

GB2435829A - Pyrimidinyl-2-piperazine compounds for use in disorders related to food intake

Info

Publication number: GB2435829A
Application number: GB0604782A
Authority: GB
Inventors: Helmut Heinrich Buschmann; Jordi-Ramon Quintana Ruiz; Ramon Merce Vidal; Xavier Codony Soler
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-03-09
Filing date: 2006-03-09
Publication date: 2007-09-12
Also published as: GB0604782D0

Description

Use of substituted pyrimidinyl-2-piperazine compounds for the treatment

of food related disorders The present invention relates to the use of pyrimidinyl-2-piperazine compounds of general formula I, R1/NCNCH2) I, for the prophylaxis andlor treatment of disorders or diseases that are at least partially mediated via 5-HT6 receptors. * * * S S SS *S

The superfamily of serotonin receptors (5-HI) 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:SS al., Biochem. Biophys. Res. Commun., 1993, 193, 268] and in humans [R. Kohen, et S...

al., J. Neurochem., 1996, 66, 47].

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.

I

Surprisingly, it has been found that the substituted pyrimidinyl-2-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 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 pyrimidinyl-2-piperazine compound of general formula I, R1/NCNcH2) E * * I, wherein n is 1,2,3,4,5 or6; *** . R1 represents H, -C1.5-alkyl, -OH, -O-C1..5-alkyl, F, Cl, Br or I; **.* * S * S. S E represents wherein the dotted line represents an optional chemical bond, A represents C-R2 and B represents N or A represents N and B represents C-R5 or A represents N and B represents N or A represents C-R2 and B represents C-R5 and 0 represents N or C-R4; or E represents R3

AB

wherein A represents NR6 and B represents N or A represents NR6 and B represents C-R5; and D represents N or C-R4; R2, R3, R4 and R5, 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-atkyl, -C(=O)-OH, -C(=O)-Cj..5-alkyl, -C1..5-alkylene-C(0)-OH, oxo (=0), thioxo (=S), -C(=O)-0-C1..5-alkyl, -0-C(=0)-C1..5-alkyl, F, Cl, Br, I, -CN, -CF3, -OCF3, -SCF3, -OH, -SH, -N H2, -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(Ci..5-alkyl), -C(0)-S. 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, -NH-S(=O)2-phenyl, -NH-S(=O)2-C1..5-alkyl, -S(=O)2-NH-phenyl, -S(=O)2-NH-C1.5-alkyl, -S(=O)2-N(C1.5-alkyl)2, phenyl, pyrrolyl, imidazolyl, pyridinyl, *: ** phenoxy and benzyl; whereby said cyclic substituents pyrrolyl, imidazolyl, pyridinyl, -S...

S(=O)2-phenyl, -NH-C(=0)-phenyl, -NH-S(=O)2-phenyl, -S(=O)2-N H-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 R3 and R5 together form a -(CH2)m-group, wherein m is 3 or 4, a -CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R3 and R4 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-CHCH-group or a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R2 and R5 together form a -CH=CH-CH=CH-group; and 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; 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.

Ci..5alkyl 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. * . S *.

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, I-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, I-pentenyl and 2-methyl-I -propenyl. *** * S **S

C1..5-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 pyrimidinyl-2-piperazine compound of general formula I given above, wherein n isl,2,3,4,5or6; R' represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br or I; E represents wherein the dotted line represents an optional chemical bond, A represents C-R2 and B represents N or A represents N and B represents C-R5 or A represents N and B represents N or A represents C-R2 and B represents C-R5 and D represents N or C-R4; or E represents R3

B A *

wherein A represents NR6 and B represents N. ..: or A represents NR6 and B represents C-R5; *. **.*

and D represents N or C-R4; *:::: R2, R3, R4 and R5, 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(=0)-NH-C2H5, -C(=O)-N(C2H5)2, -O-CH3, -0-C2H5, -0- CH2-CH2-CH3, -O-CH(CH3)2, -O-C(CH3)3, -C(=0)-OH, -C(=O)-0-CH3, -C(=0)-0-C2H5, -C(0)-0-CH2-CH2-CH3, -C(0)-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-CH(CH3)-CH2-CH3, -NH-C(CH3)3, -NH-CH(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-C H2-CH2-CH3, -N H-S(=O)2-CH2-CH2-CH2-CH3, -N H-C(=0)-phenyl, -NH-C(=O)-CH3, -N H-C(=O)-C2H5, -S(=O)2-OH, -S(=O)2-N (CH3)2, pyrrolyl, imidazolyl and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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 and Br; or optionally R3 and R5 together form a (CH2)mgroup, wherein m is 3 or 4, a -CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R3 and R4 together form a -(CH2)k-group, wherein k is 3 or 4, or a - CHCH-CH=CH-group or a -CH=C(CH3)-C(CH3)=CH-group or a -N=CH-CHCH-group or a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R2 and R5 together form a -CH=CH-CH=CH-group; and 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(=O)-CH3, -C(=O)-C2H5, -C(=O)-CH2-CH2-CH3, -C(=O)-CH(CH3)2 and -C(0)-C(CH3)3; optionally in form of a physiologically acceptable salt thereof, or a corresponding * solvate thereof.

Particularly preferred is the use of at least one substituted pyrimidinyl-2-piperazine compound of general formula I given above, wherein n is4; R1 represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br or I; E represents r wherein the dotted line represents an optional chemical bond; A represents C-R2 and B represents N or A represents N and B represents C-R5 or A represents N and B represents N or A represents C-R2 and B represents C-R5; D represents N or C-R4; R2 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, I and phenyl; R3 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, -C(0)-N H2, -C(=O)-NH-CH3, -C(=O)-N(CH3)2, -C(=O)-NH-C2H5, -C(=O)-N(C2H5)2, -O-CH3, -0- C2H5, -O-CH2-CH2-CH3, -0-CH(CH3)2, -0-C(CH3)3, -C(=0)-OH, -C(=0)-0-CH3, -C(=O)-0-C2H5, -C(=O)-O-CH2-CH2-CH3, -C(=O)-O-CH(CH3)2, -C(=0)-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, -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(=0)-phenyl, -NH-C(=O)-CH3, -NH-C(=O)-C2H5, -S(=O)2-OH, -* S S(=O)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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 and Br; R4 represents a radical selected from the group consisting of hydrogen, oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br, I and phenyl; R5 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, I and phenyl; or optionally R3 and R5 together form a -(CH2)m-group, wherein m is 3 or 4, a -CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R3 and R4 together form a -(CH2)k-group, wherein k is 3 or 4, or a - CH=CH-CH=CH-group or a -CHC(CH3)-C(CH3)=CH-group or a -N=CH-CHCH-group or a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R2 and R5 together form a -CH=CH-CH=CH-group; 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 pyrimidinyl-2-piperazine compound of general formula Ia, * :. . * * 4a R),R3a R1aNN *.*

N * * * *. . Ia,

wherein R1a represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, CI, Br or I; R3a 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, - 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, -NO2, -NH-S(=O)2-phenyl, -NH-S(=0)2-CH3, -NH-S(=O)2-C2H5, -NH-S(0)2-CH2-CH2-CH3, -NH- S(=O)2-CH2-CH2-CH2-CH3, -NH-C(=0)-phenyl, -NH-C(0)-CH3, -NH-C(0)-C2H5, -S(=O)2-OH, -S(=O)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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 and Br; R42 represents a radical selected from the group consisting of hydrogen, oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br, I and phenyl; R5a 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, I and phenyl;

S S S..

or optionally R3 and R5 together form a -(CH2)m-group, wherein m is 3 or 4, a -CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R3 and R4a 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 a -CH=CCI-CH=CHgroup or a -CH=CH-CCI=CH-group; 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 pyrimidinyl-2-piperazine compound of general formula lb, R3b R1 b{ /NN2b N Ib, wherein Rib represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -0-C(CH3)3, F, CI, Br or I; R2b 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, CI, Br, I and phenyl; R3b 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, - 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-:. **1*

CH3, -C(=O)-O-C2H5, -C(=O)-.O-CH2-CH2-CH3, -C(=O)-O-CH(CH3)2, -C(=O)-O-a 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, -NO2, -NH- S(=O)2-phenyl, -NH-S(=O)2-CH3, -NH-S(=O)2-C2H5, -NH-S(0)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, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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, CI and Br; R4b represents a radical selected from the group consisting of hydrogen, oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, CI, Br, I and phenyl; or optionally R3b and R4b 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 a -CH=CCI-CH=CH-group or a -CH=CH-CCI=C H-group; 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 pyrimidinyl-2-piperazine compound of general formula Ic, R4% \ R R1C/NN R2 R5C

N Ic,

wherein R represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, S. tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, CI, Br or I; R2C 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, I and phenyl; S * S R3C 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, - 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, -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(=O)-C2H5, -S(=O)2-OH, -S(=O)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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, CI and Br; R4C represents a radical selected from the group consisting of hydrogen, oxo (0), thioxo (=S), -CE3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br, I and phenyl; R5C represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobuty!, n-pentyl, F, Cl, Br, I and phenyl; or optionally R3C and R5C together form a -(CH2)m-group, wherein m is 3 or 4, a -CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R3C and R4C 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 a -CHCCI-CH=CH-group or a -CHCH-CCI=CH-group; or optionally R2C and R5C together form a -CH=CH-CH=CH-group; * * *1 optionally in form of a physiologically acceptable salt thereof, or a corresponding s*. S solvate thereof. 0 S. * . * 0I * Also more particularly preferred is the use of at least one substituted pyrimidinyl-2-piperazine compound of general formula Id, 4d \ R3d R1dNCN Id, wherein Rid represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br or I; R3d 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, - 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, -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** S(=O)2-OH, -S(=O)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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 and Br; e. *.I.

R represents a radical selected from the group consisting of hydrogen, oxo (=0), *: thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br, I and phenyl; or optionally R3d and R4d together form a -(CH2)k-group, wherein k is 3 or 4, or a - CH=CH-CH=CH-group or a -CHC(CH3)-C(CH3)=CH-group or a -N=CH-CH=CH-group or a -CHCCI-CH=CH-group or a -CH=CH-CCI=CH-group; 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 pyrimidinyl-2-piperazine compound of general formula le,

N

/ -V--Ri e N2e N le, * * ** ** *S*I wherein * R1e represents H, methyl, ethyl, n-propyl, isopropyl, n-butyI, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Bror I; s.. *s.. *sS5

R2 represents a radical selected from the group consisting of hydrogen, methyl, *.:s ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br, I and phenyl; and R 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, -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, -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, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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 and Br; 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 pyrimidinyl-2-piperazine compound of general formula If, N R3 /

-N J

R1f1NN N R5

N I* ** If,

wherein * * S ** R1 represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, *S** tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, CI, Br or I; R3 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, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-N(CH3)2, -C(=O)-NH-C2H5, -C(=O)-N(C2H5)2, -O-CH3, -0- 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, -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(0)-C2H5, -S(=O)2-OH, - S(=O)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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, CI and Br; R5 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, I and phenyl; or optionally R3 and R5 together form a -(CH2)m-group, wherein m is 3 or 4, a -CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; 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 pyrimidinyl-2-piperazine compound selected from the group consisting of [1] 2-(4-(4-(1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)-pyrimidine, [2] 2-(4-(4-(3, 5-dimethyl-1 H-pyrazol-I -yl)butyl)piperazin-1 -yl)-pyrimid in [3] 2-(4-(4-(3, 5-d imethyl-4-nitro-1 H-pyrazol-I -yl)butyl)piperazin-1 -yl)-pyrimid me, *SlS [4] 2-(4-(4-(4-methyl-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yI)pyrim id me, [5] 1 -(4-(4-(pyrimid in-2-yI)piperazin-1 -yl)butyl)-1 H-indazole, [6] 2-(4-(4-(4-bromo-3,5-dimethyl-1 H-pyrazol-1 -yl)butyl)piperazin-I -yI)-5-methyl pyrimid me, [7] 2-(4-(4-(4-nitro-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine, [8] 2-(4-(4-(4-chloro-I H-pyrazol-I -yI)butyl)piperazin-1 -yl)-pyrimid me, [9] ethyl I -(4-(4-(pyrimid in-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazole-4-carboxylate, [10] 2-(4-(4-(3-methyl-5-phenyl-1 H-pyrazol-1 -yl)butyl)piperazin-I -yl)pyrimidine, [11] 2-(4-(4-(4-bromo-1 H-pyrazol-I -yl)butyl)piperazin-1 -yl)pyrimidine, [121 1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yt)butyl)-I H-pyrazole-4-carbon itrile, [13] 2-(4-(4-(4-fluoro-1 H-pyrazol-1 -yI)butyl)piperazin-1 -yI)pyrimidine, [14] 2-(4-(4-(4-methoxy-1 H-pyrazol-1 -yI)butyl)piperazin-1 -yI)pyrimidine, [15] 1 -(4-(4-(pyrimidin-2-yI)piperazin-I -yI)butyl)-I H-pyrazol-4-amine, [16] N-( I -(4-(4-(pyrimid in-2-yI)piperazin-I -yI)butyl)-1 H-pyrazol-4-yI)methanesulfonamide, * : S. *5S [171 N-(1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yI)butyl)-1 H-pyrazol-4-yI)benzamide, [18] N-(1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yI)butyl)-1 H-pyrazoI-4-y)acetamide, *..

[19] N-sec-butyl-1 -(4-(4-(pyrimidin-2-yI)piperazin-I -yI)butyl)-1 H-pyrazol-4-am me, [20] 5-bromo-2-(4-(4-(4-bromo-1 H-pyrazol-1 -yI)butyl)piperazin-1 -yI)pyrim idine, [21] 5-bromo-2-(4-(4-(4-chloro-I H-pyrazol-1 -yI)butyl)piperazin-1 -yI)pyrimidine, [22] 2-(4-(4-(5-methyl-1 H-pyrazol-I -yI)butyl)piperazin- 1 -yI)pyrimid me, [23] 2-(4-(4-(3-methyl-I H-pyrazol-I -yI)butyl)piperazin- 1 -yI)pyrim id me, [24] 2-(4-(4-(4-bromo-5-methyl-1 H-pyrazol-1 -yI)butyl)piperazin-I -yI)pyrimid me, [25] 2-(4-(4-(4-bromo-3-methyl-1 H-pyrazol-1 -yl)butyl)piperazmn-1 -yl)pyrim idine, [26] 1 -(4-(4-(pyrimid mn-2-yI)piperazin-I -yI)butyl)-4, 5,6,7-tetrahyd ro-1 H-indazole, [27] 2-(4-(4-(pynmid in-2-yI)piperazin-1 -yI)butyl)-4, 5,6,7-tetrahyd ro-2 H-indazole, [28] 2-(4-(4-(5-methyl-4-phenyl-I H-pyrazol-1 -yI)butyl)piperazin-1 -yI)pyrimid me, [29] 2-(4-(4-(3-methyl-4-phenyl-I H-pyrazol-1 -yI)butyl)piperazin-1 -yI)pyrimid me, [30] 2-(4-(4-(3-ch Ioro-4-fluoro-1 H-pyrazol-I -yI)butyl)piperazin-I -yI)pyrimid me, [311 2-(4-(4-(3-chloro-4-methoxy-1 H-pyrazol-I -yI)butyl)piperazin-I -yI)pyrimid me, [321 2-(4-(4-(4-(4-methoxyphenyl)-I H-pyrazol-1 -yI)butyl)piperazin-I -y)pyrimidine, [33] 2-(4-(4-(4-(4-chloropheny!)-1 H-pyrazol-1 -yI)butyl)piperazmn-1 -yI)pyrimidine,

S *S.

[34] 2-(4-(4-(4-( I H-pyrrol-1 -yI)-l H-pyrazol-1 -yI)butyl)piperazin-I -yI)pyrimidine, * [35] 2-(4-(4-(4-phenyl-1 H-pyrazol-1 -yI)butyI)piperazin-1 -yI)pyrimidine, *5*S

S *

[36] 2-(4-(4-(3,5-diphenyl-1 H-pyrazol-1 -yI)butyl)piperazin-1 -yI)pyrimidmne, * [37] N-( I -(4-(4-(pyrimidin-2-yI)piperazmn-I -yI)butyl)-1 H-pyrazol-4-yI)benzenesulfonamide, [38] 4-methyl-N-( I -(4-(4-(pyrimid in-2-yI)piperazin-I -yI)butyl)-I H-pyrazol-4-yI)benzenesulfonamide, [39] N-( I -(4-(4-(pyrimmd in-2-yI)piperazin-I -yI)butyl)-1 H-pyrazol-4-yI)butane-1-sulfonamide, [40] N-( I -(4-(4-(pyrimidin-2-yI)piperazin-1 -yl)butyl)-1 H-pyrazol-4-yl)propane-1-sulfonamide, [41] N-( 1 -(4-(4-(pyrimid in-2-yl)piperazin-1 -yI)butyl)-I H-pyrazol-4-yI)ethane-1 -sulfonamide, [42] N, N, 3, 5-tetramethyl-I -(4-(4-(pyrim id in-2-yl)piperazin-1 -yI)butyl)-I H-pyrazole-4-sulfonamide, [43] N, N-d imethyl-I -(4-(4(pyrim id in-2-yI)piperazin-l-yI) butyl)-I H-pyrazole-4-sulfonamide, [44] 1 -(4-(4-(pyrimid in-2-yl)piperazin-I -yI)butyl)-I H-pyrazole-4-su Ifon ic acid, [45] 2-(4-(4-( I H-imidazol-1 -yI)butyl)piperazin-1 -yl)pyrimidine, * * . [46] 2-(4-(4-(4,5-dichloro-1 H-imidazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine, **S*

S *.S

[47] 2-(4-(4-(4-methyl-1 H-imidazol-1 -yI)butyl)piperazin-1 -yl)pyrimid me, * * - [48] 2-(4-(4-(2-methyl-1 H-imidazol-I -yl)butyl)piperazin-1 -yl)pyrimidine, *55I * I...

[49] 2-(4-(4-(5-methyl-1 H-imidazol-I -yl)butyl)piperazin-1 -yl)pyrimidine, [50] 2-(4-(4-( 1 H-pyrrolyl-1 -yl)butyl)piperazin-1 -yl)pyrimidine, [51] 9-(4-(4-(pyrimid in-2-yl)piperazin-1 -yl)butyl)-9H-carbazole, [52] 1 -(4-4 (-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-indole, [53] 2, 3-d iphenyl-I -(4-(4-(pyrimid in-2-yI)piperazin-1 -yl)butyl)-1 H-indole, [54] 1 -(4-(4-(pyrimid in-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazole-4-carboxamide, [55] 1 -(4-(4-(pyrimid in-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazole-4-carboxylic acid, [561 2-(4-(4-(3-methyl-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)butyl)piperazin-I-yl)pyrimidine, [57] 2-(4-(4-(4,5-diphenyl-1 H-imidazol-1 -yJ)butyl)piperazin-I -yl)pyrimidine, [58] 2-(4-(4-(2,4, 5-triphenyl-I H-imidazol-1 -yl)butyl)piperazin-I -yI)pyrimidine, [59] 2-(4-(4-(2-methyl-4,5-diphenyl-1 H-imidazol-l -yl)butyl)piperazin-I -yI)pyrimidine, [60] 2-(4-(4-(4,5-dichloro-2-methyl-I H-imidazol-I -yI)butyl)piperazin-I -yl)pyrimidine, [61] 2-(4-(4-(2-ethyl-I H-imidazol-1 -yl)butyl)piperazin-I -yI)pyrimidine, [62] 2-chloro-I -(4-(4-pyrimidin-2-yI)piperazin-1 -yI)butyl)-1 H-benzo[djimidazole, 0I [63] 2-(4-(4-(I H-I,2,4-triazol-I -yI)butyl)piperazin-I -yl)pyrimidine, *.. ; [64] 2-(4-(4-(pyrim id in-2-yI)piperazin-1 -yl)butyl)-2H-benzo[d][1,2,3]triazole, *SS ..

[65] 2-methyl-I -(4-(4-(pyrimidin-2-yl)piperazin-I -yl)butyl)-1 H-benzo[d]imidazole, * [66] 5,6-dimethyl-I -(4-(4-(pyrimidin-2-yl)piperazin-I -yl)butyl)-1 H-benzo[d]imidazole, [67] 2-(4-(4-(2-phenyl-I H-imidazol-I -yl)butyl)piperazin-I -yl)pyrimid me, [681 methyl I -(4-(4-(pyrimidin-2-yl)piperazin-1 -yI)butyl)-I H-imidazole-4-carboxylate, [69] 2-(4-(4-(4-phenyl-I H-imidazol-I -yI)butyl)piperazin-I -yI)pyrimidine, [70] 1 -(4-(4-(pyrimid in-2-yI)piperazin-I -yI)butyl)-I H-benzo[d]imidazole, [71] 3-(4-(4-(pyrimid in-2-yI)piperazin-I -yl)butyl)-3H-imidazo[4, 5-b]pyrid me, [72] 1 -(4-(4-(pyrimid in-2-yl)piperazin-1 -yl)butyJ)-1 H-im idazo[4, 5-b]pyridmne, [73] 1 -(4-(4-(pyrim id in-2-yI)piperazin-1 -yI)butyl)-1 H-benzo[dJ[ 1,2, 3]triazole, [74] 5-ch loro-1 -(4-(4-(pyrim id in-2-yI)piperazin-1 -yI)butyl)-1 H-benzo[d]imidazole and [75] 6-chloro-1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-benzo[djimidazole; 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 pyrimidinyl-2-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 pyrimidinyl-2-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; epilepsy; irritable colon syndrome; irritable bowel syndrome; bipolar disorders; schizophrenia or hyperactivity disorder (ADH 0, attention deficit/hyperactivity disorder).

More preferred is the use of at least one substituted pyrimidinyl-2-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 pyrimidinyl-2-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 med icament 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.

S

Such medicaments may be produced according to standard procedures known to

SS

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., Liebemian 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 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 medicament 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 medicament 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 * pyrimidinyl-2-piperazine compound of general formula I given above at least partially * in sustained-release form. By incorporating one or more of the substituted pyrimidinyl-2-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. * SS* 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., OraI Drug delivery", Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), 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 pyrimidinyl-2-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(C14dialkylamino(Ci4alkyl (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-*..S chloride with a monomer molar ratio of 1:2:0.1 (Eudragit RS ), copolymers of ethyl acrylate, 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 d itripalmitostearate, 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 gtycols, propylene glycol, glycerol esters, eg. triacetin, Myvacet (acetylated mono-and diglycerides, C23HO5 to C25H4707), 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.

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.

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 acrylatelmethyl 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, T., ,,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, CT. and Porter, S.C., Coatings, in Encyclopedia of *..S 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. * a * S. ** S...

In another embodiment, the med icament obtained according to the present invention may contain one or more of the substituted pyrimidinyl-2-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 pyrimidinyl-2-piperazine compound at a dosage of 0.1 -50 mg/kg/day, more preferred 0.15-10 mg/kg/day, even more preferred 0.2-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 pyrimidinyl-2-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; Pinol, A. C.; Frigola-Constansa, J; Pares-Corominas, US 5128343 and the references cited therein. The respective description is hereby incorporated by

reference and forms part of the disclosure.

The inventively used substituted pyrimidinyl-2-piperazine compounds may, for example, be obtained by the following process, according to which at least one compound of general formula II,

II S

wherein R1 has the meaning given above and X represents chlorine, bromine, iodine, ..

mesyloxy or tosyloxy, is reacted with at least one compound of general formula Ill, H-N"1" ft *5 Ill, wherein A, B, 0 and R3 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 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, diisopropylethylamine and potassium tert-butoxide, to yield a substituted pyrimidinyl- 2-piperazine compound of general formula I, R1(/)_NN-cH2) E wherein R' has the meaning given above, n is 4, and E represents D3

D

H-N 1.

whereby A, B, D and R have the meaning given above, which is optionally isolated and/or optionally purified.

S S * *

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. S. *.

The inventively used substituted pyrimidinyl-2-piperazine compounds may also be... * *S*

obtained by the following process, according to which at least one compound of * general formula IV, IV, wherein R' 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' R3

B Ill,

wherein A, B, D and R3 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 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 pyrimidinyl-2-piperazine compound of general formula I, R1/NNcH2) E wherein R1 and n have the meaning given above and E represents D3

D-S *

H-N I

\AB,whereby A, B, D and R3 have the meaning given above, which is *.

optionally isolated and/or optionally purified. S *

The inventively used substituted pyrimidinyl-2-piperazine compounds may also be obtained by the following process, according to which at least one compound of general formula V, S..., X_(.CH2)-E V, wherein E 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 VI, R1C/>NCNH VI, wherein R1 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 substituted pyrimidinyl-2-piperazine compound of general formula I, R1_(/)__N"'N_CH2)__E wherein E, R1 and n have the meaning given above, which is optionally isolated and/or optionally purified.

The inventively used substituted pyrimidinyl-2-piperazine compounds may also be, : obtained by the following process, according to which at least one compound of general formula VII, /____\ / HN N--CH2) E \ In a.., *.S. VII,

wherein E and n have the meaning given above, is reacted with at least one compound of general formula VIII, VIII, wherein R1 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 substituted pyrimidinyl-2-piperazine compound of general formula I, R1C/>NCNCH2) E wherein E, R1 and n 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 andlor 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 pyrimidinyl-2-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 *eI* 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, methanesulfon ic acid or camphersu Ifonic acid.

Salts of the inventively used substituted pyrimidinyl-2-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.

[NHR], 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 pyrimidinyl-2- piperazine compounds of general formula I in which they have attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholats, e.g. methanolat.

Solvates, preferably hydrates, of the inventively used substituted pyrimidinyl-2-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 pyrimidinyl-2-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 **". **S

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 pyrimidinyl-2-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.

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, 0. 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 e' of the literature description is hereby incorporated by reference and forms part of the

disclosure. * * b4 *

The commercial membrane is diluted (1:40 dilution) with the binding buffer: 50 mM **** Tris-HCI, 10mM MgCI2,0.5 mM EDTA(pH 7.4). The radioligand used is [3H]-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 (K, nM) were calculated by nonlinear 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.

I

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 pyrimidinyl-2-piperazine compounds according to the present invention in fasted rats is then determined as follows: * S. 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 pyrimidinyl-2-piperazine compound or a corresponding composition (vehicle) without * * said substituted pyrimidinyl-2-piperazine compound. Immediately afterwards, the rat is left with preweighed food and cumulative food intake is measured after 1, 2, 4 and 6 hours.

Said method of measuring food intake is also described in the literature publications of Kask et al., 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: 2-(4-(4-(1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)-pyrimidine Under reflux for 14 hours a mixture of 4 g (13.3 mmol) of 2-pyrimidine-1-(4-bromobutyl)-4-piperazine, 1.02 g (15 mmol) of pyrazole and 2.76 g (20 mmol) of potassium carbonate are heated in 50 ml of dimethylformamide. It is evaporated under vacuum, chloroform is added, it is washed with water, dried over sodium sulphate, evaporated under vacuum and 3.5 g of an oil are obtained which is 2-(4-(4- (1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)-pyrimidine. s..

U

1H-NMR (300 MHz, CDCI3) 6 1.50 (m, 2H); 1.90 (m, 2H); 2.40 (m, 6H); 3.80 (m, 4H); 4.12 (t, 2H, J = 6.9); 6.20 (t, 1H, J = 1,6); 6.40 (t, IH, J = 4.7); 7.42 (dd, 2H, J = 4.7; J' = 1.6); 8.25 (d, 2H, J = 4.7) * UU

U

Example 2: 2-(4-(4-(3,5-dimethyl-1 H-pyrazol-1 -yl)butyl)piperazin-1-yl)-pyrimidine. ..

1H-NMR (300 MHz, CDCI3) 6 1.58 (m, 2H); 1.85 (m, 2H); 2.20 (s, 3H); 2.25 (s.3H); 2.44 (m, 6H); 3.81 (m, 4H); 3.97 (t, 2H J = 7.2); 5.78 (s.IH); 6.43 (t, IH, J = 4,7); 8.27 (d,2H,J=4.7) Example 3: 2-(4-(4-(3,5-dimethyl-4-nitro-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)-pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.60 (m, 2H); 1.90 (m, 2H); 2. 49 (m, 9H); 2.63 (s, 3H); 3.82 (m, 4H); 4.09 (t, 2H, J = 7); 6.48 (t, 1 H, J = 4.7); 8.29 (d, 2H, J = 4.7) Example 4: 2-(4-(4-(4-methyl-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.52 (m, 2H); 1.95 (m, 2H); 2.05 (s, 3H); 2.37 (m, 6H); 3.81 (m, 4H); 4.05 (t, 2H, J = 6.8); 6.41 (t, IH; J = 4.7); 7.13 (s, IH); 7.27 (s, IH); 8.25(d,2H,J=4.7) Example 5: 1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-indazole 1H-NMR (300 MHz, CDCI3) 6 1.51 (m, 2H); 1.98 (m, 2H); 2.36 (m, 6H); 3.77 (m, 4H); 4.39 (t, 2H, J = 6.9); 6.40 (t, 1H, J = 4.7); 7.0-7.7 (m, 4H); 7.95 (s, IH); 8.25 (d, 2H, J = 4.7) Example 6: 2-(4-(4-(4-bromo-3,5-dimethyl-1 H-pyrazol-1 -yJ)butyl)piperazin-1 -yl)-5-methylpyrim idine H-NMR (300 MHz, CDCI3) 1.55 (m, 2H); 1.81 (m, 2H); 2.18 (s, 3H); 2.20 (s, 3H); 2.38 (m, 4H); 3.80 (m, 4H); 3.99 (t, 2H, J = 6.9); 6.42 (t, IH, J = 4.7); 8.25 (d, 2H, J = 4.7) Example 7: 2-(4-(4-(4-n itro-1 H-pyrazol-1 -yI)butyl)piperazin-1 -yl)pyrimid me 1H-NMR (300 MHz, Cod3) ö 1.5 (m, 2H); 1.93 (m, 2H); 2.38 (m, 6H); 3.76 (m, 4H); 4.15 (t, 2H, J = 6.7); 6.42 (t, IH, J = 4.7); 8.01 (s, IH); 8.12 (s, IH); 8.24 (d, 2H, J = 4.7) a Example 8: 2-(4-(4-(4-chloro-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)-pyrimidine * A mixture of 3,56 g (15 mmol) of N-(4-bromobutyl)-4-chloropyrazol, 2.46 g (15 mmol) of 2-(1 -piperazinyl)-pyrimidine and 2.76 g (20 mmol) of potassium carbonate in 50 ml: : a of dimethylformamide are heated under reflux for 24 hours. It is evaporated under vacuum, chloroform added, it is washed with water, dried over sodium sulphate, evaporated under vacuum and 3.2 g of an oil obtained which is 2-(4-(4-(4-chloro-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)-pyrimid me.

1H-NMR (300 MHz, Cod3) 1.52 (m, 2H); 1.90 (m, 2H); 2.43 (m, 6H); 3.80 (m, 4H); 4.0 (t, 2H, J = 6.8); 644 (t, IH, J = 4.7); 7.35 (s, IH); 7.39 (s, IH); 8.25 (d, 2H, J = 4.7) Example 9: ethyl I -(4-(4-(pyrimidin-2-yI)piperazin-1 -yl)butyl)-1 H-pyrazole-4-carboxylate 1H-NMR (300 MHz, Cod3) 1.34 (t, 3H, J = 7.1); 1.54 (m, 2H); 1.90 (m, 2H); 2.46 (m, 6H); 3.81 (m, 4H); 4.25 (m, 4H); 6.47 (t, IH, J = 4.7); 7.90 (s, 2H); 8.29 (d, 2H, J = 4.7) Example 10: 2-(4-(4-(3-methyl-5-phenyl-1 H-pyrazol-l -yl)butyl)piperazin-1 -yI)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.54 (m, 2H); 1.85 (m, 2H); 2.28 (s, 3H); 2.45 (m, 6H); 3.81 (m, 4H); 4. 07 (t, 2H, J = 7); 6.28 (s, 1H); 6.43 (t, IH, J = 4.7); 7.33 (m, 4H); 7.75 (m, 2H); 8.26 (d, 2H, J = 4.7) Example 11: 2-(4-(4-(4-bromo-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.52 (m, 2H); 1.89 (m, 2H); 244 (m.6H); 3.62 (m, 4H); 4.11 (t, 2H, J = 6,7); 6.46 (t, IH, J = 4.6); 7.42 (s, IH); 7.45 (s, IH); 8.29(d, 2H, J = 4.6) Example 12: 1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazole-4-carbonitrile 1H-NMR (300 MHz, CDCI3)6 1.54 (m, 2H); 1.96 (m, 2H); 2.40 (m, 6H); 3.81 (m, 4H); 4.20 (t, 2H, J = 6,9); 6.48 (t, IH, J = 4.7); 7.80 (s, 1H); 7.83 (s, 1H); 8.29 (d, 2H, J = 4.7) Example 13: 2-(4-(4-(4-fluoro-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine * 1H-NMR (300 MHz, CDCI3) 6 1.45 (m, 2H); 1.96 (m, 2H); 2.36 (m, 6H); 3.77 (m, 4H); 4.0 (t, 2H, J = 6,9); 6.47 (t, 1H, J = 4.7); 7.27 (m, 2H, J = 4.8); 8.29 (d, 2H, J = 4,8) Example 14: 2-(4-(4-(4-methoxy-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.54 (m, 2H); 1.89 (m, 2H); 2.42 (m, 6H); 3.77 (m, 7H); 4.06 (m, 2H); 6.42 (1, 1H, J = 4.7); 7.02 (s, IH); 7.26 (m, 2H); 8.25 (d, 2H, J = 4,6) Example 15: 1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yl)butyl)-1 H-pyrazol-4-amine 10.2 g (43.2 mmol) of nickel II chloride hexahydrate are added to a solution of 7.2 g (21 mmol) of 2-(4-(4-(4-n itro-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine in 60 ml of ethanol, with vigorous shaking. It is cooled with an ice bath and slowly 10.2 g (81 mmol) of sodium borohydride are added. It is left under stirring for 1 hour and after I hour at room temperature, water is added, it is evaporated under vacuum, acidified with concentrated hydrochloric acid, filtered, basified with ammonia and extracted with ethyl ether. In this way 4.4 g of 1-(4-(4-(pyrimidin-2-yI)piperazin-1-yI)butyl)-1 H-pyrazol-4-amine are obtained in liquid form.

1H-NMR (300 MHz, CDCI3) 6 1.50 (m, 2H); 1.85 (m, 2H); 2.43 (m, 6H); 3.4 (m, 2H); 3.8 (m, 6H); 4.0 (t, 2H, J = 6.4); 6.46 (t, 1H, J = 4.7); 6.98 (s, IH); 7.10 (s, 1H); 8.27 (d,2H,J=4.7) Example 16: N-(1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazol-4-yl)methanesulfonamide Slowly 1.8 g (16 mmol) of methansulfonyl chloride are added to a cooled solution of 4.4 g (14.6 mmol) of of I -(4-(4-(pyrimid in-2-yl)piperazin-I -yl)butyl)-1 H-pyrazol-4-amine in 30 ml of pyridine. It is left for 1 hour at 0 C, then left at room temperature for 4 hours, it is poured on iced water, extracted with chloroform and 3.7 g of N-(1-(4- (4-(pyrimidin-2-yl)piperazin-I -yl)butyl)-1 H-pyrazol-4-yl)methanesulfonamide, which can be recrystallized in ethyl ether, with a melting point of 132 C. * *** * * * S.

1H-NMR (300 MHz, COd3) 6 1.58 (m, 2H); 1.93 (m, 2H); 2.45 (m, 6H); 2.94 (s, 3H); 3.8(m, 4H); 4.11 (t, 2H, J = 6.9); 6.45(t, 1H, J = 4.7); 7.4(s, IH); 7.5(s, IH); 8.28 (d, 2H,J=4.7) S..',: S...

Example 17: N-(1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazol-4-yl)benzamide 1H-NMR (300 MHz, CDCI3) 8 1.55 (m, 2H); 1.79 (s, 3H); 1.88 (m, 2H); 2.42 (m, 6H); 3.80 (m, 4H); 4.13 (t, 2H, J = 6.8); 6. 51 (t, 1H, J = 4.7); 7.49 (m, 4H); 7.83 (m, 2H); 8.0 (s, IH); 8.11 (s, IH); 8.28 (d, 2H, J = 4.7) Example 18: N-(1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yI)butyl)-1 H-pyrazol-4-yl)acetamide 1H-NMR (300 MHz, CDCI3) 6 1.50 (m, 2H); 1.88 (m, 2H); 2.11 (s, 3H); 2.43 (m, 6H); 3.79 (m, 4H); 4.08 (t, 2H, J = 6.8); 6.47 (t, IH, J = 4.7); 7.36 (s, IH); 7.93 (s, IH); 8.28 (d, 2H, J 4.6); 9.25 (s, IH) Example 19: N-sec-butyl-1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yI)butyl)-1 H-pyrazol-4-amine 0.9 g (24 mmol) of sodium borohydride are added to a suspension of 2.8 g (12 mmol) of nickel dichloride hexahydrate, in a solution of 2 g (6 mmol) of 2-(4-(4-(4-nitro-1 H-pyrazol-1-yl)butyl)piperazin-1-yl)pyrimidine and 10 ml of methylethylketone in 50 ml of ethanol, cooled to 0 C. This temperature is maintained for 30 minutes, the temperature is allowed to rise to room temperature and the stirring continued for 2 hours; it is evaporated under vacuum, taken up again with ethyl acetate and 1.22 g N-sec-butyl-I -(4-(4-(pyrim Id in-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazol-4-amine obtained in liquid form.

1H-NMR (300 MHz, CDCI3) 1.00 (t, 3H, J = 7.0); 1.19 (d, 3H, J = 6.3); 1.6 (m, 4H); 1.90 (m, 2H); 2.50 (m, 6H); 3.0 (m, 3H); 3.9 (m, 4H); 4.1 (t, 2H, J = 6.8); 6.52 (t, IH, J = 4.7); 6.99 (s, 1H); 7.17 (s, IH); 3.37 (d, 2H, J = 4.7) Example 20: 5-bromo-2-(4-(4-(4-bromo-1 H-pyrazol-1 -yI)butyl)piperazin-1 -yl)pyrimidine.. * A solution of 1.84 g (11.5 mmol) of bromine in 15 ml of chloroform are added slowly to a solution of 3 g (10.5 mmol) of 2-(4-(4-(1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)-pyrimidine. The stirring is maintained for 18 hours, it is evaporated, taken up again with a mixture of ethyl ether/benzene, basified with 10% sodium hydroxide, washed * * with water, dried, evaporated and 3.1 g of 5-bromo-2-(4-(4-(4-bromo-1 H-pyrazol-1-yl)butyl)piperazin-1 -yl)pyrimidine are obtained. : 1H-NMR (300 MHz, CDCI3) 1.57 (m, 2H); 1.90 (m, 2H); 2.45 (m, 6H); 3.80 (t, 4H, J = 6.8); 7.44 (d, 2H, J = 4); 8.29 (s, 2H) Example 21: 5-bromo-2-(4-(4-(4-chloro-1 H-pyrazol-1 -yI)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, Cod3) ö 1.50 (m, 2H); 1.86 (m, 2H); 2.40 (m, 6H); 3.76 (m, 4H); 4.08 (m, 2H); 7.4 (t, 2H, J = 6.9); 8.25 (s, 2H) Example 22: 2-(4-(4-(5-methyl-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 1.50 (m, 2H); 1.80 (m, 2H); 2.29 (s, 3H); 2.39 (m, 6H); 3.82 (m, 4H); 4.04 (t, 2H, J = 6,9); 5.97 (s, IH); 6.40 (t, IH, J = 4.7); 7,34 (d, IH, J = 2.1); 8.24 (d, 2H, J = 4.7) Example 23: 2-(4-(4-(3-methyl-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yI)pyrimidine 1H-NMR (300 MHz, CDCI3) 1.52 (m, 2H); 1.81 (m, 2H); 2.25 (s, 3H); 2.44 (m, 6H); 3.81 (m, 4H); 4.03 (t, 2H); 5. 95 (s, IH); 6.42 (t, IH, J = 4.7); 7.23 (d, IH, J = 2.1); 8.27(d,2H,J=4.7) Exam pie 24: 2-(4-(4-(4-bromo-5-methyl-1 H-pyrazol-1 -yl)butyl)piperazi n-I -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) ö 1.52 (m, 2H); 1.83 (m, 2H); 2.26 (s, 3H); 2.45 (m, 6H); 3.80 (m, 4H); 6.45 (t, IH, J = 4.7); 7.38 (d, IH, J = 1.8); 8.27 (d, 2H, J = 4.7) Example 25: 2-(4-(4-(4-bromo-3-methyl-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 1.53 (m, 2H); 1.84 (m, 2H); 2.22 (s, 3H); 2.45 (m, 6H); . * : 3.80 (m, 4H); 6.46 (t, IH, J = 4.7); 7.31 (d, IH, J = 1.7); 8.29 (d, 2H, J = 4.7) S. Example 26: 1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yI)butyl)-4,5,6,7-tetrahydro-1 H-indazole 1H-NMR (300 MHz, CDCI3) 1.70 (m, 8H); 2.45 (m, IOH); 3.8 (m, 4H); 4.04 (t, 2H, J *.*.

<p≥6,9);6.43(t,1H,J=4.7);7.23(d,IH,J=1.8);8.26(d,2H,J=4,7) Example 27: 2-(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-4,5,6,7-tetrahydro-2H-indazole 1H-NMR (300 MHz, CDCI3) 1.70 (m, 8H); 2.45 (m, IOH); 3.8 (m, 4H); 3.97 (t, 2H, J = 6,9); 6.45 (t, IH, J = 4.7); 7.05 (d, 1H, J = 1.8); 8.27 (d, 2H, J = 4.7) Example 28: 2-(4-(4-(5-methyl-4-phenyl-1 H-pyrazol-1 -yl)butyl)piperazi n-I -yl)pyrimidine 1H-NMR (300 MHz, CDC13) 1.50 (m, 2H); 1.90 (m, 2H); 2.39 (S, 3H); 2.50 (m, 6H); 3.80 (m, 4H); 4,1 (t, 2H, J = 6.9); 6.44 (t, IH, J = 4.7); 7.35 (m, 6H); 8.27 (d, 2H, J = 4.7) Example 29: 2-(4-(4-(3-methyl-4-phenyl-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) ö 1.50 (m, 2H); 1.90 (m, 2H); 2.40 (s.3H); 2.51 (m, 6H); 3.81 (m, 4H); 4.09 (t, 2H, J = 6.9); 6.44 (t, 1H, J = 4.7); 7.34 (m, 6H); 8.28 (d, 2H, J = 4.7) Example 30: 2-(4-(4-(3-chloro-4-fluoro-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.52 (m, 2H); 1.90 (m, 2H); 2.40 (m, 6H); 3.80 (m, 4H); 4.0 (t, 2H, J = 4,8); 6.45 (t, 1H, J = 4,7); 7.30 (d, 1H, J = 4,8); 8.29 (d, 2H, J = 4,8) Example 31: 2-(4-(4-(3-chloro-4-methoxy-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yI)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.53 (m, 2H); 1.90 (m, 2H); 2.4 (m, 6H); 3.8 (m, 7H); 4.0 (m, 2H); 6.4 (t, IH, J = 4,8); 7.0 (s, IH); 7. 25 (s, IH); 8.2 (d, 2H, J = 4,8) Example 32: 2-(4-(4-(4-(4-methoxyphenyl)-1 H-pyrazol-1 -yI)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, COd3) 6 1.62 (m, 2H); 1.88 (m, 2H); 2.45 (m, 6H); 3.81 (m, 7H); ...: 4.16 (t, 2H, J = 6,8); 6.46 (t, IH, J = 4.7); 6.9 (d, 2H, J = 4,4); 7.4 (d, 2H, J = 4,4); 7,55 (S, IH); 7.7 (s, 1H); 8.28 (d, 2H, J = 2,4) :;:; Example 33: 2-(4-(4-(4-(4-chlorophenyl)-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yI)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.6 (m, 2H); 1.9 (m, 2H); 2.46 (m, 6H); 3.8 (m.4H); 4.16 (t, 2H, J = 6,8); 6.4 (t, I H, J = 4.7); 7.36 (d, 4H, J = 1,3); 7.7 (d, 2H, J = 6,2); 8.28 (d, 2H,J=2,3) Example 34: 2-(4-(4-(4-(1 H-pyrrol-1 -yI)-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yI)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.55 (m, 2H); 1.80 (m, 2H); 2.45 (m, 6H); 3.81 (t, 4H, J = 5); 4.12 (t, 2H, J = 7); 6.25 (2H, t, J = 2); 6.44 (IH, t, J = 4,7); 6.84 (m, 2H); 7.5 (d, 2H, J = 5); 8.27 (d, 2H, J = 4,7) Example 35: 2-(4-(4-(4-phenyl-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.6 (m, 2H); 1.9 (m, 2H); 2.5 (m, 4H); 3.8 (m, 6H); 4.2 (t, 2H, J = 6,8); 6.7 (t, 1H, J = 4,7); 7.2-7.7 (m, 5H); 8.0 (s, 1H); 8.2 (s, 1H); 8.4 (d, 2H, J = 2,3) Example 36: 2-(4-(4-(3,5-diphenyl-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.6 (m, 2H); 1.9 (m, 2H); 2.35 (m, 6H); 3.8 (m, 4H); 4.2 (t, 2H, J = 6.8); 6.4 (t, IH, J = 4,7); 6.6 (s, IH); 7.2-7.4 (m, 8H); 7.8 (m, 2H); 8.25 (d, 2H, J = 2,4) Example 37: N-(1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazol-4-yl)benzenesulfonamide 1H-NMR (300 MHz, CDCI3) 6 1.45 (m, 2H); 1.85 (m, 2H); 2.40 (m, 6H); 3.80 (m, 4H); . . : 4.0 (t, 2H, J = 6,7); 6. 47 (t, IH, J = 4.6); 7.0 (s, IH); 7.5 (m, 6H); 8.3 (d, 2H, J = 4.6) Example 38: 4-methyl-N-(1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazol- 4-yl)benzenesulfonamide: . . 1H-NMR (300 MHz, COd3) 6 1.5 (m, 2H); 1.85 (m, 2H); 2.28 (m, 9H); 3.8 (m, 4H); 4.0 (m, 2H); 6.45 (t, IH, J = 4.7); 7-7.65 (m, 6H); 8.27 (d, 2H, J = 4,7) :;:; Example 39: N-(1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazol-4-yl)butane-1 -sulfonamide 1H-NMR (300 MHz, COd3) 60.91 (t, 3H, J = 6,8); 1.45 (m, 4H); 1.85 (m, 4H); 2.40 (m, 6H); 3.0 (m, 2H); 3.80 (m, 4H); 4.11 (t, 2H, J = 6,5); 6.5 (t, IH, J = 4,7); 7.4 (m, 2H); 7.5 (s, IH); 8.3 (d, 2H, J = 4.7) Example 40: N-(1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazol-4-yl)propane-1 -sulfonamide 1H-NMR (300 MHz, CDCI3) 6 1.0 (t, 3H, J = 7.1); 1.55 (m, 2H); 1.9 (m, 4H); 2.45 (m, 6H); 3.0 (t, 2H, J = 7.4); 3.8 (m, 4H); 4.1 (t, 2H, J = 6,4); 6.46 (t, 1H, J = 4,7); 7.35 (m, 2H); 7.5 (s, I H); 8.3 (d, 2H, J = 4,7) Example 41: N-(1 -(4-(4-(pyrimidin-2.yl)piperazin-1 -yl)butyl)-1 H-pyrazol-4-yl)ethane-1 -sulfonamide 1H-NMR (300 MHz, CDCI3) 6 1.36 (m, 5H); 1.9 (m, 2H); 2.45 (m, 6H); 3.0 (m, 2H); 3.6 (m, 4H); 4.1 (t, 2H, J = 6.4); 6.45 (t, IH, J = 4,7); 7.39 (s, IH); 7.51 (s, IH); 8.3 (d, 2H,J=4,7) Example 42: N,N,3,5-tetramethyl-1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yl)butyl)-1 H-pyrazole-4-su Ifonamide 1H-NMR (300 MHz, CDCI3) 6 1.7 (m, 4H); 2.3-3.0 (m, 18H); 3.8 (m, 4H); 4.0 (t, 2H, J = 6,8); 6.5 (t, IH, J = 4,7); 8.2 (d, 2H, J = 2,35) Example 43: N,N-dimethyl-1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yl)butyl)-1 H-pyrazole-4-sulfonamide 1H-NMR (300 MHz, CDCI3) 6 1.6 (m, 2H); 1.9 (m, 2H); 2.3-2.7 (m, 13H); 3.8 (m, 4H); 4.2 (t, 2H, J = 6,8); 6.4 (t, IH, J = 4,7); 7.75 (d, IH, J = 4,4); 8.28 (d, 2H, J = 2,4) Example 44: 1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazole-4-sulfonic acid 1H-NMR (300 MHz, CDCI3) 6 1.95 (m, 2H); 3.3 (m, 6H); 4.0 (s, 5H); 4.27 (t, 2H, J = 6,1); 6.8 (t, 1H, J = 4,8); 7.8 (s, IH); 8.0 (s, IH); 8.43 (d, 2H, J = 2,4) Example 45: 2-(4-(4-(1 H-imidazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.6 (m, 2H); 1.8 (m, 2H); 2.5 (m, 6H); 3.80 (m, 6H); 6.5 (t, IH, J = 4,7); 6.9 (s, IH); 7.1 (s, IH); 7.5 (s, 1H); 8.4 (d, 2H, J = 4,7) Example 46: 2-(4-(4-(4,5-dichloro-1 H-imidazol1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.4-2.1 (m, 4H); 2.46 (m, 6H); 3.86 (m, 6H); 6.47 (t, 1H, J = 4,7); 7.38 (s, I H); 8.29 (d, 2H, J = 4,7) Example 47: 2-(4-(4-(4-methyl-1 H-imidazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.4-2.0 (m, 4H); 2.21 (s, 3H); 2.45 (m, 6H); 3.82 (m, 6H); 6.47 (t, I H, J = 4,7); 6.62 (s, I H); 7,35 (s, I H); 8,28 (d, 2H, J = 4,7) Example 48: 2-(4-(4-(2-methyl-1 H-imidazol-1 -yI)butyl)piperazin-1 -yl)pyrimidine 1H-NMR (300 MHz, CDCI3) 6 1.4-2.0 (m, 4H); 2.20 (s, 3H); 2.45 (m, 6H); 3.82 (m, 6H); 6,47 (t, IH, J = 4,7); 6.79 (s, IH); 7,40 (s, IH); 8,28 (d, 2H, J = 4,7) Example 49: 2-(4-(4-(5-methyl-1 H-imidazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine Example 50: 2-(4-(4-(1 H-pyrrolyl-1 -yI)butyl)piperazin-1 -yl)pyrimidine Example 51: 9-(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-9H-carbazole Example 52: 1 -(4-4 (-(pyrimidin-2-yl)piperazin-1 -yI)butyl)-1 H-indole Example 53: 2,3-diphenyl-1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-indole Example 54: 1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazole-4-carboxamide *:.*. S...

S S S..

Example 55: 1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazole-4-carboxylic acid *:.*. S...

Example 56: 2-(4-(4-(3-methyl-5-(trifluoromethyl)-1 H-pyrazol-1 -I...

yl)butyl)piperazin-1 -yl)pyrimidine Example 57: 2-(4-(4-(4,5-diphenyl-1 H-imidazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine Example 58: 2-(4-(4-(2,4,5-triphenyl-1 H-imidazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine Example 59: 2-(4-(4-(2-methyl-4,5-diphenyl-1 H-imidazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine Example 60: 2-(4-(4-(4,5-dichloro-2-methyl-1 H-imidazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine A mixture of 450 g (1.5 mol) of 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide, 225 g (1.5 mol) of 4.5-dichloro-2-methylimidazole and 300 g (2.25 mol) of potassium carbonate in 2 I of dimethylformamide is heated to 130-1 35 C for 14 hours. The mixture is evaporated under vacuum, chloroform is added, the solution is washed with water, dried over sodium sulfate and evaporated under vacuum, and 503 g (91%) of 2-(4-(4-(4,5-dichloro-2-methyl-1 H-imidazol-1-yl)butyl)piperazin-1-yl)pyrimidine are obtained in liquid form.

1H-NMR (300 MHz, CDCI3) 6 1.45-1.84 (m, 4H); 2.26-2.57 (m, 9H); 3.74-4.05 (m, 6H); 6.48 (t, J = 4.7 Hz, I H); 8.30 (d, J = 4,7 Hz, 2H) Example 61: 2-(4-(4-(2-ethyl-1 H-imidazol-I -yl)butyl)piperazin-1 -yl)pyrimidine Example 62: 2-chloro-1 -(4-(4-pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-benzo(d]imidazole * Example 63: 2-(4-(4-(1 H-I,2,4-triazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine Example 64: 2-(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyt)-2H-benzo[dJ[1,2,3jtriazole *: *. *5S*

Example 65: 2-methyl-I -(4-(4-(pyrimidin-2-yl)piperazin-I -yl)butyl)-1 H-m *.S* benzo(d]imidazole Example 66: 5,6-dimethyl-1 -(4-(4-(pyrimidin-2-yl)piperazin-I -yI)butyl)-1 H-benzo(d]imidazole Example 67: 2-(4-(4-(2-phenyl-I H-imidazol-1 -yl)butyl)piperazin-1 -yl)pyrimidine Example 68: methyl I -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-imidazole-4-carboxylate Example 69: 2-(4-(4-(4-phenyl-I H-imidazol-I -yl)butyl)piperazin-1 -yI)pyrimidine Example 70: 1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -y9butyl)-1 H-benzo[d]imidazole A mixture of 450 g (1.50 mol) of 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5jdecane bromide, 177 g (1.50 mol) of benzimidazole and 307 g (2.25 mol) of potassium carbonate in 2 I of dimethylformamide is heated to 140-145 C for 14 hours. The mixture is evaporated under vacuum, chloroform is added, the solution is washed with water, dried over sodium sulfate and evaporated under vacuum, and 457 g (91 %) of I -(4-(4-(pyrimid in-2-yl)piperazin-1 -yl)butyl)-I H-benzo[d]imidazole with a melting point of 85-88 C are obtained.

1H-NMR (300 MHz, DMSO-d6) 6 1.40 (m, 2H); 1,82 (m, 2H); 2.26-2.42 (m, 6H); 3.62- 3.71 (m, 4H); 4.24 (t, J = 6.9 Hz, 2H); 6.56 (t, J = 4.7 Hz, IH); 7.16-7.26 (m, 2H); 7.55-7.70 (m, 2H); 8.22-8.34 (m, 3H) Example 71: 3-(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-3H-imidazo[4,5-b]pyridine Example 72: 1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-imidazo[4,5-b]pyridine Example 73: 1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yl)butyl)-1 H-benzo[d][1,2,3]triazole Example 74: 5-chloro-1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yI)butyl)-1 H-benzo[d]imidazole.* Example 75: 6-chloro-1 -(4-(4-(pyrimidin-2-yl)piperazin-1 -yI)butyl)-1 H-benzo[d]imidazole Pharmacological data: The binding of the substituted pyrimidinyl-2-piperazine compounds of general formula I to the 5-HT6 receptor was determined as described above.

The binding results for some of these compounds are given in the following

table:

Compound Compound Binding to 5-HT6 according to number receptor (%]

example * * 4 I I I. ol * ** * * I.. * S * I * is *SI * S I.., I. S * * I S. i

Claims

Claims: Use of at least one substituted pyrimidinyl-2-piperazine

compound of general formula I, R1/NCNCH2) E wherein * S * S S n isl,2,3,4,5or6; R1 represents H, -C1..5-alkyl, -OH, -O-Ci.5-alkyl, F, Cl, Br or I; * * * S * ** *.

E represents *SSS * S R3 55.5 wherein the dotted line represents an optional chemical bond, A represents C-R2 and B represents N or A represents N and B represents C-R5 or A represents N and B represents N or A represents C-R2 and B represents C-R5 and D represents N or C-R4; or E represents R3 wherein A represents NR6 and B represents N or A represents NR6 and B represents C-R5; and D represents N or C-R4; R2, R3, R4 and R5, independently of one another, in each case represent a radical selected from the group consisting of hydrogen, -C1.5-aIkyl, -C2.5- alkenyl, -O-C15-alkyl, -S-C1..5-alkyl, -C(=O)-OH, -C(=O)-C1..5-alkyl, -Ci5-alkylene-C(0)-OH, oxo (=0), thioxo (=S), -C(=O)-O-C1..5-atkyl, -O-C(0)-Ci..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(=O)-NH(C1..5-alkyl), -C(=O)-N(C1..5-alkyl)2, -S(=O)2-Ci..5-alkyl, -S(=O)2-phenyl, -S(0)2-OH, -NH-C(=O)-C1..5-alkyl, -NH-C(=O)-phenyl, -NH-.". S...

S(=O)2-phenyl, -NH-S(0)2-Ci..5-alkyl, -S(=O)2-NH-phenyl, -S(=O)2-NH-C1..5-*: :: : alkyl, -S(=0)2-N(C1..5-alkyl)2, phenyl, pyrrolyl, imidazolyl, pyridinyl, phenoxy and benzyl; whereby said cyclic substituents pyrrolyl, imidazolyl, pyridinyl, -S(=O)2-phenyl, -NH-C(=0)-phenyl, -NH-S(=O)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 R3 and R5 together form a -(CH2)m-group, wherein m is 3 or 4, a -CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCICH-group; or optionally R3 and R4 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 a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R2 and R5 together form a -CH=CH-CH=CH-group; and R6 represents a radical selected from the group consisting of hydrogen, -Ci..5-alkyl, -C(0)-Ci..5-alkyl and -C(=O)-O-C1..5-alkyl; 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. * * * S S ** *S S...

2. Use of a substituted pyrimidinyl-2-piperazine compound according to claim 1, characterized in that * S * S S n is 1,2,3,4,5 or6; S... * S *S.*

R1 represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, *: tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br or I; E represents R3 wherein the dotted line represents an optional chemical bond, A represents C-R2 and B represents N or A represents N and B represents C-R5 or A represents N and B represents N or A represents C-R2 and B represents C-R5 and D represents N or C-R4; or E represents R3

AB

wherein A represents NR6 and B represents N or A represents NR6 and B represents C-R5; **S and D represents N or C-R4; R2, R3, R4 and R5, 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, -CE3, -** C(=O)-NH2, -C(=O)-NH-CH3, -C(=0)-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)-0-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-CH(CH3)-CH2- CH3, -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(0)2-C2H5, -NH-S(=O)2-CH2-CH2- CH3, -NH-S(0)2-CH2-CH2-CH2-CH3, -NH-C(=0)-phenyl, -NH-C(=O)-CH3, -N H-C(0)-C2H5, -S(=O)2-OH, -S(0)2-N(CH3)2, pyrrolyl, imidazolyl and phenyl, whereby said phenyl radical and said -NH-S(0)2-phenyl radical 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 and Br; or optionally R3 and R5 together form a CH2)m.grOUp, wherein m is 3 or 4, a - CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R3 and R4 together form a -(CH2)k-group, wherein k is 3 or 4, or a -CHCH-CH=CH-group or a -CHC(CH3)-C(CH3)=CH-group or a -NCH-CH=CH-group or a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R2 and R5 together form a -CH=CH-CH=CH-group; and R6 represents a radical selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n- perityl, -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(=O)-CH3, -C(=O)-C2H5, -C(=O)-CH2-CH2-CH3, -C(=O)-CH(CH3)2 and -C(=O)-C(CH3)3; *: . .

SSSS

optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

3. Use of a substituted pyrimidinyl-2-piperazine compound according to claim I *.

or 2, characterized in that * : : : n is4; R1 represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br or I; E represents

B

wherein the dotted line represents an optional chemical bond; A represents C-R2 and B represents N or A represents N and B represents CR5 or A represents N and B represents N or A represents C-R2 and B represents C-R5; D represents N or C-R4; R2 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, I and phenyl; R3 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, -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, -0-C(CH3)3, -C(=O)-OH, -C(=0)-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), -S...

N(CH3)2, -N(C2H5)2, -NO2, -NH-S(=O)2-phenyl, -NH-S(=O)2-CH3, -NH-S(0)2-S C2H5, -NH-S(=O)2-CH2-CH2-CH3, -NH-S(=O)2-CH2-CH2.-CH2-CH3, -NH-C(=O)-S**S phenyl, -NH-C(=O)-CH3, -NH-C(=O)-C2H5, -S(0)2-OH, -S(0)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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 and Br; R4 represents a radical selected from the group consisting of hydrogen, oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br, I and phenyl; R5 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, I and phenyl; or optionally R3 and R5 together form a -(CH2)m-group, wherein m is 3 or 4, a - CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCICH-group; or optionally R3 and R4 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-CH=CH-group or a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R2 and R5 together form a -CH=CH-CH=CH-group; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof. * : ** ** **** 4. Use of a substituted pyrimidinyl-2-piperazine compound of general formula Ia * ..

according to one or more of claims 1 to 3, * * 3a *** S * S R1a{/NN * : ::: Ia, wherein R represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br or I; R3a 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, -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, -0-C(CH3)3, -C(=0)-OH, -C(=O)-0-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, -NO2, -NH-S(=O)2-phenyl, -NH-S(=O)2-CH3, -NH-S(0)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(0)2-OH, -S(0)2-N(CH3)2, pyrrolyt and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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 and Br; R4 represents a radical selected from the group consisting of hydrogen, oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br, I and phenyl; as.. * a a.

R5a 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, CI, Br, I and phenyl;

S a...

or optionally R a and R a together form a (CH2)mgroup, wherein m is 3 or 4, a,. : -CH=CH-CH=C H-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R3 and R4 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 a -CH=CCI-CH=CHgroup or a -CHCH-CCICH-group; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

5. Use of a substituted pyrimidinyl-2-piperazine compound of general formula lb according to one or more of claims I to 3, 4b \ ,R rNfl R1 b NN R2b Ib, * S a wherein *5S Rib represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br or I; R2b 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, I and phenyl; R3b 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, -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, -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, -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(0)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(0)2-OH, -S(0)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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 and Br; R4b represents a radical selected from the group consisting of hydrogen, oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br, I and phenyl; or optionally R3b and R4b 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 a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; optionally in form of a physiologically acceptable salt thereof, or a * corresponding solvate thereof. :.,:: I. 6. Use of a substituted pyrimidinyl-2-piperazine compound of general formula Ic according to one or more of claims I to 3, R4c *:.

\ **SSS I...

a:::': Ic, wherein Rk represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -0-C2H5, -0-CH(CH3)2, -0-C(CH3)3, F, Cl, Br or I; R2C 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, I and phenyl; R3C 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, -C(=O)-NH2, -C(=O)-N H-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(=0)-OH, -C(=0)-0-CH3, -C(=0)-O-C2H5, -C(=O)-O-CH2-CH2-CH3, -C(=0)-0-CH(CH3)2, -C(=0)-0-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, -NO2, -NH-S(=O)2-phenyl, -NH-S(=O)2-CH3, -NH-S(0)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, -N H-C(0)-C2H5, -S(=O)2-OH, -S(0)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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 and Br; R4C represents a radical selected from the group consisting of hydrogen, oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, *S..

sec-butyl, isobutyl, n-pentyl, F, Cl, Br, I and phenyl; * *** S...

S S.

R5C 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, I and phenyl; or optionally R3C and R5C together form a (CH2)m9roUp, wherein m is 3 or 4, a -CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R3C and R4C 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 a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; or optionally R2C and R5C together form a -CH=CH-CH=CH-group; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

7. Use of a substituted pyrimidinyl-2-piperazine compound of general formula Id according to one or more of claims 1 to 3, 4d \ R3

N

R1 d /NN N N

N Id, * S S *S 55

wherein ** * S Rid represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br or I; * .. 55S 3d u5

R 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, -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, -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, -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(=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(0)2-OH, -S(0)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(0)2-phenyl radical 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 and Br; R represents a radical selected from the group consisting of hydrogen, oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, F, Cl, Br, I and phenyl; or optionally R3d and R 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-CH=CH-group or a -CH=CCI-CH=CH-group or a -CH=CH-CCI=CH-group; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

8. Use of a substituted pyrimidinyl-2-piperazine compound of general formula le according to one or more of claims I to 3, * ** ***S

N S / -

R1e/NN2t 5S5* 5*5* le, wherein R represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br or I; R2 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, I and phenyl; and R3 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, -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, -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, -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(=O)2-CH3, -NH-S(0)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(0)2-OH, -S(0)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(0)2-phenyl radical 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 and Br; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

S

S S S

9. Use of a substituted pyrimidinyl-2-piperazine compound of general formula If according to one or more of claims Ito 3, N R3 / S *5 ** R1f/NN N R5 N *:::: If, wherein R1 represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -OH, -OCH3, -O-C2H5, -O-CH(CH3)2, -O-C(CH3)3, F, Cl, Br or I; R3 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, -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, -0-C(CH3)3, -C(=O)-OH, -C(=O)-O-CH3, -C(=O)-O-C2H5, -C(=O)-O-CH2-CH2-CH3, -C(0)-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, -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(0)2-N(CH3)2, pyrrolyl and phenyl, whereby said phenyl radical and said -NH-S(=O)2-phenyl radical 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 and Br; R5 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, I and phenyl; or optionally R3 and R5 together form a -(CH2)m-group, wherein m is 3 or 4, a -CH=CH-CH=CH-group; a -CH=CCI-CH=CH-group or a -CH=CH-CCICH-group; optionally in form of a physiologically acceptable salt thereof, or a e corresponding solvate thereof. ISe* I...

10. Use of a substituted pyrimidinyl-2-piperazine compound according to one or more of claims 1 to 9 selected from the group consisting of [1] 2-(4-(4-( 1 H-pyrazol-1 -yl)butyl)piperazin-I -yl)-pyrimidine, [2] 2-(4-(4-(3, 5-dimethyl-1 H-pyrazol-I -yl)butyl)piperazin-I -yl)-pyrimid me, [3] 2-(4-(4-(3, 5-d imethyl-4-n itro-1 H-pyrazol-I -yl)butyl)piperazin-1 -yl)-pyrimidine, [4] 2-(4-(4-(4-methyl-1 H-pyrazol-I -yl)butyl)piperazin-1 -yl)pyrimid me, [5] 1 -(4-(4-(pyrimid in-2-yl)piperazin-1 -yl)butyl)-I H-indazole, [6] 2-(4-(4-(4-bromo-3, 5-d imethyl-I H-pyrazol-I -yl)butyl)piperazin-1 -yl)-5-methylpyrimidine,

I--

[71 2-(4-(4-(4-n itro-1 H-pyrazol-1 -yl)butyl)piperazin-1 -yl)pyrimid me, [8] 2-(4-(4-(4-ch loro-I H-pyrazol-1 -yl)butyl)piperazin- 1 -yI)-pyrimidine, [9] ethyl I -(4-(4-(pyrimid in-2-yl)piperazin-1 -yl)butyl)-I H-pyrazole-4-carboxylate, [101 2-(4-(4-(3-methyl-5-phenyl-I H-pyrazol-1 -yl)butyl)piperazin-1-yI)pyrimidine, [11] 2-(4-(4-(4-bromo-IH-pyrazol-1-yl)butyl)piperazin-1-yl)pyrimidine, * ** ** *S** [12] 1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yI)butyl)-1 H-pyrazole-4-carbonitrile, [13] 2-(4-(4-(4-fluoro-1 H-pyrazol-1 -yI)butyl)piperazin-1 -yl)pyrimidine, * * [14] 2-(4-(4-(4-methoxy-1 H-pyrazol-1 -yl)butyl)piperazin-I -yl)pyrimidine, *S** [15] 1 -(4-(4-(pyrim Id in-2-yl)piperazin-1 -yl)butyl)-I H-pyrazol-4-amine, [16] N-( 1 -(4-(4-(pyrim Id in-2-yl)piperazin-I -yl)butyl)-1 H-pyrazol-4-yl)methanesulfonamide, [17] N-( 1 -(4-(4-(pyrim Id in-2-yl)piperazin-I -yI)butyl)-I H-pyrazol-4-yl)benzamide, [18] N-( I -(4-(4-(pyrim idin-2-yl)piperazin-I -yI)butyl)-1 H-pyrazol-4-yI)acetamide, [19] N-sec-butyl-I -(4-(4-(pyrimid in-2-yl)piperazin-I -yI)butyl)-I H-pyrazol-4-amine, [20] 5-bromo-2-(4-(4-(4-bromo-I H-pyrazol-I -yl)butyl)piperazin-I-yl)pyrimidine, [21] 5-bromo-2-(4-(4-(4-ch loro-I H-pyrazol-1 -yI)butyl)piperazin-1 -yI)pyrimidine, [22] 2-(4-(4-(5-methyl1 H-pyrazol-1 -yI)butyl)piperazin-I -yI)pyrimid me, [23] 2-(4-(4-(3-methyl- 1 H-pyrazol-I -yI)butyl)piperazin-I -yI)pyrimid me, [24] 2-(4-(4-(4-bromo-5-methyl-1 H-pyrazol-1 -yI)butyl)piperazin-I-yI)pyrimidine, S * S * * [25J 2-(4-(4-(4-bromo-3-methyl-1 H-pyrazol-I -yI)butyl)piperazin-1-5*5* yI)pyrimidmne, [26] 1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yI)butyl)-4, 5,6,7-tetrahydro-1 H-* indazole, *S.. S...

[27] 2-(4-(4-(pyrim Id in-2-yI)piperazin-I -yI)butyl)-4,5,6,7-tetrahydro-2H-indazole, [28] 2-(4-(4-(5-methyl-4-phenyl-1 H-pyrazol-I -yI)butyl)piperazin-1 -yI)pyrimidine, [29] 2-(4-(4-(3-methyl-4-phenyl-I H-pyrazol-I -yI)butyl)piperazin-1-yI)pyrimidine, [30] 2-(4-(4-(3-ch Ioro-4-fluoro-I H-pyrazol-I -yI)butyl)piperazin-1-yI)pyrimidine, [311 2-(4-(4-(3-chloro-4-methoxy-I H-pyrazol-I -yI)butyl)piperazin-I-yI)pyrimidine, [32] 2-(4-(4-(4-(4-methoxyphenyl)-1 H-pyrazol-1 -yl)butyl)piperazin-1-yI)pyrimidine, [33] 2-(4-(4-(4-(4-ch lorophenyl)-1 H-pyrazol-I -yJ)butyl)piperazin-1-yI)pyrimidine, [34] 2-(4-(4-(4-( 1 H-pyrrol-I -yl)-1 H-pyrazol-I -yl)butyl)piperazin-1-yl)pyrimidine, [35] 2-(4-(4-(4-phenyl-I H-pyrazol-1 -yl)butyl)piperazin-I -yl)pyrim idine, S * * S I [36] 2-(4-(4-(3,5-diphenyl-1 H-pyrazol-I -yI)butyl)piperazin-1 -yI)pyrimidine, *55I

I *IS

[37] N-( I -(4-(4-(pyrimid in-2-yI)piperazin-1 -yl)butyl)-I H-pyrazol-4-yl)benzenesulfonamide, ** : *.S* [38] 4-methyl-N-( I -(4-(4-(pyrim idin-2-yI)piperazin-I -yl)butyl)-1 H-pyrazol-4-* * ** yI)benzenesulfonamide, [39] N-( I -(4-(4-(pyrimid in-2-yI)piperazin-1 -yI)butyl)-I H-pyrazol-4-yl)butane-I-sulfonamide, [40] N-( I -(4-(4(pyrim id in-2-yl)piperazin-I -yI)butyl)-I H-pyrazol-4-yl)propane1-sulfonamide, [41] N-( 1 -(4-(4-(pyrimid in-2-yl)piperazin-I -yl)butyl)-I H-pyrazol-4-yl)ethane-1 -sulfonamide, [42] N, N,3, 5-tetramethyl-I -(4-(4-(pyrim id in-2-yl)piperazin-1 -yl)butyl)-1 H-pyrazole-4-sulfonam ide, [43] N, N-d imethyl-I -(4-(4-(pyrim idin-2-yl)piperazin-1 -yI)butyl)-I H-pyrazole-4-sulfonamide, [44] 1 -(4-(4-(pyrimid in-2-yI)piperazin-1 -yI)butyl)-1 H-pyrazole-4-sulfon Ic acid, [45] 2-(4-(4-(1 H-imidazol-1 -yI)butyl)piperazin-1 -yI)pyrimidine, [46] 2-(4-(4-(4,

5-dichloro-1 H-imidazol-1 -yI)butyl)piperazin-1 -yI)pyrimid me, [471 2-(4-(4-(4-methyl-I H-im idazol-1 -yI)butyl)piperazin-I -yI)pyrimidine, [481 2-(4-(4-(2-methyl-1 H-imidazol-1 -yI)butyl)piperazin-I -yI)pyrimidine, [49] 2-(4-(4-(5-methyl-I H-imidazot-1 -yI)butyl)piperazin-1 -yI)pyrimidine, ** SI 5*5S [501 2-(4-(4-(1 H-pyrrolyl-1 -yI)butyl)piperazin-1 -yI)pyrimidine, [51] 9-(4-(4-(pyrimidin-2-yI)piperazin-1 -yI)butyl)-9H-carbazole, * * *1 ** *ill [52] 1 -(4-4 (-(pyrimidiri-2-yI)piperazin-1 -yI)butyl)-1 H-indole, * * **

SISS

[53] 2,3-diphenyl-1 -(4-(4-(pyrimidin-2-yI)piperazin-1 -yI)butyl)-1 H-indole, [541 1 -(4-(4-(pyrimid in-2-yI)piperazin-I -yI)butyl)-1 H-pyrazole-4-carboxamide, [55] 1 -(4-(4-(pyrimid in-2-yI)piperazin-I -yI)butyl)-I H-pyrazole-4-carboxylic acid, [56] 2-(4-(4-(3-methyl-5-(trifluoromethyl)-1 H-pyrazol-I -yI)butyl)piperazin-1-yI)pyrimidine, [57J 2-(4-(4-(4,5-diphenyl-1 H-imidazol-I -yI)butyl)piperazin-1 -yI)pyrimidine, [58] 2-(4-(4-(2,4, 5-triphenyl-I H-imidazol-1 -yI)butyl)piperazin-I -yI)pyrim id me, [59] 2-(4-(4-(2-methyl-4, 5-diphenyl-1 H-imidazol-I -yI)butyl)piperazin-1-yI)pyrimidine, [60] 2-(4-(4-(4, 5-d ichloro-2-methyl-I H-im idazol-1 -yI)butyl)piperazin-I-yI)pyrimidine, [61] 2-(4-(4-(2-ethyl-1 H-imidazol-I -yl)butyl)piperazin-I -yI)pyrimidine, [62] 2-chloro-I -(4-(4-pyrimid in-2-yl)piperazin-I -yl)butyl)-I H-benzo[djimidazole, [63] 2-(4-(4-(1 H-I,2,4-triazol-I -yl)butyl)piperazin-1 -yI)pyrimidine, [64] 2-(4-(4-(pyrimidin-2-yI)piperazin-1 -yl)butyl)-2H-benzo[d][I,2,3]triazole,

SOSS

[65] 2-methyl-I -(4-(4-(pyrim id in-2-yl)piperazin-1 -yl)butyl)-I H-benzo[d]imidazole, * S. S [661 5,6-d imethyl-1 -(4-(4-(pyrim id in-2-yl)piperazin-I -yI)butyl)-I H-* * 5 benzo[djimidazole, [67] 2-(4-(4-(2-phenyl-I H-imidazol-1 -yI)butyl)piperazin-I -yl)pyrimidine, [68] methyl I -(4-(4-(pyrimid in-2-yl)piperazin-1 -yl)butyl)-I H-imidazole-4-carboxylate, [69] 2-(4-(4-(4-phenyl-I H-imidazol-I -yl)butyl)piperazin-I -yl)pyrimidine, [70] 1 -(4-(4-(pyrimid in-2-yl)piperazin-I -yl)butyl)-I H-benzo[d]imidazole, [711 3-(4-(4-(pyrim Id in-2-yl)piperazin-I -yl)butyl)-3H-imidazo[4, 5-b]pyrid me, [721 1 -(4-(4-(pyrimid in-2-yl)piperazin-I -yl)butyl)-I H-im idazo[4, 5-b]pyrid me, [73] 1 -(4-(4-(pyrimid in-2-yl)piperazin-1 -yl)butyl)-I H-benzo[dJ[ I,2, 3]triazole, [74] 5-chloro-I -(4-(4-(pyrim idin-2-yl)piperazin-I -yI)butyl)-I H-benzo[d]imidazole and [75] 6-ch Ioro-1 -(4-(4-(pyrim Id in-2-yl)piperazin-1 -yl)butyl)-1 H-benzo[d]imidazole; optionally in form of a physiologically acceptable salt thereof, or a corresponding solvate thereof.

11. Use of at least one substituted pyrimidinyl-2-piperazine compound of general formula I, Ia, lb, Ic, Id, le or If according to one or more of claims I to 10 for the manufacture of a medicament for the regulation of appetite; for the. t%

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. a a * * a

12. Use of at least one substituted pyrimidinyl-2-piperazine compound of general formula I, Ia, Ib, Ic, Id, le or If according to one or more of claims 1 to 10 for the manufacture of a medicament for the prophylaxis and/or treatment of stroke; seizures; migraine; epilepsy; irritable colon syndrome; irritable bowel syndrome; bipolar disorders; schizophrenia or hyperactivity disorder (ADHD, attention deficit/hyperactivity disorder).