MEDICAMENTS CONTENANT DES N-SULFAMOYL-N'-ARYLPIPERAZINES UTILISES POUR LA PROPHYLAXIE OU LE TRAITEMENT DE L'OBESITE ET DES PATHOLOGIES APPARENTEES

MEDICAMENTS CONTAINING N-SULFAMOYL-N'-ARYLPIPERAZINES FOR THE PROPHYLAXIS OR TREATMENT OF OBESITY AND RELATED CONDITIONS

Abrégé français

La présente invention concerne l'utilisation de nouvelles et d'anciennes N-sulfamoyl-N'-arylpipérazines et de leurs sels d'addition acides physiologiquement compatibles pour prévenir ou traiter l'obésité et les pathologies apparentées.

Abrégé anglais

The present invention relates to the use of known and novel N-sulfamoyl-
N'~arylpiperazines and their physiologically compatible acid addition salts
for the prophylaxis or treatment of obesity and related conditions.

Revendications

31
Claims
1. The use of a compound of Formula I,
IMG>
wherein
Ar is monocyclic or bicyclic C6-,o-aryl,
whose ring carbon atoms are optionally replaced one to three times by
nitrogen,
oxygen and/or sulphur, and/or
whose C&Io-aryl ring system optionally contains three to five double bonds,
and/or
whose C6-,o-aryl ring system is optionally substituted by one, two or three
substitu-
ents which may be the same or different and which may be selected from the
group consisting of halogen, carboxy, hydroxy, hydroxycarbamoyl, tri-
fluoromethyl, cyano, nitro, pyrrolidinyl, C1.4-alkyl, C1-4-alkoxy, CO-4-
alkoxyphenyl,
Cl-4-alkylthio, C2-4-alkanoyl, C1-4-alkyloxycarbonyl, C,-4-alkylsulfonyl; and
two oxy-
gen atoms which are bonded to two adjacent carbon atoms of the C6-lo-aryl ring
system and which are bridged by C1_2-alkylen; or
whose C6-10-aryl ring system is substituted by one or two substituents which
may be
the same or different and which may be selected from the group consisting of
halogen, carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C,-
4-
alkyl, C1-4-alkoxy, Cl-4-alkylthio, C2-4-alkanoyl, Cl-4-alkyloxycarbonyl, C1-4-
alkyl-
sulfonyl; two oxygen atoms which are bonded to two adjacent carbon atoms of
the C6-1o-aryl ring system and which are bridged by C,_2-alkylen; or
whose C6,1o-aryl ring system is substituted by thienyl, naphthyl, pyridyl;
phenyl or
benzyl, each of which phenyl or benzyl being optionally substituted in the
phenyl
ring by one, two or three substituents which may be the same or different and
which may be selected from halogen, trifluoromethyl, cyano, C1_6-alkyl, C1-4-
alkoxy
or C,-4-alkylsulfonyl;
and of its physiologically compatible acid addition salts, in the preparation
of a medica-
ment for the prophylaxis or treatment of obesity in mammals and humans.

32
2. The use of a compound of Formula I and of its physiologically compatible
acid
addition salts according to claim 1, wherein
Ar is phenyl, optionally substituted by one, two or three substituents which
may be the
same or different and which may be selected from the group consisting of
halogen,
carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C1-4-alkyl,
C1-4-
alkoxy, Co-4-alkoxyphenyl, C1-4-alkylthio, C2-4-alkanoyl, C1-4.-
alkyloxycarbonyl, Cl14-
alkylsulfonyl and two oxygen atoms bonded to adjacent carbon atoms which are
bridged by C1-2-alkylen; or
is phenyl substituted by phenyl or benzyl, each of which optionally being
substituted
in the phenyl ring by one or two substituents which may be the same or
different
and which may be selected from halogen, trifluoromethyl, C1-4-alkyl and C,-4-
alkoxy;
or
is naphthyl; pyridyl; pyrimidinyl; pyrazinyl; pyridazinyl; triazinyl;
quinolinyl; isoquino-
linyl; 1,2,3,4-tetrahydroisoquinolinyl; indolyl; isoindolinyl; thieno[3,2-
d]pyrimidinyl or
pyrazolo[1,5-a]pyrimidinyl, each being optionally substituted by one or two
substitu-
ents which may be the same or different and which may be selected from the
group
consisting of halogen, hydroxycarbamoyl, trifluoromethyl, cyano, nitro,
pyrrolidinyl,
C1-4-alkyl, C1-4.-alkoxy and C,-4-alkyloxycarbonyl.
3. The use of a compound of Formula I and of its physiologically compatible
acid
addition salts according to any of claims I or 2, wherein
Ar is phenyl, optionally substituted by one or two substituents which may be
the same
or different and which may be selected from the group consisting of halogen,
hy-
droxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C1-4.-alkyl, C-4.-
alkoxy, C2-4.-
alkanoyl, C1-4-alkyloxycarbonyl, C1-4-alkylsulfonyl and two oxygen atoms
bonded to
adjacent carbon atoms which are bridged by C1-2-alkylen; or
is pyridyl; pyrimidinyl; naphthyl; quinolinyl; isoquinolinyl; 1,2,3,4-
tetrahydroisoquino-
linyl; indolyl or isoindolinyl, each optionally being substituted by one or
two sub-
stituents which may be the same or different and which may be selected from
the
group consisting of halogen, hydroxycarbamoyl, trifluoromethyl, cyano, nitro,
Cl-4-
alkyl, C1-4-alkoxy and C1-4-oxycarbonyl.
4. The use of a compound of Formula I and of its physiologically compatible
acid
addition salts according to any of claims 1 to 3, wherein

33
Ar is phenyl substituted by one or two substituents which may be the same or
different
and which may be selected from the group consisting of halogen, hydroxy,
trifluoromethyl, cyano, nitro, C1-4-alkyl, C1-4-alkoxy, C2-4-alkanoyl, C1-4-
alkylsulfonyl
and two oxygen atoms bonded to adjacent carbon atoms which are bridged by C1-2-
alkylen; or
is pyridyl; pyrimidinyl or quinolinyl; each optionally being substituted by
one or two
substituents which may be the same or different and which may be selected from
the group consisting of halogen, trifluoromethyl, cyano, nitro, C1-4-alkyl and
C1-4-
alkoxy.
5. The use of a compound of Formula I according to claim 1 and its
physiologically
compatible acid addition salts in the preparation of a medicament for the
prophylaxis or
treatment of the metabolic syndrome and/or syndrome X in mammals and humans.
6. The use of a compound of Formula I according to claim 5, wherein the
metabolic
syndrome and/or syndrome X comprise disorders or diseases selected from the
group
comprising of hypertension, in particular arterial hypertension; insulin
resistance, in par-
ticular diabetes mellitus type II; glucose intolerance; dyslipoproteinaemia,
in particular as
hypertriglyceridaemia accompanied by dyslipoproteinaemia occurring with
lowered HDL-
cholesterol, and hyperuricaemia.
7. The use of a compound of Formula I according to claim 1 and of its
physiologi-
cally compatible acid addition salts in the preparation of a medicament for
the prophy-
laxis or treatment of cardiovascular diseases in mammals and humans.
8. The use of a compound of Formula I according to claim 7, wherein the cardio-
vascular diseases comprise coronary heart disease, cerebrovascular diseases
and pe-
ripheral occlusive arterial disease.
9. The use of a compound of Formula I according to claim 1 and of its
physiologi-
cally compatible acid addition salts in the preparation of a medicament for
the prophy-
laxis or treatment of diabetic conditions or diseases which are unrelated to
obesity.
10. The use of a compound of Formula I according to claim 1 and of its
physiologi-
cally compatible acid addition salts in the preparation of a medicament for
the prophy-
laxis or treatment of epilepsy.

34
11. A compound of Formula Ia,
<IMG>
wherein
Ar1 is phenyl, optionally substituted by one, two or three substituents which
may be the
same or different and which may be selected from the group consisting of
halogen,
carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C1-4-alkyl,
C1-4-
alkoxy, C0-4-alkoxyphenyl, C1-4-alkylthio, C2-4-alkanoyl, C1-4-
alkyloxycarbonyl, C1-4-
alkylsulfonyl and two oxygen atoms bonded to adjacent carbon atoms which are
bridged by C1-2-alkylen; or
is phenyl substituted by phenyl or benzyl, each of which optionally being
substituted
in the phenyl ring by one or two substituents which may be the same or
different
and which may be selected from halogen, C1-4-alkyl, C1-4-alkoxy and
trifluoromethyl;
or
is naphthyl; pyridyl; 2-pyrimidinyl; 5-pyrimidinyl; pyrazinyl; pyridazinyl;
triazinyl; qui-
nolinyl; isoquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl; indolyl;
isoindolinyl; thieno[3,2-
d]pyrimidinyl or pyrazolo[1,5-a]pyrimidinyl each optionally being substituted
by one
or two substituents which may be the same or different and which may be
selected
from the group consisting of halogen, hydroxycarbamoyl, trifluoromethyl,
cyano, ni-
tro, pyrrolidinyl, C1-4-alkyl, C1-4-alkoxy and C1-4-alkyloxycarbonyl;
and its physiologically compatible acid addition salts for the use as a
medicament for
mammals and humans.
12. A compound of Formula Ia and its physiologically compatible acid addition
salts
for the use as medicaments for mammals and humans according to claim 11,
wherein
Ar1 is phenyl, optionally substituted by one or two substituents which may be
the same
or different and which may be selected from the group consisting of halogen,
hy-
droxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C1-4-alkyl, C1-4-
alkoxy, C2-4-
alkanoyl, C1-4-alkyloxycarbonyl, C1-4-alkylsulfonyland two oxygen atoms bonded
to
adjacent carbon atoms which are bridged by C1-2-alkylen; or
is naphthyl; pyridyl; 2-pyrimidinyl; 5-pyrimidinyl; quinolinyl; isoquinolinyl;
1,2,3,4-
tetrahydroisoquinolinyl; indoly or isoindolinyl, each optionally being
substituted by

35
one or two substituents which may be the same or different and which may be se-
lected from the group consisting of halogen, hydroxycarbamoyl,
trifluoromethyl,
cyano, nitro, C1-4-alkyl, C1-4-alkoxy and C1-4-alkyloxycarbonyl.
13. A compound of Formula Ia and its physiologically compatible acid addition
salts
for the use as medicaments for mammals and humans according to any of claims
11 or
12, wherein
Ar1 is phenyl, optionally substituted by one or two substituents which may be
the same
or different and which may be selected from the group consisting of halogen,
hy-
droxy, trifluoromethyl, cyano, nitro, C1-4-alkyl, C1-4-alkoxy, C2-4-alkanoyl,
C1-4-
alkylsulfonyl and two oxygen atoms bonded to adjacent carbon atoms which are
bridged by C1-2-alkylen; or
is pyridyl; 2-pyrimidinyl; 5-pyrimidinyl or quinolinyl; each optionally being
substituted
by one or two substituents which may be the same or different and which may be
selected from the group consisting of halogen, trifluoromethyl, cyano, nitro,
C1-4-
alkyl and C14-alkoxy.
14. A compound of Formula Ia and its physiologically compatible acid addition
salts
for the use as medicaments for mammals and humans according to any of claims
11 to
13, wherein
Ar1 is phenyl substituted by one or two substituents which may be the same or
different
and which may be selected from the group consisting of halogen,
trifluoromethyl,
C1-4-alkyl, C1-4-alkoxy and C1-4-alkylsulfonyl; or
is pyridyl; 2-pyrimidinyl; 5-pyrimidinyl or quinolinyl; each optionally being
substituted
by one or two substituents which may be the same or different and which may be
selected from the group consisting of halogen, trifluoromethyl, cyano C1-4-
alkyl and
C1-4-alkoxy.
15. A compound of Formula Ia and its physiologically compatible acid addition
salts
for the use as medicaments for mammals and humans according to any of claims
11 to
14, selected from the group consisting of
4-phenyl-piperazine-1-sulfonic acid amide;
4-(2-chloro-phenyl)-piperazine-1-sulfonic acid amide; and
4-(2-methoxy-phenyl)-piperazine-1-sulfonic acid amide.

36
16. A pharmaceutical composition comprising a pharmacologically effective
quantity of a compound of Formula Ia according to claim 11 or its
physiologically com-
patible acid addition salts and conventional pharmaceutically acceptable
auxiliaries
and/or carriers.
17. A compound of Formula Ib,
<IMG>
wherein
Ar2 is phenyl substituted once by fluoro, 3-chloro, 4-chloro, bromo, iodo,
hydroxy, C1-4-
alkyl, C2-4-alkoxy, C0-4-alkoxyphenyl, C1-4-alkylthio, C2-4-alkanoyl, C1-4-
oxycarbonyl,
hydroxycarbamoyl, carboxy, trifluoromethyl, cyano, nitro, two oxygen atoms
bonded to adjacent carbon atoms which are bridged by C1-2-alkylen, and C1-4-
alkylsulfonyl; or
is phenyl substituted by two or three substituents which may be the same or
differ-
ent and which may be selected from the group consisting of halogen, carboxy,
hy-
droxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C1-4-alkyl, C1-4-
alkoxy, C1-4-
alkylthio, C2-4-alkanoyl, C1-4-oxycarbonyl, C1-4-alkylsulfonyl and two oxygen
atoms
bonded to adjacent carbon atoms which are bridged by C1-2-alkylen; or
is phenyl substituted once by phenyl or benzyl, each of which optionally being
sub-
stituted in the phenyl ring by one or two substituents which may be the same
or dif-
ferent and which may be selected from halogen, trifluoromethyl, C1-4-alkyl and
C1-4-
alkoxy; or
is naphthyl; pyridyl; 2-pyrimidinyl; 5-pyrimidinyl; pyrazinyl; pyridazinyl;
triazinyl; qui-
nolinyl; isoquinolinyl; indolyl; isoindolinyl; thieno[3,2-d]pyrimidinyl or
pyrazolo[1,5-
a]pyrimidinyl each optionally being substituted by one or two substituents
which
may be the same or different and which may be selected from the group
consisting
of halogen, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, pyrrolidinyl, C1-
4-alkyl,
C1-4-alkoxy and C1-4-oxycarbonyl; or
is 1,2,3,4-tetrahydroisoquinolinyl substituted by one or two substituents
which may
be the same or different and which may be selected from the group consisting
of
halogen, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, pyrrolidinyl, C1-4-
alkyl, C1-
4-alkoxy and C1-4-oxycarbonyl;

37
and its physiologically compatible acid addition salts.
18. A compound of Formula Ib and its physiologically compatible acid addition
salts
according to claim 17, wherein
Ar-2 is phenyl substituted once by fluoro, 3-chloro, 4-chloro, bromo, iodo,
hydroxy,
trifluoromethyl, cyano, nitro, C1-4-alkyl, C2-4-alkoxy, C2-4-alkanoyl, C1-4-
alkylsulfonyl
and two oxygen atoms bonded to adjacent carbon atoms which are bridged by C1-2-
alkylen; or
is phenyl substituted by two substituents which may be the same or different
and
which may be selected from the group consisting of halo, hydroxy,
trifluoromethyl,
cyano, nitro, C1-4-alkyl, C1-4-alkoxy, C2-4-alkanoyl, C1-4-alkylsulfonyl and
two oxygen
atoms bonded to adjacent carbon atoms which are bridged by C1-2-alkylen; or
is pyridyl; 2-pyrimidinyl; 5-pyrimidinyl; naphthyl; quinolinyl; isoquinolinyl;
indoly or
isoindolinyl, each optionally being substituted by one or two substituents
which may
be the same or different and which may be selected from the group consisting
of
halogen, trifluoromethyl, cyano, nitro, C1-4-alkyl and C1-4-alkoxy; or
is 1,2,3,4-tetrahydroisoquinolinyl substituted by one or two substituents
which may
be the same or different and which may be selected from the group consisting
of
halogen, trifluoromethyl, cyano, nitro, C1-4-alkyl and C1-4-alkoxy.
19. A compound of Formula Ib and its physiologically compatible acid addition
salts
according to any of claims 17 or 18, wherein
Ar2 is phenyl substituted once by fluoro, 3-chloro, 4-chloro, bromo, iodo,
hydroxy,
trifluoromethyl, cyano, nitro, C1-4-alkyl, C2-4-alkoxy, C2-4-alkanoyl, C1-4-
alkylsulfonyl
and two oxygen atoms bonded to adjacent carbon atoms which are bridged by C1-2-
alkylen; or
is phenyl substituted by two substituents which may be the same or different
and
which may be selected from the group consisting of halogen, hydroxy, trifluoro-
methyl, cyano, nitro, C1-4-alkyl, C1-4-alkoxy, C2-4-alkanoyl, C1-4-
alkylsulfonyl and two
oxygen atoms bonded to adjacent carbon atoms which are bridged by C1-2-
alkylen;
or
is pyridyl; 2-pyrimidinyl; 5-pyrimidinyl; quinolinyl; each optionally being
substituted
by one or two substituents which may be the same or different and which may be
selected from the group consisting of halogen, trifluoromethyl, cyano, nitro,
C1-4-
alkyl and C1-4-alkoxy.

38
20. A compound of Formula Ib and its physiologically compatible acid addition
salts
according to any of claims 17 to 19, wherein
Ar2 is phenyl substituted once by fluoro, 3-chloro, 4-chloro, bromo, iodo,
trifluoromethyl,
C1-4-alkyl, C2-4-alkoxy and C1-4-alkylsulfonyl; or
is phenyl substituted by two substituents which may be the same or different
and
which may be selected from the group consisting of halogen, trifluoromethyl,
C1-4-
alkyl, C1-4-alkoxy and C1-4-alkylsulfonyl; or
is pyridyl; 2-pyrimidinyl; 5-pyrimidinyl or quinolinyl; each optionally being
substituted
by one or two substituents which may be the same or different and which may be
selected from the group consisting of halogen, trifluoromethyl, cyano, C1-4-
alkyl and
C1-4-alkoxy.
21. A compound of Formula Ib and its physiologically compatible acid addition
salts
according to any of claims 17 to 20, selected from the group consisting of
4-pyridin-4-yl-piperazine-1-sulfonic acid amide;
4-pyrimidin-2-yl-piperazine-1-sulfonic acid amide;
4-(4-fluoro-phenyl)-piperazine-1-sulfonic acid amide;
4-(4-chloro-3-trifluoromethyl-phenyl)-piperazine-1-sulfonic acid amide and
4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid amide.
22. A method of treating or preventing obesity, the metabolic syndrome and/or
syndrome X and/or cardiovascular diseases and/or diabetic conditions or
diseases which
are unrelated to obesity and/or epilepsy in mammals and humans, comprising
adminis-
tering to a subject in need thereof a therapeutically effective amount of a
compound of
Formula I according to claim 1 or its physiologically compatible acid addition
salts.
23. A method for producing a compound of Formula I,
<IMG>
wherein
Ar is monocyclic or bicyclic C6-10-aryl,

39
whose ring carbon atoms are optionally replaced one to three times by
nitrogen,
oxygen and/or sulphur, and/or
whose C6-10-aryl ring system optionally contains three to five double bonds,
and/or
whose C6-10-aryl ring system is optionally substituted by one, two or three
substitu-
ents which may be the same or different and which are selected from the group
consisting of halogen, carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl,
cyano, nitro, pyrrolidinyl, C1-4-alkyl, C1-4-alkoxy, C0-4-alkoxyphenyl, C1-4-
alkylthio,
C2-4-alkanoyl, C1-4-alkyloxycarbonyl, C1-4-alkylsulfonyl; and two oxygen atoms
which are bonded to two adjacent carbon atoms of the C6-10-aryl ring system
and
which are bridged by C1-2-alkylen; or
whose C6-10-aryl ring system is substituted by one or two substituents which
may be
the same or different and which may be selected from the group consisting of
halogen, carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C1-
4-
alkyl, C1-4-alkoxy, C1-4-alkylthio, C2-4-alkanoyl, C1-4-alkyloxycarbonyl, C1-4-
alkyl-
sulfonyl; two oxygen atoms which are bonded to two adjacent carbon atoms of
the C6-10-aryl ring system and which are bridged by C1-2-alkylen; or
whose C6-10-aryl ring system is substituted by thienyl, naphthyl, pyridyl;
phenyl or
benzyl, each of which phenyl or benzyl being optionally substituted in the
phenyl
ring by one, two or three substituents which may be the same or different and
which may be selected from halogen, trifluoromethyl, cyano, C1-6-alkyl, C1-4-
alkoxy
or C1-4-alkylsulfonyl;
and of its physiologically compatible acid addition salts, by either
a) reacting an arylpiperazine compound of general Formula II,
<IMG>
wherein Ar has the above meaning, with sulfamide, or
b) reacting an arylpiperazine of Formula II with a 4-dimethylaminopyridin (=
DMAP)
reagent which is protected with the tert.-butyloxycarbonyl (= boc) group, of
Formula III,

40
<IMG>
and subsequently cleaving off the boc group under acidic conditions from the
obtained
intermediate compound, or
c) reacting an arylpiperazine of Formula II with sulfamoylchloride, which is
prefera-
bly protected with the boc group, of Formula IV,
<IMG>
and subsequently cleaving off the boc group under acidic conditions from the
obtained
intermediate product,
and if desired converting resulting free bases of Formula I into their
physiologically com-
patible salts, or converting salts of the compounds of Formula I into the free
bases of
Formula I.
24. A pharmaceutical composition comprising pharmacologically effective-quanti-
ties of each of
a) at least one compound of Formula I as a first active agent, and
b) at least one active agent selected from the group consisting of biguanides;
fibric
acids; HMGCoA reductase inhibitos; and insulin sensitizers as a second active
agent.
25. Pharmaceutical composition according to claim 24, further comprising
conven-
tional pharmaceutically acceptable auxiliaries and/or carriers.
26. Pharmaceutical composition according to claim 24 which is suitable for
oral ad-
ministration.
27. Pharmaceutical composition according to claim 24 wherein the active agents
are present in one or more dosage forms selected from the group consisting of
tablets,
coated tablets, capsules, syrups, elixirs or suspensions.

41
28. Pharmaceutical composition according to claim 24, wherein the compound of
Formula I is selected from the group consisting of 4-phenyl-piperazine-l-
sulfonic acid
amide; 4-(2-chloro-phenyl)-piperazine-l-sulfonic acid amide; 4-(2-methoxy-
phenyl)-
piperazine-1-sulfonic acid amide; 4-pyridin-4-yl-piperazine-1-sulfonic acid
amide; 4-
pyrimidin-2-yl-piperazine-1-sulfonic acid amide; 4-(4-fluoro-phenyl)-
piperazine-1-sulfonic
acid amide; 4-(4-chloro-3-trifluoromethyl-phenyl)-piperazine-1-sulfonic acid
amide and/or
4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid amide.
29. Pharmaceutical composition according to claim 28 wherein the compound of
Formula I is 4-phenyl-piperazine-1-sulfonic acid amide.
30. Pharmaceutical composition according to claim 24, wherein the second
active
agent b) is a biguanide or any physiologically compatible salt, solvate,
prodrug or ester
thereof.
31. Pharmaceutical composition according to claim 30, wherein the second
active
agent b) is metformine.
32. Pharmaceutical composition according to claim 24, wherein the second
active
agent b) is a fibric acid or any physiologically compatible salt, solvate,
prodrug or ester
thereof.
33. Pharmaceutical composition according to claim 32, wherein the second
active
agent b) is fenofibrate.
34. Pharmaceutical composition according to claim 24, wherein the second
active
agent b) is a HMGCoA reductase inhibitor or any physiologically compatible
salt, solvate,
prodrug or ester thereof.
35. Pharmaceutical composition according to claim 34, wherein the second
active
agent b) is simvastatin.
36. Pharmaceutical composition according to claim 24, wherein the second
active
agent b) is an insulin sensitizer or any physiologically compatible salt,
solvate, prodrug or
ester thereof.
37. Pharmaceutical composition according to claim 36, wherein the second
active
agent b) is rosiglitazone.

42
38. A method of treating or preventing obesity, the metabolic syndrome and/or
syndrome X and/or cardiovascular diseases and/or diabetic conditions or
diseases which
are unrelated to obesity and/or epilepsy in mammals and humans, comprising
adminis-
tering to a subject in need thereof an effective amount of a combination of at
least one
compound of Formula I as a first active agent, and at least one active agent
selected
from the group consisting of biguanides; fibric acids; HMGCoA reductase
inhibitos; and
insulin sensitizers, as a second active agent.
39. A kit comprising in separate containers in a single package pharmaceutical
do-
sage forms for use in combination, comprising,
i) in one separate container a pharmaceutical dosage form comprising at least
one
compound of Formula I, and
ii) in another separate container a pharmaceutical dosage form comprising at
least
one active agent selected from the group consisting of biguanides; fibric
acids;
HMGCoA reductase inhibitos; and insulin sensitizers.

Description

CA 02567166 2006-11-17
WO 2005/110413 PCT/EP2005/052281
1
Solvay Pharmaceuticals GmbH
30173 Hannover
Medicaments containing N-sulfamoyl-N'-arylpiperazines for the
prophylaxis or treatment of obesity and related conditions
The present invention relates to known and novel N-sulfamoyi-N'-
arylpiperazines
and their physiologically compatible acid addition salts and to pharmaceutical
composi-
tions or medicaments containing these compounds for the prophylaxis or
treatment of
obesity and related conditions.
Some N-sulfamoyl-N'-arylpiperazines and their uses as herbicides are described
in
German patent application published as DE-OS 1964441 (equivalent to US patent
No.
3,709,677). Similar compounds and their uses as insecticides and acaricides
are also
described in document WO 95/09151.
Document WO 94/07867 discloses substituted 4-pyrimidine derivatives as
inhibitors
of sorbitol dehydrogenase, useful for treating or preventing diabetic
complications in a
mammal.
European patent application EP 0 470 616 A2 teaches substituted 4-pyrimidine
de-
rivatives useful as screening reagents for aidose reductase inhibitors.
International patent application WO 03/075929 provides inhibitors of histone
deace-
tylase useful for the treatment of e.g. cancer and psoriasis, which may
comprise certain
N-sulfamoyl-N'-arylpiperazines. Intermediates for synthesizing said compounds
are also
disclosed.
US patent No. 2,748,125 discloses 1-substituted 4-sulfamylpiperazines with
anti-
convulsant activity.
J.M. McManus et al. (J Med Chem 8(1965) 766-776) teach sulfamylurea hypogly-
cemic agents.
A method of discovering compounds suitable for the treatment and/or
prophylaxis
of obesity by inhibiting lipogenesis via the inhibition of carbonic anhydrases
in mammals
and humans is known from document WO 02/07821.

CA 02567166 2006-11-17
WO 2005/110413 PCT/EP2005/052281
2
It was an object of the present invention to provide novel medicaments for the
treat-
ment and/or prophylaxis of obesity and its concomitant and/or secondary
diseases or
conditions, which are very effective and can be obtained in simple manner.
It has now surprisingly been found that certain novel and known N-sulfamoyl-N'-
arylpiperazines or their physiologically compatible acid addition salts are
suitable for the
treatment and/or prophylaxis of obesity and its concomitant and/or secondary
diseases
or conditions.
According to the invention, an N-sulfamoyl-N'-arylpiperazine of general
Formula I
/-\ II
Ar-N \/N-S-NHZ I
O
wherein
Ar is monocyclic or bicyclic C6-,o-aryl,
whose ring carbon atoms are optionally replaced one to three times by
nitrogen,
oxygen and/or sulphur, and/or
whose C6-1o-aryl ring system optionally contains three to five double bonds,
and/or
whose C6-,o-aryl ring system is optionally substituted by one, two or three
substitu-
ents which may be the same or different and which may be selected from the
group consisting of halogen, carboxy, hydroxy, hydroxycarbamoyl, tri-
fluoromethyl, cyano, nitro, pyrrolidinyl, CI.4-alkyl, Cl-4-alkoxy, Co4-
alkoxyphenyl,
Cl-4-alkylthio, C2-4-alkanoyl, CI-4-alkyloxycarbonyl, Cl.4-alkylsulfonyl; and
two oxy-
gen atoms which are bonded to two adjacent carbon atoms of the Cr,1o-aryl ring
system and which are bridged by C1_2-alkylen; or
whose C6.,o-aryl ring system is substituted by one or two substituents which
may be
the same or different and which may be selected from the group consisting of
halogen, carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C,-
4-
alkyl, C,-4-alkoxy, CI-4-alkylthio, C2-4-alkanoyl, CI.4-alkyloxycarbonyl, CI.4-
alkyl-
sulfonyl; two oxygen atoms which are bonded to two adjacent carbon atoms of
the C6.,o-aryl ring system and which are bridged by C,_2-alkylen; or
whose Cr,1o-aryl ring system is substituted by thienyl, naphthyl, pyridyl;
phenyl or
benzyl, each of which phenyl or benzyl being optionally substituted in the
phenyl
ring by one, two or three substituents which may be the same or different and

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3
which may be selected from halogen, trifluoromethyl, cyano, Cl_s-alkyl, CI_4-
alkoxy
or Cl-4-alkylsulfonyl;
or its physiologically compatible acid addition salts can be used for the
treatment and/or
prophylaxis of obesity and its concomitant and/or secondary diseases or
conditions.
More specifically, in compounds of Formula I
Ar is phenyl, optionally substituted by one, two or three substituents which
may be the
same or different and which may be selected from the group consisting of
halogen,
carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, Ci.4-alkyl,
C,-4-
alkoxy, Co-4-alkoxyphenyl, CI-4-alkylthio, CZ-4-alkanoyl, Cl-4-
alkyloxycarbonyl, C,-4-
alkylsulfonyl and two oxygen atoms bonded to adjacent carbon atoms which are
bridged by CI_2-alkylen; or
is phenyl substituted by phenyl or benzyl, each of which optionally being
substituted
in the phenyl ring by one or two substituents which may be the same or
different
and which may be selected from halogen, trifluoromethyl, Cl-4-alkyl and C,-4-
alkoxy;
or
is naphthyl; pyridyl; pyrimidinyl; pyrazinyl; pyridazinyl; triazinyl;
quinolinyl; isoquino-
linyl; 1,2,3,4-tetrahydroisoquinolinyl; indolyl; isoindolinyl; thieno[3,2-
d]pyri mid inyl or
pyrazolo[1,5-a]pyri mid inyl, each being optionally substituted by one or two
substitu-
ents which may be the same or different and which may be selected from the
group
consisting of halogen, hydroxycarbamoyl, trifluoromethyl, cyano, nitro,
pyrrolidinyl,
C,-4-alkyl, C~ 4:-alkoxy and C,-4-alkyloxycarbonyl.
Where in the compounds of Formula I, Ia and/or lb or in other compounds de-
scribed within the context of the present invention substituents are or
contain Cl.4-alkyl or
C1_6-alkyl, these may each be straight-chain or branched and preferably be
methyl.
Where substituents in compounds of Formula I stand for halogen, fluorine,
chlorine,
bromine or iodine are suitable. Fluorine and chlorine are preferred. Where
substituents
contain C2-4-alkanoyl, this may be straight-chain or branched. Acetyl is
preferred as C2-4-
alkanoyl.
Ar preferably stands for optionally substituted phenyl; pyridyl, in particular
2-pyridyl
or 4-pyridyl; pyrimidinyl, in particular 2-pyrimidinyl or 5-pyrimidinyl;
naphthyl or quinolinyl.
Phenyl, pyridyl and pyrimidinyl are more preferred.
Where Ar is optionally substituted phenyl, halogen, CI-4-alkyl, CI-4-alkoxy,
trifluoro-
methyl, cyano, nitro and Cl-4-alkylsulfonyl are preferred substituents. More
preferred are

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4
halogen, C1-4-alkyl, C,.4-alkoxy and trifluoromethyl. Unsubstituted phenyl is
a preferred
alternative.
Where Ar is optionally substituted pyridyl; pyrimidinyl; naphthyl; quinolinyl;
isoquino-
linyl; 1,2,3,4-tetrahydroisoquinolinyl; indoly or isoindolinyl, halogen,
trifluoromethyl,
cyano, C,-4-alkyl and CI.4-alkoxy are preferred substituents.
Particularly preferred compounds which may be used according to the invention
and which are partly novel, are selected from the group consisting of 4-phenyl-
piperazine-1-sulfonic acid amide (= N-sulfamoyl-N'-phenylpiperazine); 4-(2-
chloro-
phenyl)-piperazine-1-sulfonic acid amide; 4-(2-methoxy-phenyl)-piperazine-1-
sulfonic
acid amide; 4-pyridin-4-yl-piperazine-1-sulfonic acid amide; 4-pyrimidin-2-yl-
piperazine-1-
sulfonic acid amide; 4-(4-fluoro-phenyl)-piperazine-1-sulfonic acid amide; 4-
(4-chloro-3-
trifluoromethy!-phenyl)-piperazine-1-sulfonic acid amide and 4-(3-chloro-5-
trifluoromethyl-
pyridin-2-yl)-piperazine-1-sulfonic acid amide.
Physiologically compatible acid addition salts of compounds of Formula I are
their
conventional salts with inorganic acids, for example sulphuric acid,
phosphoric acids or
hydrohalic acids, preferably hydrochloric acid, or with organic acids, for
example lower
aliphatic monocarboxylic, dicarboxylic or tricarboxylic acids such as maleic
acid, fumaric
acid, lactic acid, tartaric acid, citric acid, or with sulphonic acids, for
example lower al-
kanesulphonic acids such as methanesulphonic acid or trifluoromethanesulphonic
acid,
or benzenesulphonic acids optionally substituted in the benzene ring by
halogen or lower
alkyl, such as p-toluenesulphonic acid. Hydrochloric acid salts of the
compounds of For-
mula I are preferred.
In a further aspect, the invention also relates to compounds of general
Formula Ia,
O
Arl-N N-S-NHZ Ia
wherein
Ar' is phenyl, optionally substituted by one, two or three substituents which
may be the
same or different and which may be selected from the group consisting of
halogen,
carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C,-4-alkyl,
C1-4-
alkoxy, Co-4-alkoxyphenyl, Cj-4.-alkylthio, C2.4-alkanoyl, C1.4-
alkyloxycarbonyl, Cl-4-

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alkylsulfonyl and two oxygen atoms bonded to adjacent carbon atoms which are
bridged by C,_2-alkylen; or
is phenyl substituted by phenyl or benzyl, each of which optionally being
substituted
in the phenyl ring by one or two substituents which may be the same or
different
and which may be selected from halogen, CI.4-alkyl, CI.4-alkoxy and
trifluoromethyl;
or
is naphthyl; pyridyl; 2-pyrimidinyl; 5-pyrimidinyl; pyrazinyl; pyridazinyl;
triazinyl; qui-
nolinyl; isoquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl; indolyll;
isoindolinyl; thieno[3,2-
d]pyrimidinyl or pyrazolo[1,5-a]pyrimidinyl each optionally being substituted
by one
or two substituents which may be the same or different and which may be
selected
from the group consisting of halogen, hydroxycarbamoyl, trifluoromethyl,
cyano, ni-
tro, pyrrolidinyl, Cl.4-alkyl, C,-4-alkoxy and Cl-4-alkyloxycarbonyl;
and their physiologically compatible acid addition salts, for the use as
medicament for
mammals and humans; and/or to pharmaceutical compositions comprising a
pharmaco-
logically effective quantity of a compound of Formula Ia or its
physiologically compatible
acid addition salts and conventional pharmaceutically acceptable auxiliaries
and/or carri-
ers.
In still a further aspect, the present invention relates to novel N-sulfamoyl-
N'-
arylpiperazines of general Formula Ib,
O
Ar2- N-IS-NHZ Ib
\/ O
wherein
Ae is phenyl substituted once by fluoro, 3-chloro, 4-chloro, bromo, iodo,
hydroxy, C14.-
alkyl, C2.4-alkoxy, Co.-0.-alkoxyphenyl, CI-4-alkylthio, C2-4-alkanoyl, Cl-4-
oxycarbonyl,
hydroxycarbamoyl, carboxy, trifluoromethyl, cyano, nitro, two oxygen atoms
bonded to adjacent carbon atoms which are bridged by CI_2-alkylen, and CI-4-
alkylsulfonyl; or
is phenyl substituted by two or three substituents which may be the same or
differ-
ent and which may be selected from the group consisting of halogen, carboxy,
hy-
droxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C,.4-alkyl, C,-4-
alkoxy, C,-4-
alkylthio, C2-4-alkanoyl, Cl-4-oxycarbonyl, Cl-4-alkylsulfonyl and two oxygen
atoms
bonded to adjacent carbon atoms which are bridged by CI_2-alkylen; or

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6
is phenyl substituted once by phenyl or benzyl, each of which optionally being
sub-
stituted in the phenyl ring by one or two substituents which may be the same
or dif-
ferent and which may be selected from halogen, trifluoromethyl, Cl-4-alkyl and
CI-4-
alkoxy; or
is naphthyl; pyridyl; 2-pyrimidinyl; 5-pyrimidinyl; pyrazinyl; pyridazinyl;
triazinyl; qui-
nolinyl; isoquinolinyl; indolyl; isoindolinyl; thieno[3,2-d]pyrimidinyl or
pyrazolo[1,5-
a]pyrimidinyl each optionally being substituted by one or two substituents
which
may be the same or different and which may be selected from the group
consisting
of halogen, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, pyrrolidinyl, C,-
4-alkyl,
C,-4-alkoxy and CI-4-oxycarbonyl; or
is 1,2,3,4-tetrahydroisoquinolinyl substituted by one or two substituents
which may
be the same or different and which may be selected from the group consisting
of
halogen, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, pyrrolidinyl, C,-4-
alkyl, C,_
4-alkoxy and C,-4-oxycarbonyl;
and their physiologically compatible acid addition salts.
Some N-sulfamoyl-N'-arylpiperazines which are coming under the scope of
general
Formula I according to the present invention are already known, e.g. from
patent applica-
tions DE-OS 1964441 (US 3,709,677), WO 94/07867 and/or WO 95/09151, and can be
produced according to the processes described-~ in these speciflcations or
according to
analogous processes.
In general, compounds of Formula I (including compounds of Formulas Ia and Ib)
can be produced in known manner by either
a) reacting an arylpiperazine compound of general Formula II,
Ar-N NH II
wherein Ar has the above meaning, with sulfamide, or
b) reacting an arylpiperazine of Formula II with a 4-dimethylaminopyridin (=
DMAP)
reagent which is protected with the tert.-butyloxycarbonyl (= boc) group, of
Formula III,

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7
H3C CH3 O
HCX 1)" N-SI / CH3
3 O O-N -N + III
11
O \CH3
and subsequently cleaving off the boc group under acidic conditions from the
obtained
intermediate compound, or
c) reacting an arylpiperazine of Formula II with sulfamoylchloride, which is
prefera-
bly protected with the boc group, of Formula IV,
H3C CH3 0
H3Cx ~
ON-O -CI IV
11
0
and subsequently cleaving off the boc group under acidic conditions from the
obtained
intermediate product,
and if desired converting resulting free bases of Formula I into their
physiologically com-
patible salts, or converting salts of the compounds of Formula I into the free
bases of
Formula I.
In process variant a), the reaction can be carried in an organic solvent which
is inert
under the reaction conditions, in particular in an aprotic solvent such as
toluene or xy-
lene or in a mixture of such solvents. Suitable reaction temperatures are
between room
temperature and the boiling point of the solvent or solvent mixture,
preferably between
60 C and 100 C.
In process variant b), the reaction can be carried out in an organic solvent
which is
inert under the reaction conditions, in particular a dipolar-aprotic solvent
such as chloro-
form, dichloromethane or dioxane, or in a mixture of such solvents. Suitable
reaction
temperatures are between 10 C and 50 C, preferably at room temperature. The
boc-
protecting group can subsequently be cleaved off in a known manner in acidic
media,
e.g. in an ethanolic solution of hydrochloric acid.
In process variant c), the reaction can be carried out in an organic solvent
which is
inert under the reaction conditions, in particular a dipolar-aprotic solvent
such as chloro-
form or dichloromethane or in a mixture of such solvents. Suitable reaction
temperatures
are between 10 C and 50 C, preferably at room temperature. The boc protecting
group
can subsequently be cleaved off in a known manner in acidic media, e.g. in an
ethanolic

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8
solution of hydrochloric acid. Using a boc-protected sulfamoylchloride is
preferred. How-
ever, under the appropriate reaction conditions known to those skilled in the
art, also
unprotected sulfamoylchloride in the presence of a base may be used.
Compounds of Formula II are generally known compounds or such compounds can
routinely be prepared by those skilled in the art according to known processes
and from
known starting materials. For example can compounds of Formula II, wherein Ar
is op-
tionally substituted biaryl, be prepared by reacting a compound of general
Formula V,
X-Ar3-N NH V
\_j
wherein Ar3 has the meaning monocyclic or bicyclic Cr,o-aryl, whose ring
carbon atoms
are optionally replaced one to three times by nitrogen, oxygen and/or sulphur,
and/or
whose C6_,o-aryl ring system optionally contains three to five double bonds;
and X is a
cleavable leaving group like halogen, preferably bromine;
with a compound of general Formula VI,
OH
Ar4-B VI
\
OH
wherein Ar4 has the meaning thienyl, naphthyl, pyridyl; phenyl or benzyl, each
of which
phenyl or benzyl being optionally substituted in the phenyl ring by one, two
or three sub-
stituents which may be the same or different and which may be selected from
halogen,
trifluoromethyl, cyano, C,_6-alkyl, Cl.4-alkoxy or Cl.4-alkylsulfonyl; in the
presence of a
palladium catalyst.
The reaction can be carried out in a manner known as "Suzuki coupling
reaction" in
an organic solvent which is inert under the reaction conditions, in particular
in a dipolar-
protic solvent such as a lower alkanol like methanol or ethanol, or an ether
of a lower
divalent alkanol like ethylene glycol dimethyl ether, or in mixtures of such
solvents or in
mixtures of such solvents with water. Suitable reaction temperatures are
between 100 C
and 200 C, preferably between 120 C and 100 C. The reaction can expediently be
car-
ried out by using a microwave reactor. Usually, the reaction is carried out in
the presence
of a base like an alkalicarbonate, preferably potassium carbonate. Suitable
palladium
catalysts are salts of palladium-(II), like pall ad ium-(I I)-acetate.

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9
Compounds of Formulas III and IV are generally known compounds and/or can rou-
tinely be prepared by those skilled in the art according to known processes
and from
known starting materials. Compounds of Formula V and VI are generally known
com-
pounds and/or such compounds can routinely be prepared by those skilled in the
art ac-
cording to known processes and from known starting materials.
In yet another aspect, the present invention also relates to a method of
treating or
preventing obesity, the metabolic syndrome and/or syndrome X and/or
cardiovascular
diseases, in mammals and humans comprising administering to a subject in need
thereof
a therapeutically effective amount of a compound of Formula I or its
physiologically com-
patible acid addition salts.
Obesity according to the present invention is meant to comprise any increase
in
body fat that results in increased bodyweight, comprising as a preferred
alternative but
not limited to the medical definition of obesity. The invention thus also
relates to non-
medical weight loss, such as cosmetic weight loss and includes improving
bodily appear-
ance in general. Further, the term obesity also is meant to comprise drug
induced obesity
and/or juvenile obesity.
The concomitant diseases of obesity or the secondary diseases thereof which
can
each be treated with the compounds according to the invention include in
particular the
metabolic syndrome and/or syndrome X and cardiovascular diseases.
The term "metabolic syndrome" as used in this application is meant to cover a
com-
plex of clinical pictures which - besides central obesity - mainly comprises
hypertension,
in particular arterial hypertension; insulin resistance, in particular
diabetes mellitus type II;
glucose intolerance; dyslipoproteinaemia, in particular as
hypertriglyceridaemia, accom-
panied by dyslipoproteinaemia occurring with lowered HDL-cholesterol, and also
hyperu-
ricaemia, which can lead to gout. According to information from the American
Heart As-
sociation, the metabolic syndrome is closely linked to insulin resistance.
Some people
are genetically predisposed to insulin resistance. Acquired factors, such as
excess body
fat and physical inactivity, can elicit insulin resistance and the metabolic
syndrome in
these people. Most people with insulin resistance have central obesity. The
biologic
mechanisms at the molecular level between insulin resistance and metabolic
risk factors
are not fully understood and appear to be complex. One group of people at risk
for de-
veloping metabolic syndrome are those with diabetes who have a defect in
insulin action
and cannot maintain a proper level of glucose in their blood. Another is
people, mainly
those with high blood pressure, who are nondiabetic and insulin-resistant but
who com-

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pensate by secreting large amounts of insulin. This condition is known as
hyperinsuline-
mia. A third group is heart attack survivors who, unlike hypertensives, have
hyperinsu-
linemia without having abnormal glucose levels. The metabolic syndrome has
become
increasingly common in higher developed countries like the United States,
where it is
estimated that about 20-25 percent of US adults have it. There are no well-
accepted cri-
teria for diagnosing the metabolic syndrome.
The criteria proposed by the Third Report of the National Cholesterol
Education
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High
Blood
Cholesterol in Adults (Adult Treatment Panel III) are the most current and
widely used.
According to the ATP III criteria, the metabolic syndrome is identified by the
presence of
three or more of these components:
= Central obesity as measured by waist circumference (Men - Greater than 40
inches; Women - Greater than 35 inches).
= Fasting blood triglycerides greater than or equal to 150 mg/dL.
= Blood HDL cholesterol (Men - Less than 40 mg/dL; Women - Less than 50 mg/dL)
= Blood pressure greater than or equal to 130/85 mmHg.
= Fasting glucose greater than or equal to 110 mg/dL.
The term "syndrome X" is closely related to the term "metabolic syndrome" and
usu-
ally is supposed to denominate the identical disease or condition. According
to informa-
tion from the American Heart Association, the term "Syndrome X" refers,
however, addi-
tionally to a heart condition where chest pain and electrocardiographic
changes that sug-
gest ischemic heart disease are present, but where there are no angiographic
findings of
coronary disease. Patients with cardiac syndrome X also sometimes have lipid
abnor-
malities.
The term "cardiovascular diseases" in conjunction with obesity is usually
under-
stood to mean coronary heart disease, which can lead to heart failure,
cerebrovascular
diseases, which may for example be accompanied by an increased risk of
strokes, and
peripheral occlusive arterial disease.
Due to their inherent properties, the compounds of Formula I or their
physiologically
compatible acid addition salts are also expected to be useful in the treatment
of diabetic
conditions or diseases which are unrelated to obesity. Such diabetic
conditions or dis-

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11
eases comprise e.g. diabetes mellitus type II, diabetic neuropathy, diabetic
retinopathy,
diabetic nephropathy, diabetic microangiopathy or diabetic macroangiopathy.
Further concomitant and/or secondary diseases of obesity may be gall-bladder
dis-
eases such as formation of gallstones, sleep apnoea syndrome, orthopaedic
complica-
tions such as osteoarthritis and psychosocial disorders.
The compounds of Formula I are further deemed to be useful as anticonvulsants
for the prophylaxis or treatment of epilepsy in mammals and humans.
The compounds of Formula I according to the invention are inhibitors of
mammalian
carbonic anhydrases, in particular of human carbonic anhydrase isozymes of
subtypes II
and/or V(= hCA II and/ or hCA V).
Pharmacological Test Methods
The example numbers quoted in the pharmacological test methods relate to the
preparation examples described below.
1. In vitro inhibition of human carbonic anhydrase isoenzyme II (hCA II)
The test compounds of Formula I in 96 well microplates were diluted with aqua
bidest by using an automatic pipettor (CyBiWell ). From the different dilution
plates, ali-
quots of 20 NI were transferred to the 96 well black assay plates with a
pipetting station
(Tecan Genesis ). In a second step, 148 pi of potassium phosphate buffer (20
mM, pH
7.4) was added, and as a third step, 20 pi of enzyme solution (1 pM human
carbonic
anhydrase isoenzyme II from erythrocytes (Sigma-Aldrich), dissolved in
potassium phos-
phate buffer) incubated for 60 min at room temperature and the fluorescence
signal
(Tecan Ultra fluorescence reader; excitation wavelength: 280 nm; emission
wavelength:
465 nm) read at the end of the preincubation period (FLU-1). After the
preincubation
time, 20 pi of aqueous dansylamide solution (1 mM dansylamide (Sigma-Aldrich),
dis-
solved in hydrochloric acid) were added and the fluorescence signal read every
10 min
for a period of 60 min at 37 C. For calculation, the fluorescence data of the
time point 60
min (FLU-2) were used. The total volume of assay mixture amounted to 208 NI.
The final
concentration of carbonic anhydrase II was 10"' M/L, of dansylamide 2.25x10"6
and of
compounds from 10-8 M/L up to 10"5 M/L. Final concentration of DMSO as
compound
solvent was 0.1 mM. Each microplate also contained blanks without compound and
en-
zyme, controls without compound and ethoxzolamide (final concentration 5x10"8
M/L). All

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12
data reflect single measurements. Data were expressed as % inhibition after
calculation
by the formula:
% inhibition = 100((1-(FLU-2cPd-FLU-2bianrFLU-1cpd+FLU-1blank)/(FLU-2conirol-
FLU-2blanK-
FLU-1 controj-FLU-1 b1ank))
The %inhibition data for each compound and the respective final concentrations
were used for IC50 calculations by using the Prism 4 software. Concentration
action fig-
ures were calculated by applying the Prism algorithm for nonlinear regression
(curve-fit):
sigmoidal dose response with variable slope and the constraints: top: 100 and
bottom 0.
In this test model, the test substances of Formula I listed. in Table I below
showed
the IC50 values given below:
Table 1: hCA II inhibiting effect of the test substances in vitro
Example No. IC50 [NM]
2 5.1
3 7.8
4 3.7
7 1.8
8 1.7
9 7.3
4.0
11 0.5
12 1.2
13 0.9
14 0.2
0.4
16 0.3
17 1.9
18 1.6
19 0.08
0.3
21 0.2
2. In vivo oral glucose tolerance test in the rat
The studies were carried out in individually housed male fatty Zucker rats (n=
10
per group) weighing ca. 250-500 g. The rats were kept on a normal 12/12h
light/dark
cycle (lights on 07.00) and they were allowed food (lab chow) and water ad
libitum ex-

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13
cept for during experiments, when they were fasted overnight before the
glucose chal-
lenge.
The test substances of Formula I were suspended in 2% polyethylenglycol (=
PEG)
1% carboxymethylcellulose and administered by oral gavage at a dose of 100
mg/kg/day; 1/3 of the dose (1 mI/kg, 33 mg/mI) was administered at 08.30-09.30
h; the
remaining 2/3 dose (2ml/kg; 33 mg/mI) was administered between 16.00-17.00 h
and the
last 1/3 dose was given the following morning. Control animals received only
the vehicle.
On the day of the test, 45 min after the final dose of test substance/vehicle
a blood sam-
ple (0 min) was taken (tail vein) immediately after which the rats received an
oral glucose
challenge (1.25 g/kg; 118 mg/mI). Further blood samples were taken at 30, 60,
90, 120
min after the glucose challenge. The second drop of blood of each sample was
placed
on a glucose test strip before this was placed in the glucose meter for
determination of
blood glucose level (Life Scan One Touch Ultra Blood Glucose Meter and Life
Scan
One Touch Ultra Test Strips; Life Scan Inc.; Milpitas, CA 95035). The
remaining blood
of each sample was spun and the plasma was frozen at -80 C before analysis for
insulin
(1-2-3 Rat Insulin ELISA kit, Alpco Diagnostics).
The values obtained were plotted and the AUC for test compounds and vehicle
(for
glucose and insulin) were determined after which the percent control AUC,
percent con-
trol maximum value and % control baseline were estimated, to determine the
influence of
the test compound on the glucose tolerance.
In the test model described above, the test substances showed the following
results
(given as percentage % of control):
Table 2: Influence of test substances on glucose and insulin levels
Ex. Glucose Insulin
No. AUC Maximal Baseline AUC Maximal Base-
effect effect line
2 84 78 82 95 95 85
6 89 84 91 104 123 109
14 102 94 88 107 92 97
3. Acute in vivo food intake test in mice
The studies were carried out in individually housed male C57BI/6 mice (n=8 per
group). The mice were kept on an inverted 12/12h light/dark cycle (lights on
22:00).
They were allowed food (high caloric diet) and water ad libitum. Food intake
and water
consumption was measured daily. The test compound of Formula I was suspended
in

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14
1% methylcellulose in water and 2% (v/v) of Poloxamer 188 (Lutrol F68 ) and
adminis-
tered by oral gavage at a dose of 100 mg/kg/day. One half of the dose was
administered
at 7.00-9.00 h; the remaining half of the dose was administered between 15.00-
15.30 h.
In the test model described above, the test substances caused a decrease of
the
animals' 24h food intake to the percentages of food intake when compared to
control as
given in table 3 below.
Table 3: Influence of test substances on food intake
Example No. food intake
[% of control]
2 68
7 78
12 53
15 79
21 76
4. Chronic influence on food and water intake and body weight gain in vivo
Female Wistar rats (weight range 250-300 g; Charles River, Margate, Kent) were
housed in pairs in polypropylene cages with solid floors and sawdust bedding
at a tem-
perature of 21 4 C and 55 20% humidity: Animals were maintained on a reverse
phase
light-dark cycle (lights off for 8 hours from 10.00-18.00 h) during which time
the room
was illuminated by red light. Animals had free access to powdered high fat
diet (VRF1
plus 20% lard), ground chocolate, ground peanuts and tap water at all times.
The three
different diets were contained in separate glass feeding jars with aluminium
lids (Solme-
dia Laboratory Suppliers, Romford, Essex). Each lid had a 3-4 cm hole cut in
it to allow
access to the food. Animals were housed in pairs for twelve weeks. At least
two weeks
before the start of the baseline readings, animals were housed individually in
polypropyl-
ene cages with wire grid floors to enable the food intake of each rat to be
recorded.
Polypropylene trays with cage pads were placed beneath each cage to detect any
food
spillage.
At the start of the study, animals were weighed (to the nearest 0.1 g using an
elec-
tronic top-pan balance) and allocated into 6 weight-matched treatment groups,
each con-
taining 10 animals. Following a 7 day baseline run-in period, during which
time all ani-
mals were dosed orally once a day with vehicle (1% Tylose MH50, 0.1% poloxamer
188),
rats were given vehicle or test compound of Formula I for 28 days as described
in Table
4 below:

CA 02567166 2006-11-17
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Table 4: Treatment scheme of rats with compound of Formula I, example 2(= ex.
2)
Group Treatment 1 (0 h) Treatment 2 (4 h) n
A Vehicle po Vehicle po 1
0
B ex. 2, 30 mg/kg po ex. 2, 30 mg/kg po 1
0
C ex. 2, 50 mg/kg po ex. 2, 50 mg/kg po 1
0
The test substance of example 2 was suspended in 1% Tylose MH50, 0.1% polox-
amer 188 and administered by oral gavage (2 ml/kg). All dosing occurred at the
onset of
the 8 hours dark period (spanning the period immediately before and after
lights out).
The second treatments were given 4 hours after the first. Rats, feeding jars
and water
bottles were weighed (to the nearest 0.1 g) every day at the time of
administration of
vehicle or test substance. At each reading, the tray below each cage was
examined for
spilt food, which was returned to the appropriate jar before weighing.
However, spillage
of food from the feeding jars was negligible. Variations in body weight and
energy levels
of the different types of food were accounted for by expressing the food
intake results in
terms of kJ/kg rat weight. Water intake results were expressed in g/kg.
Animals were killed at the end of the study (by COa to minimise any fluid
loss) on
day 29 and blood samples (5 ml whole blood/animal) were collected by cardiac
puncture.
Plasma was sepairated by centrifugation and stored at -75 C until analysis.
Following
blood collection carcasses were weighed, frozen and stored at -75 C for body
composi-
tion analysis. Body fat, protein, water and ash levels of the carcasses were
determined
using standard chemical analysis techniques. Only fat, protein, water and ash
content
were measured as other components (mainly carbohydrate) form less than 2% of
total
body composition.
Carcasses were individually milled at the temperature of liquid nitrogen,
mixed and
two representative samples taken. Carcass water was determined by freeze-
drying the
samples to constant weight. Carcass fat was determined on the freeze-dried
samples
using a modified Soxhlet extraction protocol (petroleum ether at 40-60 C) with
a Foss
Soxtec HT2 system (Foss UK Ltd, Wheldrake, UK) according to the manufacturers
rec-
ommended protocol. Carcass protein was determined using a micro-Kjeldahl
procedure
on the freeze-dried samples using a Foss 2012 digestion block and Foss 2200
distilling
unit (Foss UK Ltd). Residual carcass ash was determined by firing the freeze-
dried sam-
ples at high temperatures using a muffle ashing furnace. Repeat determinations
of the

CA 02567166 2006-11-17
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16
chemical analysis parameters were performed as necessary (e.g. if the
duplicate sam-
ples differed by more than 1%).
Table 5: Effect of the test compound of example 2 on water, fat, protein and
ash con-
tent of carcasses: mean weight per rat
Group Water (g) Fat (g) Protein (g) Ash (g) Carcass (g)
Vehicle 210.9 2.7 144.5 11.6 67.5 1.2 12.52 0.45 438.4 12.1
ex. 2 (30 205.8 3.1 87.9 3.8** 64.8 1.2 12.13 0.48 375.4 4.8
mg/kg)
ex. 2 (50 202.2 3.6 83.6 6.9** 62.8 1.3 11.38 0.29* 365.6 3.8**
mg/k9)
Results are expressed as treatment group means (all n = 9-10 and adjusted for
differ-
ences between the groups in body weight at baseline) and standard error of the
mean
(=SEM; calculated from the residuals of the statistical model). Statistical
comparisons
were by ANCOVA (baseline body weight as covariate) followed by Williams' test.
Significant differences are denoted by **p<0.001, * p<0.01, *p<0.05 vs
vehicle,
Table 6: Effect of the test compound of example 2 on water, fat, protein and
ash con-
tent of carcasses: mean percent final body weight
Group "Water (%) Fat (%) Protein (%) Ash (%) Total (%)
Vehicle 48.8 1.0 31.9 1.4 15.7 0.4 2.91 0.12 99.3
ex. 2(30 55.2 0.8** 22.8 1.0** 17.4 0.3*0 3.24 0.12 98.6
mg/kg)
ex. 2(50 55.7 1.2** 22.3 1.8** 17.3 0.4*0 3.14 0.1 98.4
mg/kg)
Results and statistics are expressed as above.
Table 7: Effect of test compound of example 2 on plasma parameters in dietary
obese
female wistar rats
Group Glucose (mM) Insulin (ng/ml) Leptin (ng/ml
Vehicle 8.2 0.7 2.33 0.53 144.6 22.7
ex. 2 (30 mg/kg) 8.6 0.5 1.53 0.33 68.8 9.4**
ex. 2 (50 mg/kg) 7.9 0.5 1.40 0.41 58.8 11.6**
Results and statistics are expressed as above.
The present invention further provides a pharmaceutical composition or medica-
ment comprising a pharmacologically effective quantity of a compound of
Formula I or its

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17
physiologically compatible acid addition salts and preferably further
comprising conven-
tional pharmaceutically acceptable auxiliaries and/or carriers.
Suitable pharmaceutically acceptable auxiliaries and/or carriers are well
known in
the art and include pharmaceutical grade starch, mannitol, lactose, magnesium
stearate,
sodium saccharin, talcum, cellulose, glucose, sucrose (or other sugar),
magnesium car-
bonate, gelatin, oil, alcohol, detergents, emulsifiers or water (preferably
sterile). The com-
position may be a mixed preparation of a composition or may be a combined
preparation
for simultaneous, separate or sequential use (including administration). The
compounds
according to the invention or their physiologically compatible acid addition
salts for use in
the aforementioned indications may be administered by any convenient method,
for ex-
ample by oral (including by inhalation), parenteral, mucosal (e.g. buccal,
sublingual, na-
sal), rectal or transdermal administration and the compositions adapted
accordingly. For
oral administration, the compounds can be formulated as liquids or solids, for
example
solutions, syrups, suspensions or emulsions, tablets, capsules and lozenges. A
liquid
formulation will generally consist of a suspension or solution of the compound
or physio-
logically acceptable salt in a suitable aqueous or non-aqueous liquid
carrier(s) for exam-
ple water, ethanol, glycerine, polyethylene glycol or an oil.
The formulation may also contain a suspending agent, preservative, flavouring
or
colouring agent. A composition in the form of a taplet can be prepared using
any suitable
pharmaceutical carrier(s) routinely used for preparing solid formulations.
Examples of
such carriers include magnesium stearate, starch, lactose, sucrose and
microcrystalline
cellulose. A composition in the form of a capsule can be prepared using
routine encapsu-
lation procedures. For example, powders, granules or pellets containing the
active ingre-
dient can be prepared using standard carriers and then filled into a hard
gelatin capsule;
alternatively, a dispersion or suspension can be prepared using any suitable
pharmaceu-
tical carrier(s), for example aqueous gums, celluloses, silicates or oils and
the dispersion
or suspension then filled into a soft gelatin capsule. Compositions for oral
administration
may be designed to protect the active ingredient against degradation as it
passes
through the alimentary tract, for example by an outer coating of the
formulation on a tab-
let or capsule. Typical parenteral compositions consist of a solution or
suspension of the
compound or physiologically compatible acid addition salts in a sterile
aqueous or non-
aqueous carrier or parenterally acceptable oil, for example polyethylene
glycol, polyvinyl
pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution
can be lyophi-
lised and then reconstituted with a suitable solvent just prior to
administration. Composi-

CA 02567166 2006-11-17
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18
tions for nasal or oral administration may conveniently be formulated as
aerosols, drops,
gels and powders.
Aerosol formulations typically comprise a solution or fine suspension of the
active
substance in a physiologically acceptable aqueous or non-aqueous solvent and
are usu-
ally presented in single or multidose quantities in sterile form in a sealed
container, which
can take the form of a cartridge or refill for use with an atomising device.
Alternatively the
sealed container may be a unitary dispensing device such as a single dose
nasal inhaler
or an aerosol dispenser fitted with a metering valve which is intended for
disposal once
the contents of the container have been exhausted. Where the dosage form
comprises
an aerosol dispenser, it will contain a pharmaceutically acceptable
propellant. The aero-
sol dosage forms can also take the form of a pump-atomiser. Compositions
suitable for
buccal or sublingual administration include tablets, lozenges and pastilles,
wherein the
active ingredient is formulated with a carrier such as sugar and acacia,
tragacanth, or
gelatin and glycerin. Compositions for rectal or vaginal administration are
conveniently in
the form of suppositories (containing a conventional suppository base such as
cocoa
butter), pessaries, vaginal tabs, foams or enemas. Compositions suitable for
transdermal
administration include ointments, gels, patches and injections including
powder injec-
tions. Conveniently the composition is in unit dose form such as a tablet,
capsule or am-
poule. The pharmaceutical compositions according to the invention are useful
in the pre-
vention and/or treatment of obesity, concomitant and/or secondary diseases of
obesity;
other medical weight loss and non-medical related weight loss; and/or diabetic
conditions
or diseases.
The compounds of the present invention and their physiologically compatible
acid
addition salts are generally administered as pharmaceutical compositions which
are im-
portant and novel embodiments of the invention because of the presence of the
com-
pounds disclosed herein. In embodiments of the invention, a pharmaceutical
pack or kit
is provided comprising one or more container(s) filled with one or more of the
ingredients
of a pharmaceutical composition of the invention. Associated with such
container(s) can
be various written materials such as instructions for use, or a notice in the
form pre-
scribed by a governmental agency regulating the manufacture, use or sale of
pharma-
ceuticals products, which notice reflects approval by the agency of
manufacture, use, or
sale for human or veterinary administration.
Yet a further aspect of the invention provides a process for the manufacture
of a
pharmaceutical composition as described hereabove. The manufacture can be
carried
out by standard techniques well known in the art and involves combining a
compound

CA 02567166 2006-11-17
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19
according to the invention and the pharmaceutically acceptable auxiliaries
and/or carri-
ers. The composition may be in any form including a tablet, a liquid, a
capsule, and a
powder or in the form of a food product, e.g. a functional food. In the latter
case the food
product itself may act aa the pharmaceutically acceptable carrier.
The compound or composition is preferably administered to a patient in need
there-
of and in a quantity sufficient to prevent and/or treat the symptoms of the
condition, dis-
order or disease For all aspects of the invention, particularly medical ones,
the admini-
stration of a compound or composition has a dosage regime which will
ultimately be de-
termined by the attending physician and will take into consideration such
factors such as
the compound being used, animal type, age, weight, severity of symptoms,
method of
administration, adverse reactions and/or other contraindications. Specific
defined dosage
ranges can be determined by standard design clinical trials with patient
progress and
recovery being fully monitored. Such trials may use an escalating dose design
using a
low percentage of the maximum tolerated dose in animals as the starting dose
in man.
The physiologically acceptable compounds of the invention will normally be
administered
in a daily dosage regimen (for an adult patient) of, for example, an oral dose
of between
I mg and 2000 mg, preferably between 30 mg and 1000 mg, e.g. between 10 and
250
mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg
and 100
mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the
compound
of the Formula I or a physiologically acceptable gait thereof calculated as
the free base,
the compound being administered 1 to 4 times per day. The compound used
according
to the invention can also be administered to children or juveniles while the
individual
dosage regimens in these cases will need to be particularly thoroughly
adjusted by the
physician and will usually comprise lower doses than will be administered to
adults.
Suitably the compounds will be administered for a period of continuous
therapy, for
example for at least a week, but usually for a longer period of several weeks
to several
months. The invention also provides a cosmetic method (non-therapeutic) for
maintaining
a given weight, or for cosmetic weight loss, the method comprising the
administration of
a compound according to the other aspects of the invention, preferably in
combination
with a pharmaceutically acceptable carrier or diluent.
The compound or composition is preferably administered to a subject in need or
in
desideratum thereof and in a quantity sufficient to maintain a given weight or
for cos-
metic weight loss.

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In still a further aspect, the compounds of Formula I and their
physiologically com-
patible acid addition salts may favourably be administered in combination with
one or
more active agents (as a pharmaceutical combination composition) selected from
antidia-
betics; antiobesity or appetite-regulating agents; cardiovascular active
agents, in particu-
lar antihypertensives; diuretics; active agents altering lipid levels, in
particular lipid-
lowering agents; and active ingredients for the treatment and/or prevention of
complica-
tions caused by diabetes or associated with diabetes.
Suitable antidiabetics comprise e.g. insulins, amylin, derivatives of GLP-1
and GLP-
2 such as, for example, those disclosed in WO 98/08871 and orally active
hypoglycemic
active ingredients. The orally active hypoglycemic active ingredients
preferably comprise
sulfonylureas, e.g tolbutamide, glibenclamide, glimepiride, glipizide,
gliquidone, gli-
soxepide, glibomuride or gliclazide; biguanides, e.g. metformin; meglitinides,
e.g. repag-
linide; beta3 adrenergic agonists; oxadiazolidinediones; glucosidase
inhibitors e.g. alpha-
glucosidase inhibitors such as miglitol or acarbose; glucagon receptor
antagonists, GLP-
I agonists, potassium channel openers like diazoxide or those disclosed in WO
97/26265 or WO 99/03861; CB-1 (cannabinoid-1 receptor) antagonists/inverse
agonists;
insulin sensitizers like thiazolidinediones, e.g. troglitazone, ciglitazone,
pioglitazone,
rosiglitazone or the compounds disclosed in WO 97/41097, in particular 5-[[4-
[(3,4-
dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]pheny-I]methyl]-2,4-
thiazolidinedione; ac-
tivators of insulin receptor kinase; inhibitors of liver enzymes involved in
the stimulation
of gluconeogenesis and/or glycogenolysis, for example inhibitors of glycogen
phosphory-
lase; and modulators of glucose uptake and glucose excretion.
Suitable antiobesity or appetite-regulating agents comprise one or more of a 5-
HT
(serotonin) transporter inhibitor, a NE (norepinephrine) transporter
inhibitor, a CB-1 (can-
nabinoid-I receptor) antagonist/inverse agonist, a ghrelin antibody, a ghrelin
antagonist,
a H3 (histamine H3) antagonist/inverse agonist, a MCH1R (melanin concentrating
hor-
mone 1 R) antagonist, a MCH2R (melanin concentrating hormone 2R)
agonist/antagonist,
a NPY1 (neuropeptide Y Y1) antagonist, a NPY2 (neuropeptide Y Y2) agonist, a
NPY5
(neuropeptide Y Y5) antagonist, leptin, a leptin derivative, an opioid
antagonist, an orexin
antagonist, a BRS3 (bombesin receptor subtype 3) agonist, a CCK-A
(cholecystokinin-A)
agonist, a CNTF (ciliary neurotrophic factor), a CNTF derivative, a GHS
(growth hormone
secretagogue receptor) agonist, SHT2c (serotonin receptor 2c) agonist, a Mc3r
(melano-
cortin 3 receptor) agonist, a Mc4r (melanocortin 4 receptor) agonist, a
monoamine reup-
take inhibitor, a serotonin reuptake inhibitor, a GLP-1 (glucagon-like peptide
1) agonist,
topiramate, phytopharm compound 57, an ACC2 (acetyl-CoA carboxylase-2)
inhibitor, a

CA 02567166 2006-11-17
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21
beta3 adrenergic agonist, a DGATI (diacylglycerol acyltransferase 1)
inhibitor, a DGAT2
(diacylglycerol acyltransferase 2) inhibitor, a FAS (fatty acid synthase)
inhibitor, a PDE
(phosphodiesterase) inhibitor, a thyroid hormone B agonist, an UCP-1
(uncoupling pro-
tein 1), 2, or 3 activator, an acyl-estrogen, a glucocorticoid antagonist, an
11 HSD-1 (11-
beta hydroxy steroid dehydrogenase type 1) inhibitor, a SCD-1 (stearoyl-CoA
desatu-
rase-1) inhibitor, a dipeptidyl peptidase IV (DP-IV) inhibitor, a lipase
inhibitor, a fatty acid
transporter inhibitor, a dicarboxylate transporter inhibitor, a glucose
transporter inhibitor,
a phosphate transporter inhibitor, and pharmaceutically acceptable salts and
esters
thereof.
Suitable appetite-regulating agents (appetite suppressants) comprise
sibutramine
or the mono- and bisdemethylated active metabolites of sibutramine;
fenfluramine or
dexfenfluramine; mazindol, diethylpropion or phentermine; leptin or modified
leptin; dex-
amphetamine and amphetamine.
Suitable lipase inhibitors comprise orlistat, panclicins, lipase inhibitors
isolated from
micro organisms such as lipstatin (from Streptomyces toxytricini), ebelactone
B (from
Streptomyces aburaviensis), synthetic derivatives of these compounds; 2-oxy-4H-
3,1-
benzoxazin-4-one derivatives like Alizyme's ATL-962 or structurally related
compounds;
2-amino-4H-3,1-benzoxazin-4-one derivatives or extracts of plants known to
possess
lipase inhibitory activity, e.g. extracts of Alpinia officinarum or compounds
isolated from
such extracts like 3-methylethergalangin (from A. officinarum);
Suitable CBI-cannabinoid antagonists include rimonabant, SLV319, SR147778 and
CP-945598.
Suitable cardiovascular active agents comprise angiotensin II receptor
antagonists,
e.g. abitesartan, benzyllosartan, candesartan, elisartan, embusartan,
enoltasosartan,
eprosartan, fonsartan, forasartan, glycyllosartan, irbesartan, isoteoline,
losartan, mil-
fasartan, olmesartan, opomisartan, pratosartan, ripisartan, saprisartan,
saralasin, sarme-
sin, tasosartan, telmisartan, valsartan, zolasartan; Kissei KRH-94,
Lusofarmaco LR-
B/057, Lusofarmaco LR-B/081, Lusofarmaco LR B/087, Searle SC-52458, Sankyo CS-
866, Takeda TAK-536, Uriach UR-7247, A-81282, A-81988, BIBR-363, BIBS39, BIBS-
222, BMS-180560, BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170,
CI-996, CV-1 1194, DA-2079, DE-3489, DMP-81 1, DuP-167, DuP-532, GA-0056, E-
4177,
EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-
7711, EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, KRI-
1177, KT3-671, KW-3433, L-158809, L-158978, L-159282, L-159689, L-159874, L-

CA 02567166 2006-11-17
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22
161177, L-162154, L-162234, L-162441, L-163007, L-163017, LY-235656, LY-
285434,
LY-301875, LY-302289, LY-315995, ME-3221, PD-123177, PD-123319, PD-150304,
RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, SL-91.0102, U-96849, U-97018,
UP-269-6, UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148, XR-510,
YM-358, YM-31472, ZD-6888, ZD-7155 and ZD-8731 or any physiologically
compatible
salts, solvates, prodrugs or esters thereof; daglutril; non-selective alpha-
adrenoceptor
antagonists, e.g. tolazoline or phenoxybenzamine; selective alpha-adrenoceptor
antago-
nists, e.g. doxazosin, prazosin, terazosin or urapidil; beta-adrenoceptor
antagonists, e.g.
acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol,
carazolol, carteolol,
celiprolol, mepindolol, metipranolol, metoprolol, nadolol, oxprenolol,
penbutolol, pindolol,
propranolol, sotalol and timolol; mixed antagonists of alpha- and beta-
adrenoceptors,
e.g. carvedilol or labetolol; ganglion blockers, e.g. reserpine or
guanethidine; alpha2-
adrenoceptor agonists (including centrally acting alpha2-adrenoceptor
agonists), e.g.
clonidine, guanfacine, guanabenz methyldopa and moxonidine; renin-inhbitors,
e.g. al-
skiren; ACE-inhbitors, e.g. benazepril, captopril, cilazapril, enalapril,
fosinopril, imidapril,
lisinopril, moexipril, quinapril, perindopril, ramipril, spirapril or
trandolapril; mixed or selec-
tive endothelin receptor antagonists e.g. atrasentan, bosentan, clazosentan,
darusentan,
sitaxsentan, tezosentan, BMS-193884 or J-104132; direct vasodilators, e.g.
diazoxide,
dihydralazine, hydralazine or minoxidil; mixed ACE/NEP-inhbitors, e.g.
omapatrilat; ECE-
inhbitors, e.g. FR-901533; PD-069185; CGS-26303; CGS-34043; CGS-35066; CGS-
30084; CGS-35066; SM-19712; Ro0677447; selective NEP-inhibitors; vasopressin
an-
tagonists, aldosterone receptor antagonists, e.g. eplerenone or
spironolactone; angio-
tensin vaccine; and urotensin II receptor antagonists.
Suitable diuretics comprise thiazide diuretics, e.g. althiazide, bemetizide,
bendro-
flumethiazide, benzylhydrochlorothiazide, benzthiazide, buthiazide,
chlorothiazide,
cyclothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide,
paraflutizide,
polythiazide, teclothiazide, trichlormethiazide; thiazide analogue diuretics,
e.g.
chloraminofenamide, chlortalidone, clofenamide, clopamide, clorexolone,
fenquizone,
indapamide, mefruside, metolazone, quinethazone, tripamide, xipamide; loop
diuretics,
e.g. azosemide, bumetanide, furosemide, piretanide, torsemide; potassium
sparing
diuretics, e.g. amiloride, potassium canrenoate, spironolactone, triamterene
or any
physiologically compatible tautomers, salts, solvates, prodrugs or esters of
any afore
mentioned diuretic.
Suitable active agents which alter lipid levels comprise compounds which alter
lipid
metabolism, such as antihyperlipidemic active ingredients and antilipidemic
active ingre-
dients like HMGCoA reductase inhibitors, e.g. atorvastatin, berivastatin,
cerivastatin, cril-

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23
vastatin, fluvastatin, glenvastatin, lovastatin, mevastatin, pitavastatin,
pravastatin, rosu-
vastatin, simvastatin or any physiologically compatible salts, solvates,
prodrugs or esters
thereof; inhibitors of cholesterol transport/of cholesterol uptake; inhibitors
of bile acid
reabsorption or inhibitors of the microsomal triglyceride transfer protein
(MTP); com-
pounds which reduce food intake, PPAR (= peroxisome proliferator-activated
receptors)
and RXR agonists and active agents which act on the ATP-dependent potassium
chan-
nel of the beta cells; fibric acids, e.g. bezafibrate, ciprofibrate,
clofibrate, fenofibrate or
gemfibrozil; cholestyramine, colestipol, probucol, ezetimibe and
dextrothyroxine;
HMGCoA synthase inhibitor, a cholesterol absorption inhibitor, an acyl
coenzyme A-
cholesterol acyl transferase (ACAT) inhibitor, a cholesteryl ester transfer
protein (CETP)
inhibitor, a squalene synthetase inhibitor, an anti-oxidant, a PPAR a agonist,
a FXR re-
ceptor modulator, a LXR receptor agonist, a lipoprotein synthesis inhibitor, a
renin angio-
tensin system inhibitor, a microsomal triglyceride transport inhibitor, a bile
acid reabsorp-
tion inhibitor, a PEAR8 agonist, a triglyceride synthesis inhibitor, a
transcription modula-
tor, a squalene epoxidase inhibitor, a low density lipoprotein receptor
inducer, a platelet
aggregation inhibitor, a 5-LO or FLAP inhibitor, a PPAR 8 partial agonist, and
niacin or a
niacin receptor agonist, and pharmaceutically acceptable salts and esters
thereof.
Further active agents which may be suitable for use in combination with.the
com-
pound of Formula I according to the present invention may be selected from the
group
consisting of CART agonists, H3 antagonists, TNF agonists, CRF agonists, CRF
BP an-
tagonists, urocortin agonists, beta3-agonists, MSH (melanocyte-stimulating
hormone)
agonists, serotonin-reuptake inhibitors, mixed serotonin- and noradrenaline-
reuptake
inhibitors, 5HT modulators, MAO inhibitors, galanin antagonists, growth
hormone, growth
hormone-releasing compounds, TRH agonists, modulators of uncoupling proteins 2
or 3,
leptin agonists, dopamine agonists (bromocriptine, doprexin), RXR modulators,
hCNTF
agonists and TR-beta-agonists.
Preferred pharmaceutical combination compositions according to the invention
comprise combinations of at least one compound of Formula I and at least one
bigua-
nide; at least one compound of Formula I and at least one fibric acid; at
least one com-
pound of Formula I and at least one HMGCoA reductase inhibitor; and at least
one com-
pound of Formula I and at least one insulin sensitizer.
Preferred compounds of Formula I for combination with one or more of the above
mentioned active agents are 4-phenyl-piperazine-1-sulfonic acid amide; 4-(2-
chloro-
phenyl)-piperazine-1-sulfonic acid amide; 4-(2-methoxy-phenyl)-piperazine-1-
sulfonic
acid amide; 4-pyridin-4-yl-piperazine-1-sulfonic acid amide; 4-pyrimidin-2-yl-
piperazine-1-

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24
sulfonic acid amide; 4-(4-fluoro-phenyl)-piperazine-1-sulfonic acid amide; 4-
(4-chloro-3-
trifluoromethyl-phenyl)-piperazine-1-sulfonic acid amide and/or 4-(3-chloro-5-
trifluoro-
methyl-pyridin-2-yl)-piperazine-1-sulfonic acid amide.
Metformine is the preferred biguanide for combination with at least one
compound
of Formula I.
Preferred fibric acids for combination with at least one compound of Formula I
are
bezafibrate, ciprofibrate, clofibrate, fenofibrate and/or gemfibrozil.
Fenofibrate is most
preferred.
Preferred HMGCoA reductase inhibitors for combination with at least one com-
pound of Formula I are atorvastatin, berivastatin, cerivastatin, crilvastatin,
fluvastatin,
glenvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin
and/or simvas-
tatin or any physiologically compatible salts, solvates, prodrugs or esters
thereof. Most
preferred are simvastatin, lovastatin and/or pravastatin.
Preferred insulin sensitizers for combination with at least one compound of
Formula
I are thiazolidinediones, in particular troglitazone, ciglitazone,
pioglitazone and/or rosigii-
tazone. Rosiglitazone and pioglitazone are most preferred.
More preferred combinations according to the invention are the combinations of
4-
phenyl-piperazine-1-sulfonic acid amide with metformine; 4-phenyl-piperazine-1-
sulfonic
acid amide with fenoflbrate; 4-phenyl-piperazine-1-sulfonic acid amide with
simvastatin
and 4-phenyl-piperazine-1-sulfonic acid amide with rosiglitazone.
In one embodiment of the pharmaceutical combination compositions as described
above and according to the invention, the compounds of Formula I can be
obtained and
administered together with the different active agents, e.g. in one combined
unit dosage
form like in one tablet or capsule, i.e. in a physical combination. In such a
combined unit
dosage form, the compound of Formula I and the different active agents can be
segre-
gated from each other, e.g. by means of different layers in said tablet, e.g.
by the use of
inert intermediate layers known in the art; or by means of different
compartments in said
capsule. The corresponding active agents or their pharmaceutically acceptable
salts may
also be used in form of their hydrates or include other solvents used for
crystallization. A
unit dosage form may be a fixed combination. A unit dosage form, in particular
a fixed
combination of the compound of Formula I and one or more of the different
active agents
is a preferred alternative of this embodiment.

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In another embodiment the compounds of Formula I and the different active
agents
can be obtained and administered in two or more separate unit dosage forms,
e.g. in two
or more tablets or capsules, the tablets or capsules being physically
segregated from
each other. The two or more separate unit dosage forms can be administered
simultane-
ously or stepwise (separately), e.g. sequentially one after the other in
either order. Thus,
the compounds of Formula I and the different active agents can be administered
in either
order at the same time or at different times spread over the day, the optimal
dosage
regimen usually being determined by prescription of a physician.
The following examples are intended to explain the invention further, without
limit-
ing its scope.
Example 1:
N-Sulfamoyl-N'-phenylpiperazine (= 4-Phenyl-piperazine-l-sulfonic acid amide)
A mixture of 25.0 g phenyl-piperazine in 77.0 ml of toluene and 17.8 g
sulfamide was
allowed to reflux for 8 hours. The mixture was left at room temperature over
the week-
end. The resulting solids were suspended in 200 ml of methanol and maintained
at 90 C
for 60 minutes. The suspension was concentrated (-140 ml methanol) by
evaporation
under reduced pressure, cooled and filtrated, washed with diethylether and
finally dried.
The crude product was recovered and recrystallized from 200 ml methanol
(procedure
above without concentration).
Example 2:
N-Sulfamoyl-N'-phenylpiperazine hydrochloride
O
NV N-S-NH2 x HCI
O~
The crystalline fraction as obtained in example I above was treated with
ethanolic hy-
drochloric acid, evaporated and finally dissolved in 100 ml methanol at 65 C.
150 ml of
isopropylalcohol were added to this receiving solution and the methanol was
removed
under reduced pressure. Crystallisation overnight, filtration, washing with
diethylether
and drying under reduced pressure (oil pump) yielded 29.1 g of the title
compound, mp.
= 184 C.
Table 8: Elementar analysis of the compound of example 2 (MW 277.77):

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26
calculated found
C% 43.24 43.32
H % 5.81 5.86
N% 15.13 15.31
Cf % 12.76 12.77
Example 3:
4-(2-Methoxy-phenyl)-piperazine-l-sulfonic acid amide hydrochloride
O
O
N-S-NH2 x HCI
- ~~ 0
A) 12 ml of chlorosulfonyl isocyanate was added dropwise to an ice-cold
solution of
13 ml tert.-butylalcohol in 100 ml dichloromethane. After 30 minutes, 4-
dimethyl-
aminopyridine (34.5 g) was added. The resulting mixture was stirred for 1 hour
at
room temperature and diluted with dichloromethane until a clear solution
resulted.
This was washed several times with water, the organic layer separated, dried
over
NaaSO4, filtrated and largely evaporated. The residue was recrystallized from
ace-
tonitrile to yield 30.4 g of the BOC-protected DMAP-reagent, mp. 156 C.
B) 2-Methoxy-phenyl-piperazine (152 mg) was dissolved in 10 ml of
dichloromethane.
To this receiving solution, the BOC-protected DMAP-reagent as obtained above
(238 mg) was added and the resulting mixture left overnight at room
temperature.
The mixture was then evaporated and the residue purified by flash-
chromatography
(stationary phase: silica gel; mobile phase: tetrahydrofurane + 5% methanol)
to
yield 192 mg of the boa-protected intermediate.
C) 100 ml of absolute ethanol were cooled to 0 C in an ice-bath before 20 ml
of ace-
tylchloride were added dropwise and the resulting mixture was stirred for 20
minutes. From the so prepared ethanolic hydrochloric acid solution, 5 ml were
separated, the boc-protected compound as obtained above (192 mg) dissolved
therein and stirred at room temperature for 3 hours. The mixture was then
evaporated several times with ethanol, finally until dryness, to yield 225 mg
of the
title compound, mp. 191 C.

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Example 4:
4-Pyridin-2-yl-piperazine-l-sulfonic acid amide
0
\ N N-S-NH2 x HCI
N / ~
~
A) Tert.-butyl alcohol (6.5 ml) were dissolved in 30 ml dichloromethane. The
resulting
solution was added dropwise to an ice-cooled solution of chlorosulfonyl
isocyanate
(6.0 ml) in 40 ml dichloromethane. After 30 min reaction time, the resulting
mixture
was diluted with dichloromethane up to 100 ml to get a 0.854 molar stock
solution
which was used for the next step without further purification.
B) A freshly prepared stock solution of tert.-butylsulfamoylchloride (1.67 ml;
0.854 mo-
lar in dichloromethane, for preparation see above) was added to a solution of
2-
pyridyl-piperazine (232 mg) in 4 ml dichloromethane and the resulting mixture
was
stirred at room temperature for 24 hours. 3 ml of an ethanolic HCI solution
(for
preparation see ex. 3C, above) were then added, before the resulting mixture
was
left over night at room temperature. After evaporation of the solvents under
re-
duced pressure, a crude solid was isolated. Subsequent flash chromatography of
this solid (stationary phase: silicagel; mobile phase: tetrahydrofurane /
methanol /
ammonia 70 : 30 : 1 v/v/v) and drying of the product fractions yielded 200 mg
of the
title compound; liquid chromatography mass spectroscopy (= LC-MS): M+H 243 (99
% ELSD).
Example 5:
4-(4'-Fluoro-biphenyl-4-yl)-piperazine-l-sulfonic acid amide
O
F / \ N\ N-IS-NH2 x HCI
O
A) 1-(4-Bromophenyl)-piperazine (250 mg), 4-fluorobenzeneboronic acid (254
mg),
potassium carbonate (372 mg, dried and grinded) and palladium-(II)-acetate
(23.3
mg) were dissolved in 20 ml of a mixture of ethylene glycol dimethyl ether /
water /
ethanol (7 : 3 : 2 v/v/v) and put into a microwave reactor (Emrys Optimizer ).
After 5

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28
min. reaction time at 150 C, methyl tert.-butyl ether was added to the now
clear so-
lution, the organic phase was washed consecutively with water and brine and
dried
over Na2SO4. The organic phase was largely evaporated under reduced pressure.
Another equal batch was produced and the crude products of both batches were
together dissolved in dichloromethane. The organic phase was washed with
diluted
soda solution, dried over Na2SO4, the solvent largely evaporated under reduced
pressure and the residue purified by flash chromatography (stationary phase:
silica
gel, mobile phase: dichloromethane / methanol 9 : I v/v) to yield 0.6 g of 1-
(4'-
fluoro-biphenyl-4-yl)-piperazine.
'H-NMR (500MHz), S[ppm]: 7,62 d (1 H), 7,61 d (1 H), 7,22 t (2 H), 7,49 d(2H),
6,98
d(2H), 3,17 m(4H), 3,09 m(4H).
B) 1-(4'-Fluoro-biphenyl-4-yl)-piperazine (0.6 g) as obtained above, and
sulfamide (0.3
g) were dissolved in 30 ml of dioxane and then heated under reflux cooling for
3
hours. After cooling to room temperature, the solvent was largely removed
under
reduced pressure. The resulting solid was crystallized from methyl tert.-butyl
ether
to yield 0.4 g of the title compound, m.p. 243.5 - 245.2 C.
The compounds of Formula I listed in Table 9 below can also be prepared accord-
ing to the processes described in the examples above or according to processes
analo-
gous thereto:
Table 9: Further compounds of Formula I
Ex. No. Ar Salt M.P.
6 4-pyridinyl HCI 243 C
7 2-pyrimidinyl
8 2,3-dimethylphenyl HCI 202 C
9 4-fluorophenyl HCI 125 C
3-chlorophenyl
11 2-methyl-5-chlorophenyl HCI 190 C
12 3-trifluoromethyl-4-chlorophenyl HCI 180 C
13 3-cyano-2-pyridinyl HCI 190 C
14 3-chloro-5-trifluoro-2-pyridinyl HCI 159 C

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29
Ex. No. Ar Salt M.P.
15 4-acetylphenyl HCI 156 C
16 3,5-dichloro-4-pyridinyl HCI 206 C
17 2-trifluoromethyl-4-quinolyl HCI 191 C
18 4-trifluoro-2-pyrimidinyl HCI 156 C
19 5-trifluoro-2-pyridinyl HCI 169 C
20 2-nitro-4-trifluorophenyl HCI 134 C
21 2-fluoro-4-methylsulfonylphenyl HCI 184 C
22 benzo[1,3]dioxol-5-ylmethyl HCI 233 C
23 1-naphthalenyl HCI 193 C
24 4-ethoxyphenyl
25 5,6-dimethyl-thieno[2,3-D]-4-pyrimidinyi
26 2-methyl-mercaptophenyl
27 2-(tert.-butyl)-5-(trifluoromethyl)pyrazolo[1,5-
A -7- rimidin I
28 benzyloxyphenyl
29 5-cyano-6-methyl-2-nicotinic acid ethyl ester
30 3,5-dichlorophenyl HCI 185 C
31 3,4-dichlorophenyl HCI 176 C
32 2,4-difluorophenyl HCI 165 C
33 4-trifluorophenyl HCI 159 C

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Example I:
Capsules containing N-sulfamoyl-N'-phenylpiperazine hydrochloride:
Capsules with the following composition per capsule were produced:
N-Sulfamoyl-N'-phenylpiperazine hydrochloride 70 mg
Corn starch 60 mg
Lactose 250 mg
Ethylacetate (= EA) q.s.
The active substance, the corn starch and the lactose are processed into a
homogene-
ous pasty mixture using EA. The paste is ground and the resulting granules are
placed
on a suitable tray and dried at 45 C in order to remove the solvent. The dried
granules
are passed through a crusher and mixed in a mixer with the further following
auxiliaries:
Talcum 5 mg
Magnesium stearate 5 mg
Corn starch 10 mg
and are then poured into 400 mg capsules (= capsule size 0).