Use of polycyclic thiazole systems for the treatment of obesity

Details Use of polycyclic thiazole systems for the treatment of obesity Use of polycyclic thiazole systems for the treatment of obesity

2000-02-09

2001-12-11

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06329407

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to the use of polycyclic thiazole systems and of their physiologically tolerated salts and physiologically functional derivatives for producing therapeutic agents for the treatment of obesity.
EP O 749 966 describes polycyclic thiazole systems with 5-HT
3
receptor agonistic properties as active ingredients for treating CNS disorders.
The invention was based on the object of providing compounds which display a therapeutically utilizable anorectic effect.
SUMMARY OF THE INVENTION
The invention relates to a method for the treatment of obesity comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I:
in which
Y is CH
2
or CH
2
—CH
2
;
X is a direct linkage, CH
2
, O, NR3 or S;
R1, R1′ are independently H, F, Cl, Br, I, CF
3
, CN, COOH, COO(C
1
-C
6
)alkyl, CONH
2
, CONH(C
1
-C
6
)alkyl, CON[(C
1
-C
6
)alkyl]
2
, (C
1
-C
6
)-alkyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkynyl, OCF
3
, O—(C
2
-C
6
)-alkyl (where one, more than one or all hydrogen(s) in the alkyl, alkenyl and alkynyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, CN, OC(O)CH
3
, OC(O)H, O—CH
2
—Ph, NH
2
, NH—CO—CH
3
or N(COOCH
2
Ph)
2
), SO
2
—NH
2
, SO
2
NH(C
1
-C
6
)-alkyl, SO
2
N[(C
1
-C
6
)-alkyl]
2
, S—(C
1
-C
6
)-alkyl, S—(CH
2
)
n
-phenyl, SO
2
—(C
1
-C
6
)-alkyl, SO—(CH
2
)-phenyl, SO
2
—(CH
2
)
n
-phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF
3
, NO
2
, CN, OCF
3
, O—(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkyl or NH
2
), NH
2
, NH—(C
1
-C
6
)-alkyl, N((C
1
-C
6
)-alkyl)
2
, NH(C
1
-C
7
)-acyl, phenyl, biphenylyl, (O—CH
2
)
n
-phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF
3
, NO
2
, CN, OCF
3
, O—(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkyl, NH
2
, NH(C
1
-C
6
)-alkyl, N((C
1
-C
6
)-alkyl)
2
, SO
2
—CH
3
, COOH, COO—(C
1
-C
6
)-alkyl or CONH
2
), 1,2,3-triazol-5-yl (wherein the triazole ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazole ring may be optionally substituted in position 1 or 2 by methyl or benzyl);
R2 is (C
1
-C
8
)-alkyl, (C
3
-C
7
)-cycloalkyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkynyl, C(CN)═C(CH
3
)
2
, C(O)OCH
2
CH
3
, CH
2
—O—C(O)—C(CH
3
)
3
, (C
4
-C
7
)cycloalkenyl (where one, more than one or all hydrogen(s) in the alkyl, alkenyl or alkynyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, CN or O—(C
1
-C
4
)-alkyl), (CH
2
)
n
—NR6R7 (where n is 1-6 and R6 and R7 are independently H, (C
1
-C
6
)-alkyl, (C
3
-C
6
)-cycloalkyl, CO—(C
1
-C
6
)-alkyl, CHO or CO-phenyl or —NR6R7 is a ring selected from the group consisting of pyrrolidine, piperidine, morpholine, piperazine, 4-methylpiperazin-1-yl, 4-benzylpiperazin-1-yl and phthalimidyl) or (CH
2
)
n
-aryl (where n is 0-6 and aryl is selected from the group consisting of phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 1-pyrazolyl, 3- or 5-isoxazolyl, 2- or 3-pyrrolyl, 2- or 3-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 2- or 5-benzimidazolyl, 2-benzothiazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol -5-yl, indol-3-yl, indol-5-yl and N-methylimidazol-2-, -4- or -5-yl, wherein the aryl radical or heteroaryl radical may be substituted up to two times by F, Cl, Br, OH, CF
3
, NO
2
, CN, OCF
3
, O—(C
1
-C
6
)-alkyl, S—(C
1
-C
6
)-alkyl, SO—(C
1
-C
6
)-alkyl, SO
2
—(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkyl, (C
3
-C
6
)-cycloalkyl, COOH, COO(C
1
-C
6
)alkyl, COO(C
3
-C
6
)cycloalkyl, CONH
2
, CONH(C
1
-C
6
)alkyl, CON[(C
1
-C
6
)alkyl]
2
, CONH(C
3
-C
6
)cycloalkyl, NH
2
, NH—CO—(C
1
-C
6
)-alkyl, NH—CO-phenyl, pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH
2
)
n
-phenyl, O—(CH
2
)
n
-phenyl, S—(CH
2
)
n
-phenyl or SO
2
—(CH
2
)
n
-phenyl, where n=0-3);
R3 is H, (C
1
-C
6
)-alkyl, CO—(C
1
-C
5
)-alkyl, CO—(C
3
-C
6
)-cycloalkyl, SO
2
-phenyl or p-toluenesulfonyl;
and their physiologically tolerated salts and physiologically functional derivatives.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed to a method of treating obesity which encompasses prophylaxis and amelioration of obesity comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound of of formula I:
in which
Y is CH
2
or CH
2
—CH
2
;
X is a direct linkage, CH
2
, O, NR3 or S;
R1, R1′ are independently H, F, Cl, Br, I, CF
3
, CN, COOH, COO(C
1
-C
6
)alkyl, CONH
2
, CONH(C
1
-C
6
)alkyl, CON[(C
1
-C
6
)alkyl]
2
, (C
1
-C
6
)-alkyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkynyl, OCF
3
, O—(C
2
-C
6
)-alkyl (where one, more than one or all hydrogen(s) in the alkyl, alkenyl and alkynyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, CN, OC(O)CH
3
, OC(O)H, O—CH
2
—Ph, NH
2
, NH—CO—CH
3
or N(COOCH
2
Ph)
2
), SO
2
—NH
2
, SO
2
NH(C
1
-C
6
)-alkyl, SO
2
N[(C
1
-C
6
)-alkyl]
2
, S—(C
1
-C
6
)-alkyl, S—(CH
2
)
n
-phenyl, SO
2
—(C
1
-C
6
)-alkyl, SO—(CH
2
)-phenyl, SO
2
—(CH
2
)
n
-phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF
3
, NO
2
, CN, OCF
3
, O—(C
1
-C
6
)-alkyl, (Cl-C
6
)-alkyl or NH
2
), NH
2
, NH—(C
1
-C
6
)-alkyl, N((C
1
-C
6
)-alkyl)
2
, NH(C
1
-C
7
)-acyl, phenyl, biphenylyl, O—(CH
2
)
n
-phenyl (where n is 0-6 ), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF
3
, NO
2
, CN, OCF
3
, O—(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkyl, NH
2
, NH(C
1
-C
6
)-alkyl, N((C
1
-C
6
)-alkyl)
2
, SO
2
—CH
3
, COOH, COO—(C
1
-C
6
)-alkyl or CONH
2
), 1,2,3-triazol-5-yl (wherein the triazole ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazole ring may be optionally substituted in position 1 or 2 by methyl or benzyl);
R2 is (C
1
-C
8
)-alkyl, (C
3
-C
7
)-cycloalkyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkynyl, C(CN)═C(CH
3
)
2
, C(O)OCH
2
CH
3
, CH
2
—O—C(O)—C(CH
3
)
3
, (C
4
-C
7
)cycloalkenyl (where one, more than one or all hydrogen(s) in the alkyl, alkenyl and alkynyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, CN or O—(C
1
-C
4
)-alkyl), (CH
2
)
n
—NR6R7 (where n is 1-6 and R6 and R7 are independently H, (C
1
-C
6
)-alkyl, (C
3
-C
6
)-cycloalkyl, CO—(C
1
-C
6
)-alkyl, CHO or CO-phenyl or —NR6R7 is a ring selected from the group consisting of pyrrolidine, piperidine, morpholine, piperazine, 4-methylpiperazin-1-yl, 4-benzylpiperazin-1-yl and phthalimidyl) or (CH
2
)
n
-aryl (where n is 0-6 and aryl is selected from the group consisting of phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 1-pyrazolyl, 3- or 5-isoxazolyl, 2- or 3-pyrrolyl, 2- or 3-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 2- or 5-benzimidazolyl, 2-benzothiazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol-5-yl, indol-3-yl, indol-5-yl and N-methylimidazol-2-, -4- or -5-yl, wherein the aryl radical or heteroaryl radical may be optionally substituted up to two times by F, Cl, Br, OH, CF
3
, NO
2
, CN, OCF
3
, O—(C
1
-C
6
)-alkyl, S—(C
1
-C
6
)-alkyl, SO—(C
1
-C
6
)-alkyl, SO
2
—(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkyl, (C
3
-C
6
)-cycloalkyl, COOH, COO(C
1
-C
6
)alkyl, COO(C
3
-C
6
)cycloalkyl, CONH
2
, CONH(C
1
-C
6
)alkyl, CON[(C
1
-C
6
)alkyl]
2
, CONH(C
3
-C
6
)cycloalkyl, NH
2
, NH—CO—(C
1
-C
6
)-alkyl, NH—CO-phenyl, pyrrolidin-1-yl, morpholin-1

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