Polycyclic thiazole systems, processes for their preparation...

Details Polycyclic thiazole systems, processes for their preparation... Polycyclic thiazole systems, processes for their preparation...

2000-02-10

2001-02-13

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S150000, C548S150000

Reexamination Certificate

active

06187801

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to polycyclic thiazole systems and their physiologically tolerated salts and physiologically functional derivatives.
EP 0 749 966 describes polycyclic thiazole systems with 5-HT3 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 compounds of the formula I
in which
Y is CH
2
or CH
2
—CH
2
;
X is a direct linkage, CH
2
, O or S;
R1 is 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
)
n
-phenyl, SO
2
—(CH
2
)
n
-phenyl (where n is 0-6 and the phenyl 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, (C
1
-C
6
)-alkyl, 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);
R1′ is H or R1;
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 the 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);
and their physiologically tolerated salts and physiologically functional derivatives.
The invention also relates to pharmaceutical compositions containing the compounds of formula I and pharmaceutically acceptable carriers. Also, pharmaceutical compositions containing the compounds of formula I in combination with at least one additional anorectic agents are contemplated. The invention envisages treatment of obesity via administration of compounds of formula I. Methods of treatment for type II diabetes are also contemplated.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention is directed to polycyclic thiazole compounds which are useful in the treatment of type II diabetes and obesity. The compounds have general formula (I):
in which
Y is CH
2
or CH
2
-CH
2
;
X is a direct linkage, CH
2
, O or S;
R1 is F, Cl, Br, I, CF
3
,
CN, COOH, COO(C-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
)
n
-phenyl, SO
2
—(CH
2
)
n
-phenyl (where n is 0-6 and the phenyl 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, (C
1
-C
6
)-alkyl, 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);
R1′ is H or R1;
R2 is (C
1
-Cs)-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

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