8,8A-DIHYDROINDENO[1,2-D]THIAZOLE DERIVATIVES...

Details 8,8A-DIHYDROINDENO[1,2-D]THIAZOLE DERIVATIVES... 8,8A-DIHYDROINDENO[1,2-D]THIAZOLE DERIVATIVES...

2001-02-26

2002-03-05

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S113000, C544S121000, C544S122000, C544S145000, C544S238000, C544S295000, C544S296000, C544S324000, C544S357000, C544S369000, C546S270100, C514S366000, C514S232800, C514S241000, C514S254020, C514S255010, C548S150000

Reexamination Certificate

active

06352987

ABSTRACT:

This application claims priority to German Application No. 10009311.6 filed Feb. 26, 2000, the entire contents of which are hereby incorporated by reference.
FIELD OF THE INVENTION
The invention relates to polycyclic dihydrothiazoles and to their physiologically acceptable salts and physiologically functional derivatives.
BACKGROUND OF THE INVENTION
Thiazolidine derivatives having anorectic action have been described in the prior art (Austrian Patent No. 365181).
The object of the invention is to provide compounds having a therapeutically useful anorectic action.
SUMMARY OF THE INVENTION
The invention relates to compounds of formula I:
in which
R1, R1′ are independently selected from H, F, Cl, Br, I, CF
3
, NO
2
, 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, O—(C
1
-C
6
)-alkyl,
wherein one or more of the hydrogens of the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, 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
)
2
-phenyl, SO—(C
1
-C
6
)-alkyl, SO—(CH
2
)
n
-phenyl, SO
2
—(C
1
-C
6
)-alkyl, SO
2
—(CH
2
)
n
-phenyl,
wherein 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 or 2- or 3-thienyl,
wherein any of the phenyl, biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may be substituted one to three 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, where the triazole ring may be substituted in the 1-, 2- or 3-position by methyl or benzyl; or
tetrazol-5-yl, where the tetrazole ring may be substituted in the 1- or 2-position by methyl or benzyl;
R2 is H, (C
1
-C
6
)-alkyl, (C
3
-C
6
)-cycloalkyl, (CH
2
)
n
-phenyl, (CH
2
)
n
-thienyl, (CH
2
)
n
-pyridyl, (CH
2
)n-furyl, C(O)—(C
1
-C
6
)-alkyl, C(O)—(C
3
-C
6
)-cycloalkyl, C(O)—(CH
2
)
n
-phenyl, C(O)—(CH
2
)
n
-thienyl, C(O)—(CH
2
)
n
-pyridyl or C(O)—(CH
2
)
n
-furyl,
wherein n is 0-5 and in which any of phenyl, thienyl, pyridyl and furyl may be substituted up to two times by Cl, F, CN, CF
3
, (C
1
-C
3
)-alkyl, OH or O—(C
1
-C
6
)-alkyl;
R3 is H, (C
1
-C
6
)-alkyl, F, CN, N
3
, O—(C
1
-C
6
)-alkyl, (CH
2
)
n
-phenyl, (CH
2
)
n
-thienyl, (CH
2
)
n
-pyridyl, (CH
2
)
n
-furyl,
wherein n is 0-5 and in which any of phenyl, thienyl, pyridyl and furyl may be substituted up to two times by Cl, F, CN, CF
3
, (C
1
-C
3
)-alkyl, OH or O—(C
1
-C
6
)-alkyl;
OC(O)CH
3
, (C
2
-C
6
)-alkynyl, (C
2
-C
6
)-alkenyl, COO(C
1
-C
6
)-alkyl, C(O)OH, C(O)NH
2
, C(O)NHCH
3
or C(O)N(CH
3
)
2
;
R4 is (CH
2
)
n
—R5, wherein n is 0-6;
R5 is 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, 2-(1,3,5-triazinyl), 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 or N-methylimidazol-2-, -4- or -5-yl;
and R5 is substituted by
NH—SO
2
—(C
1
-C
6
)-alkyl or NH—SO
2
-phenyl,
wherein the phenyl ring may be substituted up to two times by F, Cl, CN, OH, (C
1
-C
6
)-alkyl, O—(C
1
-C
6
)-alkyl, CF
3
, COOH, COO(C
1
-C
6
)-alkyl, CONH
2
, (CH
2
)
n
—SO
2
-(C
1
-C
6
)-alkyl, where n is 1-6, (CH
2
)
m
—SO
2
—NH
2
, (CH
2
)
m
—SO
2
—NH—(C
1
-C
6
)-alkyl, (CH
2
)
m
—SO
2
—N[(C
1
-C
6
)-alkyl]
2
or (CH
2
)
m
—SO
2
—N(═CH—N(CH
3
)
2
), wherein m is 0-6;
and R5 may be further substituted 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, (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, wherein n is 0-3;
and their physiologically acceptable 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 and methods of enhancing lipid metabolism are also contemplated.
DETAILED DESCRIPTION OF THE INVENTION
The invention is directed to polycyclic thiazole compounds which are anorectics and are useful in the treatment of type II diabetes and obesity. The compounds have general formula (I):
in which
R1, R1′ are independently selected from H, F, Cl, Br, I, CF
3
, NO
2
, 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, O—(C
1
-C
6
)-alkyl,
wherein one or more of the hydrogens of the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, 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—(C
1
-C
6
)-alkyl, SO—(CH
2
)
n
-phenyl, SO
2
-(C
1
-C
6
)-alkyl, SO
2
-(CH
2
)
n
-phenyl,
wherein 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 or 2- or 3-thienyl,
wherein any of the phenyl, biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may be substituted one to three 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, where the triazole ring may be substituted in the 1-, 2- or 3-position by methyl or benzyl; or
tetrazol-5-yl, where the tetrazole ring may be substituted in the 1- or 2-position by methyl or benzyl;
R2 is H, (C
1
-C
6
)-alkyl, (C
3
-C
6
)-cycloalkyl, (CH
2
)
n
-phenyl, (CH
2
)
n
-thienyl, (CH
2
)
n
-pyridyl, (CH
2
)
n
-furyl, C(O)—(C
1
-C
6
)-alkyl, C(O)—(C
3
-C
6
)-cycloalkyl, C(O)—(CH
2
)
n
-phenyl, C(O)—(CH
2
)
n
-thienyl, C(O)—(CH
2
)
n
-pyridyl or C(O)—(CH
2
)
n
-furyl,
wherein n is 0-5 and in which any of phenyl, thienyl, pyridyl and furyl may be substituted up to two times by Cl, F, CN, CF
3
, (C
1
-C
3
)-alkyl, OH or O—(C
1
-C
6
)-alkyl;
R3 is H, (C
1
-C
6
)-alkyl, F, CN, N
3
, O—(C
1
-C
6
)-alkyl, (CH
2
)
n
-phenyl, (CH
2
)
n
-thienyl, (CH
2
)
n
-pyridyl, (CH
2
)
n
-furyl,
wherein n is 0-5 and in which any of phenyl, thienyl, pyridyl and furyl may be substituted up to two times by Cl, F, CN, CF
3
, (C
1
-C
3
)-alkyl, OH or O—(C
1
-C
6
)-alkyl;
OC(O)CH
3
, (C
2
-C
6
)-alkynyl, (C
2
-C
6
)-alkenyl, COO(C
1
-C
6
)-alkyl, C(O)OH, C(O)NH
2
, C(O)NHCH
3
or C(O)N(CH
3
)
2
;
R4 is (CH
2
)
n
—R5, wherein n is 0-6;
R5 is 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

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