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...

2001-02-23

2002-06-11

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S150000

Reexamination Certificate

active

06403624

ABSTRACT:

This application claims priority to German Application No. 10008275.0 filed Feb. 23, 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 already 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. The present compounds also find use in treatment of type II diabetes and obesity.
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
)
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 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, wherein n is 0-6, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl,
wherein any of the phenyl, biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may be optionally substituted one 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 substituted in the 1-, 2- or 3-position by methyl or benzyl; or
tetrazol-5-yl, wherein 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 or furyl may be optionally 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 Cl, Br, CH
2
—COO(C
1
-C
6
)-alkyl, CH
2
—COOH or CH
2
—CONH
2
;
R4 is (C
1
-C
8
)-alkyl, (C
3
-C
7
)-cycloalkyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkynyl, (C
4
-C
7
)-cycloalkenyl,
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 or O—(C
1
-C
4
)-alkyl;
(CH
2
)
n
-pyrrolidin-1-yl, (CH
2
)
n
-piperidin-1-yl, (CH
2
)
n
-morpholin-4-yl, (CH
2
)
n
-piperazin-1-yl, (CH
2
)
n
-N-4-methylpiperazin-1-yl, (CH
2
)
n
-N-4-benzylpiperazin-1-yl, (CH
2
)
n
-phthalimidoyl, where n is 1-6; (CH
2
)
n
-aryl, (CH
2
)
n
-heteroaryl,
wherein n is 0-6 and aryl is phenyl, biphenylyl, or 1- or 2-naphthyl and heteroaryl is 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 the aryl radical or the 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, (CH
2
)
n
—SO
2
—(C
1
-C
6
)-alkyl, (CH
2
)
n
—SO
2
—NH
2
, (CH
2
)
n
—SO
2
—N(═CH—N(CH
3
)
2
), wherein n is 0-6; (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, 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 or CONH
2
;
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, SO
2
—(CH
2
)
n
-phenyl, where n is 0-3, or (CH
2
)
n
—A—R8, where n is 1-6; is O, NH, N—C
1
-C
6
)-alkyl, NCHO, N(CO—CH
3
), S, SO or SO
2
; is (C
1
-C
8
)-alkyl, (C
3
-C
8
)-cycloalkyl,
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 or O—(C
1
-C
4
)-alkyl;
(CH
2
)
m
-aryl or (CH
2
)
m
-heteroaryl,
wherein m is 0-6 and aryl is phenyl and heteroaryl is thienyl or pyridyl and the aryl or heteroaryl moiety 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, (CH
2
)
n
—SO
2
—(C
1
-C
6
)-alkyl, (CH
2
)
n
—SO
2
—NH
2
, (CH
2
)
n
—SO
2
—N(═CH—N(CH
3
)
2
), (CH
2
)
n
—SO
2
—NH(C
1
-C
8
)-alkyl, (CH
2
)
n
—SO
2
—N[(C
1
-C
8
)-alkyl]
2
, (CH
2
)
n
—SO
2
—NH(C
3
-C
8
)-cycloalkyl, (CH
2
)
n
—SO
2
—N[(C
3
-C
8
)-cycloalkyl]
2
, where n is 0-6; (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(C
1
-C
6
)-alkyl, N[(C
1
-C
6
)-alkyl]
2
, NH—CO—(C
1
-C
6
)—alkyl, NH—CO-phenyl, NH—SO
2
-phenyl,
where 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 or CONH
2
,
NH-—SO
2
—(C
1
-C
8
)-alkyl, N(C
1
-C
6
)-alkyl-SO
2
—(C
1
-C
8
)-alkyl, pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH
2
)
p
-phenyl, O—(CH
2
)p-phenyl, S—(CH
2
)
p
-phenyl or SO
2
—(CH
2
)
p
-phenyl, wherein p 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 are also contemplated. Methods of enhancing lipid metabolism can also be achieved with the compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The invention is directed to polycyclic thiazole compounds which are anorectics and are used 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 ma

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