Substituted...

Details Substituted... Substituted...

2001-02-23

2002-06-25

Gerstl, Robert (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

06410577

ABSTRACT:

This application claims priority to German Application No. 10008274.2 filed Feb. 23, 2000, the entire contents of which are hereby incorporated by reference.
FIELD OF THE INVENTION
The invention relates to substituted 8,8a-dihydro-3aH-indeno[1,2-d]thiazoles 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, alkenyl, or alkynyl 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, biphenyl, 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; tetrazol-5-yl, where the tetrazole ring may be substituted in the 1- or 2-position by methyl or benzyl; 1,3,4-oxadiazol-2-yl; 2-amino-1,3,4-oxadiazol-5-yl,
wherein the amino function may be mono- or disubstituted by (C
1
-C
6
)-alkyl, —C(O)—(C
1
-C
6
)-alkyl, —C(O)—(cyclo-C
3
-C
7
)-alkyl, —C(O)-phenyl, —C(O)—NH—(C
1
-C
6
)-alkyl, —C(O)—NH—(cyclo-C
3
-C
7
)-alkyl, or —C(O)—NH-aryl, wherein aryl is phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl or 2- or 3-furanyl,
—C(O)-morpholin-4-yl, —C(O)-piperidin-1-yl, —C(O)-piperazin-4-yl, —C(O)—1-methyl-, 1-benzyl-piperazin-4-yl, —SO
2
—(C
1
-C
6
)-alkyl or —SO
2
-phenyl,
wherein the phenyl ring may be substituted up to two times by F, Cl, Br, CN, CF
3
, OH, OCF
3
, (C
1
-C
6
)-alkyl, O—(C
1
-C
6
)-alkyl, (CH
2
)
n
-phenyl, O—(CH
2
)
n
-phenyl, where n is 0-6, 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
;
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 H, (C
1
-C
6
)-alkyl, F, Cl, Br, 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,
where 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,
(C
2
-C
6
)-alkynyl, (C
2
-C
6
)-alkenyl, OC(O)CH
3
, (CH
2
)
n
—C(O)O(C
1
-C
6
)-alkyl, (CH
2
)
n
—C(O)OH, (CH
2
)
n
—C(O)NH
2
, (CH
2
)
n
—C(O)NHCH
3
or (CH
2
)
n
—C(O)N(CH
3
)
2
, where n is 0-3;
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; is (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 or (CH
2
)
n
-heteroaryl,
where 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,
wherein the aryl radical or the 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, (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, 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 or SO
2
—(CH
2
)
n
-phenyl, wherein n is 0-3;
(CH
2
)
n
—A—R8, wherein n is 1-6;
A is O, NH, N—(C
1
-C
6
)-alkyl, NCHO, N(CO—CH
3
), S, SO or SO
2
;
R8 is (C
1
-C
8
)-alkyl, (C
3
-C
8
)-cycloalkyl,
wherein one or more 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; is (CH
2
)
m
-aryl,
wherein m is 0-6 and aryl is phenyl, thienyl or pyridyl and the aryl moiety 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, (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 optionally 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;
R5 is H;
R6 is Cl, Br, OH, O—(C
1
-C
6
)-alkyl, O—(CH
2
)
n
-aryl, O—(CH
2
)
n
-heteroaryl
wherein n is 0-6 and aryl is phenyl and heteroaryl is 2-, 3- or 4-pyridyl or 2- or 3-thienyl;
O—C(O)—H, O—C(O)—(C
1
-C
6
)-alkyl, O—C(O)—(C
3
-C
8
)-cycloalkyl, O—C(O)-aryl, O

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