Polycyclic dihydrothiazoles having substituted alkyl...

Details Polycyclic dihydrothiazoles having substituted alkyl... Polycyclic dihydrothiazoles having substituted alkyl...

2000-11-06

2002-05-14

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

06387935

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to polycyclic dihydrothiazoles and their physiologically acceptable salts and physiologically functional derivatives. The polycyclic dihydrothiazoles are useful in the treatment and prophylaxis of obesity and type II diabetes.
BACKGROUND OF THE INVENTION
Thiazolidine derivatives having anorectic action have already been described in the prior art (Austrian Patent No. 365181).
The invention is based on the object of making available further compounds which display a therapeutically utilizable anorectic action.
SUMMARY OF THE INVENTION
The invention relates to compounds of the formula I:
in which
Y is selected from the group consisting of a direct bond, —CH
2
—, and —CH
2
—CH
2
—;
X is selected from the group consisting of CH
2
, CH(CH
3
), CH(C
2
H
5
), CH(C
3
H
7
), and CH(C
6
H
5
);
R1, R1′ are independently selected from the group consisting of H, F, Cl, Br, I, CF
3
, NO
2
, CN, COOH, COO(C
1-6
)alkyl, CONH
2
, CONH(C
1-6
)alkyl, CON[(C
1-6
)alkyl]
2
, (C
1-6
)alkyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkynyl, O—(C
1
-C
6
)-alkyl,
wherein one or more of the hydrogens in the alkyl moieties may be optionally replaced by fluorine,
or a hydrogen may be optionally 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,
where n is 0-6 and wherein the phenyl radical is optionally substituted in up to two positions 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, biphenyl, 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, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may be independently 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 the 1-, 2- or 3-position by methyl or benzyl; and tetrazol-5-yl, wherein the tetrazole ring may be optionally substituted in the 1- or 2-position by methyl or benzyl;
R2 is selected from the group consisting of 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 and C(O)—(CH
2
)
n
-furyl, where n is 0-5,
wherein the phenyl, thienyl, pyridyl, or furyl ring 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 selected from the group consisting of 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 and (CH
2
)
n
-furyl, where n is 0-5,
wherein the phenyl, thienyl, pyridyl, or furyl ring 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, C(O)OCH
3
, C(O)OCH
2
CH
3
, C(O)OH, C(O)NH
2
, C(O)NHCH
3
, C(O)N(CH
3
)
2
, or OC(O)CH
3
;
R4 is selected from the group consisting of (C
8
-C
16
)-cycloalkyl,
wherein one or more hydrogens of the alkyl moiety may be optionally replaced by fluorine,
or a hydrogen may be optionally replaced by OH, OC(O)CH
3
, OC(O)H, O—CH
2
—Ph or O—(C
1
-C
4
)-alkyl;
 (CH
2
)
n
—A—R8, where n is 1-6, except for when (CH
2
)
n
—A—R8 is —CH
2
—O—CH
2
-phenyl, then the phenyl moiety is unsubstituted; and
 (CH
2
)
r
—B—R9, where r is 1-6;
A is selected from the group consisting of O, S, SO and SO
2
;
B is selected from the group consisting of NH, N—(C
1
-C
6
)-alkyl, NCHO and N(CO—CH
3
);
R8 is selected from the group consisting of (C
5
-C
24
)-alkyl, (C
3
-C
10
)-cycloalkyl,
wherein one or more hydrogens of the alkyl radical may be optionally replaced by fluorine,
or a hydrogen may be optionally replaced by OH, OC(O)CH
3
, OC(O)H, O—CH
2
—Ph or O—(C
1-C
4
)-alkyl; and
 (CH
2
)
m
-aryl, where m is 0-6 and aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, thienyl and pyridyl;
wherein 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, SO
2
—(C
1
-C
6
)-alkyl, SO
2
—NH
2
, SO
2
—NH(C
1
-C
8
-alkyl), SO
2
—N(C
1
-C
8
-alkyl)
2
, SO
2
—NH(C
3
-C
8
-cycloalkyl), SO
2
—N(C
3
-C
8
-cycloalkyl)
2
, (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
, where m is 1-6, SO
2
—N(═CH—N(CH
3
)
2
), (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
—(C
1
-C
8
-alkyl), N(C
1
-C
6
-alkyl)—SO
2
—(C
1
-C
8
-alkyl), NH—SO
2
-phenyl,
wherein 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
,
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, where p is 0-3;
R9 is (CH
2
)
m
-aryl, where m is 0-6 and aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, thienyl and pyridyl;
wherein 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, SO
2
—(C
1
-C
6
)-alkyl, SO
2
—NH
2
, SO
2
—NH(C
1
-C
8
-alkyl), SO
2
—N(C
1
-C
8
-alkyl)
2
, SO
2
—NH(C
3
-C
8
-cycloalkyl), SO
2
—N(C
3
-C
8
-cycloalkyl)
2
, (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
, where m is 1-6, SO
2
—N(═CH—N (CH
3
)
2
), (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
—(C
1
-C
8
-alkyl), N(C
1
-C
6
-alkyl)—SO
2
—(C
1
-C
8
-alkyl), NH—SO
2
-phenyl,
wherein 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
,
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, where p is 0-3;
and a physiologically acceptable salt thereof.
The invention also relates to pharmaceutical compositions comprising the compounds of formula I, methods for treatment or prophylaxis or obesity, methods for treatment or prophylaxis of type II diabetes. The invention also contemplates administration of a compound of formula I in combination with an additional anorectic active agent useful in the treatment or prophylaxis or obestity or type II diabetes. The invention also envisages a process for preparing the pharmaceutical composition and also a process for synthesizing the inventive compounds of formula I.
Additional objects, features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
DETAILE

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