Polycyclic 2-aminodihydrothiazole systems, processes for...

Details Polycyclic 2-aminodihydrothiazole systems, processes for... Polycyclic 2-aminodihydrothiazole systems, processes for...

2000-02-08

2001-05-22

Lambkin, Deborah C. (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

06235763

ABSTRACT:

BACKGROUND OF THE INVENTION
Polycyclic 2-aminodihydrothiazole systems, processes for their preparation and their use as pharmaceuticals.
The invention relates to polycyclic 2-aminodihydrothiazole systems and their physiologically tolerated salts and physiologically functional derivatives. Thiazolidine derivatives having an anorectic effect are described in the prior art (Austrian Patent No. 365181).
The invention was based on the object of providing further 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 a direct linkage, —CH
2
— or —CH
2
—CH
2
—;
X is CH
2
, CH(CH
3
), CH(C
2
H
5
), CH(C
3
H
7
) or CH(C
6
H
5
);
R1, R1′ are independently H, F, Cl, Br, I, CF
3
, NO
2
, CN, COOH, COO(C
1
-C
6
)-alkl, 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 (where one, more than one or all hydrogen(s) in 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
)-akyl]
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 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, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, 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 triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position 1 or 2 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 (where n is 0-5 and wherein phenyl, thienyl, pyridyl, 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 (where n is 0-5 and wherein phenyl, thienyl, pyridyl, furyl may each 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), (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 NR6R7;
R6 and R7 are independently H, (C
1
-C
6
)-alkyl, (C
3
-C
6
)-cycloalkyl, phenyl (wherein the phenyl 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)), CO—(C
1
-C
6
)-alkyl, CHO, CO-phenyl, —NH
2
, —N═C(CH
3
)
2
, -(pyrrolidin-1-yl), -(piperidin-1-yl), -(morpholin4-yl), -(piperazin-1-yl) or -(4-methylpiperazin- 1 -yl),
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;
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 encompasses compounds of formula I
in which
Y is a direct linkage, —CH
2
— or —CH
2
—CH
2
—;
X is CH
2
, CH(CH
3
), CH(C
2
H
5
), CH(C
3
H
7
) or CH(C
6
H
5
);
R1, R1′ are independently 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 (where one, more than one or all hydrogen(s) in 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 (where 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, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, 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 triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position 1 or 2 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 (where n is 0-5 and wherein phenyl, thienyl, pyridyl, 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, (CI-C6)-alkyl, F, CN, N3, O-(Ci-C6)-alkyl, (CH
2
)
n
-phenyl, (CH
2
)
n
-thienyl, (CH
2
)
n
-pyridyl, (CH
2
)
n
-furyl (where n is 0-5 and wherein phenyl, thienyl, pyridyl, furyl may each 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), (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 NR6R7;
R6 and R7 are independently H, (C
1
-C
6
)-alkyl, (C
3
-C
6
)-cycloalkyl, phenyl (wherein the phenyl 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)), CO—(C
1
-C
6
)-alkyl, CHO, CO-phenyl, —NH
2
, —N═C(CH
3
)
2
, -(pyrrolidin-1-yl), -(piperidin-1-yl), -(morpholin4-yl), -(piperazin-1-yl) or -(4-methylpiperazin-1-yl),
or
NR
6
R
7
is a ring selected from the group consisting of pyrrolidine, piperidine, morpholine, piperazine, 4-methylpiperazin-1-yl, 4-benzylpiperazin-1-yl and phthalimidyl;
and their physiologically tolerated salts and physiologically functional derivatives.
In a preferred embodiment are compounds of formula I:
in which
Y is a direct linkage;
X is CH
2
;
R1, R1′ are independently H, F, Cl, 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 (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH

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