U.S. patent application number 09/774053 was filed with the patent office on 2001-08-02 for polycyclic thiazol-2-ylidene amines, processes for their preparation and their use as medicaments.
Invention is credited to Bickel, Martin, Geisen, Karl, Jahne, Gerhard, Lang, Hans-Jochen.
Application Number | 20010011096 09/774053 |
Document ID | / |
Family ID | 7899080 |
Filed Date | 2001-08-02 |
United States Patent
Application |
20010011096 |
Kind Code |
A1 |
Jahne, Gerhard ; et
al. |
August 2, 2001 |
Polycyclic thiazol-2-ylidene amines, processes for their
preparation and their use as medicaments
Abstract
The invention relates to polycyclic thiazolidin-2-ylidene amines
and their physiologically tolerated salts and physiologically
functional derivatives. Polycyclic thiazolidin-2-ylidene amines of
the formula I, 1 in which the radicals have the stated meanings,
and their physiologically tolerated salts and processes for their
preparation are described. The compounds are suitable, for example
as anorectics and in the treatment or prophylaxis of type II
diabetes.
Inventors: |
Jahne, Gerhard; (Frankfurt,
DE) ; Geisen, Karl; (Frankfurt, DE) ; Lang,
Hans-Jochen; (Hofheim, DE) ; Bickel, Martin;
(Bad Homburg, DE) |
Correspondence
Address: |
Michele M. Simkin
FOLEY & LARDNER
Washington Harbour
3000 K Street, N.W., Suite 500
Washington
DC
20007-5109
US
|
Family ID: |
7899080 |
Appl. No.: |
09/774053 |
Filed: |
January 31, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09774053 |
Jan 31, 2001 |
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09500464 |
Feb 9, 2000 |
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6207689 |
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Current U.S.
Class: |
514/366 ;
548/150; 548/151 |
Current CPC
Class: |
A61P 3/04 20180101; C07D
513/04 20130101; C07D 277/60 20130101; A61P 3/10 20180101 |
Class at
Publication: |
514/366 ;
548/150; 548/151 |
International
Class: |
A61K 031/425 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 26, 1999 |
DE |
19908536.6 |
Claims
What is claimed is:
1. A compound of the formula I 9in which Y is a direct linkage,
--CH.sub.2-- or --CH.sub.2--CH.sub.2--; X is CH.sub.2, CH-phenyl, O
or S; R1 is F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)alk- yl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alkyl, CON[(C.sub.1-C.sub.6)alkyl].su- b.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.2-C.sub.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.sub.3, OC(O)H, O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3
or N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl or NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alk- yl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, phenyl, biphenylyl,
O--(CH.sub.2).sub.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 or thienyl rings may
be independently optionally substituted up to 3 times by F, Cl, Br,
I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl); R1' is H, F,
Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2- , (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl or NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alk- yl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, phenyl, biphenylyl,
O--(CH.sub.2).sub.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 or thienyl rings may
be independently optionally substituted up to 3 times by F, Cl, Br,
I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl); R2 is
(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where n is 1-4),
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl); R3 is (C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--COOH (where n is 1-4),
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl); or R2 and R3 together form a
--CH.sub.2--CH.sub.2--, --CH.sub.2-C(CH.sub.3).sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2-- or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.su- b.2-- group; and their
physiologically tolerated salts and physiologically functional
derivatives.
2. A compound of the formula I as claimed in claim 1, wherein Y is
a direct linkage or --CH.sub.2--; X is CH.sub.2, O or S; R1 is F,
Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, Br, I, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl); R1' is H, F,
Cl, I, CF.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alkyl, CON[(C.sub.1-C.sub.6)alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.2-C.sub.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.sub.3, OC(O)H, O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3
or N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub- .2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alk- yl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, I, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH,,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl); R2 is
(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where n is 1-4),
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl); R3 is (C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--COOH (where n is 1-4),
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl); or R2 and R3 together form a
--CH.sub.2--CH.sub.2--, --CH.sub.2-C(CH.sub.3).sub.2- or
--CH.sub.2--CH.sub.2--CH.sub.2-- group; and their physiologically
tolerated salts and physiologically functional derivatives.
3. A compound of the formula I as claimed in claim 1, wherein: Y is
a direct linkage or --CH.sub.2--; X is CH.sub.2, O or S; R1 is F,
Cl, Br, CF.sub.3, NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C,)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, Br, I, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C -C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl); R1' is H, F,
Cl, Br, CF.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alkyl, CON[(C.sub.1-C.sub.6)alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.2-C.sub.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.sub.3, OC(O)H, O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3
or N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub- .2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--
(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl radical may
be substituted up to two times by F, Cl, OH, CF.sub.3, CN,
OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl or
NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alk- yl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, I, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl); R2 is
(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where n is 1-4),
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl); R3 is (C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--COOH (where n is 1-4),
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl); and their physiologically tolerated
salts and physiologically functional derivatives.
4. A compound of the formula I as claimed in claim 1, wherein: Y is
a direct linkage; X is CH.sub.2 or O; R1 is F, Cl, Br, CF.sub.3,
NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alk- yl, CON[(C.sub.1-C.sub.6)alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.2-C.sub.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.sub.3, OC(O)H, O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3
or N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alk- yl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl); R1' is H, F,
Cl, CF.sub.3, CN, COOH, COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)alkyl, CON[(C.sub.1-C.sub.6)alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.2-C.sub.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.sub.3, OC(O)H, O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3
or N(COOCH.sub.2Ph).sub.2), SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub- .2,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alk- yl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl); R2 is
(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where n is 1-4),
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl); R3 is (C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--COOH (where n is 1-4),
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl); and their physiologically tolerated
salts.
5. A pharmaceutical composition comprising a compound as claimed in
claim 1 and a pharmaceutically acceptable carrier.
6. A pharmaceutical composition comprising a compound as claimed in
claim 2 and a pharmaceutically acceptable carrier.
7. A pharmaceutical composition comprising a compound as claimed in
claim 3 and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising a compound as claimed
claim 4 and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition of claim 5 further comprising one
or more anorectic active ingredients.
10. The pharmaceutical composition of claim 6 further comprising
one or more anorectic active ingredients.
11. The pharmaceutical composition of claim 7 further comprising
one or more anorectic active ingredients.
12. The pharmaceutical composition of claim 8 further comprising
one or more anorectic active ingredients.
13. A method for the treatment of obesity comprising administering
an obesity treating effective amount of a pharmaceutical
composition of claim 5 to a patient in need thereof.
14. A method for the treatment of type HI diabetes comprising
administering a diabetes treating effective amount of the
pharmaceutical composition of claim 5 to a patient in need
thereof.
15. The method of claim 13 further comprising administering at
least one other anorectic active ingredient.
16. The method of claim 14 further comprising administering at
least one other anorectic active ingredient.
17. A process for producing a medicament comprising admixing a
compound as claimed in claim 1 with a pharmaceutically suitable
carrier, and converting this mixture into a form suitable for
administration.
18. A method for the treatment of obesity comprising administering
an obesity treating effective amount of a pharmaceutical
composition of claim 6 to a patient in need thereof.
19. A method for the treatment of type II diabetes comprising
administering a diabetes treating effective amount of the
pharmaceutical composition of claim 6 to a patient in need
thereof.
20. A method for the treatment of obesity comprising administering
an obesity treating effective amount of a pharmaceutical
composition of claim 7 to a patient in need thereof.
21. A method for the treatment of type II diabetes comprising
administering a diabetes treating effective amount of the
pharmaceutical composition of claim 7 to a patient in need
thereof.
22. A method for the treatment of obesity comprising administering
an obesity treating effective amount of a pharmaceutical
composition of claim 8 to a patient in need thereof.
23. A method for the treatment of type II diabetes comprising
administering a diabetes treating effective amount of the
pharmaceutical composition of claim 8 to a patient in need thereof.
Description
BACKGROUND OF THE INVENTION
[0001] The invention relates to polycyclic thiazol-2-ylidene amines
and to their physiologically tolerated salts and physiologically
functional derivatives.
[0002] U.S. Pat. No. 3,507,868 has described tetracyclic
imidazo[2,1-b]thiazoles and thiazolo[3,2-a]pyrimidines which are
unsubstituted in ring A and have an anorectic effect.
[0003] The invention was based on the object of providing further
compounds which display a therapeutically utilizable anorectic
effect. In this connection, the object was also in particular to
find compounds for which the anorectic effect is increased by
comparison with the compounds of U.S. Pat. No. 3,507,868 and with
which fewer side effects occur.
SUMMARY OF THE INVENTION
[0004] The invention relates to compounds of the formula I 2
[0005] in which
[0006] Y is a direct linkage, --CH.sub.2-- or
--CH.sub.2--CH.sub.2--;
[0007] X is CH.sub.2, CH-phenyl, O or S;
[0008] R1 is F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub- .2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl or NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, phenyl, biphenylyl,
O--(CH.sub.2).sub.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 or thienyl ring may
be independently optionally substituted up to 3 times by F, Cl, Br,
I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl);
[0009] R1' is H, F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub- .2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2)n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2)n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.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.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl- , (C.sub.1-C.sub.6)-alkyl or NH.sub.2),
NH.sub.2, NH--(C.sub.1-C.sub.6)-al- kyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted up to 3
times by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl, (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl);
[0010] R2 is (C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n-COOH (where
n is 1-4), (C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl);
[0011] R3 is (C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n-COOH (where
n is 1-4), (C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl); or
[0012] R2 and R3 together form a --CH.sub.2--CH.sub.2--,
--CH.sub.2--C(CH.sub.3).sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2--
or --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- group;
[0013] and their physiologically tolerated salts and
physiologically functional derivatives.
[0014] 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
[0015] The invention relates to compounds of the formula I 3
[0016] in which
[0017] Y is a direct linkage, --CH.sub.2-- or
--CH.sub.2--CH.sub.2--;
[0018] X is CH.sub.2, CH-phenyl, O or S;
[0019] R1 is F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub- .2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl or NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, phenyl, biphenylyl,
O--(CH.sub.2).sub.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 or thienyl ring may
be independently optionally substituted up to 3 times by F, Cl, Br,
I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl);
[0020] R1' is H, F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub- .2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl or NH.sub.2), NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, phenyl, biphenylyl,
O--(CH.sub.2).sub.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 or thienyl rings may
be independently optionally substituted up to 3 times by F, Cl, Br,
I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl, (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl);
[0021] R2 is (C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where
n is 1-4), (C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl);
[0022] R3 is (C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where
n is 1-4), (C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl);
[0023] or
[0024] R2 and R3 together form a --CH.sub.2--CH.sub.2--,
--CH.sub.2-C(CH.sub.3).sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2-- or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- group;
[0025] and their physiologically tolerated salts and
physiologically functional derivatives.
[0026] In a preferred embodiment, compounds of formula I are those
in which one or more radical(s) has or have the following
meaning:
[0027] Y is a direct linkage, --CH.sub.2-- or
--CH.sub.2--CH.sub.2--;
[0028] X is CH.sub.2 or O;
[0029] R1 is F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alk- yl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 phenyl, biphenylyl, naphthyl, pyridyl, furanyl or thienyl
rings each may be independently optionally substituted once or
twice by F, Cl, Br, I, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub. 6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl, (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl);
[0030] R1' is H, F, Cl, I, CF.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2- , (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl] .sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH-- (C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, I, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl);
[0031] R2 is (C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where
n is 1-4), (C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl);
[0032] R3 is (C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where
n is 1-4), (C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl);
[0033] or
[0034] R2 and R3 together form a --CH.sub.2--CH.sub.2--,
--CH.sub.2--C(CH.sub.3).sub.2-- or --CH.sub.2--CH.sub.2--CH.sub.2--
group; and their physiologically tolerated salts and
physiologically functional derivatives.
[0035] In a particularly preferred embodiment are compounds of the
formula I in which one or more radical(s) has or have the following
meaning:
[0036] Y is a direct linkage or --CH.sub.2--;
[0037] X is CH.sub.2, O or S;
[0038] R1 is F, Cl, Br, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alk- yl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, Br, I, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl);
[0039] R1' is H, F, Cl, Br, CF.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2- , (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, I, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl);
[0040] R2 is (C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where
n is 1-4), (C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl);
[0041] R3 is (C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where
n is 1-4), (C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl);
[0042] and their physiologically tolerated salts and
physiologically functional derivatives.
[0043] Most particularly preferred are compounds of the formula I
in which one or more radical(s) has or have the following
meaning:
[0044] Y is a direct linkage;
[0045] X is CH.sub.2 or O;
[0046] R1 is F, Cl, Br, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2--NH.sub.2,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alk- yl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl);
[0047] R1' is H, F, Cl, CF.sub.3, CN, COOH,
COO(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CON[(C.sub.1-C.sub.6)alkyl].sub.2- , (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.2-C.sub.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.sub.3, OC(O)H,
O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2), SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub- .2,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl (where n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, OH, CF.sub.3,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl
or NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alk- yl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.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 or
thienyl rings may be independently optionally substituted once or
twice by F, Cl, OH, CF.sub.3, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2), 1,2,3-triazol-5-yl (wherein the triazole ring may be
optionally substituted in position 1, 2 or 3 by methyl or benzyl)
or tetrazol-5-yl (wherein the tetrazole ring may be optionally
substituted in position 1 or 2 by methyl or benzyl);
[0048] R2 is (C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where
n is 1-4), (C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl);
[0049] R3 is (C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n--COOH (where
n is 1-4), (C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl or
(CH.sub.2).sub.n-furyl (where n is 0-5 and the phenyl, thienyl,
pyridyl or furyl may each be substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl);
[0050] and their physiologically tolerated salts.
[0051] The invention also relates to compounds of the formula I in
the form of their racemates, racemic mixtures and pure enantiomers,
and to their diastereomers and mixtures thereof.
[0052] The alkyl, alkenyl and alkynyl radicals in the substituents
R1, R1', R2 and R3 may be either straight-chain or branched.
[0053] Pharmaceutically acceptable salts are particularly suitable
for medical applications because of their greater solubility in
water compared with the initial compounds on which they are based.
These salts must have a pharmaceutically acceptable anion or
cation. Suitable pharmaceutically acceptable acid addition salts of
the compounds of the invention are salts of inorganic acids such as
hydrochloric acid, hydrobromic acid, phosphoric, metaphosphoric,
nitric and sulfuric acids, and organic acids such as, for example,
acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic,
fumaric, gluconic, glycolic, isethionic, lactic, lactobionic,
maleic, malic, methanesulfonic, succinic, p-toluenesulfonic,
tartaric and trifluoroacetic acids. It is particularly preferred to
use the chloride for medical purposes. Suitable pharmaceutically
acceptable basic salts are ammonium salts, alkali metal salts (such
as sodium and potassium salts) and alkaline earth metal salts (such
as magnesium and calcium salts).
[0054] Salts with a pharmaceutically unacceptable anion likewise
fall within the scope of the invention as useful intermediates for
preparing or purifying pharmaceutically acceptable salts and/or for
use in non-therapeutic, for example in vitro, applications.
[0055] The term `physiologically functional derivative` used herein
refers to any physiologically tolerated derivative of a compound
according to the invention, for example an ester, which is able
upon administration to a mammal, such as, for example, to humans,
to form (directly or indirectly) such a compound or an active
metabolite thereof.
[0056] A further aspect of this invention is prodrugs of compounds
of the invention. Such prodrugs may be metabolized in vivo to a
compound of the invention. These prodrugs may themselves be active
or not.
[0057] The compounds of the invention may also exist in various
polymorphous forms, for example, as amorphous and crystalline
polymorphous forms. All polymorphous forms of the compounds of the
invention fall within the scope of the invention and are a further
aspect of the invention.
[0058] All references hereinafter to "compound(s) of the formula
(I)" refer to compound(s) of the formula (I) as described above and
to the salts, solvates and physiologically functional derivatives
thereof as described herein.
[0059] The compounds of formula (I) are useful in the treatment of
type II diabetes and in the treatment or prophylaxis of obesity.
Treatment includes either the prophylaxis or the amelioration of
the disorder. In order to achieve the treatment, an effective
amount of a compound of formula (I) is administered to a patient in
need thereof. An "effective amount" is the amount which achieves
the treatment of the specified state.
[0060] The amount of a compound of the formula (I), which is an
"effective amount," that is necessary to achieve the desired
biological effect depends on a number of factors, for example, the
specific compound chosen, the intended use, the mode of
administration and the clinical condition of the patient. The daily
dose is generally in the range from 0.3 mg to 100 mg (typically
from 3 mg to 50 mg) per day and per kilogram body weight, for
example 3-10 mg/kg/day. An intravenous dose may be, for example, in
the range from 0.3 mg to 1.0 mg/kg, which may suitably be
administered as infusion of 10 ng to 100 ng per kilogram and per
minute. Infusion solutions suitable for these purposes may contain,
for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg,
per milliliter. Single doses may contain, for example, from 1 mg to
10 g of the active ingredient. Thus, ampoules for injections may
contain, for example, from 1 mg to 100 mg, and single dose
formulations which may be administered orally, such as, for
example, tablets or capsules, may contain, for example, from 1.0 to
1000 mg, typically from 10 to 600 mg. In the case of
pharmaceutically acceptable salts, the above weight data are based
on the weight of the aminothiazole ion derived from the salt. The
compounds of the formula (I) may be used for prophylaxis or therapy
of type II diabetes or obesity as the compound itself, but they are
preferably in the form of a pharmaceutical composition with a
pharmaceutically acceptable carrier. The carrier must, of course,
be compatible in the sense of compatibility with other ingredients
of the composition and not be harmful to the patient's health. The
carrier may be a solid or a liquid or both and is preferably
formulated with the compound as single dose, for example as tablet,
which may contain from 0.05% to 95% by weight of the active
ingredient. Further pharmaceutically active substances may likewise
be present, including further compounds of the formula (I). The
pharmaceutical compositions according to the invention may be
produced by one of the known pharmaceutical methods which
essentially consists of mixing the ingredients with
pharmacologically acceptable carriers and/or excipients.
[0061] Pharmaceutical compositions according to the invention are
those suitable for oral, rectal, topical, peroral (for example
sublingual) and parenteral (for example subcutaneous,
intramuscular, intradermal or intravenous) administration, although
the most suitable mode of administration depends in each individual
case on the nature and severity of the condition to be treated and
on the nature of the compound of the formula (I) used in each case.
Coated formulations and coated slow-release formulations also fall
within the scope of the invention. Acid- and gastric
fluid-resistant formulations are preferred. Suitable gastric
fluid-resistant coatings comprise cellulose acetate phthalate,
polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate
and anionic polymers of methacrylic acid and methyl
methacrylate.
[0062] Suitable pharmaceutical compounds for oral administration
may be in the form of separate units such as, for example,
capsules, cachets, pastilles or tablets, each of which contains a
defined amount of the compound of the formula (I); as powder or
granules; as solution or suspension in an aqueous or nonaqueous
liquid; or as an oil-in-water or water-in-oil emulsion. These
compositions may, as already mentioned, be prepared by any suitable
pharmaceutical method which includes a step in which the active
ingredient and the carrier (which may consist of one or more
additional ingredients) are brought into contact. In general, the
compositions are produced by uniform and homogeneous mixing of the
active ingredient with a liquid and/or finely dispersed solid
carrier, after which the product is shaped if necessary. Thus, for
example, a tablet may be produced by compressing or shaping the
powder or granules of the compound, where appropriate with one or
more additional ingredients. Compressed tablets may be produced by
tabletting the compound in free-flowing form, such as, for example,
a powder or granules, where appropriate mixed with a binder,
lubricant, inert diluent and/or one (or more)
surface-active/dispersing agents in a suitable machine. Shaped
tablets may be produced by shaping, in a suitable machine, the
compound which is in powder form and has been moistened with an
inert liquid diluent.
[0063] Pharmaceutical compositions suitable for peroral
(sublingual) administration comprise suckable tablets which contain
a compound of the formula (I) with a flavoring, normally sucrose,
and gum arabic or tragamayth, and pastilles which contain the
compound in an inert base such as gelatin and glycerol or sucrose
and gum arabic.
[0064] Suitable pharmaceutical compositions for parenteral
administration comprise preferably sterile aqueous preparations of
a compound of the formula (I), which are preferably isotonic with
the blood of the intended recipient. These preparations are
preferably administered intravenously, although administration may
also take place by subcutaneous, intramuscular or intradermal
injection. These preparations may preferably be produced by mixing
the compound with water and making the resulting solution sterile
and isotonic with blood. Injectable compositions according to the
invention generally contain from 0.1 to 5% by weight of the active
compound.
[0065] Suitable pharmaceutical compositions for rectal
administration are preferably in the form of single-dose
suppositories. These may be produced by mixing a compound of the
formula (I) with one or more conventional solid carriers, for
example cocoa butter, and shaping the resulting mixture.
[0066] Suitable pharmaceutical compositions for topical use on the
skin are preferably in the form of an ointment, cream, lotion,
paste, spray, aerosol or oil. Carriers which may be used are
petrolatum, lanolin, polyethylene glycols, alcohols and
combinations of two or more of these substances. The active
ingredient is generally present in a concentration of from 0.1 to
15% by weight of the composition, for example from 0.5 to 2%.
[0067] Transdermal administration is also possible. Suitable
pharmaceutical compositions for transdermal applications may be in
the form of single plasters which are suitable for long-term close
contact with the patient's epidermis. Plasters of this type
suitably contain the active ingredient in an aqueous solution which
is buffered where appropriate, dissolved and/or dispersed in an
adhesive or dispersed in a polymer. A suitable active ingredient
concentration is about 1% to 35%, preferably about 3% to 15%. As a
particular option, the active ingredient may be released by
electrotransport or iontophoresis as described, for example, in
Pharmaceutical Research, 2 (6): 318 (1986).
[0068] The invention also relates to a process for preparing the
compounds of the formula I, which comprises obtaining the compounds
of the formula I by the procedure shown in the following reaction
scheme: 4
[0069] For this purpose, compounds of the formula II 5
[0070] in which R1, R1', X and Y have the above stated meaning, are
activated and converted into a compound of the formula III in which
Z is the residue of an activated ester of an inorganic or organic
acid.
[0071] The compounds of the formula III are further reacted with
thioureas of the formula IVa 6
[0072] which may be in a tautomeric equilibrium with compounds of
the formulae IVb and IVc, and in which R2 and R3 have the stated
meanings, to give compounds of the formula I.times.HZ or
I'.times.HZ', converting, where appropriate, the compounds of the
formula I.times.HZ or I'.times.HZ with organic or inorganic bases
into their free form of the formula I or I'. These in turn may be
converted with an inorganic or organic acid into another acid
addition salt.
[0073] Examples of suitable inorganic acids are: hydrohalic acids
such as hydrochloric acid and hydrobromic acid, and sulfuric acid,
phosphoric acid and sulfamic acid.
[0074] Examples of organic acids which may be mentioned are: formic
acid, acetic acid, benzoic acid, p-toluenesulfonic acid,
benzenesulfonic acid, succinic acid, fumaric acid, maleic acid,
lactic acid, tartaric acid, citric acid, L-ascorbic acid, salicylic
acid, isethionic acid, methanesulfonic acid,
trifluoromethanesulfonic acid, 1,2-benzisothiazol-3(2H)-one,
6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide.
[0075] The procedure described above is advantageously carried out
by reacting the compounds III with the thioureas IVa in the molar
ratio of from 1:1 to 1:1.5. The reaction is advantageously carried
out in an inert solvent, for example in polar organic solvents such
as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone,
dioxane, tetrahydrofaran, acetonitrile, nitromethane or diethylene
glycol dimethyl ether. However, particularly advantageous solvents
prove to be methyl acetate and ethyl acetate, short-chain alcohols
such as methanol, ethanol, propanol, isopropanol, and lower dialkyl
ketones such as, for example, acetone, 2-butanone or 2-hexanone. It
is also possible to use mixtures of the reaction media mentioned;
thus, it is also possible to use mixtures of the solvents mentioned
with solvents which are less suitable on their own, such as, for
example, mixtures of methanol with benzene, ethanol with toluene,
methanol with diethyl ether or with tert-butyl methyl ether,
ethanol with tetrachloromethane, acetone with chloroform,
dichloromethane or 1,2-dichloroethane, it being expedient for the
more polar solvent in each case to be used in excess. The reactants
may be present in suspension or in solution in the particular
reaction medium. It is also possible in principle for the reactants
to be reacted without solvent, especially when the particular
thioamide has a low melting point. The reaction is only slightly
exothermic and may be carried out at between -10.degree. C. and
150.degree. C., preferably between 30.degree. C. and 130.degree. C.
A temperature range between 70.degree. C. and 110.degree. C. has
usually proved to be particularly favorable.
[0076] The reaction time depends substantially on the reaction
temperature and is between 2 minutes and 3 days at higher and lower
temperatures respectively. In the favorable temperature range, the
reaction time is generally between 5 minutes and 48 hours.
[0077] The compounds I and I' often separate out in the form of
their acid addition salts I.times.HZ and I'.times.HZ of low
solubility during the reaction, and it is expedient subsequently to
add a suitable precipitant. Examples of this which are used are
hydrocarbons such as benzene, toluene, cyclohexane or heptane or
tetrachloromethane; in particular, alkyl acetates such as ethyl
acetate or n-butyl acetate or dialkyl ethers such as diethyl ether,
diisopropyl ether, di-n-butyl ether or tert-butyl methyl ether have
proved to be particularly suitable. If the reaction mixture is
still a solution after the end of the reaction, the salts of the
compounds I or I' may, where appropriate after concentration of the
reaction solution, be precipitated with one of the precipitants
mentioned. It is also possible and advantageous to filter the
solution of the reaction mixture into a stirred solution of one of
the precipitants mentioned. Since the reaction of the compounds III
with the thioureas IVa takes place virtually quantitatively, the
resulting crude products are usually already analytically pure. The
reaction mixture may also be worked up by making the reaction
mixture alkaline by addition of an organic base such as, for
example, triethylamine or diisobutylamine or ammonia or morpholine
or piperidine or 1,8-diazabicyclo[ 5.4.0]undec-7-ene, and purifying
the crude reaction product after concentration by chromatography,
for example on a silica gel column. Examples of eluents which prove
to be suitable for this are mixtures of ethyl acetate with
methanol, mixtures of dichloromethane with methanol, mixtures of
toluene with methanol or ethyl acetate or mixtures of ethyl acetate
with hydrocarbons such as heptane. If the crude product is purified
in the manner described last, an acid addition product may be
obtained from the pure base of the formula I or I' obtained in this
way, by dissolving or suspending the base in an organic protic
solvent such as methanol, ethanol, propanol or isopropanol or in an
organic aprotic solvent such as ethyl acetate, diethyl ether,
diisopropyl ether, tert-butyl methyl ether, dioxane,
tetrahydrofuran, acetone or 2-butanone, and then adding to this
mixture an at least equimolar amount of an inorganic acid such as,
for example, hydrochloric acid, dissolved in an inert solvent such
as, for example, diethyl ether or ethanol or another one of the
inorganic or organic acids mentioned hereinbefore.
[0078] The compounds of the formula I and I' may be recrystallized
from a suitable inert solvent such as, for example, acetone,
2-butanone, acetonitrile, nitromethane. However, reprecipitation
from a solvent such as, for example, dimethylformamide,
dimethylacetamide, nitromethane, acetonitrile, preferably methanol
or ethanol, is particularly advantageous. The reaction of the
compounds of the formula III with the thioureas of the formula IVa
may also be carried out by adding an at least equimolar amount of a
base such as, for example, triethylamine to the reaction mixture,
and then converting, where appropriate, the compounds I or I'
obtained in this way into their acid addition products.
[0079] Examples of a suitable residue of an activated ester Z in
the compounds of the formula III are: Cl, Br, I,
O--C(O)--(C.sub.6H.sub.4)--4- --NO.sub.2, O--SO.sub.2--CH.sub.3,
O--SO.sub.2--CF.sub.3, O--SO.sub.2--(C.sub.6H.sub.4)--4--CH.sub.3,
O--SO.sub.2--C.sub.6H.sub.5.
[0080] The acid addition products I.times.HZ and I'.times.HZ may be
converted into the compounds of the formula I and I' by treatment
with bases. Examples of suitable bases are solutions of inorganic
hydroxides such as lithium, sodium, potassium, calcium or barium
hydroxide, carbonates or bicarbonates, such as sodium or potassium
carbonate, sodium or potassium bicarbonate, ammonia and amines such
as triethylamine, diisopropylamine, dicyclohexylamine, piperidine,
morpholine, methyldicyclohexylamine.
[0081] Thioureas of the formula IVa either are commercially
available or may be prepared by methods known from the
literature.
[0082] Apart from the derivatives described in the examples, also
obtained according to the invention are the compounds of the
formula I, and their acid addition products, compiled in the
following Table 1:
1TABLE 1 Examples Formula I 7 Ex. R.sub.1; R.sub.1' R.sub.2 R.sub.3
Y X Salt m.p.[.degree. C.] 1 5-SO.sub.2--NH.sub.2; 6-Cl CH.sub.3
CH.sub.3 -- CH.sub.2 HBr 298 2 5-SO.sub.2--NH.sub.2; 6-Cl
CH.sub.2--(C.sub.6H.sub.5) CH.sub.2--(C.sub.6H.sub.5) -- CH.sub.2
HBr 243 3 6-Cl CH.sub.3 CH.sub.3 -- CH.sub.2 HBr 278 4 6-Cl
CH.sub.3 CH.sub.3 -- CH.sub.2 HCl 281 5 6-Cl CH.sub.2--CH.sub.2 --
CH.sub.2 HCl 258 6 6-Cl CH.sub.2--COOH CH.sub.3 -- CH.sub.2 HBr 256
7 6-Cl CH.sub.2--COOH C.sub.6H.sub.5 -- CH.sub.2 HBr 243 8 5-F
CH.sub.2--CH.sub.2CH.sub.2-- CH.sub.3 CH.sub.2 O HCl 234 COOH 9 5-F
CH.sub.2--COOH CH.sub.3 CH.sub.2 O HCl 256 10 5-SO.sub.2--CH.sub.3
CH.sub.3 CH.sub.3 -- CH.sub.2 HCl 256 11 7-Cl CH.sub.3 CH.sub.3 --
CH.sub.2 HCl 250 12 5-Cl CH.sub.3 CH.sub.3 -- CH.sub.2 HCl 249 13
6-F CH.sub.3 CH.sub.3 -- CH.sub.2 HCI 250 14 6-Cl CH.sub.3 CH.sub.3
-- CH.sub.2 -- 171 15 6-(O--C.sub.6H.sub.4)-4-Cl CH.sub.3 CH.sub.3
-- CH.sub.2 HCI 251 16 6-O--CH.sub.2--CF.sub.3 CH.sub.3 CH.sub.3 --
CH.sub.2 HCl 276 17 6-O--CH.sub.2--CF.sub.2--CF.sub.3 CH.sub.3
CH.sub.3 -- CH.sub.2 HCl 240 18 7-(C.sub.6H.sub.4)-4-CF.sub.3)
CH.sub.3 CH.sub.3 -- CH.sub.2 -- 231 19 5-(C.sub.6H.sub.4)-4-Cl)
CH.sub.3 CH.sub.3 -- CH.sub.2 HBr 256 20
6-(O--C.sub.6--H.sub.4)-3-CH.sub.3) CH.sub.3 CH.sub.3 -- CH.sub.2
HCl 229 21 6-O--CH.sub.2--CF.sub.2--CF.sub.2-- -
CH.sub.2--CH.sub.2--CH.sub.2 -- CH.sub.2 HCl 271 CF.sub.3 22
6-O--CH.sub.2--CF.sub.2--CF.sub.2-- CH.sub.3 CH.sub.3 -- CH.sub.2
HCl 251 CF.sub.3 23 6-Cl C.sub.6H.sub.5 C.sub.6H.sub.5 -- CH.sub.2
HBr 213 24 6-Cl (C.sub.6H.sub.4)-4-Cl (C.sub.6H.sub.4)-4-CL --
CH.sub.2 -- 235 25 6-Cl (C.sub.6H.sub.4)-4-OCH.sub.3
(C.sub.6H.sub.4)-4-OCH.sub.3 -- CH.sub.2 HBr 243 26
6-(O--C.sub.6H.sub.5) CH.sub.2--CH.sub.2 -- CH.sub.2 HBr 243 27
6-(O--C.sub.6H.sub.5) CH.sub.3 CH.sub.3 -- CH.sub.2 HBr 205 28
6-(O--C.sub.6H.sub.4-3-CH.sub.3) CH.sub.2--CH.sub.2 -- CH.sub.2 HBr
250 29 6-CONH.sub.2 CH(CH.sub.3).sub.2 CH(CH.sub.3).sub.2 --
CH.sub.2 HBr 243 30 6-Cl C.sub.6H.sub.5 CH.sub.2--CH.sub.2-O--CH.s-
ub.3 -- CH.sub.2 HBr 231 31 6-Cl C.sub.6H.sub.5
CH.sub.2--CH.sub.2--C.sub.6H.sub.5 -- CH.sub.2 HBr 266 32 6-Cl
CH.sub.3 C.sub.6H.sub.4-4-C(O)O-- -- CH.sub.2 HBr 223
CH.sub.2--CH.sub.3 33 6-(CH.sub.2).sub.6--OH C.sub.6H.sub.5
C.sub.6H.sub.5 -- CH.sub.2 -- 119 34 6-(CH.sub.2).sub.6--OH
CH.sub.3 CH.sub.3 -- CH.sub.2 HCl 195 35 6-(CH.sub.2).sub.6--NH.su-
b.2 CH.sub.3 CH.sub.3 -- CH.sub.2 2HCl d. from 230 36
6-(CH.sub.2).sub.6--NH.sub.2 CH.sub.3 CH.sub.3 -- CH.sub.2 -- d.
from 120
[0083] The compounds of the formula I are distinguished by
beneficial effects on lipid metabolism, and they are particularly
suitable as anorectic agents. The compounds may be employed alone
or in combination with other anorectic active ingredients. Further
anorectic active ingredients of this type are mentioned, for
example, in the Rote Liste, chapter 01 under weight-reducing
agents/appetite suppressants. Examples include, but are not limited
to, Decorpa.COPYRGT. (from Pierre Fabre Pharma, common name,
sterculia), Xenical.COPYRGT. (from Roche, common name orlistat),
Antiadipositum X-112S (from Haenseler, common name,
D-norpseudoephedrin-HCl), Fasupond.COPYRGT. (from Eu Rho Arzneil,
common name, D-norpseudoephedrin-HCl), Mirapront.COPYRGT. N (from
Mack, Illert., common name, D-norpseudoephedrin-Poly(styrol,
divinylbenzol) sulfonate), Regenon.COPYRGT. l-retard (from Temmler
Pharma, common name, Amfepramon-HCl), Rondimen.COPYRGT. (from ASTA
Medica AWD, common name, Mefenorex-HCl), Tenuate.COPYRGT. Retard
(from Artegodan, common name, Amfepramon-HCl), Vita-Schlanktropfen
Schuck (from Schuck, common name, D-norpseudoephedrin-HCl),
Vencipon.COPYRGT. N (from Artesan, common name, Ephedrin-HCl),
Cefamadar.COPYRGT. (from Cefak, common name Madar D4), and
Helianthus tuberosus (Plantina). The compounds are suitable for the
prophylaxis and, in particular, for the treatment of obesity. The
compounds are furthermore suitable for the prophylaxis and for the
treatment of type II diabetes.
Biological Test Model
[0084] The anorectic effect was tested on male NMR.sup.1 mice.
After withdrawal of feed for 24 hours, the test product was
administered by gavage. The animals were housed singly and had free
access to drinking water and, 30 minutes after administration of
the product, they were offered condensed milk. The consumption of
condensed milk was determined, and the general behavior of the
animals was inspected, every half hour for 7 hours. The measured
milk consumption was compared with that of untreated control
animals.
2TABLE 2 Anorectic effect measured by reduction in the cumulative
milk consumption by treated animals compared with untreated
animals. Compound/ Example 8 Oral dose [mg/kg] Number of
animals/cumulative milk consumption by the treated animals N/[ml]
Number of animals/cumulative milk consumption by the untreated
animals N/[ml] Reduction in the cumulative milk consumption as % of
the controls Remarks R1 = R1' = H, 50 5/not analyzable 5/4.08 not
analyzable acute toxicity for X = CH.sub.2, Y = CH.sub.2; all
animals in the R2 - R3 = (CH.sub.2).sub.2 x group (fits); HBr
(Prior art) 1 animal Example 15 50 5/0.22 5/4.30 95 none Example 16
50 5/0.24 5/3.84 94 none Example 17 50 5/0.94 5/3.84 74 none
Example 21 50 5/0.08 5/3.58 98 none Example 22 50 5/0.08 5/4.50 98
none Example 24 50 5/0.30 5/4.26 93 none
[0085] The data from the table shows that the compounds of the
formula I exhibit a good anorectic effect. No side effects were
observed in the experimental animals.
[0086] The examples detailed below serve to illustrate the
invention without, however, restricting it. The stated
decomposition points are not corrected and generally depend on the
heating rate.
Procedure Example 1
(6-Chloro-3-methyl-3,8-dihydroindeno[1,2-d]thiazol-2-ylidene)methylamine
hydrobromide: (Compound of Example 3)
[0087] a)
6-Chloro-3-methyl-2-methylimino-2,3,8,8a-tetrahydroindeno[1,2-d]-
thiazol-3a-ol hydrobromide:
[0088] 2.47 g (10 mmol) of 2-bromo-5-chloro-1-indanone are
dissolved in 30 ml of acetone and, at room temperature, a solution
of 1.05 g (10 mmol) of N,N'-dimethylthiourea in 10 ml of acetone is
added, and the mixture is stirred at room temperature for 5 h. The
precipitate is filtered off with suction and dried in vacuo.
Crystallization from methanol/diethyl ether results in the
hydrobromide of 6-chloro-3-methyl-2-methylimino-2,3,8,8a-t-
etrahydroindeno[1,2-d]thiazol-3a-ol of melting point
181-183.degree. C.
[0089] b)
(6-Chloro-3-methyl-3,8-dihydroindeno[1,2-d]thiazol-2-ylidene)met-
hylamine:
[0090] 3.05 g (10 mmol) of
6-chloro-3-methyl-2-methylimino-2,3,8,8a-tetrah- ydroindeno[
1,2-d]thiazol-3a-ol hydrobromide are suspended in 20 ml of glacial
acetic acid and stirred under reflux for 4 h. The mixture is
allowed to cool to room temperature, and the precipitate is
filtered off with suction. The hydrobromide of
(6-chloro-3-methyl-3,8-dihydroindeno[1,-
2-d]thiazol-2-ylidene)methylamine is obtained with a melting point
of 278.degree. C.
Procedure Example 2
(8-Fluoro-1-methyl-1,4-dihydrochromeno[4,3-d]thiazol-2-ylidene-amino)aceti-
c acid hydrochloride (Compound of Example 9)
[0091] a) N-tert-Butoxycarbonylmethyl-N'-methylthiourea
[0092] is obtained by reacting 16.8 g of glycine tert-butyl ester
hydrochloride in 100 ml of ethyl acetate with 8 g of methyl
isothiocyanate and adding 13.8 ml of ethyl acetate. The mixture is
stirred at 35.degree. C. for 4 hours and then left to stand at room
temperature for 2 days. The precipitate is filtered off, the
organic phase is washed with sodium bicarbonate and with sodium
chloride solution and, after drying the extraction solution, the
solvent is evaporated off in vacuo. The thiourea is obtained as an
oil with a pale brownish color.
[0093] b)
(8-Fluoro-1-methyl-1,4-dihydrochromeno[4,3-d]thiazol-2-ylideneam-
ino)acetic acid hydrobromide
[0094] is obtained by adding 3.1 g of
N-tert-butoxycarbonylmethyl-N'-methy- lthiourea to a solution of
3.7 g of 3-bromo-6-fluoro-4-chromanone in acetone and then stirring
at room temperature for 24 hours and at 40.degree. C. for a further
8 hours. After distillation, the amorphous oily residue is induced
to crystallize in ethyl acetate at 0.degree. C. Colorless crystals,
melting point 184.degree. C.
[0095] c)
(8-Fluoro-1-methyl-1,4-dihydrochromeno[4,3-d]thiazol-2-ylideneam-
ino)acetic acid hydrochloride
[0096] is obtained by boiling 4.3 g of
(8-fluoro-1-methyl-1,4-dihydrochrom- eno[4,3-d]
thiazol-2-ylideneamino) acetic acid hydrobromide in 60 ml of
glacial acetic acid for 2 hours, then leaving to stand at room
temperature for 6 hours, subsequently cooling to about 10.degree.
C. and filtering off the crystalline precipitate. It is
recrystallized from a mixture of glacial acetic acid and a little
water and a few milliliters of aqueous hydrochloric acid, cooling
to 0.degree. C. Colorless crystals, melting point 256.degree.
C.
Procedure Example 3
(5-Methanesulfonyl-3-methyl-3,8-dihydroindeno[1,2-d]thiazol-2-ylidene)meth-
ylamine hydrochloride (Compound of Example 10)
[0097] a)
5-Methanesulfonyl-3-methyl-2-methylimino-2,3,8,8a-tetrahydroinde-
no[ 1,2-d]thiazol-3a-ol:
[0098] 1.45 g of 2-bromo-6-methanesulfonyl-1-indanone are dissolved
in 15 ml of acetone and, while stirring, 0.65 g of
N,N'-dimethylthiourea in 10 ml of acetone is added. The solution is
initially clear but, after about 10 min, the hydrobromide of
5-methanesulfonyl-3-methyl-2-methylimino-2,3,-
8,8a-tetrahydroindeno[1,2-d] thiazol-3a-ol crystallizes out.
Stirring at room temperature for 1 h is followed by filtration with
suction and washing with a little acetone. 2.1 g of hydrobromide
(melting point 265.degree. C.) are suspended in 10 ml of methanol,
and 1 ml of triethylamine is added. After 15 min, 150 ml of water
is added, and the mixture is stirred while cooling in ice for 1 h.
The product which is formed is filtered off with suction and washed
with a little cold water.
5-Methanesulfonyl-3-methyl-2-methylimino-2,3,8,8a-tetrahydroindeno[1,2-d]-
thiazol-3a-ol is obtained with a melting point of 158.degree.
C.
[0099] b)
(5-Methanesulfonyl-3-methyl-3,8-dihydroindeno[1,2-d]thiazol-2-yl-
idene)methylamine hydrochloride:
[0100] 312 mg of
5-methanesulfonyl-3-methyl-2-methylimino-2,3,8,8a-tetrahy-
droindeno[ 1,2-d]thiazol-3a-ol are stirred in 20 ml of 50%
concentrated hydrochloric acid at room temperature for 3 h. The
mixture is then heated at 60.degree. C. for 1 h. The solution is
filtered and cautiously concentrated in vacuo (.ltoreq.60.degree.
C.) and the remaining residue is stirred with ethanol. Filtration
with suction and washing with a little ethanol result in
(5-methanesulfonyl-3-methyl-3,8-dihydroindeno[1,- 2-d]
thiazol-2-ylidene)methylamine hydrochloride, melting point
>250.degree. C.
Procedure Example 4
[6-(4-Chlorophenoxy)-3-methyl-3,8-dihydroindeno[1,2-d]thiazol-2-ylidene]me-
thylamine hydrochloride (Compound of Example 15)
[0101]
6-(4-Chlorophenoxy)-3-methyl-2-methylamino-8,8a-dihydroindeno[
1,2-d]thiazol-3a-ol hydrochloride is boiled under reflux in 15 ml
of glacial acetic acid for 4 hours, the solvent is removed by
distillation under reduced pressure, and the residue is induced to
crystallize under diisopropyl ether. Melting point 250-252.degree.
C.
Procedure Example 5
Methyl[3-methyl-7-(4-trifluoromethylphenyl)-3,8-dihydroindeno[1,2-d]thiazo-
l-2-ylidene] amine hydrobromide (compound of Example 18)
[0102] a) 4-(4-Trifluoromethylphenyl)-1-indanone:
[0103] 6.33 g (0.03 mol) of 4-bromo-1-indanone and 5.7 g (0.03 mol)
of 4-trifluoromethylphenylboronic acid are suspended with 6.36 g
(0.06 mol) of sodium carbonate in a mixture of 100 ml of toluene
with 20 ml of ethanol and 20 ml of water. Under an argon
atmosphere, 320 mg (1.42 mmol) of palladium(II) acetate and 787 mg
(3 mmol) of triphenylphosphine are added, and the mixture is boiled
under reflux for 5 h. After the reaction is complete, the ethanol
content is evaporated off in vacuo, 50 ml of 0.5N sodium hydroxide
solution are added to the residue, and the mixture is stirred and
filtered with suction through a clarifying layer. The organic phase
of the filtrate is separated off, shaken 3.times. with 50 ml of
water each time, shaken once with saturated brine, dried over
sodium sulfate and concentrated in vacuo. The crude product is
chromatographed on silica gel with n-heptane/ethyl acetate 3/1.
4-(4-Trifluoromethylphenyl)-1-indanone is obtained with a melting
point of 75-78.degree. C.
[0104] b) 2-Bromo-4-(4-trifluoromethylphenyl)-1-indanone:
[0105] 2.76 g (10 mmol) of 4-(4-trifluoromethylphenyl)-1-indanone
are dissolved in 20 ml of glacial acetic acid and, after addition
of 10 .mu.l of a 48% strength solution of HBr in glacial acetic
acid, while stirring a solution of 0.516 ml (10.05 mmol) of bromine
in glacial acetic acid is added. After 3 h at room temperature, the
reaction mixture is poured into a mixture of 100 ml of water with
100 g of ice and 100 mg of sodium bisulfite, and the resulting
suspension is shaken with dichloromethane. The organic phase is
washed 3.times. with water, dried over sodium sulfate, filtered and
concentrated in vacuo. The residue is chromatographed on silica gel
with dichloromethane/n-heptane 3/1.
2-Bromo-4-(4-trifluoromethylphenyl)-1-indanone is obtained with a
melting point of 102-105.degree. C., in addition to a little
2,2-dibromo compound.
[0106] c)
3-Methyl-2-methylimino-7-(4-trifluoromethylphenyl)-2,3,8,8a-tetr-
ahydroindeno[ 12-d]thiazol-3a-ol hydrobromide:
[0107] 426 mg (1.2 mmol) of
2-bromo-4-(4-trifluoromethylphenyl)-1-indanone and 130.2 mg (1.25
mmol) of N, N'-dimethylthiourea are dissolved in 10 ml of acetone
and stirred at room temperature for 4 h. The precipitate is
filtered off with suction, washed with acetone and dried in vacuo.
The hydrobromide of
3-methyl-2-methylimino-7-(4-trifluoromethylphenyl)-2,3,8,-
8a-tetrahydroindeno[1,2-d] thiazol-3a-ol is obtained with a melting
point of 202-204.degree. C.
[0108] d)
Methyl[3-methyl-7-(4-trifluoromethylphenyl)-3,8-dihydroindeno[
1,2-d]thiazol-2-ylidene]amine hydrobromide:
[0109] 425.5 mg (1 mmol) of
3-methyl-2-methylimino-7-(4-trifluoromethylphe-
nyl)-2,3,8,8a-tetrahydroindeno[1,2-d]thiazol-3a-ol hydrobromide are
suspended in 10 ml of glacial acetic acid and stirred at
100.degree. C. for 3 h. The solvent is then evaporated off in
vacuo, and the residue is taken up in water, filtered, washed with
water and dried in vacuo.
Methyl[3-methyl-7-(4-trifluoromethylphenyl)-3,8-dihydroindeno[
1,2-d]thiazol-2-ylidene]amine hydrobromide is obtained with a
melting point of 230-233.degree. C.
Procedure Example 6
7-Phenoxy-4H,9H-2,3-dihydroimidazo[2,1-b]indeno[1,2-d]thiazole
hydrobromide (Compound of Example 24)
[0110] 0.73 g of the appropriate hydrobromide of the
9aH,4aH,4a-hydroxy derivative is heated in 20 ml of glacial acetic
acid at 100.degree. C. for 2 hours, the solvent is distilled off,
and the residue is induced to crystallize under diisopropyl ether.
Melting point 235.degree. C.
[0111] Inventors hereby incorporate by reference in its entirety
the priority application DE 19908536.6 filed Feb. 26, 1999.
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