U.S. patent application number 09/790905 was filed with the patent office on 2001-10-18 for substituted 8,8a-dihydro-3ah-indeno[1,2-d]thiazoles, processes for their preparation and their use as medicaments.
Invention is credited to Bickel, Martin, Gossel, Matthias, Jaehne, Gerhard, Lang, Hans-Jochen.
Application Number | 20010031752 09/790905 |
Document ID | / |
Family ID | 7631988 |
Filed Date | 2001-10-18 |
United States Patent
Application |
20010031752 |
Kind Code |
A1 |
Jaehne, Gerhard ; et
al. |
October 18, 2001 |
Substituted 8,8a-dihydro-3ah-indeno[1,2-d]thiazoles, processes for
their preparation and their use as medicaments
Abstract
The invention relates to substituted
8,8a-dihydro-3aH-indeno[1,2-d]thiazol- es and to their
physiologically acceptable salts and physiologically functional
derivatives. Compounds of formula I, 1 in which the radicals are as
defined above, and their physiologically acceptable salts and
processes for their preparation are described. The compounds are
suitable, for example, as anorectics.
Inventors: |
Jaehne, Gerhard; (Frankfurt,
DE) ; Lang, Hans-Jochen; (Hofheim, DE) ;
Gossel, Matthias; (Hofheim, DE) ; Bickel, Martin;
(Bad Homburg, DE) |
Correspondence
Address: |
HELLER EHRMAN WHITE & MCAULIFFE
815 CONNECTICUT AVE
WASHINGTON
DC
20006
US
|
Family ID: |
7631988 |
Appl. No.: |
09/790905 |
Filed: |
February 23, 2001 |
Current U.S.
Class: |
514/232.8 ;
514/23; 514/254.02; 514/317; 514/366; 536/54; 544/133; 544/368;
546/196; 548/150 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
3/10 20180101; C07D 277/60 20130101 |
Class at
Publication: |
514/232.8 ;
514/23; 514/254.02; 514/317; 514/366; 544/133; 536/54; 544/368;
546/196; 548/150 |
International
Class: |
A61K 031/7052; A61K
031/5377; A61K 031/496; A61K 031/454; A61K 031/428 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 23, 2000 |
DE |
100 08 274.2 |
Claims
What is claimed is:
1. A compound of formula (I): 12in which R1, R1' are independently
selected from 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.1-C.sub.6)-alkyl, wherein one
or more of the hydrogens of the alkyl, alkenyl, or alkynyl radicals
may be replaced by fluorine, or one hydrogen may be replaced by OH,
OC(O)CH.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, wherein 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 or 2- or 3-thienyl, wherein any of
the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings
may be optionally substituted one to 3 times by F, Cl, Br, I, OH,
CF.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 substituted in the 1-, 2- or
3-position by methyl or benzyl; tetrazol-5-yl, where the tetrazole
ring may be substituted in the 1 - or 2-position by methyl or
benzyl; 1,3,4-oxadiazol-2-yl; 2-amino-1 ,3,4-oxadiazol-5-yl,
wherein the amino function may be mono- or disubstituted by
(C.sub.1-C.sub.6)-alkyl, --C(O)--(C.sub.1-C.sub.6)-alkyl,
--C(O)--(cyclo-C.sub.3-C.sub.7)-alkyl, --C(O)-phenyl,
--C(O)--NH--(C.sub.1-C.sub.6)-alkyl,
--C(O)--NH--(cyclo-C.sub.3-C.sub.7)-alkyl, or --C(O)--NH-aryl,
wherein aryl is phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl or 2-
or 3-furanyl, --C(O)-morpholin-4-yl, --C(O)-piperidin-1-yl,
--C(O)-piperazin-4-yl, --C(O)--1-methyl-, 1-benzyl-piperazin-4-yl,
--SO.sub.2--(C.sub.1-C.sub.6)- -alkyl or --SO.sub.2-phenyl, wherein
the phenyl ring may be substituted up to two times by F, Cl, Br,
CN, CF.sub.3, OH, OCF.sub.3, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n-phenyl,
O--(CH.sub.2).sub.n-phenyl, where n is 0-6, 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; R2 is H, (C.sub.1-C.sub.6)-alkyl,
(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,
(CH.sub.2).sub.n-furyl, C(O)--(C.sub.1-C.sub.6)- -alkyl,
C(O)--(C.sub.3-C.sub.6)-cycloalkyl, C(O)--(CH.sub.2).sub.n-phenyl,
C(O)--(CH.sub.2).sub.n-thienyl, C(O)--(CH.sub.2).sub.n-pyridyl or
C(O)--(CH.sub.2).sub.n-furyl, wherein n is 0-5 and in which any of
phenyl, thienyl, pyridyl or furyl may be optionally substituted up
to two times by Cl, F, CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl; R3 is H, (C.sub.1-C.sub.6)-alkyl, F,
Cl, Br, CN, N.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n-phenyl, (CH.sub.2).sub.n-thienyl,
(CH.sub.2).sub.n-pyridyl, (CH.sub.2).sub.n-furyl, where n is 0-5
and in which any of phenyl, thienyl, pyridyl or furyl may be
optionally substituted up to two times by Cl, F, CN, CF.sub.3,
(C.sub.1-C.sub.3)-alkyl, OH or O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.2-C.sub.6)-alkenyl,
OC(O)CH.sub.3, (CH.sub.2).sub.n--C(O)O(C.sub.1- -C.sub.6)-alkyl,
(CH.sub.2).sub.n--C(O)OH, (CH.sub.2).sub.n--C(O)NH.sub.2,
(CH.sub.2).sub.n--C(O)NHCH.sub.3 or
(CH.sub.2).sub.n--C(O)N(CH.sub.3).sub- .2, where n is 0-3; R4 is
(C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.7)-cyclo- alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.4-C.sub.7)-cycloalkenyl, wherein one or more of the
hydrogens of the alkyl radicals may be replaced by fluorine or one
hydrogen may be replaced by OH, OC(O)CH.sub.3, OC(O)H,
O--CH.sub.2--Ph or O--(C.sub.1-C.sub.4)-alkyl; is
(CH.sub.2).sub.n-pyrrolidin-1-yl, (CH.sub.2).sub.n-piperidin-1-yl,
(CH.sub.2).sub.n-morpholin-4-yl, (CH.sub.2).sub.n-piperazin-1-yl,
(CH.sub.2).sub.n-N-4-methylpiperazin-1-y- l,
(CH.sub.2).sub.n--N-4-benzylpiperazin-1-yl,
(CH.sub.2).sub.n-phthalimid- oyl, where n is 1-6;
(CH.sub.2).sub.n-aryl or (CH.sub.2).sub.n-heteroaryl, where n is
0-6 and aryl is phenyl, biphenylyl or 1 - or 2-naphthyl and
heteroaryl is 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl,
2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, l-pyrazolyl, 3- or
5-isoxazolyl, 2- or 3-pyrrolyl, 2- or 3-pyridazinyl, 2-, 4- or
5-pyrimidinyl, 2-pyrazinyl, 2-(1,3,5-triazinyl), 2- or
5-benzimidazolyl, 2-benzothiazolyl, 1,2,4-triazol-3-yl,
1,2,4-triazol-5-yl, tetrazol-5-yl, indol-3-yl, indol-5-yl or
N-methylimidazol-2-, -4- or -5-yl, wherein the aryl radical or the
heteroaryl radical may be optionally substituted up to two times by
F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, S--(C.sub.1-C.sub.6)-alkyl,
SO--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6- )-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2, (CH.sub.2).sub.n--SO.sub.2--
-N(.dbd.CH--N(CH.sub.3).sub.2), wherein n is 0-6,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, COOH,
COO(C.sub.1-C.sub.6)-alkyl, COO(C.sub.3-C.sub.6)-cycloalkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
CONH(C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--CO-phenyl,
NH--SO.sub.2-(C.sub.1-C.sub.6)-alkyl, NH--SO.sub.2-phenyl, wherein
the phenyl ring may be substituted up to two times by F, Cl, CN,
OH, (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3,
COOH, COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2; pyrrolidin-1-yl,
morpholin-1-yl, piperidin-1-yl, piperazin-1-yl,
4-methylpiperazin-1-yl, (CH.sub.2).sub.n-phenyl,
O--(CH.sub.2).sub.n-phenyl, S--(CH.sub.2).sub.n-phenyl or
SO.sub.2--(CH.sub.2).sub.n-phenyl, wherein n is 0-3;
(CH.sub.2).sub.n--A--R8, wherein n is 1-6; A is O, NH,
N--(C.sub.1-C.sub.6)-alkyl, NCHO, N(CO--CH.sub.3), S, SO or
SO.sub.2; R8 is (C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, wherein one or more hydrogens of the
alkyl radicals may be replaced by fluorine or one hydrogen may be
replaced by OH, OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph or
O--(C.sub.1-C.sub.4)-alkyl; is (CH.sub.2).sub.m-aryl, wherein m is
0-6 and aryl is phenyl, thienyl or pyridyl and the aryl moiety may
be optionally substituted up to two times by F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
S--(C.sub.1-C.sub.6)-alkyl, SO--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--N(.dbd.- CH--N(CH.sub.3).sub.2),
(CH.sub.2).sub.n--SO.sub.2--NH(C.sub.1-C.sub.8)-al- kyl,
(CH.sub.2).sub.n--SO.sub.2--N[(C.sub.1-C.sub.8)-alkyl].sub.2,
(CH.sub.2).sub.n--SO.sub.2--NH(C.sub.3-C.sub.8)-cycloalkyl,
(CH.sub.2).sub.n--SO.sub.2--N[(C.sub.3-C.sub.8)-cycloalkyl.sub.2],
where n is 0-6, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, COOH, COO(C.sub.1-C.sub.6)-alkyl,
COO(C.sub.3-C.sub.6)-cycloalkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
CONH(C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N[(C.sub.1-C.sub.6)-alkyl].sub.2,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--CO-phenyl,
NH--SO.sub.2-phenyl, where the phenyl ring may be optionally
substituted up to two times by F, Cl, CN, OH,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3,
COOH, COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2;
NH--SO.sub.2-(C.sub.1-C.sub.8)-- alkyl,
N(C.sub.1-C.sub.6)-alkyl-SO.sub.2--(C.sub.1-C.sub.8)-alkyl,
pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl,
4-methylpiperazin-1-yl, (CH.sub.2).sub.p-phenyl,
O--(CH.sub.2).sub.p-phen- yl, S--(CH.sub.2).sub.p-phenyl or
SO.sub.2--(CH.sub.2).sub.p-phenyl, wherein p is 0-3; R5 is H; R6 is
Cl, Br, OH, O--(C.sub.1-C.sub.6)-alkyl, O--(CH.sub.2).sub.n-aryl,
O--(CH.sub.2).sub.n-heteroaryl wherein n is 0-6 and aryl is phenyl
and heteroaryl is 2-, 3- or 4-pyridyl or 2- or 3-thienyl;
O--C(O)--H, O--C(O)--(C.sub.1-C.sub.6)-alkyl,
O--C(O)--(C.sub.3-C.sub.8)-cycloalkyl, O--C(O)-aryl,
O--C(O)-heteroaryl, wherein aryl is phenyl and heteroaryl is
pyridyl, thienyl or furanyl; O-alpha- or -beta-glucuronic acid, SH,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl, wherein n
is 0-6, S--C(O)--(C.sub.1-C.sub.6)-- alkyl,
S--C(O)--(C.sub.3-C.sub.8)-cycloalkyl, S--C(O)-phenyl;
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl, wherein n
is 0-6, SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl- , wherein n is 0-6, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, NH--(C.sub.3-C.sub.7)-cycloalkyl,
N[(C.sub.1-C.sub.6)-alkyl].sub.2, morpholin-4-yl, pyrrolidin-1-yl,
piperidin-1-yl, piperazin-1-yl, 1-methylpiperazin-4-yl,
1-benzylpiperazin-4-yl, NH-phenyl, NH--CH.sub.2-phenyl,
NH--C(O)--(C.sub.1-C.sub.6)-alkyl or NH--C(O)-phenyl; or 13and
their physiologically acceptable salts and physiologically
functional derivatives.
2. The compound of claim 1, wherein R1, R1' are independently
selected from 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.1-C.sub.6)-alkyl, wherein one
or more hydrogens of the alkyl radicals may be replaced by
fluorine, or one hydrogen may be replaced by OH, OC(O)CH.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)-a- lkyl,
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, wherein n is 0-6 and the phenyl
radical may be optionally 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)-alky- l, 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 or 2- or 3-thienyl, wherein any of
the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings
may be optionally substituted one to 3 times by F, Cl, Br, I, OH,
CF.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 substituted in the 1-, 2- or
3-position by methyl or benzyl; tetrazol-5-yl, where the tetrazole
ring may be substituted in the 1 - or 2-position by methyl or
benzyl; R2 is H, (C.sub.1-C.sub.6)-alkyl,
(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,
(CH.sub.2).sub.n-furyl, C(O)--(C.sub.1-C.sub.6)- -alkyl,
C(O)--(C.sub.3-C.sub.6)-cycloalkyl, C(O)--(CH.sub.2).sub.n-phenyl,
C(O)--(CH.sub.2).sub.n-thienyl, C(O)--(CH.sub.2).sub.n-pyridyl or
C(O)--(CH.sub.2).sub.n-furyl, wherein n is 0-5 and in which any of
phenyl, thienyl, pyridyl or furyl may 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 H, (C.sub.1-C.sub.6)-alkyl, F,
Cl, Br, CN, N.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n-phenyl, (CH.sub.2).sub.n-thienyl,
(CH.sub.2).sub.n-pyridyl, (CH.sub.2).sub.n-furyl, wherein n is 0-5
and in which any of phenyl, thienyl, pyridyl and furyl may 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,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.2-C.sub.6)-alkenyl,
OC(O)CH.sub.3, (CH.sub.2).sub.n--C(O)O(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--C(O)OH, (CH.sub.2).sub.n--C(O)NH.sub.2,
(CH.sub.2).sub.n--C(O)NHCH.sub.3 or
(CH.sub.2).sub.nC(O)N(CH.sub.3).sub.2, wherein n is 0-3; R4 is
(C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.4-C.sub.7)-cycloalkenyl, wherein one or more of the
hydrogens of the alkyl radicals may be replaced by fluorine or one
hydrogen may be replaced by OH, OC(O)CH.sub.3, OC(O)H,
O--CH.sub.2--Ph or O--(C.sub.1-C.sub.4)-alkyl;
(CH.sub.2).sub.n-pyrrolidin-1-yl, (CH.sub.2).sub.n-piperidin-1-yl,
(CH.sub.2).sub.n-morpholin-4-yl, (CH.sub.2).sub.n-piperazin-1-yl,
(CH.sub.2).sub.n-N-4-methylpiperazin-1-y- l,
(CH.sub.2).sub.n--N-4-benzylpiperazin-1-yl,
(CH.sub.2).sub.n-phthalimid- oyl, where n is 1-6;
(CH.sub.2).sub.n-aryl or (CH.sub.2).sub.n-heteroaryl, wherein n is
0-6 and aryl is phenyl, biphenylyl or 1- or 2-naphthyl and
heteroaryl is 2-, 3- or 4-pyridyl, or 2- or 3-thienyl, and the aryl
radical or the heteroaryl radical may be optionally substituted up
to two times by F, Cl, Br, OH, CF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--N(.dbd.- CH--N(CH.sub.3).sub.2), where
n is 0-6, NH--SO.sub.2-(C.sub.1-C.sub.6)-alk- yl,
NH--SO.sub.2-phenyl, wherein the phenyl ring may be substituted up
to two times by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2; (C.sub.1-C.sub.6)-alkyl,
COOH, COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2; or
(CH.sub.2).sub.n--A--R8, wherein n is 1-6; A is O, NH,
N--(C.sub.1-C.sub.6)-alkyl, or SO.sub.2; R8 is
(C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, wherein one
or more hydrogens of the alkyl radicals may be replaced by fluorine
or one hydrogen may be replaced by OH, OC(O)CH.sub.3, OC(O)H,
O--CH.sub.2--Ph or O--(C.sub.1-C.sub.4)-alkyl;
(CH.sub.2).sub.m-aryl or (CH.sub.2).sub.n-heteroaryl, wherein m is
0-6 and aryl is phenyl, thienyl or pyridyl and the aryl moiety or
the heteroaryl moiety may be optionally substituted up to two times
by F, Cl, Br, OH, CF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2-- -(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--N(.dbd.CH--N(CH.sub.3).sub.2), wherein
n is 0-6, NH--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
NH--SO.sub.2-phenyl, where the phenyl ring may be optionally
substituted up to two times by F, Cl, CN, OH,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3,
COOH, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2, where n is 0-6, COOH,
COO(C.sub.1-C.sub.6)-alkyl, or CONH.sub.2; R5 is H; R6 is Cl, Br,
OH, O--(C.sub.1-C.sub.6)-alkyl, O--(CH.sub.2).sub.n-aryl, or
O--(CH.sub.2).sub.n-heteroaryl, wherein n is 0-6 and aryl is phenyl
and heteroaryl is 2-, 3- or 4-pyridyl or 2- or 3-thienyl;
O--C(O)--H, O--C(O)--(C.sub.1-C.sub.6)-alkyl,
O--C(O)--(C.sub.3-C.sub.8)-cycloalkyl, O--C(O)-aryl,
O--C(O)-heteroaryl, wherein aryl is phenyl and heteroaryl is
pyridyl, thienyl or furanyl; O-alpha- or -beta-glucuronic acid, SH,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl, wherein n
is 0-6, S--C(O)--(C.sub.1-C.sub.6)-alkyl,
S--C(O)--(C.sub.3-C.sub.8)-cycloalkyl, S--C(O)-phenyl;
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl, wherein n
is 0-6, SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl, wherein n is 0-6, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, NH--(C.sub.3-C.sub.7)-cycloalkyl,
N[(C.sub.1-C.sub.6)-alkyl].sub.2, morpholin-4-yl, pyrrolidin-1-yl,
piperidin-1-yl, piperazin-1-yl, 1-methylpiperazin-4-yl,
1-benzylpiperazin-4-yl, NH-phenyl, NH--CH.sub.2-phenyl,
NH--C(O)--(C.sub.1-C.sub.6)-alkyl or NH--C(O)-phenyl, or 14or
.dbd.NOH and their physiologically acceptable salts and
physiologically functional derivatives.
3. The compound of claim 1, wherein, R1, R1' are independently
selected from H, F, Cl, Br, --OH, O--(C.sub.1-C.sub.6)-alkyl or
(C.sub.1-C.sub.6)-alkyl, wherein one of the hydrogens of the alkyl
radicals may be replaced by OH; R2 is H, (C.sub.1-C.sub.6)-alkyl or
C(O)--(C.sub.1-C.sub.6)-alkyl; R3 is Cl, Br,
(CH.sub.2).sub.n-COO(C.sub.1- -C.sub.6)-alkyl,
(CH.sub.2).sub.n--COOH or (CH.sub.2).sub.n--CONH.sub.2, wherein n
is 0 or 1; R4 is (C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.6)-cycloalkyl, wherein one of the hydrogens of the
alkyl radicals may be replaced by OH; (CH.sub.2).sub.n-aryl or
(CH.sub.2).sub.n-heteroaryl, wherein n is 0-6 and aryl is phenyl
and heteroaryl is 1- or 2-naphthyl, 2-, 3- or 4-pyridyl or 2- or
3-thienyl and the aryl radical or heteroaryl radical may be
optionally substituted up to two times by F, Cl, Br, OH, CF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2, where n is 0-6;
(C.sub.1-C.sub.6)-alkyl, COOH, COO(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2; or (CH.sub.2).sub.n--A--R8, wherein n is 1-6; A is O or
SO.sub.2; R8 is (C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, wherein one of the hydrogens of the
alkyl radicals may be replaced by OH; (CH.sub.2).sub.m-aryl or
(CH.sub.2).sub.m-heteroaryl, where m is 0-6 and aryl is phenyl and
heteroaryl is thienyl and the aryl moiety or the heteroaryl moiety
may be optionally substituted up to two times by F, Cl, Br, OH,
CF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(C.sub.1-C.sub.6)-
-alkyl, SO.sub.2--NH.sub.2, COOH, COO(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2; R5 is H; R6 is OH or O--(C.sub.1-C.sub.6)-alkyl,
wherein n is 0-6; O--C(O)--(C.sub.1-C.sub.6)-alkyl, O--C(O)-aryl,
O--C(O)-heteroaryl, wherein aryl is phenyl and heteroayl is
thienyl; O-alpha or -beta-glucuronic acid,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl, where n is 0-6, NH.sub.2,
morpholin-4-yl, NH--C(O)--(C.sub.1-C.sub.6)-alkyl or
NH--C(O)-phenyl or R5 and R6 together form .dbd.O or 15, where n is
2-6, and their physiologically acceptable salts.
4. A pharmaceutical composition, comprising one or more compounds
as claimed in claim 1.
5. A pharmaceutical composition, comprising one or more compounds
as claimed in claim 2.
6. A pharmaceutical composition, comprising one or more compounds
as claimed in claim 3.
7. A pharmaceutical composition comprising one or more compounds as
claimed in claim 1, and further comprising one or more anorectic
active ingredients.
8. A pharmaceutical composition comprising one or more compounds as
claimed in claim 2, and further comprising one or more anorectic
active ingredients.
9. A pharmaceutical composition comprising one or more compounds as
claimed in claim 3, and further comprising one or more anorectic
active ingredients.
10. A method for the prophylaxis or treatment of obesity comprising
administering to a patient in need thereof one or more compounds as
claimed in claim 1.
11. The method of claim 10, further comprising administering an
additional anorectic active agent.
12. A method for the prophylaxis or treatment of obesity comprising
administering to a patient in need thereof one or more compounds as
claimed in claim 2.
13. The method of claim 12, further comprising administering an
additional anorectic active agent.
14. A method for the prophylaxis or treatment of obesity comprising
administering to a patient in need thereof one or more compounds as
claimed in claim 3.
15. The method of claim 14, further comprising administering an
additional anorectic active agent.
16. A method for the prophylaxis or treatment of type II diabetes
comprising administering to a patient in need thereof one or more
compounds as claimed in claim 1.
17. The method of claim 16, further comprising administering an
additional anorectic active agent.
18. A method for the prophylaxis or treatment of type II diabetes
comprising administering to a patient in need thereof one or more
compounds as claimed in claim 2.
19. The method of claim 18, further comprising administering an
additional anorectic active agent.
20. A method for the prophylaxis or treatment of type II diabetes
comprising administering to a patient in need thereof one or more
compounds as claimed in claim 3.
21. The method of claim 20, further comprising administering an
additional anorectic active agent.
22. A method for enhancing lipid metabolism comprising
administering to a patient in need thereof one or more compounds as
claimed in claim 1.
23. The method of claim 22, further comprising administering an
additional anorectic active agent.
24. A method for enhancing lipid metabolism comprising
administering to a patient in need thereof one or more compounds as
claimed in claim 2.
25. The method of claim 24, further comprising administering an
additional anorectic active agent.
26. A method for enhancing lipid metabolism comprising
administering to a patient in need thereof one or more compounds as
claimed in claim 3.
27. The method of claim 26, further comprising administering an
additional anorectic active agent.
28. A process for preparing a pharmaceutical composition comprising
one or more of the compounds as claimed in claim 1, which comprises
mixing the active compound with a pharmaceutically suitable
excipient and forming a composition suitable for
administration.
29. A process for preparing a pharmaceutical composition comprising
one or more of the compounds as claimed in claim 2, which comprises
mixing the active compound with a pharmaceutically suitable
excipient and forming a composition suitable for
administration.
30. A process for preparing a pharmaceutical composition comprising
one or more of the compounds as claimed in claim 3, which comprises
mixing the active compound with a pharmaceutically suitable
excipient and forming a composition suitable for
administration.
31. A process for preparing compounds as claimed in claim 1, which
comprises reacting, according to the equation below, 16a compound
of formula VII in which the radicals are as defined for formula I
with a thioamide of formula R4--C(S)--NH.sub.2, in which R4 is as
defined for formula I to give compounds of formula I in which R2 is
hydrogen and, if appropriate, derivatizing these compounds further
at the R2 position such that the other radicals R2 given to formula
I are formed.
Description
[0001] This application claims priority to German Application No.
10008274.2 filed Feb. 23, 2000, the entire contents of which are
hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention relates to substituted
8,8a-dihydro-3aH-indeno[1,2-d]- thiazoles and to their
physiologically acceptable salts and physiologically functional
derivatives.
BACKGROUND OF THE INVENTION
[0003] Thiazolidine derivatives having anorectic action have
already been described in the prior art (Austrian patent No.
365181).
[0004] The object of the invention is to provide compounds having a
therapeutically useful anorectic action. The present compounds also
find use in treatment of type II diabetes and obesity.
SUMMARY OF THE INVENTION
[0005] The invention relates to compounds of formula I: 2
[0006] in which
[0007] R1, R1' are independently selected from 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.1-C.sub.6)-alkyl,
[0008] wherein one or more of the hydrogens of the alkyl, alkenyl,
or alkynyl radicals may be replaced by fluorine, or one hydrogen
may be replaced by OH, OC(O)CH.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;
[0009] 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,
[0010] wherein 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;
[0011] NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl].s- ub.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 or 2- or
3-thienyl,
[0012] wherein any of the phenyl, biphenyl, naphthyl, pyridyl,
furanyl or thienyl rings may be optionally substituted one to 3
times by F, Cl, Br, I, OH, CF.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;
[0013] 1,2,3-triazol-5-yl, wherein the triazole ring may be
substituted in the 1-, 2- or 3-position by methyl or benzyl;
[0014] tetrazol-5-yl, where the tetrazole ring may be substituted
in the 1- or 2-position by methyl or benzyl;
[0015] 1,3,4-oxadiazol-2-yl; 2-amino-1,3,4-oxadiazol-5-yl,
[0016] wherein the amino function may be mono- or disubstituted by
(C.sub.1-C.sub.6)-alkyl, --C(O)--(C.sub.1-C.sub.6)-alkyl,
--C(O)--(cyclo-C.sub.3-C.sub.7)-alkyl, --C(O)-phenyl,
--C(O)--NH--(C.sub.1-C.sub.6)-alkyl,
--C(O)--NH--(cyclo-C.sub.3-C.sub.7)-- alkyl, or --C(O)--NH-aryl,
wherein aryl is phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl or 2-
or 3-furanyl,
[0017] --C(O)-morpholin-4-yl, --C(O)-piperidin-1-yl,
--C(O)-piperazin-4-yl, --C(O)--1-methyl-, 1-benzyl-piperazin-4-yl,
--SO.sub.2--(C.sub.1-C.sub.6)-alkyl or --SO.sub.2-phenyl,
[0018] wherein the phenyl ring may be substituted up to two times
by F, Cl, Br, CN, CF.sub.3, OH, OCF.sub.3, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n-phenyl,
O--(CH.sub.2).sub.n-phenyl, where n is 0-6, 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;
[0019] R2 is H, (C.sub.1-C.sub.6)-alkyl,
(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,
(CH.sub.2).sub.n-furyl, C(O)--(C.sub.1-C.sub.6)- -alkyl,
C(O)--(C.sub.3-C.sub.6)-cycloalkyl, C(O)--(CH.sub.2).sub.n-phenyl,
C(O)--(CH.sub.2).sub.n-thienyl, C(O)--(CH.sub.2).sub.n-pyridyl or
C(O)--(CH.sub.2).sub.n-furyl,
[0020] wherein n is 0-5 and in which any of phenyl, thienyl,
pyridyl or furyl may be optionally substituted up to two times by
Cl, F, CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl;
[0021] R3 is H, (C.sub.1-C.sub.6)-alkyl, F, Cl, Br, CN, N.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl,
(CH.sub.2).sub.n-furyl,
[0022] where n is 0-5 and in which any of phenyl, thienyl, pyridyl
or furyl may be optionally substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl,
[0023] (C.sub.2-C.sub.6)-alkynyl, (C.sub.2-C.sub.6)-alkenyl,
OC(O)CH.sub.3, (CH.sub.2).sub.n--C(O)O(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--C(O)OH, (CH.sub.2).sub.n--C(O)NH.sub.2,
(CH.sub.2).sub.n--C(O)NHCH.sub.3 or
(CH.sub.2).sub.n--C(O)N(CH.sub.3).sub- .2, where n is 0-3;
[0024] R4 is (C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.4-C.sub.7)-cycloalkenyl,
[0025] wherein one or more of the hydrogens of the alkyl radicals
may be replaced by fluorine or one hydrogen may be replaced by OH,
OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph or
O--(C.sub.1-C.sub.4)-alkyl; is (CH.sub.2).sub.n-pyrrolidin-1-yl,
(CH.sub.2).sub.n-piperidin-1-yl, (CH.sub.2).sub.n-morpholin-4-yl,
(CH.sub.2).sub.n-piperazin-1-yl,
(CH.sub.2).sub.n-N-4-methylpiperazin-1-yl,
(CH.sub.2).sub.n--N-4-benzylpi- perazin-1-yl,
(CH.sub.2).sub.n-phthalimidoyl, where n is 1-6;
[0026] (CH.sub.2).sub.n-aryl or (CH.sub.2).sub.n-heteroaryl,
[0027] where n is 0-6 and aryl is phenyl, biphenylyl or 1- or
2-naphthyl and heteroaryl is 2-, 3- or 4-pyridyl, 2- or 3-thienyl,
2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl,
1-pyrazolyl, 3- or 5-isoxazolyl, 2- or 3-pyrrolyl, 2- or
3-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl,
2-(1,3,5-triazinyl), 2- or 5-benzimidazolyl, 2-benzothiazolyl,
1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol-5-yl, indol-3-yl,
indol-5-yl or N-methylimidazol-2-, -4- or -5-yl,
[0028] wherein the aryl radical or the heteroaryl radical may be
optionally 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,
S--(C.sub.1-C.sub.6)-alkyl, SO--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--N(.dbd.- CH--N(CH.sub.3).sub.2),
wherein n is 0-6, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, COOH, COO(C.sub.1-C.sub.6)-alkyl,
COO(C.sub.3-C.sub.6)-cycloalkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
CONH(C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--CO-phenyl,
NH--SO.sub.2-(C.sub.1-C.sub.6)-alkyl, NH--SO.sub.2-phenyl,
[0029] wherein the phenyl ring may be substituted up to two times
by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2;
[0030] pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl,
piperazin-1-yl, 4-methylpiperazin-1-yl, (CH.sub.2).sub.n-phenyl,
O--(CH.sub.2).sub.n-phen- yl, S--(CH.sub.2).sub.n-phenyl or
SO.sub.2--(CH.sub.2).sub.n-phenyl, wherein n is 0-3;
[0031] (CH.sub.2).sub.n--A--R8, wherein n is 1-6;
[0032] A is O, NH, N--(C.sub.1-C.sub.6)-alkyl, NCHO,
N(CO--CH.sub.3), S, SO or SO.sub.2;
[0033] R8 is (C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl,
[0034] wherein one or more hydrogens of the alkyl radicals may be
replaced by fluorine or one hydrogen may be replaced by OH,
OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph or
O--(C.sub.1-C.sub.4)-alkyl; is (CH.sub.2).sub.m-aryl,
[0035] wherein m is 0-6 and aryl is phenyl, thienyl or pyridyl and
the aryl moiety may be optionally substituted up to two times by F,
Cl, Br, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, S--(C.sub.1-C.sub.6)-alkyl,
SO--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--N(.dbd.- CH--N(CH.sub.3).sub.2),
(CH.sub.2).sub.n--SO.sub.2--NH(C.sub.1-C.sub.8)-al- kyl,
(CH.sub.2).sub.n--SO.sub.2--N[(C.sub.1-C.sub.8)-alkyl].sub.2,
(CH.sub.2).sub.n--SO.sub.2--NH(C.sub.3-C.sub.8)-cycloalkyl,
(CH.sub.2).sub.n--SO.sub.2--N[(C.sub.3-C.sub.8)-cycloalkyl.sub.2],
where n is 0-6, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, COOH, COO(C.sub.1-C.sub.6)-alkyl,
COO(C.sub.3-C.sub.6)-cycloalkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
CONH(C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N[(C.sub.1-C.sub.6)-alkyl].sub.2,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--CO-phenyl,
NH--SO.sub.2-phenyl,
[0036] where the phenyl ring may be optionally substituted up to
two times by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2;
[0037] NH--SO.sub.2-(C.sub.1-C.sub.8)-alkyl,
N(C.sub.1-C.sub.6)-alkyl-SO.s- ub.2--(C.sub.1-C.sub.8)-alkyl,
pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl,
4-methylpiperazin-1-yl, (CH.sub.2).sub.p-phenyl,
O--(CH.sub.2).sub.p-phenyl, S--(CH.sub.2).sub.p-phenyl or
SO.sub.2--(CH.sub.2).sub.p-phenyl, wherein p is 0-3;
[0038] R5 is H;
[0039] R6 is Cl, Br, OH, O--(C.sub.1-C.sub.6)-alkyl,
O--(CH.sub.2).sub.n-aryl, O--(CH.sub.2).sub.n-heteroaryl
[0040] wherein n is 0-6 and aryl is phenyl and heteroaryl is 2-, 3-
or 4-pyridyl or 2- or 3-thienyl;
[0041] O--C(O)--H, O--C(O)--(C.sub.1-C.sub.6)-alkyl,
O--C(O)--(C.sub.3-C.sub.8)-cycloalkyl, O--C(O)-aryl,
O--C(O)-heteroaryl,
[0042] wherein aryl is phenyl and heteroaryl is pyridyl, thienyl or
furanyl; O-alpha- or -beta-glucuronic acid, SH,
S--(C.sub.1-C.sub.6)-alky- l, S--(CH.sub.2).sub.n-phenyl, wherein n
is 0-6, S--C(O)--(C.sub.1-C.sub.6- )-alkyl,
S--C(O)--(C.sub.3-C.sub.8)-cycloalkyl, S--C(O)-phenyl;
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl, wherein n
is 0-6, SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl- , wherein n is 0-6, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, NH--(C.sub.3-C.sub.7)-cycloalkyl,
N[(C.sub.1-C.sub.6)-alkyl].sub.2, morpholin-4-yl, pyrrolidin-1-yl,
piperidin-1-yl, piperazin-1-yl, 1-methylpiperazin-4-yl,
1-benzylpiperazin-4-yl, NH-phenyl, NH--CH.sub.2-phenyl,
NH--C(O)--(C.sub.1-C.sub.6)-alkyl or NH--C(O)-phenyl;
[0043] or 3
[0044] and their physiologically acceptable salts and
physiologically functional derivatives.
[0045] 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 INVENTION
[0046] The invention is directed to polycyclic thiazole compounds
which are anorectics and are useful in the treatment of type II
diabetes and obesity. The compounds have general formula (I): 4
[0047] in which
[0048] R1, R1' are independently selected from 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.1-C.sub.6)-alkyl,
[0049] wherein one or more of the hydrogens of the alkyl, alkenyl,
or alkynyl radicals may be replaced by fluorine, or one hydrogen
may be replaced by OH, OC(O)CH.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;
[0050] 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,
[0051] wherein 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;
[0052] NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl].s- ub.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 or 2- or
3-thienyl,
[0053] wherein any of the phenyl, biphenyl, naphthyl, pyridyl,
furanyl or thienyl rings may be optionally substituted one to 3
times by F, Cl, Br, I, OH, CF.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;
[0054] 1,2,3-triazol-5-yl, wherein the triazole ring may be
substituted in the 1-, 2- or 3-position by methyl or benzyl;
[0055] tetrazol-5-yl, where the tetrazole ring may be substituted
in the 1- or 2-position by methyl or benzyl;
[0056] 1,3,4-oxadiazol-2-yl; 2-amino-1,3,4-oxadiazol-5-yl,
[0057] wherein the amino function may be mono- or disubstituted by
(C.sub.1-C.sub.6)-alkyl, --C(O)--(C.sub.1-C.sub.6)-alkyl,
--C(O)-(cyclo-C.sub.3-C.sub.7)-alkyl, --C(O)-phenyl,
--C(O)--NH-(C.sub.1-C.sub.6)-alkyl,
--C(O)--NH--(cyclo-C.sub.3-C.sub.7)-a- lkyl, or --C(O)--NH-aryl,
wherein aryl is phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl or 2-
or 3-furanyl,
[0058] --C(O)-morpholin-4-yl, --C(O)-piperidin-1-yl,
--C(O)-piperazin-4-yl, --C(O)--1-methyl-, 1-benzyl-piperazin-4-yl,
--SO.sub.2--(C.sub.1-C.sub.6)-alkyl or --SO.sub.2-phenyl,
[0059] wherein the phenyl ring may be substituted up to two times
by F, Cl, Br, CN, CF.sub.3, OH, OCF.sub.3, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n-phenyl,
O--(CH.sub.2).sub.n-phenyl, where n is 0-6, 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;
[0060] R2 is H, (C.sub.1-C.sub.6)-alkyl,
(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,
(CH.sub.2).sub.n-furyl, C(O)--(C.sub.1-C.sub.6)- -alkyl,
C(O)--(C.sub.3-C.sub.6)-cycloalkyl, C(O)--(CH.sub.2).sub.n-phenyl,
C(O)--(CH.sub.2).sub.n-thienyl, C(O)--(CH.sub.2).sub.n-pyridyl or
C(O)--(CH.sub.2).sub.n-furyl,
[0061] wherein n is 0-5 and in which any of phenyl, thienyl,
pyridyl or furyl may be optionally substituted up to two times by
Cl, F, CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl;
[0062] R3 is H, (C.sub.1-C.sub.6)-alkyl, F, Cl, Br, CN, N.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl,
(CH.sub.2).sub.n-furyl,
[0063] where n is 0-5 and in which any of phenyl, thienyl, pyridyl
or furyl may be optionally substituted up to two times by Cl, F,
CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl,
[0064] (C.sub.2-C.sub.6)-alkynyl, (C.sub.2-C.sub.6)-alkenyl,
OC(O)CH.sub.3, (CH.sub.2).sub.n--C(O)O(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--C(O)OH, (CH.sub.2).sub.n--C(O)NH.sub.2,
(CH.sub.2).sub.n--C(O)NHCH.sub.3 or
(CH.sub.2).sub.n--C(O)N(CH.sub.3).sub- .2, where n is 0-3;
[0065] R4 is (C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.4-C.sub.7)-cycloalkenyl,
[0066] wherein one or more of the hydrogens of the alkyl radicals
may be replaced by fluorine or one hydrogen may be replaced by OH,
OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph or
O--(C.sub.1-C.sub.4)-alkyl; is (CH.sub.2).sub.n-pyrrolidin-1-yl,
(CH.sub.2).sub.n-piperidin-1-yl, (CH.sub.2).sub.n-morpholin-4-yl,
(CH.sub.2).sub.n-piperazin-1-yl,
(CH.sub.2).sub.n-N-4-methylpiperazin-1-yl,
(CH.sub.2).sub.n--N-4-benzylpi- perazin-1-yl,
(CH.sub.2).sub.n-phthalimidoyl, where n is 1-6;
[0067] (CH.sub.2).sub.n-aryl or (CH.sub.2).sub.n-heteroaryl,
[0068] where n is 0-6 and aryl is phenyl, biphenylyl or 1- or
2-naphthyl and heteroaryl is 2-, 3- or 4-pyridyl, 2- or 3-thienyl,
2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl,
1-pyrazolyl, 3- or 5-isoxazolyl, 2- or 3-pyrrolyl, 2- or
3-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl,
2-(1,3,5-triazinyl), 2- or 5-benzimidazolyl, 2-benzothiazolyl,
1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol-5-yl, indol-3-yl,
indol-5-yl or N-methylimidazol-2-, -4- or -5-yl,
[0069] wherein the aryl radical or the heteroaryl radical may be
optionally 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,
S--(C.sub.1-C.sub.6)-alkyl, SO--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--N(.dbd.- CH--N(CH.sub.3).sub.2),
wherein n is 0-6, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, COOH, COO(C.sub.1-C.sub.6)-alkyl,
COO(C.sub.3-C.sub.6)-cycloalkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
CONH(C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--CO-phenyl,
NH--SO.sub.2-(C.sub.1-C.sub.6)-alkyl, NH--SO.sub.2-phenyl,
[0070] wherein the phenyl ring may be substituted up to two times
by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2;
[0071] pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl,
piperazin-1-yl, 4-methylpiperazin-1-yl, (CH.sub.2).sub.n-phenyl,
O--(CH.sub.2).sub.n-phen- yl, S--(CH.sub.2).sub.n-phenyl or
SO.sub.2--(CH.sub.2).sub.n-phenyl, wherein n is 0-3;
[0072] (CH.sub.2).sub.n-A-R8, wherein n is 1-6;
[0073] A is O, NH, N--(C.sub.1-C.sub.6)-alkyl, NCHO,
N(CO--CH.sub.3), S, SO or SO.sub.2;
[0074] R8 is (C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl,
[0075] wherein one or more hydrogens of the alkyl radicals may be
replaced by fluorine or one hydrogen may be replaced by OH,
OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph or
O--(C.sub.1-C.sub.4)-alkyl; is (CH.sub.2).sub.m-aryl,
[0076] wherein m is 0-6 and aryl is phenyl, thienyl or pyridyl and
the aryl moiety may be optionally substituted up to two times by F,
Cl, Br, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, S--(C.sub.1-C.sub.6)-alkyl,
SO--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--N(.dbd.- CH--N(CH.sub.3).sub.2),
(CH.sub.2).sub.n--SO.sub.2--NH(C.sub.1-C.sub.8)-al- kyl,
(CH.sub.2).sub.n--SO.sub.2--N[(C.sub.1-C.sub.8)-alkyl].sub.2,
(CH.sub.2).sub.n--SO.sub.2--NH(C.sub.3-C.sub.8)-cycloalkyl,
(CH.sub.2).sub.n--SO.sub.2--N[(C.sub.3-C.sub.8)-cycloalkyl.sub.2],
where n is 0-6, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, COOH, COO(C.sub.1-C.sub.6)-alkyl,
COO(C.sub.3-C.sub.6)-cycloalkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
CONH(C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N[(C.sub.1-C.sub.6)-alkyl].sub.2,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--CO-phenyl,
NH--SO.sub.2-phenyl,
[0077] where the phenyl ring may be optionally substituted up to
two times by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2;
[0078] NH--SO.sub.2-(C.sub.1-C.sub.8)-alkyl,
N(C.sub.1-C.sub.6)-alkyl-SO.s- ub.2--(C.sub.1-C.sub.8)-alkyl,
pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl,
4-methylpiperazin-1-yl, (CH.sub.2).sub.p-phenyl,
O--(CH.sub.2).sub.p-phenyl, S--(CH.sub.2).sub.p-phenyl or
SO.sub.2--(CH.sub.2).sub.p-phenyl, wherein p is 0-3;
[0079] R5 is H;
[0080] R6 is Cl, Br, OH, O--(C.sub.1-C.sub.6)-alkyl,
O--(CH.sub.2).sub.n-aryl, O--(CH.sub.2).sub.n-heteroaryl
[0081] wherein n is 0-6 and aryl is phenyl and heteroaryl is 2-, 3-
or 4-pyridyl or 2- or 3-thienyl;
[0082] O--C(O)--H, O--C(O)--(C.sub.1-C.sub.6)-alkyl,
O--C(O)--(C.sub.3-C.sub.8)-cycloalkyl, O--C(O)-aryl,
O--C(O)-heteroaryl,
[0083] wherein aryl is phenyl and heteroaryl is pyridyl, thienyl or
furanyl; O-alpha- or -beta-glucuronic acid, SH,
S--(C.sub.1-C.sub.6)-alky- l, S--(CH.sub.2).sub.n-phenyl, wherein n
is 0-6, S--C(O)--(C.sub.1-C.sub.6- )-alkyl,
S--C(O)--(C.sub.3-C.sub.8)-cycloalkyl, S--C(O)-phenyl;
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl, wherein n
is 0-6, SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl- , wherein n is 0-6, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, NH--(C.sub.3-C.sub.7)-cycloalkyl,
N[(C.sub.1-C.sub.6)-alkyl].sub.2, morpholin-4-yl, pyrrolidin-1-yl,
piperidin-1-yl, piperazin-1-yl, 1-methylpiperazin-4-yl,
1-benzylpiperazin-4-yl, NH-phenyl, NH--CH.sub.2-phenyl,
NH--C(O)--(C.sub.1-C.sub.6)-alkyl or NH--C(O)-phenyl;
[0084] or 5
[0085] and their physiologically acceptable salts and
physiologically functional derivatives.
[0086] In a preferred embodiment, the compounds of formula I are
where
[0087] R1, R1' are independently selected from 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.1-C.sub.6)-alkyl,
[0088] wherein one or more hydrogens of the alkyl radicals may be
replaced by fluorine, or one hydrogen may be replaced by OH,
OC(O)CH.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;
[0089] 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,
[0090] wherein n is 0-6 and the phenyl radical may be optionally
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;
[0091] NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl].s- ub.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 or 2- or
3-thienyl,
[0092] wherein any of the phenyl, biphenyl, naphthyl, pyridyl,
furanyl or thienyl rings may be optionally substituted one to 3
times by F, Cl, Br, I, OH, CF.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;
[0093] 1,2,3-triazol-5-yl, wherein the triazole ring may be
substituted in the 1-, 2- or 3-position by methyl or benzyl;
[0094] tetrazol-5-yl, where the tetrazole ring may be substituted
in the 1- or 2-position by methyl or benzyl;
[0095] R2 is H, (C.sub.1-C.sub.6)-alkyl,
(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,
(CH.sub.2).sub.n-furyl, C(O)--(C.sub.1-C.sub.6)- -alkyl,
C(O)--(C.sub.3-C.sub.6)-cycloalkyl, C(O)--(CH.sub.2).sub.n-phenyl,
C(O)--(CH.sub.2).sub.n-thienyl, C(O)--(CH.sub.2).sub.n-pyridyl or
C(O)--(CH.sub.2).sub.n-furyl,
[0096] wherein n is 0-5 and in which any of phenyl, thienyl,
pyridyl or furyl may 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;
[0097] R3 is H, (C.sub.1-C.sub.6)-alkyl, F, Cl, Br, CN, N.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl,
(CH.sub.2).sub.n-furyl,
[0098] where n is 0-5 and in which any of phenyl, thienyl, pyridyl
or furyl may 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,
[0099] (C.sub.2-C.sub.6)-alkynyl, (C.sub.2-C.sub.6)-alkenyl,
OC(O)CH.sub.3, (CH.sub.2).sub.n--C(O)O(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--C(O)OH, (CH.sub.2).sub.n--C(O)NH.sub.2,
(CH.sub.2).sub.n--C(O)NHCH.sub.3 or
(CH.sub.2).sub.n--C(O)N(CH.sub.3).sub- .2, where n is 0-3;
[0100] R4 is (C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.4-C.sub.7)-cycloalkenyl,
[0101] wherein one or more of the hydrogens of the alkyl radicals
may be replaced by fluorine or one hydrogen may be replaced by OH,
OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph or
O--(C.sub.1-C.sub.4)-alkyl;
[0102] (CH.sub.2).sub.n-pyrrolidin-1-yl,
(CH.sub.2).sub.n-piperidin-1-yl, (CH.sub.2).sub.n-morpholin-4-yl,
(CH.sub.2).sub.n-piperazin-1-yl,
(CH.sub.2).sub.n-N-4-methylpiperazin-1-yl,
(CH.sub.2).sub.n--N-4-benzylpi- perazin-1-yl,
(CH.sub.2).sub.n-phthalimidoyl, where n is 1-6;
(CH.sub.2).sub.n-aryl or (CH.sub.2).sub.n-heteroaryl,
[0103] where n is 0-6 and aryl is phenyl, biphenylyl or 1- or
2-naphthyl and heteroaryl is 2-, 3- or 4-pyridyl, or 2- or
3-thienyl, and the aryl radical or the heteroaryl radical may be
optionally substituted up to two times by F, Cl, Br, OH, CF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--N(.dbd.- CH--N(CH.sub.3).sub.2), where
n is 0-6, NH--SO.sub.2-(C.sub.1-C.sub.6)-alk- yl,
NH--SO.sub.2-phenyl,
[0104] wherein the phenyl ring may be substituted up to two times
by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2;
[0105] (C.sub.1-C.sub.6)-alkyl, COOH, COO(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2; or
[0106] (CH.sub.2).sub.n--A--R8, wherein n is 1-6;
[0107] A is O, NH, N--(C.sub.1-C.sub.6)-alkyl, or SO.sub.2;
[0108] R8 is (C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl,
[0109] wherein one or more hydrogens of the alkyl radicals may be
replaced by fluorine or one hydrogen may be replaced by OH,
OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph or
O--(C.sub.1-C.sub.4)-alkyl;
[0110] (CH.sub.2).sub.m-aryl or (CH.sub.2).sub.n-heteroaryl,
[0111] wherein m is 0-6 and aryl is phenyl, thienyl or pyridyl and
the aryl moiety or the heteroaryl moiety may be optionally
substituted up to two times by F, Cl, Br, OH, CF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--N(.dbd.- CH--N(CH.sub.3).sub.2),
wherein n is 0-6, NH--SO.sub.2--(C.sub.1-C.sub.6)-- alkyl,
NH--SO.sub.2-phenyl,
[0112] where the phenyl ring may be optionally substituted up to
two times by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2, where n is 0-6, COOH,
COO(C.sub.1-C.sub.6)-alkyl, or CONH.sub.2;
[0113] R5 is H;
[0114] R6 is Cl, Br, OH, O--(C.sub.1-C.sub.6)-alkyl,
O--(CH.sub.2).sub.n-aryl, or O--(CH.sub.2).sub.n-heteroaryl,
[0115] wherein n is 0-6 and aryl is phenyl and heteroaryl is 2-, 3-
or 4-pyridyl or 2- or 3-thienyl;
[0116] O--C(O)--H, O--C(O)--(C.sub.1-C.sub.6)-alkyl,
O--C(O)--(C.sub.3-C.sub.8)-cycloalkyl, O--C(O)-aryl,
O--C(O)-heteroaryl,
[0117] wherein aryl is phenyl and heteroaryl is pyridyl, thienyl or
furanyl; O-alpha- or -beta-glucuronic acid, SH,
S--(C.sub.1-C.sub.6)-alky- l, S--(CH.sub.2).sub.n-phenyl, wherein n
is 0-6, S--C(O)--(C.sub.1-C.sub.6- )-alkyl,
S--C(O)--(C.sub.3-C.sub.8)-cycloalkyl, S--C(O)-phenyl;
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl, wherein n
is 0-6, SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl- , wherein n is 0-6, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, NH--(C.sub.3-C.sub.7)-cycloalkyl,
N[(C.sub.1-C.sub.6)-alkyl].sub.2, morpholin-4-yl, pyrrolidin-1-yl,
piperidin-1-yl, piperazin-1-yl, 1-methylpiperazin-4-yl,
1-benzylpiperazin-4-yl, NH-phenyl, NH--CH.sub.2-phenyl,
NH--C(O)--(C.sub.1-C.sub.6)-alkyl or NH--C(O)-phenyl,
[0118] or 6
[0119] and their physiologically acceptable salts and
physiologically functional derivatives.
[0120] In a particularly preferred embodiment are compounds of
formula I wherein:
[0121] R1, R1' are independently selected from H, F, Cl, Br, --OH,
O--(C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-alkyl,
[0122] wherein one of the hydrogens of the alkyl radicals may be
replaced by OH;
[0123] R2 is H, (C.sub.1-C.sub.6)-alkyl or
C(O)--(C.sub.1-C.sub.6)-alkyl;
[0124] R3 is Cl, Br, (CH.sub.2).sub.n-COO(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--COOH or (CH.sub.2).sub.n--CONH.sub.2,
[0125] wherein n is 0 or 1;
[0126] R4 is (C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.6)-cycloalkyl, wherein one of the hydrogens of the
alkyl radicals may be replaced by OH;
[0127] (CH.sub.2).sub.n-aryl or (CH.sub.2).sub.n-heteroaryl,
[0128] wherein n is 0-6 and aryl is phenyl and heteroaryl is 1- or
2-naphthyl, 2-, 3- or 4-pyridyl or 2- or 3-thienyl and the aryl
radical or heteroaryl radical may be optionally substituted up to
two times by F, Cl, Br, OH, CF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.su- b.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--NH.sub.2, where n is 0-6;
(C.sub.1-C.sub.6)-alkyl, COOH, COO(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2; or
[0129] (CH.sub.2).sub.n--A--R8, wherein n is 1-6;
[0130] A is O or SO.sub.2;
[0131] R8 is (C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl,
wherein one of the hydrogens of the alkyl radicals may be replaced
by OH;
[0132] (CH.sub.2).sub.m-aryl or (CH.sub.2).sub.m-heteroaryl,
[0133] where m is 0-6 and aryl is phenyl and heteroaryl is thienyl
and the aryl moiety or the heteroaryl moiety may be optionally
substituted up to two times by F, Cl, Br, OH, CF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--NH.sub.2, COOH, COO(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2;
[0134] R5 is H;
[0135] R6 is OH or O--(C.sub.1-C.sub.6)-alkyl, wherein n is
0-6;
[0136] O--C(O)--(C.sub.1-C.sub.6)-alkyl, O--C(O)-aryl,
O--C(O)-heteroaryl,
[0137] wherein aryl is phenyl and heteroayl is thienyl;
[0138] O-alpha or -beta-glucuronic acid,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl- ,
SO.sub.2--(CH.sub.2).sub.n-phenyl, where n is 0-6, NH.sub.2,
morpholin-4-yl, NH--C(O)--(C.sub.1-C.sub.6)-alkyl or
NH--C(O)-phenyl
[0139] or
[0140] R5 and R6 together form .dbd.O or 7
[0141] where n is 2-6,
[0142] and their physiologically acceptable salts.
[0143] The invention relates to compounds of formula I, in the form
of their racemates, racemic mixtures and pure enantiomers, and to
their diastereomers and mixtures thereof.
[0144] The alkyl, alkenyl and alkynyl radicals in the substituents
R1, R1', R2, R3, R4, R6, R8 and A may be either straight-chain or
branched.
[0145] Pharmaceutically acceptable salts are particularly suitable
for medicinal applications compared with the starting materials or
base compounds, due to their higher water solubility. These salts
have a pharmaceutically acceptable anion or cation. Suitable
pharmaceutically acceptable acid addition salts of the compounds
according to the invention are salts of inorganic acids, including
but not limited to, hydrochloric acid, hydrobromic acid, phosphoric
acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric
acid, and of organic acids, such as, for example, acetic acid,
benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic
acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid,
lactic acid, lactobionic acid, maleic acid, malic acid,
methanesulfonic acid, succinic acid, p-toluenesulfonic acid,
tartaric acid and trifluoroacetic acid. For medicinal purposes, the
chlorine salt, is one of the preferred. Suitable pharmaceutically
acceptable basic salts are ammonium salts, alkali metal salts (such
as sodium salts and potassium salts) and alkaline earth metal salts
(such as magnesium salts and calcium salts).
[0146] Salts having a pharmaceutically unacceptable anion are
likewise included in the scope of the invention as useful
intermediates for the production or purification of
pharmaceutically acceptable salts and/or for use in nontherapeutic,
for example in-vitro, applications. In addition, pharmaceutically
unacceptable anions may be useful for the separation of enantiomers
and diasteromers.
[0147] The term "physiologically functional derivative" used here
relates to any physiologically acceptable derivative of a compound
of formula I according to the invention, for example an ester,
which on administration to a mammal, such as, for example, man, is
able (directly or indirectly) to form a compound of formula I or an
active metabolite thereof.
[0148] The physiologically functional derivatives also include
prodrugs of the compounds according to the invention. Such prodrugs
are able to be metabolized in vivo to a compound according to the
invention. These prodrugs may be active or inactive.
[0149] The compounds according to the invention may also be present
in various polymorphic forms, for example as amorphous and
crystalline polymorphic forms. All polymorphic forms of the
compounds according to the invention are included in the scope of
the invention and are a further aspect of the invention.
[0150] Hereinbelow, all references to "compound(s) according to
formula (I)" refer to compound(s) of formula (I) as described
above, and to their salts, solvates and physiologically functional
derivatives as described herein.
[0151] The amount of a compound according to formula (I) which is
necessary in order to achieve the desired biological effect is
dependent on a number of factors, for example the specific compound
selected, the intended use, the manner of administration and the
clinical condition of the patient. In general, the daily dose is in
the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per
day per kilogram of 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 be suitably administered as an infusion of 10
ng to 100 ng per kilogram per minute. Suitable infusion solutions
for these purposes may contain, for example, from 0.1 ng to 10 mg,
typically from 1 ng to 10 mg per milliliter. Individual doses may
contain, for example, from 1 mg to 10 g of the active compound.
Thus, ampoules for injection may contain, for example, from 1 mg to
100 mg, and orally administrable individual dose formulations, 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 abovementioned weight
details relate to the weight of the dihydrothiazolium ion derived
from the salt. For the prophylaxis or therapy of the abovementioned
conditions, the compounds according to formula (I) may be used
themselves as the compound, but they are also present in the form
of a pharmaceutical composition with a tolerable excipient. The
excipient is a pharmaceutically aceptable excipient, this means
that it is compatible with the other constituents of the
composition and is not harmful to the patient's health. The
excipient may be a solid or a liquid or both and is preferably
formulated with the compound as an individual dose, for example as
a tablet which may contain from 0.05% to 95% by weight of the
active compound. Further pharmaceutically active substances may
also be present, including further compounds according to formula
(I). The pharmaceutical compositions according to the invention may
be prepared by one of the known pharmaceutical methods, which
essentially consist in mixing the constituents with
pharmacologically acceptable excipients and/or auxiliaries.
[0152] Pharmaceutical compositions according to the invention are
those which are suitable for oral, rectal, topical, peroral, (e.g.
sublingual) and parenteral (e.g. subcutaneous, intramuscular,
intradermal or intravenous) administration, although the most
suitable manner of administration in each individual case is
dependent on the nature and severity of the condition to be treated
and on the nature of the compound according to formula (I) used in
each case. Sugar-coated formulations and sugar-coated delayed
release formulations are also included in the scope of the
invention. Acid-resistant and enteric formulations are preferred.
Suitable enteric coatings include cellulose acetate phthalate,
polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate
and anionic polymers of methacrylic acid and methyl
methacrylate.
[0153] Suitable pharmaceutical compounds for oral administration
may be present in separate units, such as, for example, capsules,
cachets, lozenges or tablets which in each case contain a certain
amount of the compound according to formula (I); as powders or
granules; as solution or suspension in an aqueous or nonaqueous
liquid; or as an oil-in-water or water-in-oil emulsion. As already
mentioned, these compositions may be prepared by any suitable
pharmaceutical method which includes a step in which the active
compound and the excipient (which may consist of one or more
additional constituents) are brought into contact. In general, the
compositions are prepared by uniform and homogeneous mixing of the
active compound with a liquid and/or finely divided solid
excipient, after which the product, if necessary, is shaped. Thus a
tablet, for example, may be prepared by pressing or shaping a
powder or granules of the compound, if appropriate with one or more
additional constituents. Pressed tablets may be prepared by
tableting the compound in free-flowing form, such as, for example,
a powder or granules, if appropriate mixed with a binder,
lubricant, inert diluent and/or one (a number of)
surface-active/dispersi- ng agents in a suitable machine. Shaped
tablets may be prepared by shaping the pulverulent compound,
moistened with an inert liquid diluent, in a suitable machine.
[0154] Pharmaceutical compositions which are suitable for peroral
(sublingual) administration include lozenges, which contain a
compound according to formula (I) with a flavoring, customarily
sucrose and gum arabic or tragacanth, and pastilles which include
the compound in an inert base such as gelatin and glycerol or
sucrose and gum arabic.
[0155] Suitable pharmaceutical compositions for parenteral
administration preferably include sterile aqueous preparations of a
compound according to formula (I), which are preferably isotonic
with the blood of the intended recipient. These preparations are
preferably administered intravenously, although the administration
may also take place subcutaneously, intramuscularly or
intradermally as an injection. These preparations may be prepared
by mixing the compound with water and rendering the obtained
solution sterile and isotonic with the blood. Injectable
compositions according to the invention in general contain from 0.1
to 5% by weight of the active compound.
[0156] Suitable pharmaceutical compositions for rectal
administration are preferably present as individual dose
suppositories. These may be prepared by mixing a compound according
to formula (I) with one or more conventional solid excipients, for
example cocoa butter, and shaping the resulting mixture.
[0157] Suitable pharmaceutical compositions for topical application
to the skin are preferably present as ointment, cream, lotion,
paste, spray, aerosol or oil. Excipients which may be used are
petroleum jelly, lanolin, polyethylene glycols, alcohols and
combinations of two or more of these substances. The active
compound is in general present in a concentration of from 0.1 to
15% by weight of the composition, for example of from 0.5 to
2%.
[0158] Transdermal administration is also possible. Suitable
pharmaceutical compositions for transdermal administration may be
present as individual patches which are suitable for long-term
close contact with the epidermis of the patient. Such patches
suitably contain the active compound in an optionally buffered
aqueous solution, dissolved and/or dispersed in an adhesive or
dispersed in a polymer. A suitable active compound concentration is
from about 1% to 35%, preferably from about 3% to 15%. As a
particular possibility, the active compound may be released by
electrotransport or iontophoresis, as described, for example, in
Pharmaceutical Research, 2(6):318 (1986).
[0159] The invention furthermore relates to a process for the
preparation of the compounds of formula I, the process comprises
reactions steps according to the scheme set forth below: 8
[0160] As part of this reaction scheme, compounds of Formula II,
9
[0161] in which R1, R1' and R3 are as defined above, are converted
into a compound of Formula III using N-bromosuccinimide.
[0162] The compounds of Formula III are then reacted with metal
salts of organic acids (MOacyl), such as, for example, silver
acetate, to yield compounds of Formula IV.
[0163] Another option is to convert compounds of Formula III by
nucleophilic exchange with O-, S- or N-nucleophiles into the
corresponding O-, S- or N-substituted compounds of Formula VI in
which the radicals R1, R1', R3, R5 and R6 are as defined above.
[0164] Compounds of Formula IV may be converted into compounds of
Formula V, for example by acid hydrolysis.
[0165] Under standard conditions, the compounds of Formulae V and
VI may be converted by reaction with bromine into the corresponding
alpha-bromoketones of Formula VII, in which, for example, R5 may be
hydrogen and R6 may be OH. Reaction of the thioamides of formula
R4-C(S)--NH.sub.2, in which R4 is as defined above, with compounds
of formula VII gives compounds of formula I in which R2 is
hydrogen. Using standard methods, these compounds may be converted
into compounds of formula I in which R2 is as described further
above.
[0166] Suitable inorganic acids for salt formation are, for
example: hydrohalic acids, such as hydrochloric acid and
hydrobromic acid, and also sulfuric acid, phosphoric acid and
amidosulfonic acid.
[0167] Organic acids which are suitable for salt formation are, for
example: 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.
[0168] In the reaction scheme described above, it is advantageous
to react the compounds of Formula VII with the thioamides
R4-C(S)--NH.sub.2 in a molar ratio of from 1:1 to 1:1.5. The
reaction is carried out in an inert solvent, for example in polar
organic solvents, such as dimethylformamide, dimethylacetamide,
N-methyl-2-pyrrolidone, dimethyl sulfoxide, dioxane,
tetrahydrofuran, acetonitrile, nitromethane or diethylene glycol
dimethyl ether. Particularly preferred solvents, include but are
not limited to methyl acetate and ethyl acetate, short-chain
alcohols, such as methanol, ethanol, propanol, isopropanol, and
lower dialkyl ketones, such as, for example, acetone, butan-2-one
or hexan-2-one. Mixtures of the reaction media mentioned may also
be used; and mixtures of the solvents mentioned with solvents
which, taken per se, are less suitable, such as, for example,
mixtures of methanol with benzene, ethanol with toluene, methanol
with diethyl ether or with tert-butyl methyl ether, ethanol with
carbon tetrachloride, acetone with chloroform, dichloromethane or
1,2-dichloroethane, may also be used, where the more polar solvent
in each case should be used in an excess. The reactants may be
suspended or dissolved in the respective reaction medium. In
principle, the reactants may also be reacted in the absence of a
solvent, in particular if the respective thioamide has a melting
point which is as low as possible. The reaction, which proceeds in
a slightly exothermic manner, may be carried out between
-10.degree. C. and 150.degree. C., preferably between 30.degree. C.
and 100.degree. C. A temperature range between 50.degree. C. and
90.degree. C. has generally been found to be favorable.
[0169] The reaction time is largely dependent on the reaction
temperature and is between 2 minutes and 3 days at relatively high
and relatively low temperatures, respectively. In the favorable
temperature range, the reaction time is generally between 5 minutes
and 48 hours. In the course of the reaction, the compounds of
Formula I frequently form a poorly soluble deposit in the form of
their acid addition salts, addition of a suitable precipitating
agent is subsequently added. Those precipitating agents used are,
for example, hydrocarbons such as benzene, toluene, cyclohexane or
heptane or carbon tetrachloride; 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 prove particularly suitable. If the reaction mixture
remains in solution after the end of the reaction, the salts of the
compounds of Formula I may be precipitated using one of the
precipitating agents mentioned, if appropriate after concentration
of the reaction solution. Furthermore, the solution of the reaction
mixture may also be advantageously filtered into the solution of
one of the precipitating agents mentioned, with stirring. Work-up
of the reaction mixture may also be carried out such that the
reaction mixture is rendered 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 the crude reaction product
is purified by chromatography, for example on a silica gel column,
after concentration (e.g., by vacuum). Suitable eluents for the
chromatography are, for example, 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 purification of the crude
product is carried out in the manner previously described, an acid
addition product of Formula I may be obtained from the pure base of
the compound of formula I thus obtained 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 butan-2-one, and then
treating this mixture with at least an 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 of the inorganic or organic acids mentioned further
above.
[0170] The compounds of formula I may be recrystallized from an
inert suitable solvent such as, for example, acetone, butan-2-one,
acetonitrile or nitromethane. However, particularly preferred is
reprecipitation from a solvent such as, for example,
dimethylformamide, dimethylacetamide, nitromethane, acetonitrile,
preferably methanol or ethanol.
[0171] The reaction of the compounds of formula VII with the
thioamides R4-C(S)--NH.sub.2 may also be carried out such that at
least an equimolar amount of a base, such as, for example,
triethylamine, is added to the reaction mixture and the resulting
free bases of Formula I are then optionally converted into their
acid addition products.
[0172] The acid addition products of the compounds of Formula I may
be reacted to give the free bases of Formula I by treatment with
bases. Suitable bases are, for example, solutions of inorganic
hydroxides, such as lithium hydroxide, sodium hydroxide, potassium
hydroxide, calcium hydroxide or barium hydroxide, carbonates or
hydrogen carbonates, such as sodium carbonate or potassium
carbonate, sodium hydrogen carbonate or potassium hydrogen
carbonate, ammonia and amines, such as triethylamine,
diisopropylamine, dicyclohexylamine, piperidine, morpholine,
methyldicyclohexylamine.
[0173] Thioamides of formula R4-C(S)--NH.sub.2 are either
commercially available or may be obtained, for example, by reaction
of the corresponding carboxamide with phosphorus pentasulfide in
pyridine (R. N. Hurd, G. Delameter, Chem. Rev. 61, 45 (1961)), or
with Lawesson's reagent in toluene, pyridine, hexamethylphosphoric
triamide [Scheibye, Pedersen and Lawesson: Bull. Soc. Chim. Belges
87, 229 (1978)], preferably in a mixture of tetrahydrofuran with
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyr- imidinone or
1,3-dimethyl-2-imidazolidinone. Hydroxyl, amino or additional
carbonyl functions are in this case protected using a removable
protective function, such as, for example, a benzyl,
tert-butyloxycarbonyl or benzyloxycarbonyl radical, or converted
into an optionally cyclic acetal. Methods for this are described,
for example, in Th. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Synthesis, Second Edition, 1991, John Wiley & Sons,
New York.
[0174] Thioamides of formula R4-C(S)--NH.sub.2 may also be obtained
by reacting nitrites of formula R4-CN with hydrogen sulfide
(Houben-Weyl IX, 762) or thioacetamide (E. C. Taylor, J. A.
Zoltewicz, J. Am. Chem. Soc. 82, 2656 (1960)) or O,O-diethyl
dithiophosphoric acid. The reactions with hydrogen sulfide are
preferably carried out in an organic solvent, such as methanol or
ethanol, those with thioacetamide in a solvent such as
dimethylformamide with addition of hydrochloric acid, and those
with O,O-diethyl dithiophosphoric acid in a solvent such as ethyl
acetate under acidic, e.g. HCl, conditions at room temperature or
with warming.
[0175] The examples given below serve to illustrate the invention,
but without restricting it. The measured melting or decomposition
points (m.p.) were not corrected and are generally dependent on the
heating rate.
1TABLE 1 Examples 10 Formula I Example R1; R' R2 R3 R4 R5 R6 Salt
m.p.[.degree. C.] 1 6-Cl; H H H Phenyl H OH -- 152 2 H; H H H
phenyl-2- H OH -- 110 OH (decomp.)
[0176] The compounds of formula I are distinguished by favorable
effects on lipid metabolism; in particular, they are suitable as
anorectics. Other favorable effects on lipid metabolism include
lowering cholesterol or low density lipoproteins (LDL) and
increasing high density lipoproteins (HDL). The compounds may be
employed on their own or in combination with other anorectically
active compounds. Such further anorectically active compounds are
mentioned, for example, in the Rote Liste, chapter 01 under
slimming preparations/anorectics. 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. D (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 in particular for the treatment of type II diabetes.
[0177] The efficacy of the compounds was tested as follows:
[0178] Biological test model:
[0179] The anorectic action was tested on female NMRI mice. After
withdrawal of food for 24 hours, a test preparation of the
invention was administered via a stomach tube. Kept individually
and with free access to drinking water, the animals were offered
evaporated milk 30 minutes after the administration of the
preparation. The consumption of evaporated milk was determined
half-hourly for 1.5 hours and the general condition of the animals
was observed. The measured milk consumption was compared with that
of untreated control animals.
2TABLE 2 Anorectic action, measured as reduction of the cumulated
milk consumption of treated animals compared to untreated animals.
11 Oral dose Number of animals/ cumulated milk consumption of the
treated animals Number of animals/ cumulated milk consumption of
the untreated control animals Reduction of the cumulated milk
consumption in Formula [mg/kg] N/[ml] N/[ml] % of the control
Example 1 30 5/1.06 5/1.54 31%
[0180] The data in the above table indicate that the compounds of
formula I exhibit very good anorectic action. The preparation of
some examples is described in detail below; the other compounds of
formula I were obtained in a similar manner:
EXAMPLE 1
(Compound 1)
[0181]
6-Chloro-2-phenyl-8,8a-dihydroindeno[1,2-d]thiazole-3a,8-diol:
[0182] a) 3-Bromo-5-chloroindan-1-one:
[0183] 8.33 g (50 mmol) of 5-chloroindan-1-one and 8.9 g (50 mmol)
of N-bromosuccinimide were suspended in 175 ml of carbon
tetrachloride, admixed with 1 g of benzoyl peroxide and, with
stirring, heated under reflux for 3 h. The cooled reaction solution
was filtered, extracted 2.times. with 100 ml of water, dried over
magnesium sulfate, filtered and concentrated under reduced
pressure. The residue was dissolved in 120 ml of a 1:1 mixture of
hot n-heptane and cyclohexane, boiled with activated carbon and
filtered, and the filtrate was concentrated under reduced pressure.
This gave 3-bromo-5-chloroindan-1-one having a melting point of
96-97.degree. C.
[0184] b) 3-Acetoxy-5-chloroindan-1-one:
[0185] 4.91 g (20 mmol) of 3-bromo-5-chloroindan-1-one and 3.34 g
(20 mmol) of silver acetate were suspended in 100 ml of acetic acid
and, with stirring, and heated under reflux for 5 h. The cooled
reaction solution was concentrated under reduced pressure and the
residue was purified by chromatography on silica gel using
toluene/acetone 10/1. This gave 3-acetoxy-5-chloroindan-1-one of
melting point 65-67.degree. C.
[0186] c) 5-Chloro-3-hydroxyindan-1-one:
[0187] With addition of 50 ml of 3N HCl, 1.98 g (8.8 mmol) of
3-acetoxy-5-chloroindan-1-one were dissolved in 10 ml of
acetonitrile. The reaction mixture was stirred at room temperature
for 48 h. The solvent acetonitrile was then distilled off under
reduced pressure and the precipitated crude product was filtered
off and purified by chromatography on silica gel using
toluene/acetone 5/1. The product, 5-chloro-3-hydroxyindan-1-one,
had a melting point of 125-128.degree. C.
[0188] d) 2-Bromo-5-chloro-3-hydroxyindan-1-one:
[0189] 0.69 g (3.78 mmol) of 5-chloro-3-hydroxyindan-1-one was
dissolved in 100 ml of diethyl ether; 1 drop of bromine was added
with stirring, and the mixture was stirred until the color had
disappeared. The mixture was then cooled to -5.degree. C., and
0.194 ml (3.78 mmol) of bromine in 2 ml of dichloromethane was
added dropwise over a period of 30 min. Stirring was then continued
for 30 min, 50 ml of water was added and the organic phase was
separated off, dried over magnesium sulfate and filtered. The
filtrate was concentrated under reduced pressure and the residue
was dried under reduced pressure. This gave
2-bromo-5-chloro-3-hydroxyindan-1-one having a melting point of
118-119.degree. C.
[0190] e)
6-Chloro-2-phenyl-8,8a-dihydroindeno[1,2-d]thiazole-3a,8-diol:
[0191] 0.6 g (2.3 mmol) of 2-bromo-5-chloro-3-hydroxyindan-1-one
and 0.473 g (3.45 mmol) of thiobenzamide were dissolved in 5 ml of
isopropanol. 0.478 ml (3.45 mmol) of triethylamine was added, and
the mixture was then stirred at room temperature for 12 h and
subsequently at 50.degree. C. for 8 h. The cooled reaction mixture
was concentrated under reduced pressure and the residue was
purified by chromatography on silica gel by initially using
n-heptane/ethyl acetate 3/1 and then toluene/acetone 5/1. This gave
6-chloro-2-phenyl-8,8a-dihydroindeno[1,2-d]thiazole-3a,8-diol
having a melting point of 151-153.degree. C. (with
decomposition).
* * * * *