Polycyclic 2-aminodihydrothiazole systems, processes for their preparation and their use as pharmaceuticals

The invention relates to polycyclc 2-aminodihydrothiazole systems and their physiologically tolerated salts and physiologically functional derivatives. Compounds of the formula I, ##STR1## 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.

BACKGROUND OF THE INVENTION
 Polycyclic 2-aminodihydrothiazole systems, processes for their preparation
 and their use as pharmaceuticals.
 The invention relates to polycyclic 2-aminodihydrothiazole systems and
 their physiologically tolerated salts and physiologically functional
 derivatives. Thiazolidine derivatives having an anorectic effect are
 described in the prior art (Austrian Patent No. 365181).
 The invention was based on the object of providing further compounds which
 display a therapeutically utilizable anorectic effect.
 SUMMARY OF THE INVENTION
 The invention relates to compounds of the formula I
 ##STR2##
 in which
 Y is a direct linkage, --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --;
 X is CH.sub.2, CH(CH.sub.3), CH(C.sub.2 H.sub.5), CH(C.sub.3 H.sub.7) or
 CH(C.sub.6 H.sub.5);
 R1, R1' are independently H, F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
 COO(C.sub.1 -C.sub.6)-alkl, 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
 (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.2 Ph).sub.2), SO.sub.2 --NH.sub.2, SO.sub.2 NH(C.sub.1
 -C.sub.6)-alkyl, SO.sub.2 N[(C.sub.1 -C.sub.6)-akyl].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, thienyl rings may be 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 triazol ring may be optionally substituted
 in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the
 tetrazol ring may be optionally substituted in position 1 or 2 by methyl
 or benzyl);
 R2 is H, (C.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 (where n is 0-5 and wherein phenyl, thienyl,
 pyridyl, 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, 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
 wherein phenyl, thienyl, pyridyl, 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), (C.sub.2 -C.sub.6)-alkynyl, (C.sub.2 -C.sub.6)-alkenyl,
 C(O)OCH.sub.3, C(O)OCH.sub.2 CH.sub.3, C(O)OH, C(O)NH.sub.2,
 C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2 or OC(O)CH.sub.3 ;
 R4 is NR6R7;
 R6 and R7 are independently H, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3
 -C.sub.6)-cycloalkyl, phenyl (wherein the phenyl ring 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)), CO--(C.sub.1
 -C.sub.6)-alkyl, CHO, CO-phenyl, --NH.sub.2, --N.dbd.C(CH.sub.3).sub.2,
 -(pyrrolidin-1-yl), -(piperidin-1-yl), -(morpholin4-yl), -(piperazin-1-yl)
 or -(4-methylpiperazin- 1 -yl),
 or
 NR6R7 is a ring selected from the group consisting of pyrrolidine,
 piperidine, morpholine, piperazine, 4-methylpiperazin-1-yl,
 4-benzylpiperazin-1-yl and phthalimidyl;
 and their physiologically tolerated salts and physiologically functional
 derivatives.
 The invention also relates to pharmaceutical compositions containing the
 compounds of formula I and pharmaceutically acceptable carriers. Also
 pharmaceutical compositions containing the compounds of formula I in
 combination with at least one additional anorectic agents are
 contemplated. The invention envisages treatment of obesity via
 administration of compounds of formula I. Methods of treatment for type II
 diabetes are also contemplated.
 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
 The invention encompasses compounds of formula I
 ##STR3##
 in which
 Y is a direct linkage, --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --;
 X is CH.sub.2, CH(CH.sub.3), CH(C.sub.2 H.sub.5), CH(C.sub.3 H.sub.7) or
 CH(C.sub.6 H.sub.5);
 R1, R1' are independently 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
 (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.2 Ph).sub.2), SO.sub.2 --NH.sub.2, SO.sub.2 NH(C.sub.1
 -C.sub.6)-alkyl, SO.sub.2 N[(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, thienyl rings may be
 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 triazol
 ring may be optionally substituted in position 1, 2 or 3 by methyl or
 benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally
 substituted in position 1 or 2 by methyl or benzyl);
 R2 is H, (C.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 (where n is 0-5 and wherein phenyl, thienyl,
 pyridyl, 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, (CI-C6)-alkyl, F, CN, N3, O-(Ci-C6)-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 wherein phenyl, thienyl,
 pyridyl, 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),
 (C.sub.2 -C.sub.6)-alkynyl, (C.sub.2 -C.sub.6)-alkenyl, C(O)OCH.sub.3,
 C(O)OCH.sub.2 CH.sub.3, C(O)OH, C(O)NH.sub.2, C(O)NHCH.sub.3,
 C(O)N(CH.sub.3).sub.2 or OC(O)CH.sub.3 ;
 R4 is NR6R7;
 R6 and R7 are independently H, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3
 -C.sub.6)-cycloalkyl, phenyl (wherein the phenyl ring 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)), CO--(C.sub.1
 -C.sub.6)-alkyl, CHO, CO-phenyl, --NH.sub.2, --N.dbd.C(CH.sub.3).sub.2,
 -(pyrrolidin-1-yl), -(piperidin-1-yl), -(morpholin4-yl), -(piperazin-1-yl)
 or -(4-methylpiperazin-1-yl),
 or
 NR.sub.6 R.sub.7 is a ring selected from the group consisting of
 pyrrolidine, piperidine, morpholine, piperazine, 4-methylpiperazin-1-yl,
 4-benzylpiperazin-1-yl and phthalimidyl;
 and their physiologically tolerated salts and physiologically functional
 derivatives.
 In a preferred embodiment are compounds of formula I:
 in which
 Y is a direct linkage;
 X is CH.sub.2 ;
 R1, R1' are independently H, F, Cl, 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
 (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.2 Ph).sub.2), SO.sub.2 --NH.sub.2, SO.sub.2 NH(C.sub.1
 -C.sub.6)-alkyl, SO.sub.2 N[(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 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, thienyl rings may be
 optionally substituted once or twice 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 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 (where n is 0-5 and wherein phenyl, thienyl,
 pyridyl, 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 H, (C.sub.1 -C.sub.6)-alkyl, F, (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 wherein phenyl, thienyl, pyridyl, 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), (C.sub.2
 -C.sub.6)-alkynyl, (C.sub.2 -C.sub.6)-alkenyl, C(O)OCH.sub.3,
 C(O)OCH.sub.2 CH.sub.3, C(O)OH, C(O)NH.sub.2, C(O)NHCH.sub.3,
 C(O)N(CH.sub.3).sub.2 or OC(O)CH.sub.3);
 R4 is NR6R7;
 R6 and R7 are independently H, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3
 -C.sub.6)-cycloalkyl, phenyl (wherein the phenyl ring 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), CO--(C.sub.1
 -C.sub.6)-alkyl, CHO, CO-phenyl, --NH.sub.2, --N.dbd.C(CH.sub.3).sub.2,
 -(pyrrolidin-1-yl), -(piperidin-1-yl), -(morpholin-4-yl),
 -(piperazin-1-yl) or -(4-methylpiperazin-1 -yl),
 NR6R7 is a ring selected from the group consisting of pyrrolidine,
 piperidine, morpholine, piperazine, 4-methylpiperazin-1-yl,
 4-benzylpiperazin-1-yl and phthalimidyl;
 and their physiologically tolerated salts and physiologically functional
 derivatives.
 In a particularly preferred embodiment are compounds of formula I wherein:
 Y is a direct linkage;
 X is CH.sub.2 ;
 R1, R1' are independently 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.1 -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.2 Ph).sub.2), SO.sub.2 --(C.sub.1 -C.sub.6)-alkyl, SO.sub.2
 --(CH.sub.2).sub.n -phenyl (where n is 0-3 and the phenyl radical may be
 substituted 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, thienyl rings may be optionally substituted once or twice by F,
 Cl, OH, CF.sub.3, CN, OCF.sub.3, O--(C.sub.1 -C.sub.4)-alkyl, (C.sub.1
 -C.sub.4)-alkyl, NH.sub.2, NH(C.sub.1 -C.sub.4)-alkyl, N((C.sub.1
 -C.sub.4)-alkyl).sub.2, SO.sub.2 --CH.sub.3, COOH, COO--(C.sub.1
 -C.sub.4)-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 H, (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 or (CH.sub.2).sub.n
 -furyl (wherein phenyl, thienyl, pyridyl, 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, F or (C.sub.1 -C.sub.4)-alkyl;
 R4 is NR6R7;
 R6 and R7 are independently H, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3
 -C.sub.6)-cycloalkyl, phenyl (wherein the phenyl ring 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), CO--(C.sub.1
 -C.sub.6)-alkyl, CHO, CO-phenyl, --NH.sub.2, --N.dbd.C(CH.sub.3).sub.2,
 -(pyrrolidin-1-yl), -(piperidin-1-yl), -(morpholin-4-yl),
 -(piperazin-1-yl) or -(4-methylpiperazin-1-yl),
 NR6R7 is a ring selected from the group consisting of pyrrolidine,
 piperidine, morpholine, piperazine, 4-methylpiperazin-1-yl,
 4-benzylpiperazin-1-yl and phthalimidyl;
 and their physiologically tolerated salts.
 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.
 The alkyl, alkenyl and alkynyl radicals in the substituents R1, R1', R2,
 R3, R4, R6 and R7 may be either straight-chain or branched.
 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).
 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.
 The term "physiologically functional derivative" used herein refers to any
 physiologically tolerated derivative of a compound of the formula I
 according to the invention, for example an ester, which is able on
 administration to a mammal, such as, for example, to humans, to form
 (directly or indirectly) a compound of the formula I or an active
 metabolite thereof.
 The physiologically functional derivatives also include 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.
 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.
 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.
 The compounds of formula (I) are useful in the treatment of type II
 diabetes and in the treatment 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.
 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
 dihydrothiazolium ion derived from the salt. The compounds of the formula
 (I) may be used in treatment of obesity and type II diabetes in the form
 of a 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.
 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.
 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 defmed 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 fmely 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.
 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.
 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.
 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.
 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%.
 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).
 The invention further relates to a process for preparing the compounds of
 the formula I, which comprises obtaining the compounds of the formula I by
 the procedure as shown in the following reaction scheme:
 ##STR4##
 For this purpose, compounds of the formula II,
 ##STR5##
 in which R1, R1', R3 and X and Y have the 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.
 The compounds of the formula III are reacted further with thioureas of the
 formula IV
 ##STR6##
 in which R4 has the stated meaning, to give compounds of the formula
 I'.times.HZ or I', converting where appropriate the compounds of the
 formula I' with organic or inorganic acids H--B into their acid addition
 salts of the formula I'.times.HB or converting salts obtained of the
 formula I'.times.HZ with organic or inorganic bases into the free basic
 compounds of the formula I'.
 Examples of suitable inorganic acids are: hydrohalic acids such as
 hydrochloric acid and hydrobromic acid, and sulfuric acid, phosphoric acid
 and sulfamic acid.
 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. The procedure described above is
 advantageously carried out by reacting the compounds m with the thioureas
 IV 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, tetrahydrofuran, acetonitrile, nitromethane or diethylene glycol
 dimethyl ether. However, solvents which prove to be particularly
 advantageous are 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 either in suspension or solution in the
 particular reaction medium. It is also possible in principle for the
 reactants to be reacted without a 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 20.degree. C. and 50.degree. C. A
 temperature range between 0.degree. C. and 40.degree. C. usually proves to
 be particularly favorable.
 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.
 The compounds I'.times.HZ frequently separate out in the form of their acid
 addition salts of low solubility during the reaction, but it is expedient
 subsequently to add a suitable precipitant. Examples of ones which may be
 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, it is possible to precipitate the salts of the
 compounds I'.times.HZ, where appropriate after concentrating the reaction
 solution, with one of said precipitants. It is also possible and
 advantageous to filter the solution of the reaction mixture into a
 solution of one of said precipitants with stirring. Since the reaction of
 the compounds III with the thioureas IV 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 adding an organic base such as, for
 example, triethylarnine 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. Eluents which prove suitable for this 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 crude product
 is purified in the manner described last, it is possible to obtain from
 the pure base of the formula I' obtained in this way an acid addition
 product of the formula I'.times.H--B 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 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. The compounds of the formula I' may be
 recrystallized from a suitable inert solvent such as, for example,
 acetone, butan-2-one, acetonitrile, nitromethane. However, reprecipitation
 from a solvent such as, for example, dimethylformamide, dimethylacetamide,
 nitromethane, acetonitrile, preferably acetone or ethyl acetate, is
 particularly advantageous.
 The reaction of the compounds of the formula III with the thioureas of the
 formula IV 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 the compounds I' obtained in this way where appropriate
 into their acid addition products I'.times.H--B.
 Suitable as residue of an activated ester Z in the compounds of the formula
 III are, for example: Cl, Br, I, O--C(O)--(C.sub.6 H.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.6
 H.sub.4)-4-CH.sub.3, O--SO.sub.2 -C.sub.6 H.sub.5.
 The acid addition products I'.times.HZ and I x 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.
 Thioureas of the formula IV either are commercially available or may be
 prepared by methods known from the literature.
 The compounds of the formula I x HZ or I where R2 is (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, and where n is 0-5 may be obtained by either
 aa) reacting the acid addition salts of the formula I'.times.HZ in a
 solvent of the formula R2--OH, where R2 has the meaning described above,
 at a temperature of from -20.degree. C. to 100.degree. C., preferably at
 -5.degree. C. to 50.degree. C., for from 2 hours to 4 days, preferably 4
 hours to 2 days, or
 ab) reacting the free bases of the formula I' in a solvent of the formula
 R2--OH, where R2 has the meaning described above, with equimolar, less
 than stoichiometric or catalytic, preferably catalytic, amounts of an
 inorganic or organic acid as described hereinbefore, or with addition of
 an acid ionic exchanger at a temperature of from -20.degree. C. to
 100.degree. C., preferably at -5.degree. C. to 50.degree. C., for from 2
 hours to 4 days, preferably 4 hours to 2 days, or
 ac) carrying out the reactions according to aa) and ab) in an inert aprotic
 solvent such as dichloromethane, chloroform, 1,2-dichloroethane, heptane,
 benzene, toluene, acetonitrile, nitromethane, dioxane, tetrahydrofuran,
 ethylene glycol dimethyl ether, diethyl ether, diisopropyl ether,
 tert-butyl methyl ether, acetone, butan-2-one or a lower alkyl acetate
 such as, for example, ethyl acetate, by adding from 1 to 5, preferably
 1.5-2, equivalents of a compound of the formula R2--OH, or
 ad) converting compounds of the formula I' in a polar aprotic solvent such
 as, for example, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether,
 nitromethane, acetonitrile or dimethylformamide, dimethylacetamide or
 N-methyl-2-pyrrolidone, with the aid of a base such as, for example,
 sodium hydride, lithium diisopropylamide, KOH or potassium carbonate, into
 their alcoholate, and then reacting the latter with addition of an
 alkylating agent of the formula R2--W where W.dbd.chlorine, bromine,
 iodine, O--C(O)--CH.sub.3, O-C(O)--CF.sub.3, O--C(O)--C.sub.6 H.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.6 H.sub.4 -4-CH.sub.3, O--SO.sub.2 --C.sub.6 H.sub.4 -4--NO.sub.2,
 at -20 to 150.degree. C., preferably at -15 to 50.degree. C., for from 10
 minutes to 2 days, preferably for 20 minutes to 12 hours. Compounds of the
 formula I x HZ or I with R2.dbd.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,
 C(O)--(CH.sub.2).sub.n -furyl, where n is 0-5, may be obtained by either:
 ba) proceeding as described under aa)-ac) with the difference that an acid
 R2--OH is employed in place of an alcohol R2--OH, and from 1 to 2
 equivalents of the acid R2--OH, preferably 1.5 equivalents of the acid
 R2--OH, are employed, and the inorganic or organic acid catalyst described
 in aa)-ac) is not added but the acid cation exchanger is advantageously
 employed or
 bb) reacting a compound of the formula I' with an acid of the formula
 R2--OH in a Mitsunobu Reaction (O. Mitsunobu, Synthesis 1981, 1) to give a
 compound of the formula I or
 bc) reacting a carbonyl chloride of the formula R2--Cl or a carboxylic
 anhydride of the formula R2--O--R2 with a compound of the formula I' in an
 alcohol esterification (Houben-Weyl, Methoden der Organischen Chemie,
 Georg Thieme Verlag Stuttgart, Volume E5, pp. 656-715).
 The examples detailed below serve to illustrate the invention without,
 however, restricting it. The measured melting or decomposition points
 (m.p.) have not been corrected and generally depend on the heating rate.
 TABLE 1
 Examples
 ##STR7##
 Example R1; R1' R2 R3 R4 Y X Salt m.p.
 [.degree. C.]
 A01 5-NO.sub.2 H H NH.sub.2 -- CH.sub.2 --
 &gt;260
 A02 5-NO.sub.2 H H NH(CH.sub.3) -- CH.sub.2 --
 &gt;260
 A03 6-Cl H H NH.sub.2 -- CH.sub.2 HCl
 241
 A04 6-Cl H H NH(CH.sub.3) -- CH.sub.2 HCl
 249
 A05 5-SO.sub.2 CH.sub.3 H H NH.sub.2 -- CH.sub.2 --
 &gt;230
 A06 5-SO.sub.2 CH.sub.3 H H NH(CH.sub.3) -- CH.sub.2 --
 &gt;230
 A07 5-SO.sub.2 CH.sub.3 ; 6-Cl H H NH(C.sub.6 H.sub.5) --
 CH.sub.2 -- 130
 A08 7-Cl H H NH(CH.sub.3) -- CH.sub.2 --
 180
 A09 5-Cl H H NH(CH.sub.3) -- CH.sub.2 --
 207
 A10 6-F H H NH(CH.sub.3) -- CH.sub.2 --
 206
 A12 6-C.sub.6 H.sub.5 H H NH(CH.sub.3) -- CH.sub.2 HBr
 265
 A13 6-(C.sub.6 H.sub.4 -3-CF.sub.3) H H NH(CH.sub.3) --
 CH.sub.2 HBr 199
 A14 6-CN H H NH(CH.sub.3) -- CH.sub.2 HBr
 287
 A15 6-(thien-3-yl) H H NH(CH.sub.3) -- CH.sub.2 HBr
 180
 A16 6-(C.sub.6 H.sub.4 -3-F) H H NH(CH.sub.3) -- CH.sub.2
 HBr 228
 A17 6-Cl H H NH.sub.2 -- CH.sub.2 HBr
 292
 A18 6-(C.sub.6 H.sub.4 -4-CH.sub.3) H H NH(CH.sub.3) --
 CH.sub.2 HBr 196
 A19 6-Cl H H NH.sub.2 -- CH.sub.2 HCl
 251
 A20 6-(C.sub.6 H.sub.4 -4-CF.sub.3) H H NH(CH.sub.3) --
 CH.sub.2 HBr 195
 A21 6-(C.sub.6 H.sub.3 -3,5-di-CF.sub.3) H H NH(CH.sub.3)
 CH.sub.2 HBr 266
 A22 6-(C.sub.6 H.sub.4 -3-Cl) H H NH(CH.sub.3) -- CH.sub.2
 HBr 203
 A23 6-(C.sub.6 H.sub.4 -3-OCF.sub.3) H H NH(CH.sub.3) --
 CH.sub.2 HBr 236
 A24 6-(C.sub.6 H.sub.4 -4-Cl) H H NH(CH.sub.3) -- CH.sub.2
 HBr 186
 A25 5-C(CH.sub.3).sub.3 H H NH(CH.sub.3) -- CH.sub.2 HBr
 273
 A26 6-(C.sub.6 H.sub.4 -2-CF.sub.3) H H NH(CH.sub.3) --
 CH.sub.2 HBr 196
 A27 6-(C.sub.6 H.sub.4 -3-OCH.sub.3) H H NH(CH.sub.3) --
 CH.sub.2 HBr 195
 A28 6-(naphth-1-yl) H H NH(CH.sub.3) -- CH.sub.2 HBr
 211
 A29 7-(C.sub.6 H.sub.4 -4-CF.sub.3) H H NH(CH.sub.3) --
 CH.sub.2 HBr 191
 A30 7-(C.sub.6 H.sub.4 -4-CF.sub.3) H H NH.sub.2 --
 CH.sub.2 HBr 230
 A31 5-(C.sub.6 H.sub.4 -4-Cl) H H N(CH.sub.3).sub.2 --
 CH.sub.2 HBr 223
 A32 5-(C.sub.6 H.sub.4 -4-CF.sub.3) H H NH.sub.2 --
 CH.sub.2 HBr 229
 A33 6-OCF.sub.3 H H NH(CH.sub.3) -- CH.sub.2 HBr
 267
 A34 5-C(CH.sub.3).sub.3 H H NH.sub.2 -- CH.sub.2 HBr
 272
 A35 6-OCF.sub.3 H H NH.sub.2 -- CH.sub.2 HBr
 253
 A36 6-Cl H H NH-- -- CH.sub.2 HBr
 237
 N.dbd.C(CH.sub.3).sub.2
 A37 6-Cl H H NH--NH.sub.2 -- CH.sub.2
 HBr 146
 A38 6-Cl H CH.sub.3 NH.sub.2 -- CH.sub.2
 HBr 229
 A39 6-O-CH.sub.2 --CF.sub.2 --CF.sub.2 --CF.sub.3 H H
 NH(CH.sub.3) -- CH.sub.2 HCl 239
 CF.sub.3
 A40 6-Cl H H NH.sub.2 -- CH.sub.2 --
 87
 A41 6-CCH H H NH.sub.2 -- CH.sub.2 HBr
 &gt;300
 A42 6-O-(C.sub.6 H.sub.4 -4-Cl) H H NH.sub.2 -- CH.sub.2
 HBr 227
 A43 6-Cl H F NH.sub.2 -- CH.sub.2 --
 159
 A44 6-Cl H F NH--CH.sub.3 -- CH.sub.2 --
 182
 A45 H H F NH.sub.2 -- CH.sub.2 --
 160
 A46 H H F NH--CH.sub.3 -- CH.sub.2 --
 165
 A47 (-) 6-Cl H F NH--CH.sub.3 -- CH.sub.2 --
 Decomp.

from 225
 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
 treatment of obesity. The compounds are furthermore suitable for the
 treatment of type II diabetes.
 The activity of the compounds has been tested as follows:
 Biological test model:
 The anorectic effect was tested on male NMRI 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.
 TABLE 2
 Anorectic effect measured by reduction in the cumulative milk
 consumption by treated animals compared with untreated animals.
 Compound/Example
 ##STR8##
 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 control animals N/[ml] Reduction in the cumulative milk
 # consumption as % of the controls
 Example A04 50 8/0.56 8/3.18 82
 Example A14 50 12/0.68 12/3.87 82
 Example A19 50 5/0.28 5/4.00 93
 Example A31 50 5/0.42 5/4.18 90
 Example A32 50 5/0.80 5/5.42 85
 Example A33 50 5/0.80 5/3.12 74
 Example A34 50 5/0.54 5/3.12 83
 Example A36 50 5/1.54 5/5.06 70
 Example A39 50 5/0.58 5/3.58 84
 Example A40 50 5/0.18 5/3.52 95
 Example A44 50 5/0.32 5/3.40 91
 Example A46 50 5/0.88 5/4.52 81
 Example A49 10 5/0.44 5/3.72 88
 Example A50 10 5/0.22 5/4.02 94
 Example A51 10 5/0.84 5/3.80 78
 The above data shows that the compounds of the formula I exhibit a very
 good anoretic effect.
 The preparation of some examples is described in detail below, and the
 other compounds of the formula I were obtained analogously:

Procedure Example 1:
 2-Amino-5-nitro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol (compound of Example
 1):
 a) 2-Bromo-6-nitroindan-1-one:
 7.1 g (0.04 mol) of 5-nitroindan-1-one are dissolved in 135 ml of glacial
 acetic acid, and 1.12 ml of 48 percent hydrobromic acid solution are
 added. Then 2.06 ml of bromine in 40 ml of glacial acetic acid are added
 dropwise at room temperature to the solution, which is then stirred for 2
 h. The reaction mixture is poured into ice-water and extracted with
 dichloromethane and, after drying, the solvent is removed from the organic
 phase in vacuo. The residue is purified by column filtration (silica gel;
 dichloromethane). 2-Bromo-6-nitroindan-1-one is obtained with a melting
 point of 113.degree. C.
 b) 2-Amino-5-nitro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol:
 1.28 g (5 mmol) of 2-bromo-6-nitroindan-1-one are dissolved in 30 ml of
 acetone and, while stirring, 530 mg of thiourea in 10 ml of acetone are
 added. The solution is initially clear but, after a few minutes, the
 hydrobromide of 2-amino-5-nitro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol
 crystallizes out. It is stirred at room temperature for 1 h, filtered off
 with suction and washed with a little acetone. The air-dried hydrobromide
 is dissolved in about 10 ml of methanol and, after addition of 0.7 ml of
 triethylamine, stirred for 15 min. Then 50 ml of water are added, and the
 mixture is stirred at room temperature for 1 h. The crystals which have
 formed are filtered off with suction and washed with a little cold water.
 2-Amino-5-nitro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol is obtained with a
 melting point above 250.degree. C.
 Procedure Example 2:
 3a-Hydroxy-2-methylamino-8,8a-dihydro-3aH-indeno[1,2-d]thiazole-6-carbonitr
 ile hydrobromide (compound of Example 14):
 a) 1-Oxoindane-5-carbonitrile:
 9.5 g of 5-bromo-1-indanone and 4.93 g of CuCN are suspended in 10 ml of
 dimethylformamide and boiled under reflux for 4 hours. A solution of 18 g
 of iron(III) chloride in 5 ml of concentrated hydrochloric acid with 30 ml
 of water are added dropwise to the cooled, dark-brown viscous suspension
 while stirring, and the mixture is then stirred at 70.degree. C. for 30
 minutes. The reaction mixture is extracted by shaking three times with 50
 ml of toluene, and the combined organic phases are extracted by shaking
 with 50 ml of 2N hydrochloric acid and 50 ml of 2N sodium hydroxide
 solution and then washed with water until neutral. The toluene extract is
 dried over magnesium sulfate and concentrated in vacuo, and the residue is
 recrystallized from n-heptane. 1-oxoindane-5-carbonitrile is obtained with
 a melting point of 123-125.degree. C.
 b) 2-Bromo-1-oxoindane-5-carbonitrile:
 3.93 g of 1-oxoindane-5-carbonitrile are dissolved in 40 ml of glacial
 acetic acid and, after addition of 0.1 ml of hydrobromic acid (48%
 strength in water), at room temperature a solution of 1.34 ml of bromine
 in 8 ml of acetic acid is added dropwise. The reaction mixture is stirred
 at room temperature for 3 h and then added to a mixture of 20 g of ice and
 40 g of water, 0.5 g of sodium bisulfite is added and the mixture is
 extracted by shaking twice with 50 ml of dichloromethane each time. The
 organic phase is washed with 50 ml of water, dried over magnesium sulfate,
 concentrated in vacuo and chromatographed on silica gel with toluene/ethyl
 acetate 25/1. 2-Bromo-l-oxoindane-5-carbonitrile is obtained with a
 melting point of 115-118.degree. C.
 c)
 3a-Hydroxy-2-methylamino-8,8a-dihydro-3aH-indeno[1,2-d]thiazole-6-carbonit
 rile hydrobromide:
 236 mg of 2-bromo-1-oxoindane-5-carbonitrile are dissolved in 10 ml of
 acetone and, at 0.degree. C., 135 mg of N-methylthiourea are added. The
 mixture is stirred at room temperature for 3 h and at ice-bath temperature
 for 90 minutes. The precipitate is filtered off with suction, washed with
 acetone and dried in vacuo. The hydrobromide of
 3a-hydroxy-2-methylamino-8,8a-dihydro-3aH-indeno[1,2-d]thiazole-6-carbonit
 rile is obtained with a melting point of 287-288.degree. C.
 Procedure Example 3:
 2-Amino-5-(4-trifluoromethylphenyl)-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol
 hydrobromide (compound of Example 32):
 a) 6-(4-Trifluoromethylphenyl)indan-1-one):
 6.33 g of 6-bromoindan-1-one are suspended with 5.7 g of
 4-trifluoromethylbenzeneboronic acid and 6.36 g of sodium carbonate in a
 mixture of 100 ml of dry toluene with 20 ml of dry ethanol and 20 ml of
 water and, after addition of 338 mg of palladium(II) acetate and 787 mg of
 triphenylphosphine, refluxed under argon for 4 h. The reaction mixture is
 cooled, the ethanol content is removed in vacuo, and the residue is
 stirred with 40 ml of 0.5 N sodium hydroxide solution for 10 minutes and
 filtered off with suction through a clarifying layer. The resulting
 solution is washed three times with 50 ml of water and once with 50 ml of
 saturated brine, dried over magnesium sulfate, concentrated in vacuo and
 chromatographed on silica gel with dichloromethane/heptane
 3/1.6-(4-Trifluoromethylphenyl)indan-1-one is obtained and is employed
 without further purification in the next stage.
 b) 2-Bromo-6-(4-trifluoromethylphenyl)indan-1-one:
 The bromination is carried out as described in Procedure Example 2b and
 affords 2-bromo-6-(4-trifluoromethylphenyl)indan-1-one with a melting
 point of 105.degree. C.
 c)
 2-Amino-5-(4-trifluoromethylphenyl)-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol
 hydrobromide:
 1.06 g of 2-bromo-6-(4-trifluoromethylphenyl)indan-1-one are dissolved with
 266 mg of thiourea in 10 ml of dry acetone and stirred at ice-bath
 temperature for 4 h. The precipitate is filtered off with suction, washed
 with acetone and dried in vacuo. The hydrobromide of
 2-amino-5-(4-trifluoromethylphenyl)-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol
 is obtained with a melting point of 228-230.degree. C.
 Procedure Example 4:
 2-Amino-6-chloro-8a-methyl-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol
 hydrobromide (compound of Example 38):
 20 g of 5-chloroindan-1-one are dissolved in 600 ml of dry toluene and,
 after addition of 27.4 ml of N,N-dimethylhydrazine and 1 g of
 p-toluenesulfonic acid, boiled with a water trap for 4 h. The reaction
 mixture is concentrated in vacuo, and the residue is dissolved in ethyl
 acetate and washed with sodium bicarbonate solution and then with water.
 The organic phase is dried over sodium sulfate and concentrated in vacuo,
 and the residue is chromatographed on silica gel with ethyl
 acetate/heptane 1/2. N'-(5-chloroindan-1-ylidene)-N,N-dimethylhydrazine is
 obtained as an oil.
 33.1 ml of a 2M solution of lithium diisopropylamide in
 THF/heptane/ethylbenzene are added dropwise to 300 ml of dry
 tetrahydrofuran (THF) under argon. At -70.degree. C., 12 g of
 N'-(5-chloroindan-1-ylidene)-N,N-dimethylhydrazine, dissolved in 100 ml of
 dry THF, are added dropwise to this solution. After the reaction mixture
 has been stirred at -70.degree. C. for 1 h and at -40.degree. C. for a
 further 3 h, 3.882 ml of methyl iodide are added dropwise and the mixture
 is stirred further overnight. 200 ml of water are added dropwise to the
 reaction mixture which has warmed to room temperature; the THF is removed
 in vacuo, and the residue is extracted with ethyl acetate. The ethyl
 acetate extract is treated with active carbon, dried over sodium sulfate,
 filtered, concentrated in vacuo and chromatographed on silica gel with
 ethyl acetate/heptane 1/2.
 N'-(5-chloro-2-methylindan-1-ylidene)-N,N-dimethylhydrazine is obtained as
 an oil.
 5.5 g of N'-(5-chloro-2-methylindan-1-ylidene)-N,N-dimethylhydrazine are
 emulsified in 100 ml of 2N sulfuric acid and boiled under reflux for 4 h.
 The cooled reaction mixture is cautiously extracted with ethyl acetate;
 the organic extract is extracted several times with saturated sodium
 bicarbonate solution, dried over sodium sulfate, filtered, dried in vacuo
 and chromatographed on silica gel with ethyl acetate/hetpane 1/5.
 5-Chloro-2-methylindan-1-one is obtained as an oil.
 Bromination of 5-chloro-2-methylindan-1-one is carried out as described in
 Procedure Example 2b) and affords 2-bromo-5-chloro-2-methylindan-1-one as
 an oil, which is employed without further purification in the next stage.
 1.5 g of 2-bromo-5-chloro-2-methylindan-1-one are dissolved together with
 460 mg of thiourea in 50 ml of triacetone and boiled under reflux for 8 h.
 The precipitate is filtered off with suction, washed with acetone and
 dried in vacuo.
 2-Amino-6-chloro-8a-methyl-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol
 hydrobromide is obtained and melts at 229.degree. C. with decomposition.
 Procedure Example 5:
 6-(2,2,3,3,4,4,4-Heptafluorobutoxy)-2-methylamino-8,8a-dihydroindeno[1,2-d]
 thiazol-3a-ol hydrochloride (compound of Example 39):
 a)
 6-(2,2,3,3,4,4,4-Heptafluorobutoxy)-2-methylamino-8,8a-dihydroindeno[1,2-d
 ]thiazol-3a-ol hydrobromide is obtained by reacting 1.7 g of
 2-bromo-5-(2,2,3,3,4,4,4-heptafluorobutoxy)indan-1-one with 0.31 g of
 N-methylthiourea in 30 ml of ethyl acetate and stirring at room
 temperature for 24 hours as colorless crystalline precipitate. Melting
 point 280-282.degree. C. (decomposition)
 b)
 6-(2,2,3,3,4,4,4-Heptafluorobutoxy)-2-methylamino-8,8a-dihydroindeno[1,2-d
 ]thiazol-3a-ol is obtained by treating 0.9 g of .sup.6
 -(2,2,3,3,4,4,4-heptafluorobutoxy)-2-methylamino-8,8a-dihydroindeno[1,2-d]
 thiazol-3a-ol hydrobromide with 0.72 g of triethylamine in 30 ml of
 ethanol. After leaving to stand overnight, the crystalline precipitate is
 filtered off and washed several times with water. Colorless crystals,
 melting point 178-180.degree. C.
 c)
 6-(2,2,3,3,4,4,4-Heptafluorobutoxy)-2-methylamino-8,8a-dihydroindeno[1,2-d
 ]thiazol-3a-ol hydrochloride is obtained by adding an ethereal solution of
 gaseous hydrogen chloride to a solution of 0.6 g of
 6-(2,2,3,3,4,4,4-heptafluorobutoxy)-2-methylamino-8,8a-dihydroindeno[1,2-d
 ]thiazol-3a-ol in 20 ml of ethyl acetate. The mixture is stirred at room
 temperature for about 1 day, and the colorless crystalline precipitate is
 filtered off. Melting point 238-240.degree. C.
 Procedure Example 6:
 2-Amino-6-chloro-8a-fluoro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol (compound
 of Example 43):
 a) 5-Chloro-2-fluoroindan-1-one:
 25 ml of a 1.6 molar solution of n-butyllithium in n-hexane are slowly
 added dropwise to a solution of 5.24 ml of diisopropylamine in 60 ml of
 dry tetrahydrofuran at a temperature of&lt;-50.degree. C.; the mixture is
 then stirred at -50.degree. C. for a further 10 minutes. A solution of
 6.33 g of 5-chloroindan-1-one in 60 ml of dry tetrahydrofuran is then
 slowly added, and the mixture is stirred at -50.degree. C. for a further
 20 minutes. Finally, 11.4 g of diphenyl-N-fluorosulfimide, dissolved in 60
 ml of dry tetrahydrofuran, are added dropwise. The mixture is allowed to
 warm to 0.degree. C. with stirring over the course of 2 hours, 120 ml of
 saturated sodium bicarbonate solution are added dropwise, the
 tetrahydrofuran is distilled out in vacuo, and the residue is extracted by
 shaking twice with 150 ml of ethyl acetate. The organic phase is washed
 with water and saturated brine, dried over magnesium sulfate, concentrated
 and purified by chromatography on silica gel with diisopropyl
 ether/n-heptane 1/1. 5-Chloro-2,2-difluoroindan-1-one is obtained with a
 melting point of 102-104.degree. C. in addition to
 5-chloro-2-fluoroindan-1-one.
 b) 5-Chlor-2-bromo-2-fluoroindan-1-one:
 Bromination of 5-chloro-2-fluoroindan-1-one takes place as described in
 Procedure Example 2b) and affords 5-chloro-2-bromo-2-fluoroindan-1-one
 with a melting point of 104-105.degree. C.
 2-Amino-6-chloro-8a-fluoro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol:
 263 mg of 5-chloro-2-bromo-2-fluoroindan-1-one and 152 mg of thiourea are
 dissolved in 2.5 ml of dry dimethyl sulfoxide and stirred at 50.degree. C.
 for 8 h. Excess triethylamine is added to the reaction mixture, which is
 then concentrated in vacuo. The residue is purified by chromatography on
 silica gel with ethyl acetate as eluent. 2-Amino-6-chloro-8a-fluoro-8
 ,8a-dihydroindeno[1,2-d]thiazol-3a-ol is obtained with a melting point of
 159.degree. C.
 Inventors hereby incorporate by reference the prior application DE
 19908539.0 filed Feb. 26, 1999.