RU2252219C2 - Indeno-, naphtho-, and benzocycloheptadihydrothiazole derivatives, production thereof and uses as anorexia pharmaceuticals - Google Patents

Abstract

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles of formula I

, containing in substituted alkyl residues in 2-posiiton, as well as physiologically accepted salts thereos, having anorexia action. In formula Y is direct bond; X is CH₂; R1 and R1' are independently H, Cl; R2 and R3 are H; R4 is (C₈-C₁₆-cycloalkyl, (CH₂)n-A-R8, wherein n = 1-6, excepted group of formula -CH₂-O-CH₂-phenyl with unsubstituted phenyl; A is O, S; R8 is methyl or (CH₂)_m-aryl, where in m = 0-6; and aryl may represent phenyl, wherein aryl group may be optionally substituted with one or two substituents, selected from Cl, O-(C₁-C₆)-alkyl or (C₁-C₆)-alkyl. Also disclosed is method for production thereof.

EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

Description

Polycyclic dihydrothiazoles containing substituted alkyl radicals in position 2, the method for their preparation and their use as medicines.

The invention relates to polycyclic dihydrothiazoles, as well as their physiologically acceptable salts and physiologically active derivatives.

Thiazolidine derivatives with anorexic (i.e., appetite suppressant) action are already described in the prior art (Austrian patent No. 365181).

The basis of the invention is the task of obtaining new compounds exhibiting a therapeutically suitable anorexic effect.

Thus, the invention relates to compounds of formula (I):

where Y is a direct bond, —CH ₂ -, —CH ₂ —CH ₂ -;

X is CH ₂ , CH (CH ₃ ), CH (C ₂ H ₅ ), CH (C ₃ H ₇ ), CH (C ₆ H ₅ );

R1, R1 ', independently of one another, are H, F, Cl, Br, I, CF ₃ NO ₂ , CN, COOH, COO- (C ₁ -C ₆ ) -alkyl, CONH ₂ , CONH- (C ₁ -C ₆ ) -alkyl, CON - [(C ₁ -C ₆ ) -alkyl] ₂ , (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) - alkynyl, O- (C ₁ -C ₆ ) -alkyl, moreover, in the alkyl radicals one, several or all hydrogen atoms can be replaced by fluorine or one hydrogen atom can be replaced by OH, OC (O) CH ₃ , OC (O ) H, O-CH ₂ -C ₆ H ₅ , NH ₂ , NH-CO-CH ₃ or N (COOCH ₂ C ₆ H ₅ ) ₂ ; SO ₂ —NH ₂ , SO ₂ NH- (C ₁ -C ₆ ) -alkyl, SO ₂ N - [(C ₁ -C ₆ ) -alkyl] ₂ , S- (C ₁ -C ₆ ) -alkyl, S - (CH ₂ ) _n- phenyl, SO- (C ₁ -C ₆ ) -alkyl, SO- (CH ₂ ) _n- phenyl, SO ₂ - (C ₁ -C ₆ ) -alkyl, SO ₂ - (CH ₂ ) _{n is} phenyl, wherein n can be 0-6 and the phenyl residue can be substituted with substituents in an amount up to two inclusive, selected from F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ ; NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , NH- (C ₁ -C ₇ ) -acyl, phenyl, biphenyl. O- (CH ₂ ) _n- phenyl, wherein n may be 0-6, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, wherein phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings, respectively, can be substituted with up to three substituents, inclusive, selected from F, Cl, Br, I, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , SO ₂ -CH ₃ , COOH, COO- (C ₁ -C ₆ ) -alkyl, CONH ₂ ; 1,2,3-triazol-5-yl, wherein the triazole ring at position 1, 2 or 3 may be substituted with methyl or benzyl;

tetrazol-5-yl, wherein the tetrazole ring at position 1 or 2 may be substituted with methyl or benzyl;

R2 is H, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, (CH ₂ ) _n- phenyl, (CH ₂ ) _n- thienyl, (CH ₂ ) _n- pyridyl, (CH ₂ ) _n- furyl, C (O) - (C ₁ -C ₆ ) -alkyl, C (O) - (C ₃ -C ₆ ) -cycloalkyl, C (O) - (CH ₂ ) _n- phenyl, C (O) - (CH ₂ ) _n- thienyl, C (O) - (CH ₂ ) _n- pyridyl, C (O) - (CH ₂ ) _n- furyl, where n may mean 0-5 and where phenyl, thienyl , pyridyl, furyl, respectively, can be substituted with substituents in an amount up to two inclusive, selected from Cl, F, CN, CF ₃ , (C ₁ -C ₃ ) -alkyl, OH, O- (C ₁ -C ₆ ) - alkyl;

R3 is H, (C ₁ -C ₆ ) -alkyl, F, CN, N ₃ , O- (C ₁ -C ₆ ) -alkyl, (CH ₂ ) _n- phenyl, (CH ₂ ) _n- thienyl, ( CH ₂ ) _{n is} pyridyl, (CH ₂ ) _{n is} furyl, wherein n may be 0-5 and where phenyl, thienyl, pyridyl, furyl, respectively, may be substituted with up to two inclusive substituents selected from Cl, F, CN, CF ₃ , (C ₁ -C ₃ ) -alkyl, OH, O- (C ₁ -C ₆ ) -alkyl; (C ₂ -C ₆ ) alkynyl, (C ₁ -C ₆ ) alkenyl, C (O) OCH ₃ , C (O) OCH ₂ CH ₃ , C (O) OH, C (O) NH ₂ , C (O) NCHH ₃ , C (O) N (CH ₃ ) ₂ , OC (O) CH ₃ ;

R4 is (C ₈ -C ₁₆ ) cycloalkyl, wherein in the alkyl radicals one or more hydrogen atoms can be replaced by fluorine or one hydrogen atom can be replaced by OH, OC (O) CH ₃ , OC (O) H, O -CH ₃ phenyl or O- (C ₁ -C ₄ ) -alkyl;

(CH ₂ ) _n —A — R8, wherein n may be 1-6; wherein the —CH ₂ —O — CH ₂ phenyl group is excluded, where phenyl is unsubstituted;

(CH ₂ ) _r —B — R9, wherein r may be 1-6;

And means O, S, SO, SO ₂ ;

B is NH, N- (C ₁ -C ₆ ) -alkyl, NCHO, N (CO-CH ₃ );

R8 means (C ₅ -C ₂₄ ) -alkyl, (C ₃ -C ₁₀ ) -cycloalkyl, moreover, in the alkyl radicals one or more hydrogen atoms can be replaced by fluorine or one hydrogen atom can be replaced by OH, OC (O) CH ₃ , OS (O) H, O-CH ₂ phenyl or O- (C ₁ -C ₄ ) -alkyl; (CH ₂ ) _{m is} aryl, where m = 0-6 and aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl, and the aryl moiety may be substituted with up to two inclusive substituents selected from F, Cl, Br, OH , CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, S- (C ₁ -C ₆ ) -alkyl, SO- (C ₁ -C ₆ ) -alkyl, SO ₂ - (C ₁ -C ₆ ) -alkyl, SO ₂ -NH ₂ , SO ₂ -NH- (C ₁ -C ₈ ) -alkyl, SO ₂ -N - [(C ₁ -C ₈ ) -alkyl] ₂ , SO ₂ -NH- (C ₃ -C ₈ ) -cycloalkyl, SO ₂ -N - [(C ₃ -C ₈ ) -cycloalkyl] ₂ , (CH ₂ ) _m -SO ₂ -NH ₂ , (CH ₂ ) _m -SO ₂ -NH- (C ₁ -C ₆ ) -alkyl, (CH ₂ ) _m -SO ₂ -N - [(C ₁ -C ₆ ) -alkyl] ₂ , where m may mean 1-6, SO ₂ -N - (= CH-N _{(CH3) 2),} (C ₁ -C ₆₎ -alkyl, (C ₃ -C ₆₎ -cycloalkyl, COOH, COO- (C ₁ -C ₆₎ -alkyl, CO - (C ₃ -C ₆₎ -cycloalkyl, CONH _2, CONH- (C ₁ -C ₆₎ -alkyl, CON - [(C ₁ -C ₆₎ -alkyl] _2, CONH- (C ₃ -C ₆₎ -cycloalkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , NH-CO- (C ₁ -C ₆ ) -alkyl, NH-CO phenyl, NH-SO ₂ - (C ₁ -C ₈ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] -SO ₂ - (C ₁ -C ₈ ) -alkyl, NH-SO ₂ - phenyl, moreover, the phenyl ring can be substituted with substituents in an amount up to two inclusive, selected from F, Cl, CN, OH, (C ₁ -C ₆ ) -alkyl, O- (C ₁ -C ₆ ) -alkyl, CF ₃ , COOH, COO- (C ₁ -C ₆ ) -alkyl or CONH ₂ ; pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH ₂ ) _p- phenyl, O- (CH ₂ ) _p- phenyl, S- (CH ₂ ) _p- phenyl or SO ₂ - (CH ₂ ) _p- phenyl, wherein p may be 0-3;

R9 is (CH ₂ ) m-aryl, m = 0-6, and aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl;

and the aryl moiety may be substituted with substituents in an amount up to two inclusive, selected from F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, S- (C ₁ -C ₆ ) -alkyl, SO- (C ₁ -C ₆ ) -alkyl, SO ₂ - (C ₁ -C ₆ ) -alkyl, SO ₂ -NH ₂ , SO ₂ -NH- (C ₁ -C ₈ ) -alkyl, SO ₂ -N - [(C ₁ -C ₈ ) -alkyl] ₂ , SO ₂ -NH- (C ₃ -C ₈ ) -cycloalkyl, SO ₂ -N - [(C ₃ -C ₈ ) -cycloalkyl] ₂ , (CH ₂ ) _m —SO ₂ —NH ₂ , (CH ₂ ) _m —SO ₂ —NH- (C ₁ -C ₆ ) -alkyl, (CH ₂ ) _m —SO ₂ —N- [ (C ₁ -C ₆ ) -alkyl] ₂ , where m may mean 1-6, SO ₂ -N - (= CH-N (CH ₃ ) ₂ ), (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) cycloalkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, COO- (C ₃ -C ₆ ) -cycloalkyl, CONH ₂ , CONH- (C ₁ -C ₆ ) -alkyl, CON- [(C ₁ -C ₆ ) -alkyl] ₂ , CONH- (C ₃ -C ₆ ) -cycloalkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , NH-CO- (C ₁ -C ₆ ) -alkyl, NH-CO-phenyl, NH- SO ₂ - (C ₁ -C ₈ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] -SO ₂ - (C ₁ -C ₈ ) -alkyl, NH-SO ₂ -phenyl, wherein the phenyl ring may be substituted with substituents in an amount up to two inclusive, selected from F, Cl, CN, OH, (C ₁ -C ₆ ) -alkyl, O- (C ₁ -C ₆ ) -alkyl, CF ₃ , COOH, COO- ( C ₁ -C ₆ ) -alkyl or CONH ₂ ; pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH ₂ ) _p- phenyl, O- (CH ₂ ) _p- phenyl, S- (CH ₂ ) p-phenyl or SO ₂ - (CH ₂ ) _p- phenyl, wherein p may be 0-3;

as well as their physiologically acceptable salts.

Preferred compounds of formula (I), where

Y is a direct bond;

X is CH ₂ ;

R1, R1 ', independently of one another, are H, F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOH, COO- (C ₁ -C ₆ ) -alkyl, CONH ₂ , CONH- (C ₁ -C ₆ ) -alkyl, CON - [(C ₁ -C ₆ ) -alkyl] ₂ , (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, O- (C ₁ -C ₆ ) -alkyl, moreover, in the alkyl radicals one, several or all hydrogen atoms can be replaced by fluorine or one hydrogen atom can be replaced by OH, OC (O) CH ₃ , OC ( O) H, O — CH ₂ —C ₆ H ₅ , NH ₂ , NH — CO — CH ₃ or N (COOCH ₂ C ₆ H ₅ ) ₂ ; SO ₂ -NH ₂ , SO ₂ NH- (C ₁ -C ₆ ) -alkyl, SO ₂ N - [(C ₁ -C ₆ ) -alkyl] ₂ , S- (C ₁ -C ₆ ) -alkyl, S - (CH ₂ ) _n- phenyl, SO- (C ₁ -C ₆ ) -alkyl, SO- (CH ₂ ) _n- phenyl, SO ₂ - (C ₁ -C ₆ ) -alkyl, SO ₂ - (CH ₂ ) _{n is} phenyl, wherein n can be 0-6 and the phenyl residue can be substituted with substituents in an amount up to two inclusive, selected from F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ ; NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , NH- (C ₁ -C ₇ ) -acyl, phenyl, biphenyl. O- (CH ₂ ) _n- phenyl, wherein n may be 0-6, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, wherein phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings, respectively, can be substituted with up to three substituents, inclusive, selected from F, Cl, Br, I, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , SO ₂ -CH ₃ , COOH, COO- (C ₁ -C ₆ ) -alkyl, CONH ₂ ;

1,2,3-triazol-5-yl, wherein the triazole ring at position 1, 2 or 3 may be substituted with methyl or benzyl;

tetrazol-5-yl, wherein the tetrazole ring at position 1 or 2 may be substituted with methyl or benzyl;

R2 is H, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, (CH ₂ ) _n- phenyl, (CH ₂ ) _n- thienyl, (CH ₂ ) _n- pyridyl, (CH ₂ ) _n- furyl, C (O) - (C ₁ -C ₆ ) -alkyl, C (O) - (C ₃ -C ₆ ) -cycloalkyl, C (O) - (CH ₂ ) _n- phenyl, C (O) - (CH ₂ ) _n- thienyl, C (O) - (CH ₂ ) _n- pyridyl, C (O) - (CH ₂ ) _n- furyl, where n may mean 0-5 and where phenyl, thienyl , pyridyl, furyl, respectively, can be substituted with substituents in an amount up to two inclusive, selected from Cl, F, CN, CF ₃ , (C ₁ -C ₃ ) -alkyl, OH, O- (C ₁ -C ₆ ) - alkyl;

R3 is H, (C ₁ -C ₆ ) -alkyl, F, CN, N ₃ , O- (C ₁ -C ₆ ) -alkyl, (CH ₂ ) _n- phenyl, (CH ₂ ) _n- thienyl, ( CH ₂ ) _{n is} pyridyl, (CH ₂ ) _{n is} furyl, wherein n may be 0-5 and where phenyl, thienyl, pyridyl, furyl, respectively, may be substituted with up to two inclusive substituents selected from Cl, F, CN, CF ₃ , (C ₁ -C ₃ ) -alkyl, OH, O- (C ₁ -C ₆ ) -alkyl; (C ₂ -C ₆ ) alkynyl, (C ₂ -C ₆ ) alkenyl, C (O) OCH ₃ , C (O) OCH ₂ CH ₃ , C (O) OH, C (O) NH ₂ , C (O) NHCH ₃ , C (O) N (CH ₃ ) ₂ , OC (O) CH ₃ ;

R4 is (C ₈ -C ₁₆ ) cycloalkyl, wherein in the alkyl radicals one or more hydrogen atoms can be replaced by fluorine or one hydrogen atom can be replaced by OH, OC (O) CH ₃ , OC (O) H, O -CH ₂ -phenyl or O- (C ₁ -C ₄ ) -alkyl;

(CH ₂ ) _n —A — R8, wherein n may be 1-6;

wherein the —CH ₂ —O — CH ₂ phenyl group is excluded, where phenyl is unsubstituted;

(CH ₂ ) _r -B-R9, wherein r may be 1-6;

And means O, S, SO, SO ₂ ;

B is NH, N- (C ₁ -C ₆ ) -alkyl, NCHO, N (CO-CH ₃ );

R ₈ means (C ₅ -C ₂₄ ) -alkyl, (C ₃ -C ₁₀ ) -cycloalkyl, moreover, in the alkyl radicals one or more hydrogen atoms can be replaced by fluorine or one hydrogen atom can be replaced by OH, OC (O ) CH ₃ , OS (O) H, O-CH ₂ phenyl or O- (C ₁ -C ₄ ) -alkyl;

(CH ₂ ) _m -aryl, with m = 0-6 and aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl;

and the aryl moiety may be substituted with substituents in an amount up to two inclusive, selected from F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, S- (C ₁ -C ₆ ) -alkyl, SO- (C ₁ -C ₆ ) -alkyl, SO ₂ - (C ₁ -C ₆ ) -alkyl, SO ₂ -NH ₂ , SO ₂ -NH- (C ₁ -C ₈ ) -alkyl, SO ₂ -N - [(C ₁ -C ₈ ) -alkyl] ₂ , SO ₂ -NH- (C ₃ -C ₈ ) -cycloalkyl, SO ₂ -N - [(C ₃ -C ₈ ) -Cycloalkyl] ₂ , (CH ₂ ) _m —SO ₂ —NH ₂ , (CH ₂ ) _m —SO ₂ —NH- (C ₁ -C ₆ ) -alkyl, (CH ₂ ) _m —SO ₂ —N- [ (C ₁ -C ₆ ) -alkyl] ₂ , and m may mean 1-6, SO ₂ -N - (= CH-N (CH ₃ ) ₂ ), (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) cycloalkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, COO- (C ₃ -C ₆ ) -cycloalkyl, CONH ₂ , CONH- (C ₁ -C ₆ ) -alkyl, CON- [(C ₁ -C ₆ ) -alkyl] ₂ , CONH- (C ₃ -C ₆ ) -cycloalkyl la, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , NH-CO- (C ₁ -C ₆ ) -alkyl, NH-CO- phenyl, NH-SO ₂ - (C ₁ -C ₈ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] -SO ₂ - (C ₁ -C ₈ ) -alkyl, NH-SO ₂ -phenyl wherein the phenyl ring can be substituted with up to two inclusive substituents selected from F, Cl, CN, OH, (C ₁ -C ₆ ) -alkyl, O- (C ₁ -C ₆ ) -alkyl, CF ₃ , COOH , COO- (C ₁ -C ₆ ) -alkyl or CONH ₂ ; pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH ₂ ) _p- phenyl, O- (CH ₂ ) _p- phenyl, S- (CH ₂ ) _p- phenyl or SO ₂ - (CH ₂ ) _p- phenyl, wherein p may be 0-3;

R9 is (CH ₂ ) _m aryl, m = 0-6 and aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl; and the aryl moiety may be substituted with substituents in an amount up to two inclusive, selected from F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, S- (C ₁ -C ₆ ) -alkyl, SO- (C ₁ -C ₆ ) -alkyl, SO ₂ - (С ₁ -С ₆ ) -alkyl, SO ₂ -NH ₂ , SO ₂ -NН- (С ₁ -С ₈ ) -alkyl, SO ₂ -N - [(C ₁ -C ₈ ) -alkyl] ₂ , SO ₂ -NH- (C ₃ -C ₈ ) -cycloalkyl, SO ₂ -N - [(C ₃ -C ₈ ) -cycloalkyl] ₂ , (CH ₂ ) _m —SO ₂ —NH ₂ , (CH ₂ ) _m —SO ₂ —NH- (C ₁ -C ₆ ) -alkyl, (CH ₂ ) _m —SO ₂ —N- [ (C ₁ -C ₆ ) -alkyl] ₂ , and m may mean 1-6, SO ₂ -N - (= CH-N (CH ₃ ) ₂ ), (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) cycloalkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, COO- (C ₃ -C ₆ ) -cycloalkyl, CONH ₂ , CONH- (C ₁ -C ₆ ) -alkyl, CON- [(C ₁ -C ₆ ) -alkyl] ₂ , CONH- (C ₃ -C ₆ ) -cycloalkyl a, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ -alkyl] ₂ , NH-CO- (C ₁ -C ₆ ) -alkyl, NH-CO-phenyl , NH-SO ₂ - (C ₁ -C ₈ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] -SO ₂ - (C ₁ -C ₈ ) -alkyl, NH-SO ₂ -phenyl, moreover, the phenyl ring can be substituted with substituents in an amount up to two inclusive, selected from F, Cl, CN, OH, (C ₁ -C ₆ ) -alkyl, O- (C ₁ -C ₆ ) -alkyl, CF ₃ , COOH, COO- (C ₁ -C ₆ ) -alkyl or CONH ₂ ; pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH ₂ ) _p- phenyl, O- (CH ₂ ) _p- phenyl, S- (CH ₂ ) _p- phenyl or SO ₂ - (CH ₂ ) _p- phenyl, wherein p may be 0-3;

as well as their physiologically acceptable salts.

Particularly preferred compounds of formula (I), where

Y is a direct bond;

X is CH ₂ ;

R1, R1 ', independently of one another, are H, F, Cl, Br, I, CF ₃ , NO ₂ , CN, COOH, COO- (C ₁ -C ₆ ) -alkyl, CONH ₂ , CONH- (C ₁ -C ₆ ) -alkyl, CON - [(C ₁ -C ₆ ) -alkyl] ₂ , (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, O- (C ₁ -C ₆ ) -alkyl, moreover, in the alkyl radicals one, several or all hydrogen atoms can be replaced by fluorine or one hydrogen atom can be replaced by OH, OC (O) CH ₃ , OC ( O) H, O — CH ₂ —C ₆ H ₅ , NH ₂ , NH — CO — CH ₃ or N (COOCH ₂ C ₆ H ₅ ) ₂ ; SO ₂ -NH ₂ , SO ₂ NH- (C ₁ -C ₆ ) -alkyl, SO ₂ N - [(C ₁ -C ₆ ) -alkyl] ₂ , S- (C ₁ -C ₆ ) -alkyl, S - (CH ₂ ) _n- phenyl, SO- (C ₁ -C ₆ ) -alkyl, SO- (CH ₂ ) _n- phenyl, SO ₂ - (C ₁ -C ₆ ) -alkyl, SO ₂ - (CH ₂ ) _{n is} phenyl, wherein n can be 0-6 and the phenyl residue can be substituted with substituents in an amount up to two inclusive, selected from F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ ;

NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , NH- (C ₁ -C ₇ ) -acyl, phenyl, biphenyl, O- (CH ₂ ) _{n is} phenyl, wherein n may be 0-6, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, moreover phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl rings, respectively, can be substituted with up to three substituents, inclusive, selected from F, Cl, Br, I, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ - C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , SO ₂ -CH ₃ , COOH, COO- (C ₁ -C ₆ ) -alkyl, CONH ₂ ;

1,2,3-triazol-5-yl, wherein the triazole ring at position 1, 2 or 3 may be substituted with methyl or benzyl;

tetrazol-5-yl, wherein the tetrazole ring at position 1 or 2 may be substituted with methyl or benzyl;

R2 is H, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, (CH ₂ ) _n- phenyl, (CH ₂ ) _n- thienyl, (CH ₂ ) _n- pyridyl, (CH ₂ ) _n- furyl, C (O) - (C ₁ -C ₆ ) -alkyl, C (O) - (C ₃ -C ₆ ) -cycloalkyl, C (O) - (CH ₂ ) _n- phenyl, C (O) - (CH ₂ ) _n- thienyl, C (O) - (CH ₂ ) _n- pyridyl, C (O) - (CH ₂ ) _n- furyl, where n may mean 0-5 and where phenyl, thienyl , pyridyl, furyl, respectively, can be substituted with substituents in an amount up to two inclusive, selected from Cl, F, CN, CF ₃ , (C ₁ -C ₃ ) -alkyl, OH, O- (C ₁ -C ₆ ) - alkyl;

R3 is H, F;

R4 means (C ₈ -C ₁₆ ) -cycloalkyl, wherein in the alkyl radicals one or more hydrogen atoms can be replaced by fluorine or one hydrogen atom can be replaced by OH, OC (O) CH ₃ , OC (O) H, O -CH ₂ phenyl or O- (C ₁ -C ₄ ) -alkyl;

(CH ₂ ) _n —A — R8, wherein n may be 1-6;

wherein the —CH ₂ —O — CH ₂ phenyl group is excluded, where phenyl is unsubstituted;

(CH ₂ ) _r -B-R9, wherein r may be 1-6;

A means O, S;

B is NH, N- (C ₁ -C ₆ ) -alkyl, NCHO, N (CO-CH ₃ );

R8 means (C ₅ -C ₂₄ ) -alkyl, (C ₃ -C ₁₀ ) -cycloalkyl, moreover, in the alkyl radicals one or more hydrogen atoms can be replaced by fluorine or one hydrogen atom can be replaced by OH, OC (O) CH ₃ , OS (O) H, O-CH ₂ phenyl or O- (C ₁ -C ₄ ) -alkyl;

(CH ₂ ) _m -aryl, with m = 0-6 and aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl; and the aryl moiety may be substituted with substituents in an amount up to two inclusive, selected from F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, S- (C ₁ -C ₆ ) -alkyl, SO- (C ₁ -C ₆ ) -alkyl, SO ₂ - (C ₁ -C ₆ ) -alkyl, SO ₂ -NH ₂ , SO ₂ -NH- (C ₁ -C ₈ ) -alkyl, SO ₂ -N - [(C ₁ -C ₈ ) -alkyl] ₂ , SO ₂ -NH- (C ₃ -C ₈ ) -cycloalkyl, SO ₂ -N - [(C ₃ -C ₈ ) -cycloalkyl] ₂ , (CH ₂ ) _m —SO ₂ —NH ₂ , (CH ₂ ) _m —SO ₂ —NH- (C ₁ -C ₆ ) -alkyl, (CH ₂ ) _m —SO ₂ —N- [ (C ₁ -C ₆ ) -alkyl] ₂ , where m may mean 1-6, SO ₂ -N - (= CH-N (CH ₃ ) ₂ ), (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, COO- (C ₃ -C ₆ ) -cycloalkyl, CONH ₂ , CONH- (C ₁ -C ₆ ) -alkyl, CON- [(C ₁ -C ₆ ) -alkyl] ₂ , CONH- (C ₃ -C ₆ ) -cycloalkyl, NH ₂ , NH - (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , NH-CO- (C ₁ -C ₆ ) -alkyl, NH-CO-phenyl, NH -SO ₂ - (C ₁ -C ₈ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] -SO ₂ - (C ₁ -C ₆ ) -alkyl, NH-SO ₂ -phenyl, with phenyl the ring may be substituted with substituents in an amount up to two inclusive, selected from F, Cl, CN, OH, (C ₁ -C ₆ ) -alkyl, O- (C ₁ -C ₆ ) -alkyl, CF ₃ , COOH, COO- (C ₁ -C ₆ ) -alkyl or CONH ₂ ; pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH ₂ ) _p- phenyl, O- (CH ₂ ) _p- phenyl, S- (CH ₂ ) _p- phenyl or SO ₂ - (CH ₂ ) _p- phenyl, wherein p may be 0-3;

R9 is (CH ₂ ) _m aryl, m = 0-6 and aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl; and the aryl moiety may be substituted with substituents in an amount up to two inclusive, selected from F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, S- (C ₁ -C ₆ ) -alkyl, SO- (C ₁ -C ₆ ) -alkyl, SO ₂ - (C ₁ -C ₆ ) -alkyl, SO ₂ -NH ₂ , SO ₂ -NH- (C ₁ -C ₈ ) -alkyl, SO ₂ -N - [(C ₁ -C ₈ ) -alkyl] ₂ , SO ₂ -NH- (C ₃ -C ₈ ) -cycloalkyl, SO ₂ -N - [(C ₃ -C ₈ ) -cycloalkyl] ₂ , (CH ₂ ) _m —SO ₂ —NH ₂ , (CH ₂ ) _m —SO ₂ —NH- (C ₁ -C ₆ ) -alkyl, (CH ₂ ) _m —SO ₂ —N- [ (C ₁ -C ₆ ) -alkyl] ₂ , where m may mean 1-6, SO ₂ -N - (= CH-N (CH ₃ ) ₂ ), (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) cycloalkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, COO- (C ₃ -C ₆ ) -cycloalkyl, CONH ₂ , CONH- (C ₁ -C ₆ ) -alkyl, CON- [(C ₁ -C ₆ ) -alkyl] ₂ , CONH- (C ₃ -C ₆ ) -cycloalkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , NH-CO- (C ₁ -C ₆ ) -alkyl, NH-CO-phenyl, NH-SO ₂ - (C ₁ -C ₈ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] -SO ₂ - (C ₁ -C ₆ ) -alkyl, NH-SO ₂ -phenyl, wherein the phenyl ring may be substituted with substituents in up to two inclusive, selected from F, Cl, CN, OH, (C ₁ -C ₆ ) -alkyl, O- (C ₁ -C ₆ ) -alkyl, CF ₃ , COOH, COO- (C ₁ -C ₆ ) -alkyl or CONH ₂ ; pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH ₂ ) _p- phenyl, O- (CH ₂ ) _p- phenyl, S- (CH ₂ ) _p- phenyl or SO ₂ - (CH ₂ ) _p- phenyl, wherein p may be 0-3;

as well as their physiologically acceptable salts.

Particularly preferred are compounds of formula (I) wherein

Y is a direct bond;

X is CH ₂ ;

R1, R1 ', independently of one another, are H, F, Cl, Br, I, (C ₁ -C ₆ ) -alkyl;

R 2 is H, (C ₁ -C ₆ ) -alkyl;

R3 is H, F;

R4 is (C ₈ -C ₁₆ ) -cycloalkyl or (CH ₂ ) _n -A-R8, wherein n may be 1-6 and, excluding the —CH ₂ —O — CH ₂ -phenyl group, where phenyl is unsubstituted;

A means O, S;

R8 is (C ₅ -C ₂₄ ) -alkyl or (CH ₂ ) _m- aryl, with m = 0-6 and aryl may be phenyl, and the aryl part may be substituted with up to two substituents, selected from F, Cl , Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) -alkyl, S- (C ₁ -C ₆ ) -alkyl, SO- (C ₁ -C ₆ ) - alkyl, SO ₂ - (C ₁ -C ₆ ) -alkyl, SO ₂ -NH ₂ , SO ₂ -NH- (C ₁ -C ₈ ) -alkyl, SO ₂ -N - [(C ₁ -C ₈ ) - alkyl] ₂ , SO ₂ —NH- (C ₃ -C ₈ ) -cycloalkyl, SO ₂ -N - [(C ₃ -C ₈ ) -cycloalkyl] ₂ , (CH ₂ ) _m —SO ₂ —NH ₂ , ( CH ₂ ) _m -SO ₂ -NH- (C ₁ -C ₆ ) -alkyl, (CH ₂ ) _m -SO ₂ -N - [(C ₁ -C ₆ ) -alkyl] ₂ , where m may mean 1- 6, SO ₂ -N - (= CH-N (CH ₃ ) ₂ ), (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, COO- (C ₃ -C ₆ ) -c icloalkyl, CONH ₂ , CONH- (C ₁ -C ₆ ) -alkyl, CON - [(C ₁ -C ₆ ) -alkyl] ₂ , CONH- (C ₃ -C ₆ ) -cycloalkyl, NH ₂ , NH- ( C ₁ -C ₆ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] ₂ , NH-CO- (C ₁ -C ₆ ) -alkyl, NH-CO-phenyl, NH-SO ₂ - ( C ₁ -C ₈ ) -alkyl, N - [(C ₁ -C ₆ ) -alkyl] -SO ₂ - (C ₁ -C ₈ ) -alkyl, NH-SO ₂ -phenyl, the phenyl ring being optionally substituted in an amount up to two inclusive, selected from F, Cl, CN, OH, (C ₁ -C ₆ ) -alkyl, O- (C ₁ -C ₆ ) -alkyl, CF ₃ , COOH, COO- (C ₁ -C ₆ ) -alkyl or CONH ₂ ; pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH ₂ ) _p- phenyl, O- (CH ₂ ) _p- phenyl, S- (CH ₂ ) _p- phenyl or SO ₂ - (CH ₂ ) _p- phenyl,

wherein p may be 0-3; as well as their physiologically acceptable salts.

The invention relates to compounds of formula (I) in the form of their racemates, racemic mixtures and pure enantiomers, as well as their diastereomers and their mixtures.

Alkyl, alkenyl and alkynyl radicals in the substituents R1, R1 ’, R2, R3, R4, R8 and A can be either linear or branched.

Pharmaceutically acceptable salts, based on their higher solubility in water compared to the starting or basic compounds, are particularly suitable for medical applications. These salts must contain a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are inorganic salts such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, as well as organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, ma leinic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid. For medical purposes, hydrochloric acid salt is particularly preferably used. Suitable pharmaceutically acceptable base 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 are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for non-therapeutic use, for example, in vitro applications.

As used herein, the term “physiologically functional derivative” means any physiologically acceptable derivative of a compound of formula (I) according to the invention, for example, an ester which, when administered to a mammal, such as a human being, is capable of (directly or indirectly) forming a compound of the formula ( I) or its active metabolite.

Physiologically functional derivatives also include prodrug forms of the compounds of the invention. Such prodrugs can be metabolized in vivo to the compounds of the invention. These prodrugs themselves may be active or not.

The compounds according to the invention can also be in various polymorphic forms, for example, in the form of amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and constitute a further aspect of the invention.

In the following text, all references to “compound (s) according to formula (I)” refer to the compound (s) of formula (I) as described above, as well as their salts, solvates and physiologically active derivatives, as described herein .

The amount of the compound according to formula (I), which is necessary to achieve the desired biological effect, depends on a number of factors, for example, on the specific compound chosen, the intended use, the route of administration and the clinical condition of the patient. In general, the daily dose is in the range of 0.3 mg to 100 mg (usually 3 mg to 50 mg) per day per kilogram of body weight, for example 3-10 mg / kg per day. An intravenous dose may be, for example, from 0.3 mg to 1.0 mg / kg, which may suitably be administered as an infusion in an amount of 10-100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, usually from 1 ng to 10 mg, of biologically active substance per milliliter. Single doses may contain, for example, from 1 mg to 10 g of a biologically active substance. Thus, ampoules for injection may contain, for example, 1-100 mg, orally administered dosage forms as single doses, such as tablets or capsules, may contain, for example, 1.0-1000 mg, usually 10-600 mg , biologically active substance. In the case of pharmaceutically acceptable salts, the above weight data refers to the weight of the dihydrothiazole ion produced from the salt. For the prophylaxis or therapy of the above conditions, the compounds according to formula (I) can be used individually as a compound, however, preferably they are, together with an acceptable carrier, in the form of a pharmaceutical composition. The carrier, of course, should be acceptable in the sense that it is compatible with other components of the composition and is not harmful to the health of the patient. The carrier may be a solid or liquid, or both of them, and is preferably used together with the compound to prepare the dosage form in a single dose, for example, in the form of a tablet, which may contain 0.05-95 wt.% Biologically active substance. Other pharmaceutically active substances may also be present, including other compounds according to formula (I). The pharmaceutical compositions of the invention can be prepared according to one of the known pharmaceutical methods, which essentially consist in mixing the components with pharmacologically acceptable carriers and / or excipients.

The pharmaceutical compositions of the invention are those suitable for oral, rectal, local, oral (e.g., sublingual) and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable route of administration in each case depends on the genus. and the severity of the condition being treated and the kind of compound used in each case according to formula (I). The scope of the invention also includes coated tablets and coated sustained-release dosage forms. Acid and gastric acid resistant dosage forms are preferred. Suitable gastric juice resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in separate units, such as, for example, capsules, coated capsules, sucking tablets or tablets, which respectively contain a certain amount of the compound according to formula (I); in the form of powders or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water emulsion or water-in-oil emulsion. These compositions, as already mentioned, can be prepared according to any suitable pharmaceutical methods, which include the step of contacting the biologically active substance and the carrier (which may consist of one or more additional components). In general, compositions are prepared by uniformly and homogeneously mixing the biologically active substance with a liquid and / or highly dispersed solid carrier, after which the product is molded if necessary. Thus, for example, a tablet may be prepared in that the powder or granulate of the compound is compressed or molded, if necessary, together with one or more additional components. Compressed tablets can be prepared by tabletting in a suitable machine, free-flowing compounds, such as powder or granules, optionally mixed with a binder, anti-slip tablets, an inert diluent and / or one (several) surfactant / dispersant. Molded tablets may be prepared by molding, in a suitable machine, a powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions that are suitable for oral (sublingual) use include sucking tablets that contain the compound according to formula (I) together with a flavoring substance, usually sucrose and gum arabic or tragacanth, and lozenges that contain the compound in an inert basis, like gelatin and glycerin or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administration include preferably sterile aqueous compositions of the compound according to formula (I), which are preferably isotonic with the blood of the intended recipient. These compositions are preferably administered intravenously, although subcutaneous, intramuscular or intradermal administration by injection can also be carried out. These compositions can preferably be prepared by a method in which the compound is mixed with water and the resulting solution is made sterile and isotonic with blood. The injectable compositions according to the invention contain, in general, 0.1-5 wt.% Of the active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single dose suppositories. They can be prepared by a method in which the compound according to formula (I) is mixed with one or more conventional solid carriers, such as cocoa butter, and the resulting mixture is brought into shape.

Pharmaceutical compositions suitable for topical application to the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. As carriers, you can use petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these substances. The biologically active substance is, in General, in a concentration of 0.1-15 wt.%, In relation to the weight of the composition, for example, 0.5-2 wt.%.

Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal administration may be in the form of separate patches which are suitable for long-term close contact with the epidermis of the patient. Such patches conveniently contain a biologically active substance, if necessary, in a buffered aqueous solution, dissolved and / or dispersed in an adhesive composition or dispersed in a polymer. A suitable concentration of biologically active substance is about 1-35%, preferably about 3-15%. As a special feature, as, for example, described in Pharmaceutical Research, 2 (6), 318 (1986), a biologically active substance can be released by electrotransport or electrophoresis.

The object of the invention, further, is a method for producing compounds of General formula (I), characterized in that the compounds of formula (I) are obtained by acting according to the following reaction scheme:

for this compound of general formula (II):

where R1, R1 ’, R3 and X and Y have the indicated meaning, are activated and are transferred to the compound of formula (III), where Z is the residue of an activated inorganic or organic acid ester.

The compounds of formula (III) are then reacted with thioamides of formula (VI):

where R4 has the indicated meaning to obtain compounds of formula (VII), respectively, of formula (I '), and, if necessary, compounds of general formula (I') are converted, using organic or inorganic acids, into their acid addition salts of formula (VII) ) or the resulting salts of formula (VII) are converted into the free basic forms of the compounds of formula (I ′) with organic or inorganic bases.

As inorganic acids, for example, hydrohalic acids, such as hydrochloric acid and hydrobromic acid, as well as sulfuric acid, phosphoric acid and amidosulfonic acid, are used.

Organic acids include, 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-benzisothiazole-3 (2H) -one, 6-methyl-1,2,3-oxathiazine-4 (3H) -one-2,2-dioxide.

The above method is preferably carried out so that the compounds of formula (III) are reacted with thioamides of formula (VI) in a molar ratio of 1: 1 to 1: 1.5. The reaction is preferably 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. Particularly preferred solvents may, however, be methyl acetate and ethyl acetate, short chain alcohols, such as methanol, ethanol, propanol, isopropanol, as well as lower dialkyl ketones, such as, for example, acetone, butan-2-one or hexane-2- he. Mixtures of these reaction media may also be used; and you can also use mixtures of these solvents with solvents that are less suitable for independent use, such as mixtures of methanol with benzene, ethanol with toluene, methanol with diethyl ether or tert-butyl methyl ether, ethanol with carbon tetrachloride, acetone with chloroform, dichloromethane or 1,2-dichloroethane, and the corresponding polar solvent is more appropriate to use in excess. The reaction components may be suspended or dissolved in an appropriate reaction medium. In principle, reaction components can also be reacted without solvent, especially when the corresponding thioamide has the lowest possible melting point. The reaction proceeds only slightly exothermically, and it can be carried out at a temperature of 10-150 ° C, preferably 30-100 ° C. Especially favorable is, as a rule, the temperature range from 50 ° C to 90 ° C.

The duration of the reaction largely depends on the reaction temperature and ranges from 2 minutes to 3 days at higher, respectively, lower temperatures. In a favorable temperature range, the reaction time is generally from 5 minutes to 48 hours.

Since the compounds of formula (VII) are often precipitated during the reaction in the sparingly soluble form of their acid addition salts, it is convenient to add a further suitable precipitant. As such, for example, hydrocarbons such as benzene, toluene, cyclohexane or heptane or carbon tetrachloride are used; in particular, acetic acid alkyl esters 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 are particularly suitable. If, at the end of the reaction, the reaction mixture remains in solution, then salts of the compounds of formula (VII), if necessary, can be precipitated after concentration of the reaction solution using one of these precipitators. In addition, a solution of the reaction mixture can also conveniently be added dropwise to a solution of one of these precipitators with stirring. Since the reaction of compounds of formula (III) with thioamides of formula (VI) proceeds practically quantitatively, the resulting crude products are most often already analytically pure. Processing of the reaction mixture can also be carried out in such a way that the reaction mixture is alkalinized by the 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 after concentration is purified by chromatography, for example, on a column of silica gel. Suitable eluting media for this purpose 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 by the latter method described, then from the thus obtained pure base of formula (I ′), the product of the addition of the acids of formula (VII) can be obtained in such a way that the base is dissolved or suspended in a protic organic solvent such as methanol, ethanol, propanol or isopropanol, or in an aprotic organic solvent such as ethyl acetate, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, acetone or butan-2-one, and this mixture is then mixed 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 further inorganic or organic acids mentioned above.

The compounds of formula (I ’) can be recrystallized from an inert suitable solvent, such as, for example, acetone, butan-2-one, acetonitrile, nitromethane. Particularly preferred, however, is reprecipitation from a solvent, such as, for example, dimethylformamide, dimethylacetamide, nitromethane, acetonitrile, preferably methanol or ethanol.

The reaction of compounds of formula (II) with thioamides of formula (VI) can also be carried out in such a way that at least an equimolar amount of a base, such as, for example, triethylamine, and the compounds of formula (I ′) thus obtained are added to the reaction mixture, then if necessary, the acids of the formula (VII) are converted to their products.

In the compounds of formula (III), for example, Cl, Br, I, O — C (O) - (C ₆ H ₄ ) -4-NO ₂ , O-SO ₂ -CH ₃ , are used as the residue of the activated ester Z, O-SO ₂ -CF ₃ , O-SO ₂ - (C ₆ H ₄ ) -4-CH ₃ , O-SO ₂ -C ₆ H ₄ .

The addition products of the acids of formula (VII) and (I) x HZ by treatment with bases can be converted into compounds of the general formulas (I) and (I ’). As bases, for example, 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 like triethylamine, diisopropylamine, dicyclohexylamine, piperidine, morpholine, methyldicyclohexylamine.

Thioamides of general formula (VI) are either commercially available or can be prepared, for example, by reacting the corresponding carboxylic acid amide of formula (V) 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. Beiges, 87, 229 (1978)], preferably in a mixture of tetrahydrofuran with 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone or 1,3-dimethyl-2-imidazolidinone. In this case, it is advisable to protect hydroxyl groups, amino groups or additional carbonyl groups with a leaving protective group, such as, for example, a benzyl residue, a tert-butyloxycarbonyl residue, a benzyloxycarbonyl residue, respectively, by transferring, if necessary, cyclic acetal. Methods for this purpose are described, for example, in Th. W. Greene and R. G. M. Wuts "Protective Groups in Organic Synthesis", second edition, 1991, John Wiley and Sons, New York.

Thioamides of the formula (VI) are also prepared in such a way that the nitriles of the general formula (IV):

enter into interaction with hydrogen sulfide (Guben-Vale, IX, 762) or thioacetamide (E.C. Taylor, J.A. Zoltewicz, J. Am. Chem. Soc., 82, 2656 (1960)) or O, O-diethyldithiophosphoric acid. The reaction with hydrogen sulfide is preferably carried out in an organic solvent such as methanol or ethanol, the interaction with thioacetamide is carried out in a solvent such as dimethylformamide, with the addition of hydrochloric acid, the interaction with O, O-diethyldithiophosphoric acid is carried out in a solvent such as ethyl acetate, in acidic, for example, Hcl, conditions at room temperature or when heated.

The following examples serve to illustrate the invention without, however, limiting its scope of protection. The measured melting or decomposition temperatures (mp) are given without corrections and, in general, depend on the heating rate.

The compounds of formula (I) are characterized by beneficial effects on fat metabolism, in particular they are suitable as anorexic agents. The compounds can be used individually or in combination with other anorexic biologically active substances. Such other anorexic active substances are indicated, for example, in the "Roten Liste", chapter 01, under the heading "Weight Loss / Appetite Reducing Agent". The compounds are suitable for prophylaxis, and especially for the treatment of obesity. The compounds are furthermore suitable for prophylaxis, and in particular for the treatment of type II diabetes.

The effectiveness of the compounds was tested as follows.

Biological testing model.

Anorexic action testing was performed on male or female NMRI mice. After food deprivation, the test drug was administered through a gastric tube for 24 hours. With individual keeping and with free access to drinking water, animals were offered condensed milk 30 minutes after drug administration. Every half hour for 7 hours, the consumption of condensed milk was determined and the general condition of the animals was observed. The measured milk flow was compared with that in the case of untreated control animals.

table 2
Anorexic effect, defined as a decrease in cumulative milk consumption by processed animals compared to untreated

Compound Example

Oral dose [mg / kg] Number of animals / cumulated milk consumption by treated animals (males) N / [ml] Number of animals / cumulated unprocessed milk consumption
and control animals (males) N / [ml] Reduced cumulative milk consumption in% of control Example 1 fifty 5 / 0.42 5 / 2.90 86 Example 2 fifty 5 / 0.34 5 / 2.90 88 Example 3 fifty 5 / 0.78 5 / 2.90 73 Example 5 fifty 5 / 0.42 5 / 4.18 90 Example 6 fifty 5 / 0.22 5 / 4.20 95 Example 8 fifty 5 / 0.28 5 / 4.20 93 Example 9 fifty 5 / 0.26 5 / 3.46 93 Compound Example

Oral dose [mg / kg] Number of animals / cumulated milk consumption by treated animals (females) N / [ml] Number of animals / cumulated unprocessed milk consumption
and control animals (females) N / [ml] Reduced cumulative milk consumption in% of control Example 10 fifty 5 / 1,04 5 / 4.64 78 Example 11 fifty 5 / 1.34 5 / 4.64 71 Example 12 fifty 5 / 1.36 5 / 4.64 71

From the table it can be seen that the compounds of formula (I) exhibit a very good anorexic effect.

The preparation of some compounds of formula (I) is described in detail below, the remaining compounds of formula (I) are prepared in a similar manner.

Example 1 (compound 1):

6-Chloro-2-phenoxymethyl-8,8a-dihydroindeno [1,2-d] thiazol-3a-ol

a) 2-Bromo-5-chloroindan-1-one

10 g (0.06 mol) of 5-Chlorindan-1-one at room temperature and dissolved with stirring in 120 ml of glacial acetic acid. 0.05 ml of a 48% solution of HBr in water and then 3.074 ml (0.06 mol) of bromine dissolved in 25 ml of glacial acetic acid are added dropwise. After stirring for 2 hours at room temperature, the reaction ends (control by thin layer chromatography). The solution of the crude product is slowly added dropwise with stirring to 300 ml of ice water. The precipitated crude product is filtered off with suction and washed thoroughly with water. The wet residue was separated from the filter with ethyl acetate and the phases of the filtrate were separated. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved by heating in 120 ml of n-heptane, the hot solution is filtered through a pleated filter and then the solution is left to stand at a temperature of 0 ° C for crystallization. The crystallized product is filtered off with suction and dried in vacuo.

Mp: 94-96 ° C.

b) 6-Chloro-2-phenoxymethyl-8,8a-dihydroindeno [1,2-d] thiazol-3a-ol

0.49 g of 2-Bromo-5-chloroindan-1-one at room temperature is dissolved in 10 ml of anhydrous acetone and mixed with 335 mg of 2-phenoxythioacetamide. It is stirred for 6 hours at room temperature, the crystallized hydrobromide of the product is filtered off with suction, the residue is washed with acetone and dried in vacuum. The free base is obtained by adding salt to a mixture of 30 ml of ethyl acetate and 20 ml of a saturated solution of sodium bicarbonate and stirring for 20 minutes. The organic phase is separated, washed with a saturated solution of sodium chloride and dried over magnesium sulfate. It is filtered off and the filtrate is concentrated in vacuo. Get 6-chloro-2-phenoxymethyl-8,8a-dihydroindeno [1,2-d] thiazol-3a-ol with a melting point of 121 ° C.

Example 2 (compound 6):

6-Chloro-2- (2,4-dichlorophenoxymethyl) -8,8a-dihydroindeno [1,2-d] thiazol-3a-ol hydrobromide

0.25 g of 2-Bromo-5-chloroindan-1-one and 0.24 g of 2- (2,4-dichlorophenoxy) thioacetamide are dissolved in 5 ml of anhydrous acetone at room temperature and stirred for 12 hours at room temperature. The precipitate formed is filtered off with suction, washed with acetone and dried under high vacuum. 6-Chloro-2- (2,4-dichlorophenoxymethyl) -8,8a-dihydroindeno [1,2-d] thiazol-3a-ol hydrobromide is obtained with a melting point of 170 ° C. (decomposition).

Example 3 (compound 9):

2- (4-tert-Butylphenoxymethyl) -6-chloro-8,8a-dihydroindeno- [1,2-d] thiazol-3a-ol

0.49 g of 2-Bromo-5-chloroindan-1-one and 0.45 g of 2- (4-tert-butylphenoxy) thioacetamide are dissolved in 10 ml of anhydrous acetone at room temperature and stirred for 12 hours at room temperature. The precipitated hydrobromide is filtered off with suction and washed with acetone. The residue was suspended in a small amount of ethyl acetate and treated with saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Get 2- (4-tert-butylphenoxymethyl) -6-chloro-8,8a-dihydroindeno [1,2-d] thiazol-3a-ol with a melting point of 122-124 ° C.

Example 4 (compound 12):

2-Benzylsulfanylmethyl-6-chloro-8,8a-dihydroindeno [1,2-d] thiazol-3a-ol

a) 2-Benzylsulfanylthioacetamide

At room temperature, 1.2 g of benzylsulfanylacetonitrile was dissolved in 10 ml of anhydrous ethanol, mixed with 1.25 ml of diethyl dithiophosphate and stirred for 6 hours at the boil under reflux. The cooled reaction solution was concentrated in vacuo and purified chromatographically on silica gel using a mixture of ethyl acetate and n-heptane in a ratio of 1: 2. The 2-benzylsulfanylthioacetamide thus obtained is used in the next step.

b) 2-Benzylsulfanylmethyl-6-chloro-8,8a-dihydroindeno- [1,2-d] thiazol-3a-ol

0.54 g of 2-benzylsulfanylthioacetamide is dissolved in 10 ml of anhydrous acetone at room temperature, 0.67 g of 2-bromo-5-chloroindan-1-one is added and stirred for 4 hours at room temperature. The precipitate formed is filtered off with suction, washed with acetone, treated with ethyl acetate, saturated sodium bicarbonate solution is added and shaken twice. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. Get 2-benzylsulfanylmethyl-6-chloro-8,8a-dihydroindeno [1,2-d] -thiazol-3a-ol with a melting point of 102-104 ° C.

Claims (5)

1. The compounds of formula (I):

Where Y is a direct bond; X is CH ₂ ; R1, R1 ', independently of one another, mean H, Cl; R2 is H; R3 is H; R4 is (C ₈ -C ₁₆ ) cycloalkyl; (CH ₂ ) _n —A — R8 where n may be 1-6; wherein the —CH ₂ —O — CH ₂ phenyl group is excluded, wherein phenyl is unsubstituted; A means O, S; R8 is methyl or (CH ₂ ) _m- aryl, with m = 0-6 and aryl may be phenyl, where the aryl moiety may be substituted with up to two substituents, inclusive, selected from Cl, O- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl; as well as their physiologically acceptable salts. 2. The compounds of claim 1 for use as a medicament for the prevention or treatment of obesity. 3. The compounds of claim 1 in combination with at least one other anorexic active substance for use as a medicament for the prevention or treatment of obesity. 4. A method of obtaining a medicinal product containing one or more compounds according to claim 1, characterized in that the biologically active substance is mixed with a pharmaceutically acceptable carrier and this mixture is adjusted to a form suitable for administration. 5. The method of producing compounds according to claim 1, characterized in that according to the following reaction scheme

Base

the compound of formula (VII), where X, Y, R1, R1 ', R3 and R4 are as defined for formula (I), are reacted with a base to produce a compound of formula (I ^/ ).