KR20070021229A - Substituted oxazolobenzoisothiazole dioxide derivatives, method for production and use thereof - Google Patents

Abstract

The present invention relates to compounds of formula (I) and physiologically acceptable salts thereof. The compound lowers blood sugar levels and is suitable as a medicament for the prevention and treatment of diabetes.

[Formula I]

In the above formula, each substituent is as defined.

Diabetes mellitus, hypoglycemia, oxazolobenzoisothiazoles, insulin resistance

Description

Substituted oxazolobenzoisothiazole dioxide derivatives, method for production and use according to substituted oxazolobenzoisothiazole dioxide derivatives

The present invention relates to substituted oxazole-benzoisothiazole dioxad derivatives and physiologically acceptable salts thereof.

Benzoisothiazole dioxide derivatives of similar structure have been described in the prior art, the use of which is for the treatment of diabetes (WO 02/11722).

The present invention is based on the object of providing a compound capable of preventing and treating diabetes. For this purpose, the compounds of the present invention are intended to exhibit therapeutically useful blood sugar lowering action. In particular, the compounds of the present invention are intended to exhibit improved effects or improved ADME profiles (absorption, distribution, metabolism and excretion) over the compounds of WO 02/11722.

The present invention therefore relates to compounds of formula (I) and physiologically acceptable salts thereof.

In the above formula,

X is O, C-R2;

Y is O, C-R2, and if either group X and Y is O, the other is C-R1,

Wherein R 1 and R 2 independently of one another are H, aryl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, -COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene -COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkylene-aryl, heterocycle, ( C ₁ -C ₆ ) -alkylene-heterocycle, CF ₃ , OCF ₃ , CN, (CH ₂ ) _1-6 -OH, O- (C ₁ -C ₆ ) -alkyl, CO- (C ₁ -C ₆ ) -alkyl, -C (O) O-alkyl, COOH, CON (R9) (R10), wherein the aryl radical and heterocycle radical are F, Cl, Br, (CH ₂ ) _0-2 OH, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine , Piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (C ₁ -C ₆ ) -alkyl, S (O) _0-2- (C ₁ -C ₆ ) -alkyl, S0 ₂ -N (R9) (R10), CO- (C ₁ -C ₆ ) -Alkyl, -COOH, (C ₁ -C ₆ ) -alkylene-COOH, COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ )- Alkyl, (C ₃ -C ₁₀ ) -cycloalkyl, pe It may be substituted one or more times with ni, wherein the piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) The piperazinone, morpholine, thiomorpholine and phenyl rings are F, Cl, Br, (CH ₂ ) _0-2 0H, COOH, CN, N0 ₂ , -O- (C ₁ -C ₆ ) -alkyl,- _{NH-O- (C 1 -C 6} ) - alkyl, - (CO) -NH-O- (C 1 -C 6) - alkylene -N (R9) (R10), - (CO) - (C 1 May be substituted one or more times with -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl, CF ₃ , OCF ₃ , N (R 9) (R 10);

R 3 is H, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-aryl, -C (O) -aryl, (C ₁ -C ₆ ) -alkylene-heterocycle, CO -(C ₁ -C ₆ ) -alkyl, wherein the aryl and heterocycle radicals are F, Cl, Br, (C ₁ -C ₆ ) -alkyl, COOH, COO (C ₁ -C ₆ ) -alkyl, CF ₃ Or may be substituted one or more times with OCF ₃ ;

R 4 and R 5 independently of one another are H, F, Cl, Br, (C ₁ -C ₆ ) -alkyl, CF ₃ , OCF ₃ , N0 ₂ , N (R9) (R10), CN, 0- (C _1- C ₆ ) -alkyl, CO- (C ₁ -C ₆ ) -alkyl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, CON (R 9) (R 10), (C ₁ -C ₆ ) -alkyl Lene-CON (R9) (R10), COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, S (O) _0-2 - (C ₁ -C ₆₎ - _{alkyl, S (O) 2 -N (} R9) (R10), CH 2 0H, CH 2 0CH 3 , and;

R 6 and R 7 are independently of each other H, F, Cl, Br, (C ₁ -C ₆ ) -alkyl, cyclopropyl, tetrafluorocyclopropyl, difluorocyclopropyl, or R 6 and R 7 together are a group = CH ₂ To form;

R 8 is H, CH ₃ , CF ₃ , CH ₂ 0H;

R 9 is H, (C ₁ -C ₄ ) -alkyl;

R 10 is H, (C ₁ -C ₄ ) -alkyl; R9 and R10 together with the N atoms to which they are attached form a 3-9 membered ring system.

Preferred are compounds of formula I and physiologically acceptable salts thereof, wherein at least one radical has the following meaning:

R 1 is aryl, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkylene-aryl, heterocycle, (C ₁ -C ₆ ) -alkyl Ren-heterocycle, CF ₃ , OCF ₃ , CN, (CH ₂ ) _1-6 -OH, O- (C ₁ -C ₆ ) -alkyl, CO- (C ₁ -C ₆ ) -alkyl, -C ( O) O-alkyl, COOH, CON (R9) (R10), wherein the aryl radicals and heterocycle radicals are F, Cl, Br, (CH ₂ ) _0-2 OH, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- ( C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (C ₁ -C ₆ ) -Alkyl, S (O) _0-2- (C ₁ -C ₆ ) -alkyl, S0 ₂ -N (R9) (R10), CO- (C ₁ -C ₆ ) -alkyl, -COOH, (C ₁ -C ₆ ) -alkylene-COOH, -COO (C ₁ -C ₆ ) -alkyl, (C ₀ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₁₀ ) -cycloalkyl, phenyl may be substituted one or more times, wherein the piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazin, N- ( C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and phenyl rings are F, Cl, Br, (CH ₂ ) _0-2 0H, COOH, CN, N0 ₂ , -O- (C ₁ -C ₆ ) -alkyl, -NH-O- (C ₁ -C ₆ ) -alkyl,-(CO) -NH-O- (C ₁ -C ₆ ) -alkylene-N (R9) (R10) , - (CO) - (C 1 -C 6) - _{alkyl, - (C 1 -C 6)} - alkyl, CF _3, OCF _3, N one or more times with (R9) (R10) may be substituted, and;

R 2 is H, aryl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, -COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl; (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkylene-aryl, heterocycle, (C ₁ -C ₆ ) -alkylene-heterocycle , CF ₃ , OCF ₃ , CN, (CH ₂ ) _1-6 -OH, O- (C ₁ -C ₆ ) -alkyl, CO- (C ₁ -C ₆ ) -alkyl, -C (O) O- Alkyl, COOH, CON (R9) (R10), wherein the aryl radical and heterocycle radical are F, Cl, Br, (CH ₂ ) _0-2 OH, (C ₁ -C ₆ ) -alkyl, (C _2- C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (C ₁ -C ₆ ) -alkyl, S (O) _0-2- (C ₁ -C ₆ ) -alkyl, S0 ₂ -N (R9) (R10), CO- (C ₁ -C ₆ ) -alkyl, -COOH, (C ₁ -C ₆ ) -Alkylene-COOH, COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₁₀ ) -cycloalkyl , May be substituted one or more times with phenyl;

R 3 is H, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-aryl, -C (O) -aryl, (C ₁ -C ₆ ) -alkylene-heterocycle, CO - alkyl, - (C ₁ -C ₆₎

R 4 and R 5 independently of one another are H, F, Cl, Br, (C ₁ -C ₆ ) -alkyl, CF ₃ , OCF ₃ , N0 ₂ , N (R9) (R10), CN, 0- (C _1- C ₆ ) -alkyl, CO- (C ₁ -C ₆ ) -alkyl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, CON (R 9) (R 10), (C ₁ -C ₆ ) -alkyl Lene-CON (R9) (R10), COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, S (O) _0-2 - (C ₁ -C ₆₎ - _{alkyl, S (O) 2 -N (} R9) (R10), CH 2 0H, CH 2 0CH 3 , and;

R 6 and R 7 are independently of each other H, F, Cl, Br, (C ₁ -C ₆ ) -alkyl, cyclopropyl, tetrafluorocyclopropyl, difluorocyclopropyl, or R 6 and R 7 together are a group = CH ₂ To form;

R 8 is H, CH ₃ , CF ₃ , CH ₂ 0H;

R 9 is H, (C ₁ -C ₄ ) -alkyl;

R 10 is H, (C ₁ -C ₄ ) -alkyl; R9 and R10 together with the N atoms to which they are attached form a 3-9 membered ring system.

Particular preference is given to compounds of the formula I in which at least one radical has the following meaning and physiologically acceptable salts thereof:

R 1 is phenyl, naphthyl, thionaphthyl, pyridyl, wherein phenyl, naphthyl, thionaphthyl and pyridyl are F, Cl, Br, (CH ₂ ) _0-2 OH, (C ₁ -C ₆ ) -Alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, CF ₃ , OCF ₃ , N (R 9) (R 10), piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (C ₁ -C ₆ ) -alkyl, S (O) _0-2- (C ₁ -C ₆ ) -alkyl, S0 ₂ -N (R9) (R10), CO- (C ₁ -C ₆ ) -alkyl, -COOH , (C ₁ -C ₆ ) -alkylene-COOH, COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₁₀ ) -cycloalkyl, phenyl may be substituted one or more times, wherein the piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- ( C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and phenyl rings are F, Cl, Br, (CH ₂ ) _0-2 0H, COOH, CN, N0 ₂ , -O- (C ₁ -C ₆ ) -alkyl, -NH-O- (C ₁ -C ₆ ) -alkyl,-(CO) -NH-O- (C ₁ -C ₆ ) -alkylene-N (R9 ) (R 10),-(CO)-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl, CF ₃ , OCF ₃ , N (R9) (R10) Can be;

R 2 is H, (C ₁ -C ₆ ) -alkyl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, -COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl Lene-COO (C ₁ -C ₆ ) -alkyl;

R 3 is H, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-aryl, -C (O) -aryl, (C ₁ -C ₆ ) -alkylene-heterocycle, CO - alkyl, - (C ₁ -C ₆₎

R4 and R5 are H;

R6 and R7 are H;

R8 is H;

R 9 is H, (C ₁ -C ₄ ) -alkyl;

R 10 is H, (C ₁ -C ₄ ) -alkyl.

Very particular preference is given to compounds of the formula I in which at least one radical has the following meanings and physiologically acceptable salts thereof:

R 1 is phenyl, naphthyl, thionaphthyl and pyridyl, wherein phenyl, naphthyl, thionaphthyl and pyridyl are F, Cl, Br, (CH ₂ ) _0-2 OH, (C ₁ -C ₆ ) -Alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, CF ₃ , OCF ₃ , N (R 9) (R 10), piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (C ₁ -C ₆ ) -alkyl, S (O) _0-2- (C ₁ -C ₆ ) -alkyl, S0 ₂ -N (R9) (R10), CO- (C ₁ -C ₆ ) -alkyl, -COOH , (C ₁ -C ₆ ) -alkylene-COOH, COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₁₀ ) -cycloalkyl, phenyl may be substituted one or more times, wherein the piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- ( C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and phenyl rings are F, Cl, Br, (CH ₂ ) _0-2 0H, COOH, CN, N0 ₂ , -O- (C _1- C ₆ ) -alkyl, -NH-O- (C ₁ -C ₆ ) -alkyl,-(CO) -NH-O- (C ₁ -C ₆ ) -alkylene-N ( R9) (R10), - ( CO) - (C 1 -C 6) - _{alkyl, - (C 1 -C 6)} - _{alkyl, CF 3, OCF 3, N} (R9) ( one or more times with R10) substituted Can be;

R 2 is H, (C ₁ -C ₆ ) -alkyl, -C (O) O- (C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkylene-C (O) O- ( C ₁ -C ₆ ) -alkyl, -COOH,-(C ₁ -C ₆ ) -alkylene-COOH;

R 3 is H, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-aryl, -C (O) -aryl, (C ₁ -C ₆ ) -alkylene-heterocycle, CO - alkyl, - (C ₁ -C ₆₎

R4 and R5 are H;

R6 and R7 are H;

R8 is H;

R9 is H;

R 10 is H.

Explanation:

라디칼의 의미가 X가 C-R2이고 Y가 O인 경우

이고,Oxazole residues

If the meaning of radical is X is C-R2 and Y is O

ego,

이다. 더욱이, X가 C-R2이고 Y가 O인 화합물이 바람직하다.The meaning of a radical is X is O and Y is C-R2

to be. Furthermore, compounds wherein X is C-R2 and Y is O are preferred.

The present invention relates to compounds of formula (I) in their racemates, racemate mixtures and pure enantiomeric forms, and diastereomers and mixtures thereof.

Where radicals or substituents may be present more than once in a compound of formula (I), all of these radicals or substituents have the meanings defined independently of one another and may be the same or different.

Pharmaceutically acceptable salts are particularly suitable for pharmaceutical applications because their water solubility is greater than that of the initial or base compounds. The salt should contain a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are inorganic acid salts such as hydrochloric acid, bromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and for example acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid And organic acid salts such as fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. magnesium and calcium salts), tromethamol (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine.

Salts with pharmaceutically unsuitable anions such as, for example, trifluoroacetic acid, are present as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for non-therapeutic uses, for example, in vitro applications. It falls within the scope of the invention.

As used herein, the term “physiologically functional derivative” refers to any physiologically acceptable derivative of a compound of formula (I) of the invention, for example a compound of formula (I) or an active metabolite thereof when administered to a mammal (eg a human) Refers to an ester capable of forming (directly or indirectly).

Physiologically functional derivatives are described, for example, in H. Okada et al., Chod Pharm. Bull. 1994, 42, 57-61, including prodrugs of the compounds of the invention. Such prodrugs can be metabolized into the compounds of the present invention in vivo. The prodrug may itself be active or inactive.

The compounds of the present invention may also exist in various polymorphic forms, for example amorphous and crystalline polymorphic forms. Polymorphic forms of all compounds of the invention are within the scope of this invention and are further embodiments of the invention.

All references herein to “compounds of Formula I” refer to compounds of Formula I as described above and salts, solvates thereof and physiologically functional derivatives as described herein.

By alkyl radical is meant a straight or branched chain hydrocarbon containing one or more carbons, for example methyl, ethyl, isopropyl, tert-butyl, hexyl.

Alkyl radicals are suitable groups such as F, Cl, Br, I, CF ₃ , NO ₂ , N ₃ , CN, COOH, COO (C ₁ -C ₆ ) alkyl, CONH ₂ , CONH (C ₁ -C ₆ ) alkyl, CON [(C ₁ -C ₆ ) alkyl] ₂ , cycloalkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, 0- (C ₁ -C ₆ ) -alkyl, O-CO- (C ₁ -C _{6) -alkyl, O-CO- (C 1 -C} 6) - _{aryl, O-CO- (C 1 -C} 6) - heterocycle;

P0 ₃ H ₂ , S0 ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (C ₁ -C ₆ ) -alkyl, S0 ₂ N [(C ₁ -C ₆ ) -alkyl] ₂ , S- (C _1- C ₆ ) -alkyl, S- (CH ₂ ) n-aryl, S- (CH ₂ ) n-heterocycle, SO- (C ₁ -C ₆ ) -alkyl, SO- (CH ₂ ) n-aryl, SO -(CH ₂ ) n-heterocycle, S0 _2- (C ₁ -C ₆ ) -alkyl, S0 _2- (CH ₂ ) n-aryl, S0 _2- (CH ₂ ) n-heterocycle, S0 ₂ -NH (CH ₂ ) n-aryl, S0 ₂ -NH (CH ₂ ) n-heterocycle, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) -aryl, S0 ₂ -N (C _1- C ₆ ) -alkyl) (CH ₂ ) n-heterocycle, SO ₂ -N ((CH ₂ ) n-aryl) ₂ , S0 ₂ -N ((CH ₂ ) n- (heterocycle) ₂ one or more times And n may be 0 to 6, wherein the aryl radical or heterocycle radical is F, Cl, Br, OH, CF ₃ , N ₂ , CN, OCF ₃ , 0- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ ;

C (NH) (NH ₂ ), NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , NH (C ₁ -C ₇ ) -acyl, NH -CO- (C ₁ -C ₆₎ - _{alkyl, NH-COO- (C 1 -C} 6) - alkyl, CO- NH-aryl, NH-CO- heterocyclyl, NH-COO- aryl, NH-COO- heterocycle, NH-CO-NH- (C 1 -C 6) - alkyl, NH-CO-NH- aryl, NH-CO-NH- _{heterocyclyl, N (C 1 -C 6)} - alkyl, -CO- ( C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-COO- (C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-CO-aryl, N (C _1- C ₆ ) -alkyl-CO-heterocycle, N (C ₁ -C ₆ ) -alkyl-COO-aryl, N (C ₁ -C ₆ ) -alkyl-COO-heterocycle, N (C ₁ -C ₆ ) -alkyl-CO-NH- (C ₁ -C ₆ ) -alkyl), N (C ₁ -C ₆ ) -alkyl-CO-NH-aryl, N (C ₁ -C ₆ ) -alkyl-CO- NH- _{heterocycle, N ((C 1 -C 6} ) - _{alkyl) -CO-N- (C 1 -C} 6) - _{alkyl) 2, N ((C 1} -C 6) - alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -aryl, N ((C ₁ -C ₆ ) -alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -heterocycle, N ((C ₁ -C ₆ ) -alkyl) -CO-N- (aryl) ₂ , N ((C ₁ -C ₆ ) -alkyl) -CO-N- (heterocycle) ₂ , N (aryl) -CO- (C ₁ -C ₆ ) -alkyl, N (heterocycle) -CO- (C ₁ -C ₆ ) -Alkyl, N _{(aryl) -COO- (C 1 -C 6)} - alkyl, N _{(heterocycle) -COO- (C 1 -C 6)} - alkyl, N (aryl) -CO- aryl, N (heteroaryl Cycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C ₁ -C ₆ ) -alkyl), N (heterocycle ) -CO-NH- (C ₁ -C ₆ ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- ( C ₁ -C ₆ ) -alkyl) ₂ , N (heterocycle) -CO-N- (C ₁ -C ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((C ₁ -C ₆ )- Alkyl) -aryl, N (heterocycle) -CO-N ((C ₁ -C ₆ ) -alkyl) -aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO- N- (aryl) ₂ , aryl, O- (CH ₂ ) n-aryl, O- (CH ₂ ) n-heterocyclo may be substituted up to two times, where n is 0 to 6, wherein an aryl radical or Heterocycle radicals include F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , 0- (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 to 3 Can be substituted once.

Alkenyl radicals mean straight or branched hydrocarbon chains containing two or more carbons and one or more double bonds, for example vinyl, allyl, pentenyl.

Alkenyl radicals are suitable groups such as F, Cl, Br, I, CF ₃ , N0 ₂ , N ₃ , CN, COOH, COO (C ₁ -C ₆ ) alkyl, CONH ₂ , CONH (C _1- C ₆ ) alkyl, CON [(C ₁ -C ₆ ) alkyl] ₂ , cycloalkyl, (C ₁ -C ₁₀ ) -alkyl, (C ₂ -C ₆ ) -alkynyl, 0- (C ₁ -C ₆ ) _{-alkyl-O-CO- (C 1 -C 6} ) - _{alkyl, O-CO- (C 1 -C} 6) - _{aryl, O-CO- (C 1 -C} 6) - heterocycle;

P0 ₃ H ₂ , S0 ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (C ₁ -C ₆ ) -alkyl, S0 ₂ N [(C ₁ -C ₆ ) -alkyl] ₂ , S- (C _1- C ₆ ) -alkyl, S- (CH ₂ ) n-aryl, S- (CH ₂ ) n-heterocycle, SO- (C ₁ -C ₆ ) -alkyl, SO- (CH ₂ ) n-aryl, SO -(CH ₂ ) n-heterocycle, S0 _2- (C ₁ -C ₆ ) -alkyl, S0 _2- (CH ₂ ) n-aryl, S0 _2- (CH ₂ ) n-heterocycle, S0 ₂ -NH (CH ₂ ) n-aryl, S0 ₂ -NH (CH ₂ ) n-heterocycle, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) n-aryl, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) n-heterocycle, SO ₂ -N ((CH ₂ ) n-aryl) ₂ , S0 ₂ -N ((CH ₂ ) n- (heterocycle) ₂ as 1 May be substituted more than once, where n may be 0 to 6, wherein the aryl radical or heterocycle radical is F, Cl, Br, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ ;

C (NH) (NH ₂ ), NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , NH (C ₁ -C ₇ ) -acyl, NH -CO- (C ₁ -C ₆₎ - _{alkyl, NH-COO- (C 1 -C} 6) - alkyl, CO- NH-aryl, NH-CO- heterocyclyl, NH-COO- aryl, NH-COO- heterocycle, NH-CO-NH- (C 1 -C 6) - alkyl, NH-CO-NH- aryl, NH-CO-NH- _{heterocyclyl, N (C 1 -C 6)} - alkyl, -CO- ( C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-COO- (C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-CO-aryl, N (C _1- C ₆ ) -alkyl-CO-heterocycle, N (C ₁ -C ₆ ) -alkyl-COO-aryl, N (C ₁ -C ₆ ) -alkyl-COO-heterocycle, N (C ₁ -C ₆ ) -alkyl-CO-NH- (C ₁ -C ₆ ) -alkyl), N (C ₁ -C ₆ ) -alkyl-CO-NH-aryl, N (C ₁ -C ₆ ) -alkyl-CO- NH- _{heterocycle, N ((C 1 -C 6} ) - _{alkyl) -CO-N- (C 1 -C} 6) - _{alkyl) 2, N ((C 1} -C 6) - alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -aryl, N ((C ₁ -C ₆ ) -alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -heterocycle, N ((C ₁ -C ₆ ) -alkyl) -CO-N- (aryl) ₂ , N ((C ₁ -C ₆ ) -alkyl) -CO-N- (heterocycle) ₂ , N (aryl) -CO- (C ₁ -C ₆ ) -alkyl, N (heterocycle) -CO- (C ₁ -C ₆ ) -Alkyl, N _{(aryl) -COO- (C 1 -C 6)} - alkyl, N _{(heterocycle) -COO- (C 1 -C 6)} - alkyl, N (aryl) -CO- aryl, N (heteroaryl Cycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C ₁ -C ₆ ) -alkyl), N (heterocycle ) -CO-NH- (C ₁ -C ₆ ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C ₁ -C ₆ ) -alkyl) ₂ , N (heterocycle) -CO-N- (C ₁ -C ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((C ₁ -C ₆ ) -Alkyl) aryl, N (heterocycle) -CO-N ((C ₁ -C ₆ ) -alkyl) aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO-N -(Aryl) ₂ , aryl, O- (CH ₂ ) n-aryl, O- (CH ₂ ) n-heterocyclo can be substituted up to 2 times, wherein n is 0 to 6, wherein an aryl radical or hetero The cycle radicals are F, Cl, Br, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (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, 1-3 to ₂ CONH It may be substituted.

Alkynyl radicals mean straight or branched chain hydrocarbons containing two or more carbons and one or more triple bonds, for example ethynyl, propynyl, hexynyl.

Alkynyl radicals are suitable groups such as F, Cl, Br, I, CF ₃ , N0 ₂ , N ₃ , CN, COOH, COO (C ₁ -C ₆ ) alkyl, CONH ₂ , CONH (C _1- C ₆ ) alkyl, CON [(C ₁ -C ₆ ) alkyl] ₂ , cycloalkyl, (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₁₀ ) -alkyl, 0- (C ₁ -C ₆ ) _{-alkyl-O-CO- (C 1 -C 6} ) - _{alkyl, O-CO- (C 1 -C} 6) - _{aryl, O-CO- (C 1 -C} 6) - heterocycle;

P0 ₃ H ₂ , S0 ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (C ₁ -C ₆ ) -alkyl, S0 ₂ N [(C ₁ -C ₆ ) -alkyl] ₂ , S- (C _1- C ₆ ) -alkyl, S- (CH ₂ ) n-aryl, S- (CH ₂ ) n-heterocycle, SO- (C ₁ -C ₆ ) -alkyl, SO- (CH ₂ ) n-aryl, SO -(CH ₂ ) n-heterocycle, S0 _2- (C ₁ -C ₆ ) -alkyl, S0 _2- (CH ₂ ) n-aryl, S0 _2- (CH ₂ ) n-heterocycle, S0 ₂ -NH (CH ₂ ) n-aryl, S0 ₂ -NH (CH ₂ ) n-heterocycle, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) n-aryl, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) n-heterocycle, SO ₂ -N ((CH ₂ ) n-aryl) ₂ , S0 ₂ -N ((CH ₂ ) n- (heterocycle) ₂ once May be substituted, wherein n may be 0 to 6, wherein the aryl radical or heterocycle radical is F, Cl, Br, OH, CF ₃ , N ₂ , CN, OCF ₃ , 0- (C _1- C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ ;

C (NH) (NH ₂ ), NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , NH (C ₁ -C ₇ ) -acyl, NH -CO- (C ₁ -C ₆₎ - _{alkyl, NH-COO- (C 1 -C} 6) - alkyl, CO- NH-aryl, NH-CO- heterocyclyl, NH-COO- aryl, NH-COO- heterocycle, NH-CO-NH- (C 1 -C 6) - alkyl, NH-CO-NH- aryl, NH-CO-NH- _{heterocyclyl, N (C 1 -C 6)} - alkyl, -CO- ( C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-COO- (C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-CO-aryl, N (C _1- C ₆ ) -alkyl-CO-heterocycle, N (C ₁ -C ₆ ) -alkyl-COO-aryl, N (C ₁ -C ₆ ) -alkyl-COO-heterocycle, N (C ₁ -C ₆ ) -alkyl-CO-NH- (C ₁ -C ₆ ) -alkyl), N (C ₁ -C ₆ ) -alkyl-CO-NH-aryl, N (C ₁ -C ₆ ) -alkyl-CO- NH- _{heterocycle, N ((C 1 -C 6} ) - _{alkyl) -CO-N- (C 1 -C} 6) - _{alkyl) 2, N ((C 1} -C 6) - alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -aryl, N ((C ₁ -C ₆ ) -alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -heterocycle, N ((C ₁ -C ₆ ) -alkyl) -CO-N- (aryl) ₂ , N ((C ₁ -C ₆ ) -alkyl) -CO-N- (heterocycle) ₂ , N (aryl) -CO- (C ₁ -C ₆ ) -alkyl, N (heterocycle) -CO- (C ₁ -C ₆ ) -Alkyl, N _{(aryl) -COO- (C 1 -C 6)} - alkyl, N _{(heterocycle) -COO- (C 1 -C 6)} - alkyl, N (aryl) -CO- aryl, N (heteroaryl Cycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C ₁ -C ₆ ) -alkyl), N (heterocycle) _{greater) -CO-NH- (C 1 -C} 6) - alkyl), N (aryl) -CO-NH- aryl, N (heterocycle) -CO-NH- aryl, N (aryl) -CO-N- (C ₁ -C ₆ ) -alkyl) ₂ , N (heterocycle) -CO-N- (C ₁ -C ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((C ₁ -C ₆ ) -Alkyl) aryl, N (heterocycle) -CO-N ((C ₁ -C ₆ ) -alkyl) aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO-N -(Aryl) ₂ , aryl, O- (CH ₂ ) n-aryl, O- (CH ₂ ) n-heterocyclo can be substituted up to 2 times, wherein n is 0 to 6, wherein an aryl radical or hetero Cycle radicals are F, Cl, Br, I, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (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, 1 to 1 as CONH ₂ It may be substituted three times.

By aryl radicals are meant phenyl, naphthyl-, biphenyl-, tetrahydronaphthyl-, alpha- or beta-tetralon-, indanyl- or indan-1-onyl radicals.

Aryl radicals are suitable groups such as F, Cl, Br, I, CF ₃ , NO ₂ , N ₃ , CN, COOH, COO (C ₁ -C ₆ ) alkyl, CONH ₂ , CONH (C ₁ -C ₆ ) alkyl, CON [(C ₁ -C ₆ ) alkyl] ₂ , cycloalkyl, (C ₁ -C ₁₀ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alky _{carbonyl, 0- (C 1 -C 6)} - alkyl, _{O-CO- (C 1 -C 6} ) - _{alkyl, O-CO- (C 1 -C} 6) - aryl, O-CO- (C ₁ -C ₆ ) -heterocycle;

P0 ₃ H ₂ , S0 ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (C ₁ -C ₆ ) -alkyl, S0 ₂ N [(C ₁ -C ₆ ) -alkyl] ₂ , S- (C _1- C ₆ ) -alkyl, S- (CH ₂ ) n-aryl, S- (CH ₂ ) n-heterocycle, SO- (C ₁ -C ₆ ) -alkyl, SO- (CH ₂ ) n-aryl, SO -(CH ₂ ) n-heterocycle, S0 _2- (C ₁ -C ₆ ) -alkyl, S0 _2- (CH ₂ ) n-aryl, S0 _2- (CH ₂ ) n-heterocycle, S0 ₂ -NH (CH ₂ ) n-aryl, S0 ₂ -NH (CH ₂ ) n-heterocycle, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) n-aryl, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) n-heterocycle, SO ₂ -N ((CH ₂ ) n-aryl) ₂ , S0 ₂ -N ((CH ₂ ) n- (heterocycle) ₂ once May be substituted, wherein n may be 0 to 6, wherein the aryl radical or heterocycle radical is F, Cl, Br, OH, CF ₃ , N ₂ , CN, OCF ₃ , 0- (C _1- C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ ;

C (NH) (NH ₂ ), NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , NH (C ₁ -C ₇ ) -acyl, NH -CO- (C ₁ -C ₆₎ - _{alkyl, NH-COO- (C 1 -C} 6) - alkyl, CO- NH-aryl, NH-CO- heterocyclyl, NH-COO- aryl, NH-COO- heterocycle, NH-CO-NH- (C 1 -C 6) - alkyl, NH-CO-NH- aryl, NH-CO-NH- _{heterocyclyl, N (C 1 -C 6)} - alkyl, -CO- ( C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-COO- (C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-CO-aryl, N (C _1- C ₆ ) -alkyl-CO-heterocycle, N (C ₁ -C ₆ ) -alkyl-COO-aryl, N (C ₁ -C ₆ ) -alkyl-COO-heterocycle, N (C ₁ -C ₆ ) -alkyl-CO-NH- (C ₁ -C ₆ ) -alkyl), N (C ₁ -C ₆ ) -alkyl-CO-NH-aryl, N (C ₁ -C ₆ ) -alkyl-CO- NH- _{heterocycle, N ((C 1 -C 6} ) - _{alkyl) -CO-N- (C 1 -C} 6) - _{alkyl) 2, N ((C 1} -C 6) - alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -aryl, N ((C ₁ -C ₆ ) -alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -heterocycle, N ((C ₁ -C ₆ ) -alkyl) -CO-N- (aryl) ₂ , N ((C ₁ -C ₆ ) -alkyl) -CO-N- (heterocycle) ₂ , N (aryl) -CO- (C ₁ -C ₆ ) -alkyl, N (heterocycle) -CO- (C ₁ -C ₆ ) -Alkyl, N _{(aryl) -COO- (C 1 -C 6)} - alkyl, N (hete Rosa _{cycle) -COO- (C 1 -C 6)} - alkyl, N (aryl) -CO- aryl, N ( Heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C ₁ -C ₆ ) -alkyl), N (hetero _{cycle) -CO-NH- (C 1 -C} 6) - alkyl), N (aryl) -CO-NH- aryl, N (heterocycle) -CO-NH- aryl, N (aryl) -CO-N- (C ₁ -C ₆ ) -alkyl) ₂ , N (heterocycle) -CO-N- (C ₁ -C ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((C ₁ -C ₆ ) -Alkyl) aryl, N (heterocycle) -CO-N ((C ₁ -C ₆ ) -alkyl) aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO-N -(Aryl) ₂ , aryl, O- (CH ₂ ) n-aryl, O- (CH ₂ ) n-heterocyclo can be substituted up to 2 times, wherein n is 0 to 6, wherein an aryl radical or hetero Cycle radicals are F, Cl, Br, I, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (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, 1 to 1 as CONH ₂ It may be substituted three times.

By cycloalkyl radical is meant a ring system comprising one or more rings consisting only of carbon atoms, in saturated or partially unsaturated form (with one or two double bonds), for example cyclopropyl, cyclopentyl, cyclo Pentenyl, cyclohexyl or adamantyl.

Cycloalkyl radicals are suitable groups such as F, Cl, Br, I, CF ₃ , NO ₂ , N ₃ , CN, COOH, COO (C ₁ -C ₆ ) alkyl, CONH ₂ , CONH (C _1- C ₆ ) alkyl, CON [(C ₁ -C ₆ ) alkyl] ₂ , cycloalkyl, (C ₁ -C ₁₀ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ )- _{alkynyl, 0- (C 1 -C 6)} - alkyl, _{O-CO- (C 1 -C 6} ) - _{alkyl, O-CO- (C 1 -C} 6) - aryl, O-CO- (C ₁ - C ₆ ) -heterocycle; P0 ₃ H ₂ , S0 ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (C ₁ -C ₆ ) -alkyl, S0 ₂ N [(C ₁ -C ₆ ) -alkyl] ₂ , S- (C _1- C ₆ ) -alkyl, S- (CH ₂ ) n-aryl, S- (CH ₂ ) n-heterocycle, SO- (C ₁ -C ₆ ) -alkyl, SO- (CH ₂ ) n-aryl, SO -(CH ₂ ) n-heterocycle, S0 _2- (C ₁ -C ₆ ) -alkyl, S0 _2- (CH ₂ ) n-aryl, S0 _2- (CH ₂ ) n-heterocycle, S0 ₂ -NH (CH ₂ ) n-aryl, S0 ₂ -NH (CH ₂ ) n-heterocycle, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) n-aryl, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) n-heterocycle, SO ₂ -N ((CH ₂ ) n-aryl) ₂ , S0 ₂ -N ((CH ₂ ) n- (heterocycle) ₂ once May be substituted, wherein n may be 0 to 6, wherein the aryl radical or heterocycle radical is F, Cl, Br, OH, CF ₃ , N ₂ , CN, OCF ₃ , 0- (C _1- C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ ;

C (NH) (NH ₂ ), NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , NH (C ₁ -C ₇ ) -acyl, NH -CO- (C ₁ -C ₆₎ - _{alkyl, NH-COO- (C 1 -C} 6) - alkyl, CO- NH-aryl, NH-CO- heterocyclyl, NH-COO- aryl, NH-COO- heterocycle, NH-CO-NH- (C 1 -C 6) - alkyl, NH-CO-NH- aryl, NH-CO-NH- _{heterocyclyl, N (C 1 -C 6)} - alkyl, -CO- ( C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-COO- (C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-CO-aryl, N (C _1- C ₆ ) -alkyl-CO-heterocycle, N (C ₁ -C ₆ ) -alkyl-COO-aryl, N (C ₁ -C ₆ ) -alkyl-COO-heterocycle, N (C ₁ -C ₆ ) -alkyl-CO-NH- (C ₁ -C ₆ ) -alkyl), N (C ₁ -C ₆ ) -alkyl-CO-NH-aryl, N (C ₁ -C ₆ ) -alkyl-CO- NH- _{heterocycle, N ((C 1 -C 6} ) - _{alkyl) -CO-N- (C 1 -C} 6) - _{alkyl) 2, N ((C 1} -C 6) - alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -aryl, N ((C ₁ -C ₆ ) -alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -heterocycle, N ((C ₁ -C ₆ ) -alkyl) -CO-N- (aryl) ₂ , N ((C ₁ -C ₆ ) -alkyl) -CO-N- (heterocycle) ₂ , N (aryl) -CO- (C ₁ -C ₆ ) -alkyl, N (heterocycle) -CO- (C ₁ -C ₆ ) -Alkyl, N _{(aryl) -COO- (C 1 -C 6)} - alkyl, N _{(heterocycle) -COO- (C 1 -C 6)} - alkyl, N (aryl) -CO- aryl, N (heteroaryl Cycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C ₁ -C ₆ ) -alkyl), N (heterocycle ) -CO-NH- (C ₁ -C ₆ ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- ( C ₁ -C ₆ ) -alkyl) ₂ , N (heterocycle) -CO-N- (C ₁ -C ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((C ₁ -C ₆ )- Alkyl) aryl, N (heterocycle) -CO-N ((C ₁ -C ₆ ) -alkyl) aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO-N- (Aryl) ₂ , aryl, O- (CH ₂ ) n -aryl, O- (CH ₂ ) n -heterocyclo, which may be substituted up to 2 times, wherein n is 0 to 6, wherein an aryl radical or heterocycle The radicals are F, Cl, Br, I, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (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 to 3 Can be substituted once.

Heterocycle or heterocycle radical means a ring and ring system comprising, in addition to carbon, heteroatoms such as, for example, nitrogen, oxygen and sulfur. The definition also includes ring systems in which a heterocycle or heterocycle radical is bonded to a benzene nucleus.

Suitable "heterocycle rings" or "heterocycle radicals" are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazol Zolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl, quinoxridinyl, Chromanyl, chromenyl, cynolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furyl, furazanyl, imi Dazolidinyl, amidazolinyl, amidazolyl, 1H-indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromenyl, isoindazolyl, isoindolinyl , Isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyrididi , Oxahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadia Zolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenantridinyl, phenanthrolinyl, phenazinyl, piperidinyl, pterridinyl, furinyl, pyranyl, pyrazinyl, pyrazolidinyl, Pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyrimidimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, py Rollyl, Tetrahydrofuranyl, Tetrahydroisoquinolinyl, Tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, Tinazolyl, 1,2,3-thiadiazolyl, 1,2,4 -Thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl.

Pyridyl refers to both 2-, 3- and 4-pyridyl. Thienyl refers to both 2- and 3-thienyl. Furyl refers to both 2- and 3-furyl.

Also included are the corresponding N-oxides of the compounds of the invention, for example 1-oxy-2-, 3- or 4-pyridyl.

Also included are derivatives of heterocycles of the present compound that are benzo bonded one or more times.

Heterocycle rings or heterocycle radicals are suitable groups such as F, Cl, Br, I, CF ₃ , NO ₂ , N ₃ , CN, COOH, COO (C ₁ -C ₆ ) alkyl, CONH ₂ , CONH (C ₁ -C ₆ ) alkyl, CON [(C ₁ -C ₆ ) alkyl] ₂ , cycloalkyl, (C ₁ -C ₁₀ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C _2- C ₆ ) -alkynyl, 0- (C ₁ -C ₆ ) -alkylO-CO- (C ₁ -C ₆ ) -alkyl, O-CO- (C ₁ -C ₆ ) -aryl, O-CO- (C ₁ -C ₆ ) -heterocycle; P0 ₃ H ₂ , S0 ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (C ₁ -C ₆ ) -alkyl, S0 ₂ N [(C ₁ -C ₆ ) -alkyl] ₂ , S- (C _1- C ₆ ) -alkyl, S- (CH ₂ ) n-aryl, S- (CH ₂ ) n-heterocycle, SO- (C ₁ -C ₆ ) -alkyl, SO- (CH ₂ ) n-aryl, SO -(CH ₂ ) n-heterocycle, S0 _2- (C ₁ -C ₆ ) -alkyl, S0 _2- (CH ₂ ) n-aryl, S0 _2- (CH ₂ ) n-heterocycle, S0 ₂ -NH (CH ₂ ) n-aryl, S0 ₂ -NH (CH ₂ ) n-heterocycle, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) n-aryl, S0 ₂ -N (C ₁ -C ₆ ) -alkyl) (CH ₂ ) n-heterocycle, SO ₂ -N ((CH ₂ ) n-aryl) ₂ , S0 ₂ -N ((CH ₂ ) n- (heterocycle) ₂ once May be substituted, wherein n may be 0 to 6, wherein the aryl radical or heterocycle radical is F, Cl, Br, OH, CF ₃ , N ₂ , CN, OCF ₃ , 0- (C _1- C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, NH ₂ ;

C (NH) (NH ₂ ), NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ , NH (C ₁ -C ₇ ) -acyl, NH -CO- (C ₁ -C ₆₎ - _{alkyl, NH-COO- (C 1 -C} 6) - alkyl, CO- NH-aryl, NH-CO- heterocyclyl, NH-COO- aryl, NH-COO- heterocycle, NH-CO-NH- (C 1 -C 6) - alkyl, NH-CO-NH- aryl, NH-CO-NH- _{heterocyclyl, N (C 1 -C 6)} - alkyl, -CO- ( C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-COO- (C ₁ -C ₆ ) -alkyl, N (C ₁ -C ₆ ) -alkyl-CO-aryl, N (C _1- C ₆ ) -alkyl-CO-heterocycle, N (C ₁ -C ₆ ) -alkyl-COO-aryl, N (C ₁ -C ₆ ) -alkyl-COO-heterocycle, N (C ₁ -C ₆ ) -alkyl-CO-NH- (C ₁ -C ₆ ) -alkyl), N (C ₁ -C ₆ ) -alkyl-CO-NH-aryl, N (C ₁ -C ₆ ) -alkyl-CO- NH- _{heterocycle, N ((C 1 -C 6} ) - _{alkyl) -CO-N- (C 1 -C} 6) - _{alkyl) 2, N ((C 1} -C 6) - alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -aryl, N ((C ₁ -C ₆ ) -alkyl) -CO-N ((C ₁ -C ₆ ) -alkyl) -heterocycle, N ((C ₁ -C ₆ ) -alkyl) -CO-N- (aryl) ₂ , N ((C ₁ -C ₆ ) -alkyl) -CO-N- (heterocycle) ₂ , N (aryl) -CO- (C ₁ -C ₆ ) -alkyl, N (heterocycle) -CO- (C ₁ -C ₆ ) -Alkyl, N (aryl) -COO- (C ₁ -C ₆ ) -alkyl, N (heterocycle) -COO- (C ₁ -C ₆ ) -alkyl, N (aryl) -CO-aryl, N ( Heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C ₁ -C ₆ ) -alkyl), N (hetero _{cycle) -CO-NH- (C 1 -C} 6) - alkyl), N (aryl) -CO-NH- aryl, N (heterocycle) -CO-NH- aryl, N (aryl) -CO-N- (C ₁ -C ₆ ) -alkyl) ₂ , N (heterocycle) -CO-N- (C ₁ -C ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((C ₁ -C ₆ ) -Alkyl) aryl, N (heterocycle) -CO-N ((C ₁ -C ₆ ) -alkyl) aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO-N Or (aryl) ₂ , aryl, O- (CH ₂ ) n -aryl, O- (CH ₂ ) n -heterocyclo, which may be substituted up to two times, where n is 0 to 6, where an aryl radical or hete Cyclocycle radicals are F, Cl, Br, I, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (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, 1 to 1 as CONH ₂ It may be substituted three times.

The amount of compound of formula (I) needed to achieve the desired physiological effect may vary depending on many factors, including, for example, the particular compound chosen, the intended use, the mode of administration, and the clinical condition of the patient. The daily dose is generally between 0.3 mg and 100 mg (typically 3 mg and 50 mg) per kilogram of body weight, for example 3-10 mg / kg / day. Intravenous dosages are, for example, 0.3 mg to 1.0 mg / kg, which are suitably administered in 10 ng to 100 ng infusions per kilogram per minute. Infusion solutions suitable for the purposes of the present invention may, for example, comprise 0.1 ng to 10 mg, typically 1 ng to 10 mg per ml. Single doses may comprise, for example, 1 mg to 10 g of active ingredient. Thus, the ampoules for infusion may, for example, comprise 1 mg to 100 mg, and single dose formulations, for example capsules or tablets, which may be administered orally, for example comprise 1.0 to 1000 mg, generally 10 to 600 mg. For the treatment of this condition, the compound of formula (I) can be used as the compound itself, but is preferably in the form of a pharmaceutical composition with an acceptable carrier. Of course, the carrier must be acceptable in that it is compatible with the other ingredients of the composition and is not detrimental to the health of the patient. The carrier may be a solid or a liquid or a solid and a liquid and is preferably prepared with the compound in a single dosage form, for example a tablet, so that the single dosage form contains from 0.05 to 95% of the active ingredient. Other pharmaceutically active substances may likewise be present, including other compounds of formula (I). The pharmaceutical compositions of the present invention may be prepared by one of the known pharmaceutical methods for mixing the ingredients with pharmaceutically acceptable carriers and / or excipients.

The pharmaceutical compositions of the present invention are suitable for oral, rectal, topical, oral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, transdermal or intravenous) administration but are most suitable. The mode of administration depends, respectively, on the nature and severity of the condition being treated and on the nature of the compound of formula (I) used. Coated formulations and coated sustained release formulations are also within the scope of the present invention. Acid resistant and gastric juice resistant formulations are preferred. Suitable gastric juice resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutical compositions suitable for oral administration may be in the form of discrete units such as, for example, capsules, cachets, candy tablets or tablets, which are respectively powders or granules, solutions or suspensions in aqueous or non-aqueous liquids. Or a water-in-oil emulsion or an oil-in-water emulsion. The compositions can be prepared by any suitable pharmaceutical method including the step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients) as already mentioned. The composition is generally prepared by homogeneous and homogeneous mixing of the active ingredient with a liquid and / or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, tablets can be prepared by compacting or molding the powder or granules of the compound, suitably one or more additional ingredients. Compressed tablets may contain compounds in free-flowing form such as, for example, powders or granules, powders or granules, suitably mixed with a binder, a glidant, an inert diluent and / or one or more interfacial-active / dispersing agents in a suitable machine. It can manufacture by tableting. Molded tablets can be prepared by molding the compound in powder form and moistening with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions suitable for oral (sublingual) administration include, but are not limited to, compounds of formula (I) and flavorings, usually on inert substrates containing sucrose and gum arabic or tragacanth and inert substrates such as gelatin and glycerol or sucrose and gum arabic. Pastilles comprising a compound of formula (I).

Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous formulations of the compounds of formula (I), which are preferably isotonic with the blood of the recipient to be administered. Such formulations are preferably administered intravenously, but administration can also be carried out by subcutaneous, intramuscular or transdermal infusion. Such formulations may preferably be prepared by mixing the compound with water, sterilizing the resulting solution and making it isotonic with blood. Injectable compositions of the invention generally contain 0.1 to 5% by weight of active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single dose suppositories. They can be prepared by mixing the compound of formula (I) with one or more conventional solid carriers such as cocoa butter and shaping the resulting mixture.

Pharmaceutical compositions suitable for topical use of the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Carriers that can be used are petrolatum, lanolin, polyethylene glycol, alcohols and combinations of two or more of these substances. The active ingredient is generally present at a concentration of 0.1-15% by weight of the composition, for example 0.5-2%.

Percutaneous administration is also possible. Pharmaceutical compositions suitable for percutaneous administration may be in the form of a single paste suitable for close contact with the epidermis of a patient for long periods of time. Such plaster is suitably buffered and optionally contains the active ingredient in an aqueous solution dissolved in an adhesive and / or dispersed or dispersed in a polymer. Suitable active ingredient concentrations are about 1 to 35%, preferably about 3 to 15%. It is particularly possible for the active ingredient to be released by electrotransportation or ion osmosis, for example as described in Pharmaceutical Research, 2 (6): 318 (1986).

The compounds of formula (I) can also be administered in combination with other active ingredients.

Further active ingredients suitable for the combination product are all antidiabetic agents mentioned in the Rote Liste 2003, chapter 12. They can be mixed with the compounds of the formula (I) of the invention in particular for improving the synergy of the effect. Administration of the active ingredient combination may be carried out in the form of a separate administration of the active ingredient to a patient or in the form of a combination product in which multiple active ingredients are present in one pharmaceutical formulation. Most of the active ingredients listed below are disclosed in the USP Dictionary of USAN and International Drug Names, US Pahrmacopeia, Rockville 2001.

Antidiabetic agents include, for example, insulin and insulin derivatives, such as Lantus® (www.lantus.com) or HMR 1964, rapid acting insulins (see, for example, US Pat. No. 6,221,633), for example, international In WO 97/26265, WO 99/03861, WO 01/04156, WO 00/34331, WO 00/34332, WO 91/11457 and US Pat. No. 6,380,357. GLP-1 derivatives as disclosed, and orally effective hypoglycemic active ingredients.

Orally effective hypoglycemic active ingredients are preferably sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, eg Potassium channel openers, insulin sensitizers, staphylococcal and / or glycogen breakdown, such as those disclosed in WO 97/26265 and WO 99/03861 (Novo Nordisk A / S). Inhibition of liver enzymes associated with the stimulation of, lipid metabolism regulating compounds such as glucose uptake modulators, antihyperlipidemic and antilipidemic active ingredients, compounds that reduce food intake, PPAR and PXR agonists, and ATP-dependent potassium in beta cells Active ingredients that act on the channel.

In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.

In one embodiment of the invention, the compound of formula (I) is administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, tikeside, pamakeside.

In one embodiment of the invention, the compound of formula I is administered in combination with a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.

In one embodiment of the invention, the compound of formula I is administered in combination with a PPAR alpha agonist such as, for example, GW 9578, GW 7647.

In one embodiment of the invention, the compounds of formula (I) are for example mixed PPAR alpha / gamma agonists such as GW 1536, AVE 8042, AVE 8134, AVE 0847 or International Application No. PCT / US 11833, International Application It is administered in combination with a mixed PPAR alpha / gamma agonist as described in PCT / US 11490, German Patent Publication No. 10142734.4.

In one embodiment of the invention, the compound of formula (I) is administered in combination with fibrate such as, for example, fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, the compound of formula (I) is administered in combination with an MTP inhibitor such as, for example, Implipidide, BMS-201038, R-103757.

In one embodiment of the invention, the compound of formula (I) is administered in combination with a bile acid absorption inhibitor such as, for example, HMR 1741 (see, eg, US Pat. No. 6,245,744 or 6,221,897).

In one embodiment of the invention, the compound of formula (I) is administered in combination with a CETP inhibitor such as, for example, JTT-705.

In one embodiment of the invention, the compound of formula I is administered in combination with a polymerizable bile acid adsorbent such as, for example, cholestyramine, cholesevelam.

In one embodiment of the invention, the compound of formula I is administered in combination with an LDL receptor inducer such as, for example, HMR1171, HMR1586 (see US Pat. No. 6,342,512).

In one embodiment of the invention, the compound of formula (I) is administered in combination with an AVAT inhibitor such as, for example, avacimid.

In one embodiment of the invention, the compound of formula (I) is administered in combination with a lipoprotein lipase inhibitor such as, for example, NO-1886.

In one embodiment of the invention, the compound of formula I is administered in combination with a squalene synthetase inhibitor such as, for example, BMS-188494.

In one embodiment of the invention, the compound of formula I is administered in combination with a lipoprotein antagonist such as, for example, CI-1027 or nicotinic acid.

In one embodiment of the invention, the compound of formula I is administered in combination with a lipase inhibitor such as, for example, oristat.

In one embodiment of the invention, the compound of formula I is administered in combination with insulin.

In one embodiment of the invention, the compound of formula (I) is administered in combination with a sulfonylurea such as, for example, tolbutamide, glybenclamide, glyphide or glymepiride.

In one embodiment of the invention, the compound of formula (I) is administered in combination with a meglitinidide such as, for example, metformin.

In one embodiment, the compounds of formula (I) are for example thiazolidinediones such as troglitazone, siglitazone, pioglitazone, rosiglitazone, or International Publication No. WO 97/41097. Reddy's Research Foundation], in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] phenyl] methyl] -2,4-thiazoli It is administered in combination with dindione.

In one embodiment, the compound of formula (I) is administered in combination with an α-glucosidase inhibitor such as, for example, miglitol or acarbose.

In one embodiment, the compound of formula (I) is combined with an active ingredient that acts on the ATP-dependent potassium channel of beta cells such as, for example, tolbutamide, glybenclamide, glipizide, glymepiride or repaglinide Administered.

In one embodiment, the compound of formula (I) is a combination of one or more of the above-mentioned compounds, for example, a combination of sulfonyl and metformin, sulfonylurea and acarbose, repaglinide and metformin, insulin and sulfonylurea , Insulin and metformin, insulin and troglitazone, and a combination of insulin and lovastatin.

In a further embodiment, the compound of formula (I) is a CART modulator [see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A, et al., M .: Hormone and Metabolic Research (2001 ), 33 (9), 554-558], NPY antagonist (eg, naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino) methyl] cyclohexylmethyl} amide; hydrochloride (CGP 71683A)), MC4 agonist (eg 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo -2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxonethyl] amide; Publication WO 01/91752)), orexin antagonists (eg 1- (2-methylbenzoxazol-6-yl) -3- [1,5] naphthyridin-4-ylurea; hydrochloride (SB- 334867-A)), H3 agonist (3-cyclohexyl-1- (4,4dimethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl) propane- 1-one oxalate (international Dog No. No. WO 00/63208)); TNF agonists, CRF antagonists (eg [2-methyl-9- (2,4,6-trimethylphenyl) -9H-1,3,9-triazafluoren-4-yl] dipropylamine ( International Publication No. WO 00/66585)), CRF BP antagonists (eg urocortin), urocortin agonists, β3 agonists (eg 1- (4-chloro-3-methanesulphate) Phenylmethylphenyl) -2- [2- (2,3-dimethyl-1H-indol-6-yloxy) ethylamino] ethanol; hydrochloride (WO 01/83451)), MSH (melanosite-stimulated Hormone) agonists, CCK-A agonists (eg {2- [4- (4-5,7-dimethylindol-1-yl} acetic acid trifluoroacetic acid salt (WO 99/15525) Serotonin reuptake inhibitors (e.g., dexfenfluramine), mixed serotonin-based and noradrenaline compounds (e.g. WO 00/71549), 5HT agonists (e.g., 1- (3-ethylbenzofuran-7-yl) pyrazine oxalate (WO 01/09111), bombesin agonist, galanin Antibiotics, growth hormones (eg, human growth hormones), growth hormone-releasing compounds (6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3,4-dihydro-1H-isoquinoline 2-carboxylic acid tertiary butyl ester (WO 01/85695), TRH agonists (see, eg, EP 0 462 884)), unbound protein 2 or 3 modulators , Leptin agonists (see, e.g., Lee, Daniel 'W .; Leinung, Matthew C .; Rozhavskaya-Arena, Marina; Grasso, Patricia.Leptin agonists as a potential approach to the treatment of obesity.Drugs of the Future ( 2001), 26 (9), 873-881), DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. For example, WO 00/78312), an RXR modulator, or a TR-β agonist are administered in combination.

In one embodiment of the invention, other active ingredients include leptin [see, eg, “Perspectives in the therapeutic use of leptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.

In one embodiment, the other active ingredient is dexamphetamine or amphetamine.

In one embodiment, the other active ingredient is an antihypertensive agent, such as, for example, an ACE inhibitor.

In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.

In another embodiment, the other active ingredient is sibutramine.

In one embodiment, the other active ingredient is orlistat.

In one embodiment, the other active ingredient is marginol or phentermine.

In one embodiment, the compound of formula (I) is a bulking agent, preferably an insoluble bulking agent [see, e.g., carob / Caromax® (Zunft HJ; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18 (5), 230-6.], Caromax is a carob-containing product (Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt / Main), and the caromax is possible in one formulation or in separate administration of the compound of formula I with the caromax, and the caromax is in the binding, for example, a confectionery or muesli. It may be administered in the form of food such as a muesli bar.

It will be appreciated that all suitable combinations of the compounds of the present invention, including the one or more compounds and optionally one or more other pharmaceutically active substances, are considered to be within the scope of protection of the present invention.

The examples listed below are intended to illustrate the invention and do not limit it.

Formula I

The activity of these compounds was tested as follows:

Enzyme test system for detecting phosphatase inhibition

Compounds of formula (I) tested the effect of phosphatase inhibition in in vitro assays. Enzyme preparation and analysis were performed as follows.

Enzyme Manufacturing:

A) Cell Culture:

Sf9 cells (Spodoptera frugiperda) type; Obtainable from Invitrogen] is incubated in Grace's supplemented medium with 10% heat-inactivated fetal bovine serum (Gibco-BRL) in a rotary flask at 28 ° C. according to the protocol of Summers and Smith. See A Manual for Methods for Baculoviruns Vectors and Insect Culture Procedures [Bulletin No. 15555]. Texas A & M University, Texas Agricultural Experiment Station, College Station, TX, 1987].

Design of Recombinant Baculovirus Transport Mediators: The cDNA encoding of regulatory and catalytic regions of human PTP1B without the carboxy-terminal hydrophobic region (corresponding to 1-22 aa) is dependent on the combined replication site and the appropriate cDNA prototype (e.g., Achieved by polymerase chain reaction via a primer with an in vitro RPS) and replicated to a baculovirus expression mediator (Amersham Pharmacia Biotech). Recombinant baculovirus was prepared with the help of a Bac-to-Bac baculovirus expression system (commercially available Gibco-BRL). Genes were cloned into pFASTBAC donor plasmid (commercially available from Life Technologies). Sufficient DH10BAC E. coli cells (Escherichia the resulting plasmid coli ) (commercially available from Life Technologies). After translocation and antibiotic selection, recombinant plasmid DNA was isolated from selected E. coli biogroups and used for transformation of Sf9 insect cells. Virus particles in the supernatant medium were amplified three times below the virus storage capacity of 500 ml.

B) Preparation of Recombinant Proteins:

Baculovirus infection of 500 ml spin culture of Sf9 cells was essentially performed as described by Summers and Smith (above). Sf9 cells were pelleted by centrifugation at 300 g for 5 minutes at a density of 1-3 × 10 ⁶ cells / ml, the supernatant was removed, and the cells were placed in 1 × 10 ⁷ cells in a suitable recombinant virus stock (MOI 10). Resuspend at a density of / ml. After careful stirring at room temperature for 1.5 hours, fresh medium was added to give a cell density of 1 × 10 ⁶ cells / ml. The cells were then incubated in a suspension at 28 ° C. for a suitable period after post infection.

C) Cell fraction and complete cell extract of infected Sf9 cells:

After post infection, aliquots were subjected to analysis of protein expression by SDS-PAGE and Western blot analysis. Cell fractions were performed as described in the literature. See Cromlish, W. and Kennedy, B. Biochem. Pharmacol. 52: 1777-1785, 1996. Complete cell extracts were obtained from 1 ml aliquots of infected Sf9 cells after a certain time post infection. Pelletized cells (300 × g, 5 min) were washed in phosphate-buffered saline (4 ° C.), resuspended in 50 μl of water and disrupted by repeated cooling / thawing. Protein concentrations were determined with the aid of bovine serum albumin as the Bradford method and standard.

Analytical Process:

A) Dephosphorylation of Phosphate Peptides

This assay is based on the release of phosphate from matched substrate peptides detected in the nanomolecular concentration range by the malachite green / ammonium molybdate method adapted for microtiter plate arrangement. Lanzetta, PA, Alvarez, LJ, Reinach , PS, Candia, OA Anal Biochem. 100: 95-97, 1979]. Dodecatriphosphopopeptide TRDIYETDYYRK (Biotrend, Cologne) is amino acids 1142-1153 of the catalytic region of the insulin receptor and is (self) phosphorylated on tyrosine residues 1146, 1150 and 1151. Recombinant hPTP1B is diluted with assay buffer (40 nM Tris / HCl, pH 7.4, 1 mM EDTA, 20 mM DTT), equal to the activity of protein 1000-1500 nmol / min / mg, and the target in 90 μl total volume (analysis buffer) Pre-culture (15 min, 30 ° C.) in the absence or presence of test substrate (5 μL) at one concentration (final concentration of DMSO 2% maximum). To initiate the dephosphorylation reaction, peptide substrate (10 μl, preheated to 30 ° C.) was added to the enzyme formulation preincubated with or without test substrate (final concentration 0.2-200 μM) and the culture was continued for 1 hour. . The reaction was stopped by adding 100 μl of malachite green hydrochloride (0.45%, 3 parts), ammonium molybdate tetrahydrate (4. 1% in 4N HCl) and 20% of 0.5% Tween. After 30 minutes of incubation at 22 ° C. for developing color, absorption at 650 nm was measured using a microtiter plate detector (molecular apparatus). Samples and paper were measured in triplicates. PTP1B activity was determined as nanomoles of phosphate released per minute and per mg of protein containing potassium phosphate as reference. Inhibition of recombinant hPTP1B by the test substance was measured as a percentage of the phosphatase control. IC ₅₀ values show significant agreement for the four factor nonlinear logistic regression curve.

B) cleavage of p-nitrophenyl phosphate:

This assay is based on the uptake of the nonphysiological substrate p-nitrophenyl phosphate during cleavage to give nitrophenols under standard conditions. Tonks, N.K., Diltz, C.D :, Fischer, E.H. J. Biol. Chem. 263: 6731-6737, 1988; Burke T. R., Ye, B., Yan, X. J., Wang, S. M., Jia, Z. C., Chen, L., Zhang, Z. Y., Barford, D. Biochemistry 35: 15989-15996, 1996]. The inhibitor is pipetted at a suitable dilution with a reaction mixture containing 0.5-5 mM p-nitrophenyl phosphate. The following buffer (total volume 100 μl) was used: (a) 100 mM sodium acetate (pH 5.5), NaCl 50 mM, 0.1% (w / v) bovine serum albumin, glutathione 5 mM, DTT 5 mM, EGTA 0.4 mM and EDTA 1 mM, (b) Hepes / J = KOH 50 mM (pH 7.4), NaCl 100 mM, 0.1% (w / v) bovine serum albumin, glutathione 5 mM, DTT 5 mM and EDTA 1 mM. The reaction was initiated by the addition of enzyme and carried out in microtiter plates at 25 ° C. for 1 hour. The reaction was stopped by adding 100 μl 0.2N NaOH. Enzyme activity was determined by measuring absorption at 405 nm with a suitable modification for absorption of the test substance and p-nitrophenyl phosphate. The results were expressed as a percentage of the control by comparing the content of p-nitrophenol (nmol / min / mg of protein) formed in the test substance-treated sample with the content in the untreated sample. Mean and standard deviation were calculated and IC50 values were determined by regression analysis of the linear portion of the inhibition curve.

From the table it is clear that the compounds of formula I are very suitable for lowering blood glucose levels by inhibiting the activity of phosphotyrosine phosphatase 1B (PTP1B). Therefore, they are particularly suitable for the treatment of type I and II diabetes, insulin resistance, dyslipidemia, metabolic syndrome / syndrome X, specific obesity and weight loss in mammals.

Compounds of formula (I) also include hyperglyceridemia, hypertension, atherosclerosis, disruption of the immune system, autoimmune diseases such as asthma, arthritis, osteoarthritis, osteoporosis, due to inhibition of PTP1B, It is suitable for the treatment of diseases caused by proliferative abnormalities such as cancer and psoriasis, reduction or increased production of growth factors, hormones or cytokines leading to the release of growth hormone.

The compounds are also suitable for the treatment of abnormalities of the nervous system, such as, for example, Alzheimer's disease or multiple sclerosis. The compounds are also suitable for the treatment of disturbances of calmness, for example, depression, anxiety conditions, anxiety neurosis, other mental manifestations such as schizophrenia, abnormalities associated with circadian rhythms, and treatment of drug abuse.

They are further suitable for the treatment of sleep abnormalities, sleep apnea, female and male sexual abnormalities, inflammation, acne, skin pigmentation, steroid metabolic disorders, skin diseases and mycosis.

The preparation of Example 4 in Table 1 is described in detail below, and other compounds of formula I were obtained similarly:

Exam Part:

A solution of 2-fluoro-5-nitrobenzyl bromide (30 g, 0.128 mol) in acetonitrile (250 mL) was added to a solution of Na ₂ SO ₃ (27.36 g, 0.128 mol) in H ₂ O (375 mL) The mixture is stirred at rt for 24 h. The solvent is distilled in vacuo, the residue is stirred with 100 ml of isopropanol, the solid is filtered off and washed with a small amount of isopropanol and diethyl ether.

Yield: 28.15 g

A sulfonic acid (1) introduction of a sodium salt of POCl ₃ (430㎖) of (35.19g, 0.1368mol), and PCl ₅ (28.78g, 0.137mol) is added. The mixture is heated at reflux for 5 hours, concentrated in vacuo and the residue is taken over ice / water. The reaction product is separated into a pale yellow solid and filtered.

Yield: 30.3 g

A solution of sulfonyl chloride (1) (30.0 g, 0.12 mol) in CH ₂ Cl ₂ (125 mL) was added dropwise to concentrated ammonia (90 mL, 1.2 mol) at room temperature. The mixture is stirred for 20 hours at room temperature and oxidized to pH 1 with HCl (IN). The organic phase is distilled off under reduced pressure, during which the reaction product is separated into a pale yellow solid. The reaction product is filtered.

Yield: 25.01 g (89.4%)

Diazabicycloundecene (34.1 g, 33.42 mL, 0.22 mol) is added to a solution of compound (1) (25 g, 0.107 mol) in DMF (1 L) at room temperature and the reaction mixture is stirred at 130 ° C. for 2 hours. . The solvent is distilled in vacuo, the residue is mixed with water (400 mL), HCl (2N, 400 mL) is added and the product is extracted several times with dichloromethane. The combined organic phases are dried (Na ₂ SO ₄ ) and the solvent is distilled off under reduced pressure. The residue is stirred with a small amount of cold isopropanol and the reaction product is filtered off.

Yield: 20.8 g (91.3%)

535 mg of the nitro compound is dissolved in 100 ml of a methanol / THF mixture (1: 1) and 5 mol% Pd (10% on activated carbon) is added. Hydrogenation is carried out with hydrogen in the hydrogenation apparatus at room temperature until the stop of hydrogen evolution (reaction time: 1 hour).

For workup, the catalyst is filtered through a celite filtration device and the filtrate is concentrated under reduced pressure. The oily residue is stirred with a small amount of diethyl ether, filtered off, washed with n-pentane and dried in vacuo.

Yield: 397 mg (86% of theory)

1.84 g (10 mmol) of aniline prepared above was suspended in 240 mL of anhydrous dichloromethane, and 2.55 g (11 mmol) of 1,1'thiocarbonyldi-2 (1H) -pyridone was added while stirring at 20 ° C. The reaction mixture is stirred at 20 ° C. for 5 hours.

For workup, the reaction mixture is washed three times with 50 ml of water and the organic phase is subsequently dried over Na ₂ SO ₄ and filtered with a desiccant.

Solvent removal under reduced pressure yields a pale yellow oil which crystallizes after addition of a small amount of diethyl ether.

2.12 (9.4 mmol) of yellow crystals were obtained and the yield was 94% of theory.

MS (ES +): 227.2

1 H-NMR (500 MHz, d ₆ -DMSO): δ = 4.57 (s, 2 H), 6.85 (d, J = 8.56 Hz, 1 H), 7.33 (ps d, J = 8.56 Hz, 1 H), 7.40 (ps s, 1 H), 10.84 (br s, 1 H)

226 mg of isothiocyanate prepared above was dissolved in 10 ml of anhydrous tetrahydrofuran, and stirred with 2-bromo-1- [3,5-di (3) by reaction with sodium azide in DMF as a solvent. 2-azido-1- [3,5-di (tert-butyl) -4-hydroxyphenyl] ethan-1-one prepared from tert-butyl) -4-hydroxyphenyl] ethan-1-one 339 mg (1.5 mmol) and triphenylphosphine 315 mg (1.2 mmol) are added. The reaction mixture is heated to solvent reflux for 1 hour.

For workup, the reaction solution was concentrated under reduced pressure and the oily residue was chromatographed on silica gel using ethyl acetate / heptane (mixture ratio 1: 1) as the mobile phase [40-63μ, Merck]. Chromatography

Yield: 288 mg (63% of theory)

MS (ES +): 455.99

1 H-NMR (500 MHz, d ₆ -DMSO): δ = 1.42 (s, 18 H), 4.64 (s, 2 H), 6.82 (d,

J = 8.6 Hz, 1H), 7.15 (s, 1H), 7.22 (s, 1H), 7.31 (s, 2H), 7.48 (dd, J = 8.6 and 2.1 Hz, 1H), 7.70 (d , J = 2.1 Hz, 1 H), 10.11 (s, 1 H), 10.15 (s, 1 H)

Claims (14)

Compounds of formula (I) and physiologically acceptable salts thereof. [Formula I]

In the above formula, X is O, C-R2; Y is O, C-R2, and if either group X and Y is O, the other is C-R1, Wherein R 1 and R 2 independently of one another are H, aryl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, -COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene -COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkylene-aryl, heterocycle, ( C ₁ -C ₆ ) -alkylene-heterocycle, CF ₃ , OCF ₃ , CN, (CH ₂ ) _1-6 -OH, O- (C ₁ -C ₆ ) -alkyl, CO- (C ₁ -C ₆ ) -alkyl, -C (O) O-alkyl, COOH, CON (R9) (R10), wherein the aryl radical and heterocycle radical are F, Cl, Br, (CH ₂ ) _0-2 OH, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, pipera Jean, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN , 0- (C ₁ -C ₆ ) -alkyl, S (O) _0-2- (C ₁ -C ₆ ) -alkyl, S0 ₂ -N (R9) (R10), CO- (C ₁ -C ₆ ) -Alkyl, -COOH, (C ₁ -C ₆ ) -alkylene-COOH, COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -Alkyl, (C ₃ -C ₁₀ ) -cycloalkyl, pe It may be substituted one or more times with ni, wherein the piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) The piperazinone, morpholine, thiomorpholine and phenyl rings are F, Cl, Br, (CH ₂ ) _0-2 0H, COOH, CN, N0 ₂ , -O- (C ₁ -C ₆ ) -alkyl,- _{NH-O- (C 1 -C 6} ) - alkyl, - (CO) -NH-O- (C 1 -C 6) - alkylene -N (R9) (R10), - (CO) - (C 1 May be substituted one or more times with -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl, CF ₃ , OCF ₃ , N (R 9) (R 10); R 3 is H, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-aryl, -C (O) -aryl, (C ₁ -C ₆ ) -alkylene-heterocycle, CO -(C ₁ -C ₆ ) -alkyl, wherein the aryl and heterocycle radicals are F, Cl, Br, (C ₁ -C ₆ ) -alkyl, COOH, COO (C ₁ -C ₆ ) -alkyl, CF ₃ Or may be substituted one or more times with OCF ₃ ; R 4 and R 5 independently of one another are H, F, Cl, Br, (C ₁ -C ₆ ) -alkyl, CF ₃ , OCF ₃ , N0 ₂ , N (R9) (R10), CN, 0- (C _1- C ₆ ) -alkyl, CO- (C ₁ -C ₆ ) -alkyl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, CON (R 9) (R 10), (C ₁ -C ₆ ) -alkyl Lene-CON (R9) (R10), COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, S (O) _0-2 - (C ₁ -C ₆₎ - _{alkyl, S (O) 2 -N (} R9) (R10), CH 2 0H, CH 2 0CH 3 , and; R 6 and R 7 are independently of each other H, F, Cl, Br, (C ₁ -C ₆ ) -alkyl, cyclopropyl, tetrafluorocyclopropyl, difluorocyclopropyl, or R 6 and R 7 together are a group = CH ₂ To form; R 8 is H, CH ₃ , CF ₃ , CH ₂ 0H; R 9 is H, (C ₁ -C ₄ ) -alkyl; R 10 is H, (C ₁ -C ₄ ) -alkyl; R9 and R10 together with the N atoms to which they are attached form a 3-9 membered ring system. The method of claim 1, R 1 is aryl, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkylene-aryl, heterocycle, (C ₁ -C ₆ ) -alkyl Ren-heterocycle, CF ₃ , OCF ₃ , CN, (CH ₂ ) _1-6 -OH, O- (C ₁ -C ₆ ) -alkyl, CO- (C ₁ -C ₆ ) -alkyl, -C ( O) O-alkyl, COOH, CON (R9) (R10), wherein the aryl radicals and heterocycle radicals are F, Cl, Br, (CH ₂ ) _0-2 OH, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- ( C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (C ₁ -C ₆ ) -Alkyl, S (O) _0-2- (C ₁ -C ₆ ) -alkyl, S0 ₂ -N (R9) (R10), CO- (C ₁ -C ₆ ) -alkyl, -COOH, (C ₁ -C ₆ ) -alkylene-COOH, -COO (C ₁ -C ₆ ) -alkyl, (C ₀ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₁₀ ) -cycloalkyl, phenyl may be substituted one or more times, wherein the piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazin, N- The (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and phenyl rings are F, Cl, Br, (CH ₂ ) _0-2 0H, COOH, CN, N0 ₂ , -O- ( C ₁ -C ₆ ) -alkyl, -NH-O- (C ₁ -C ₆ ) -alkyl,-(CO) -NH-O- (C ₁ -C ₆ ) -alkylene-N (R9) (R10 ), - (CO) - ( C 1 -C 6) - _{alkyl, - (C 1 -C 6)} - _{alkyl, CF 3, OCF 3, N} ( one or more times by R9) (R10) may be substituted, and; R 2 is H, aryl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, -COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl; (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkylene-aryl, heterocycle, (C ₁ -C ₆ ) -alkylene-heterocycle , CF ₃ , OCF ₃ , CN,-(CH ₂ ) _1-6 -OH, O- (C ₁ -C ₆ ) -alkyl, CO- (C ₁ -C ₆ ) -alkyl, C (O) O- Alkyl, COOH, CON (R9) (R10), wherein the aryl radical and heterocycle radical are F, Cl, Br, (CH ₂ ) _0-2 OH, (C ₁ -C ₆ ) -alkyl, (C _2- C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (C ₁ -C ₆ ) -alkyl, S (O) _0-2- (C ₁ -C ₆ ) -alkyl, S0 ₂ -N (R9) (R10), CO- (C ₁ -C ₆ ) -alkyl, -COOH, (C ₁ -C ₆ ) -Alkylene-COOH, -COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₁₀ ) -cyclo May be substituted one or more times with alkyl, phenyl; R 3 is H, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-aryl, -C (O) -aryl, (C ₁ -C ₆ ) -alkylene-heterocycle, CO - alkyl, - (C ₁ -C ₆₎ R 4 and R 5 independently of one another are H, F, Cl, Br, (C ₁ -C ₆ ) -alkyl, CF ₃ , OCF ₃ , N0 ₂ , N (R9) (R10), CN, 0- (C _1- C ₆ ) -alkyl, CO- (C ₁ -C ₆ ) -alkyl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, -CON (R 9) (R 10), (C ₁ -C ₆ )- Alkylene-CON (R9) (R10), COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, S (O) _{0- 2 - (C 1 -C 6)} - _{alkyl, S (O) 2 -N (} R9) (R10), CH 2 0H, CH 2 0CH 3 , and; R 6 and R 7 are independently of each other H, F, Cl, Br, (C ₁ -C ₆ ) -alkyl, cyclopropyl, tetrafluorocyclopropyl, difluorocyclopropyl, or R 6 and R 7 together are a group = CH ₂ To form; R 8 is H, CH ₃ , CF ₃ , CH ₂ 0H; R 9 is H, (C ₁ -C ₄ ) -alkyl; R 10 is H, (C ₁ -C ₄ ) -alkyl; A compound of formula (I) and physiologically acceptable salts thereof, wherein R 9 and R 10 together with the N atom to which they are attached form a 3-9 membered ring system. The method according to claim 1 or 2, R 1 is phenyl, naphthyl, thionaphthyl, pyridyl, wherein phenyl, naphthyl, thionaphthyl and pyridyl are F, Cl, Br, (CH ₂ ) _0-2 OH, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆₎ - alkenyl, (C ₂ -C ₆₎ - Al _{kinil, CF 3, OCF 3, N} (R9) (R10), non-piperidinyl, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (C ₁ -C ₆ ) -alkyl, S (O) _0-2- (C ₁ -C ₆ ) -alkyl, S0 ₂ -N (R9) (R10), CO- (C ₁ -C ₆ ) -alkyl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, (C _3- C ₁₀ ) -cycloalkyl, phenyl may be substituted one or more times, wherein the piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C _1- C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and phenyl rings are F, Cl, Br, (CH ₂ ) _0-2 0H, COOH, CN, N0 ₂ , -O- (C ₁ -C ₆ ) -alkyl, -NH-O- (C ₁ -C ₆ ) -alkyl,-(CO) -NH-O- (C ₁ -C ₆ ) -alkylene-N (R9) (R10), - (CO) - (C 1 -C 6) - _{alkyl, - (C 1 -C 6)} - alkyl, CF _3, OCF _3, N one or more times with (R9) (R10) may be substituted And; R 2 is H, (C ₁ -C ₆ ) -alkyl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, -COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl Lene-COO (C ₁ -C ₆ ) -alkyl; R 3 is H, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-aryl, -C (O) -aryl, (C ₁ -C ₆ ) -alkylene-heterocycle, CO - alkyl, - (C ₁ -C ₆₎ R4 and R5 are H; R6 and R7 are H; R8 is H; R 9 is H, (C ₁ -C ₄ ) -alkyl; A compound of formula I, and a physiologically acceptable salt thereof, wherein R 10 is H, (C ₁ -C ₄ ) -alkyl. The method according to any one of claims 1 to 3, R 1 is phenyl, naphthyl, thionaphthyl and pyridyl, wherein phenyl, naphthyl, thionaphthyl and pyridyl are F, Cl, Br, (CH ₂ ) _0-2 OH, (C ₁ -C ₆ ) -Alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, CF ₃ , OCF ₃ , N (R 9) (R 10), piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C ₁ -C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (C ₁ -C ₆ ) -alkyl, S (O) _0-2- (C ₁ -C ₆ ) -alkyl, S0 ₂ -N (R9) (R10), CO- (C ₁ -C ₆ ) -alkyl, COOH, (C ₁ -C ₆ ) -alkylene-COOH, COO (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, (C _3- C ₁₀ ) -cycloalkyl, phenyl may be substituted one or more times, wherein the piperidinone, piperazine, piperazinone, N- (C ₁ -C ₆ -alkylene) -piperazine, N- (C _1- C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and phenyl rings are F, Cl, Br, (CH ₂ ) _0-2 0H, COOH, CN, N0 ₂ , -O- (C ₁ -C ₆ ) -alkyl, -NH-O- (C ₁ -C ₆ ) -alkyl,-(CO) -NH-O- (C ₁ -C ₆ ) -alkylene-N (R 9) (R10),-(CO)-(C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkyl, CF ₃ , OCF ₃ , N (R9) (R10) substituted one or more times Can be; R 2 is H, (C ₁ -C ₆ ) -alkyl, -C (O) O- (C ₁ -C ₆ ) -alkyl,-(C ₁ -C ₆ ) -alkylene-C (O) O- ( C ₁ -C ₆ ) -alkyl, -COOH,-(C ₁ -C ₆ ) -alkylene-COOH; R 3 is H, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-aryl, -C (O) -aryl, (C ₁ -C ₆ ) -alkylene-heterocycle, CO - alkyl, - (C ₁ -C ₆₎ R4 and R5 are H; R6 and R7 are H; R8 is H; R9 is H; And a physiologically acceptable salt thereof. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament. A medicament comprising at least one compound according to any one of claims 1 to 4. A medicament comprising at least one compound according to any one of claims 1 to 4 and at least one other active ingredient. The method according to claim 7, wherein the other active ingredient is at least one antidiabetic, hypoglycemic active ingredient, HMGCoA reductase inhibitor, cholesterol absorption inhibitor, PPAR gamma agonist, PPAR alpha agonist, PPAR alpha / gamma agonist, fibrate, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymer bile acid absorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein antagonists, lipase inhibitors, insulin, Sulfonylureas, biguanides, meglitinides, thiazolidinediones,

-Glucosidase inhibitors, active ingredients acting on ATP-dependent potassium channels of beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP Antagonists, urocortin agonists,

3 agonists, melanocyte-stimulating hormone (MSH) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenaline compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones , Growth hormone releasing compounds, TRH agonists, unbound protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, PPAR modulators, RXR modulators or TR-

Agonists or agents comprising amphetamines. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for lowering blood sugar. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for treating type II diabetes. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of lipid and carbohydrate metabolic disorders. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of atherosclerosis manifestations. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of insulin resistance. A method for preparing a medicament comprising at least one compound according to any one of claims 1 to 4, comprising mixing the active ingredient with a pharmaceutically suitable carrier and converting the mixture into a suitable dosage form.