DE102007005045A1 - New phenothiazine derivative for use in preparing medicine for blood sugar lowering and for treatment of diabetes, nicotine dependence, alcohol dependence, central nervous system disorders, schizophrenia, and Alzheimer's disease - Google Patents

New phenothiazine derivative for use in preparing medicine for blood sugar lowering and for treatment of diabetes, nicotine dependence, alcohol dependence, central nervous system disorders, schizophrenia, and Alzheimer's disease Download PDF

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DE102007005045A1
DE102007005045A1 DE102007005045A DE102007005045A DE102007005045A1 DE 102007005045 A1 DE102007005045 A1 DE 102007005045A1 DE 102007005045 A DE102007005045 A DE 102007005045A DE 102007005045 A DE102007005045 A DE 102007005045A DE 102007005045 A1 DE102007005045 A1 DE 102007005045A1
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alkylene
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Sanofi SA
Sanofi Aventis France
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Priority to AT08706994T priority patent/ATE514692T1/en
Priority to JP2009546671A priority patent/JP2010516721A/en
Priority to EP08706994A priority patent/EP2114937B1/en
Priority to PCT/EP2008/000163 priority patent/WO2008089892A1/en
Priority to UY30881A priority patent/UY30881A1/en
Priority to TW097102588A priority patent/TW200900400A/en
Priority to CL200800212A priority patent/CL2008000212A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

A phenothiazine derivative is new. A phenothiazine derivative of formula (I) is new. R1 : H, 1-6C alkyl, 0-6C alkylaryl, CO-1-6C alkyl, 2-6C alkyl-COO-0-6C alkyl, or 2-6C alkyl-O-1-6C alkyl; R2, R3 : H, F, Cl, Br, CN, NO 2, 0-6C alkyl-COO-0-6C alkyl, 0-6C alkyl-O-0-6C alkyl, 1-6C alkyl, 0-6C alkyl-CO-1-6C alkyl, 0-6C alkylphenyl, SCF 3, SF 5, or SCH 3; R4, R5 : H, F, Cl, Br, CN, SCN, NO 2, =O, 0-6C alkyl-COO-0-6C alkyl, -CO-COO-0-6C alkyl, 0-6C alkyl-O-0-6C alkyl, 1-6C alkyl, 0-6C alkyl-CO-1-6C alkyl, 0-6C alkyl-CONH-0-6C alkyl, 0-6C alkyl-CON[0-6C alkyl] 2, 0-6C alkyl-NH-0-6C alkyl, 0-6C alkyl-NH-COO-0-6C alkyl, 0-6C alkyl-CON[0-6C alkyl]-O-0-6C alkyl, 0-6C alkyl-N[0-6C alkyl] 2, 0-6C alkylaryl, SF 5, 0-6C alkyl-S(O) x-1-6C alkyl, S(O) x-1-6C alkyl-COO-0-6C alkyl, S(O) x-2-6C alkyl-O-0-6C alkyl, -SO 2-NH-0-6C alkyl, -SO 2-N-[0-6C alkyl] 2, S(O) x-0-6C alkyl-heterocycle, S(O) x-1-6C alkyl-CO-heterocycle, -NH-SO 2-1-6C alkyl, 0-6C alkylcycloalkyl, or 0-6C alkyl-heterocycle; x : 0-2; R6, R7 : H, F, Cl, Br, CN, NO 2, =O, =S, =N-O-0-6C alkyl, 0-6C alkyl-COO-0-6C alkyl, 0-6C alkyl-O-0-6C alkyl, 0-6C alkyl-O-CO-1-6C alkyl, 1-6C alkyl, 0-6C alkyl-CO-1-6C alkyl, 0-6C alkylaryl, SF 5, or S(O) x-1-6C alkyl; Ring A : 5-10-membered heterocyclic ring optionally with another 5-10-membered ring; and Ring B : 4-8-membered cycloalkyl ring, 4-10-membered heterocyclic ring or 6-10-membered cycloaryl. Independent claims are included for: (1) a medicament comprising (I) and further active ingredients; and (2) production of medicine by mixing (I) with carrier and preparing into a form suitable for administration. [Image] ACTIVITY : Antialcoholic; Neuroprotective; Nootropic; Hypoglycemic; CNS-Gen; Antidiabetic; Antismoking; Neuroleptic. MECHANISM OF ACTION : Glucokinase activator. 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyrany-4-yl)-N-thiazol-2-yl-propionamide was tested for activation of human glucokinase in an enzymatic test. Effective concentration at 150% (EC 1 5 0) was 4.2 mu M and fold induction was 2.0.

Description

Die Erfindung betrifft substituierte Phenothiazine sowie deren physiologisch verträgliche Salze.The The invention relates to substituted phenothiazines and their physiological compatible salts.

Es sind bereits Penothiazin Derivate wie zum Beispiel Chlorpromazin (3-(2-Chlor-4α,10α-dihydro-10H-phenothiazin-10-yl)-N,N-dimethylpropan-1-amin) als Neuroleptika bekannt.It are already penothiazine derivatives such as chlorpromazine (3- (2-chloro-4α, 10α-dihydro-10H-phenothiazine-10-yl) -N, N-dimethylpropane-1-amine) known as neuroleptics.

Der Erfindung lag die Aufgabe zugrunde, Verbindungen zur Behandlung von Diabetes zu entwickeln. Diese Verbindungen sollen inbesondere den Blutzuckerspiegel absenken.Of the Invention was the object of compounds for treatment to develop from diabetes. These compounds should in particular Lower the blood sugar level.

Die Erfindung betrifft daher Verbindungen der Formel I,

Figure 00010001
worin bedeuten
R1 H, (C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, CO-(C1-C6)-Alkyl, (C2-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C2-C6)-Alkylen-O-(C1-C6)-Alkyl
R2, R3 unabhängig voneinander H, F, Cl, Br, CN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Phenyl, SCF3, SF5, SCH3;
R4, R5 unabhängig voneinander H, F, Cl, Br, CN, SCN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, -CO-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-CONH(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-NH(C0-C6)-Alkyl, (C0-C6)-Alkylen-NH-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-N[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-Aryl, SF5, (C0-C6)-Alkyl-S(O)X(C1-C6)-Alkyl, S(O)x(C1-C6)-Alkylen-COO-(C0-C6)-Alkyl, S(O)x(C2-C6)-Alkylen-O-(C0-C6)-Alkyl, -SO2-NH-(C0-C6)-Alkyl, -SO2-N-[(C0-C6)-Alkyl]2, S(O)x(C0-C6)-Alkylen-Heterocyclus, S(O)x(C1-C6)-Alkylen-CO-Heterocyclus, -NH-SO2-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Cycloalkyl, (C0-C6)-Alkylen-Heterocyclus, (C0-C6)-Alkylen-Aryl;
x 0, 1, 2;
R6, R7 unabhängig voneinander H, F, Cl, Br, CN, NO2, =O, =S, =N-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-CO-(C1-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, SF5, S(O)x(C1-C6)-Alkyl;
A 5 bis 10 gliedriger Heterocyclus, wobei der Heterocyclus mit einem weiteren 5 bis 10 gliedrigen Ring anneliert sein kann;
B 4 bis 8 gliedriger Cycloalkylring, ein 4 bis 10 gliedriger Heterocyclus oder ein 6 bis 10 gliedriger Arylring;
sowie deren physiologisch verträgliche Salze.The invention therefore relates to compounds of the formula I,
Figure 00010001
in which mean
R 1 is H, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, CO- (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-O- (C 1 -C 6 ) -alkyl
R 2 , R 3 independently of one another are H, F, Cl, Br, CN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene O- (C 0 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -Alkylene-phenyl, SCF 3 , SF 5 , SCH 3 ;
R4, R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, -CO-COO- (C 0 -C 6 ) alkyl, (C 0 -C 6 ) alkylene-O- (C 0 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CONH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -Alkyl] 2 , (C 0 -C 6 ) -alkylene-NH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-NH-COO- (C 0 -C 6 ) -alkyl , (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -alkyl] -O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-N [(C 0 -C 6 ) -alkyl] 2 , (C 0 -C 6 ) -alkylene-aryl, SF 5 , (C 0 -C 6 ) -alkyl-S (O) X (C 1 -C 6 ) -alkyl, S (O) x (C 1 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, S (O) x (C 2 -C 6 ) -alkylene-O- (C 0 -C 6 ) -Alkyl, -SO 2 -NH- (C 0 -C 6 ) -alkyl, -SO 2 -N - [(C 0 -C 6 ) -alkyl] 2 , S (O) x (C 0 -C 6 ) -Alkylene heterocycle, S (O) x (C 1 -C 6 ) -alkylene-CO-heterocycle, -NH-SO 2 - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene -Cycloalkyl, (C 0 -C 6 ) -alkylene heterocycle, (C 0 -C 6 ) -alkylene-aryl;
x 0, 1, 2;
R6, R7 are independently H, F, Cl, Br, CN, NO 2, = O, = S, = NO- (C 0 -C 6) -alkyl, (C 0 -C 6) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O-CO- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, SF 5 , S (O) x (C 1 -C 6 ) alkyl;
A is 5 to 10 membered heterocycle, which heterocycle may be fused to another 5 to 10 membered ring;
B is 4 to 8 membered cycloalkyl ring, a 4 to 10 membered heterocycle or a 6 to 10 membered aryl ring;
and their physiologically acceptable salts.

Bevorzugt sind Verbindungen der Formel I, worin ein oder mehrere Reste folgende Bedeutung haben:
R1 H, (C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, CO-(C1-C6)-Alkyl, (C2-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C2-C6)-Alkylen-O-(C1-C6)-Alkyl;
R2, R3 unabhängig voneinander H, F, Cl, Br, CN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Phenyl, SCF3, SF5, SCH3;
R4, R5 unabhängig voneinander H, F, Cl, Br, CN, SCN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, -CO-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C0)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-CONH(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-NH(C0-C6)-Alkyl, (C0-C6)-Alkylen-NH-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-N[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-Aryl, SF5, (C0-C6)-Alkyl-S(O)x(C1-C6)-Alkyl, S(O)x(C1-C6)-Alkylen-COO-(C0-C6)-Alkyl, S(O)x(C2-C6)-Alkylen-O-(C0-C6)-Alkyl, -SO2-NH-(C0-C6)-Alkyl, -SO2-N-[(C0-C6)-Alkyl]2, S(O)x(C0-C6)-Alkylen-Heterocyclus, S(O)x(C1-C6)-Alkylen-CO-Heterocyclus, -NH-SO2-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Cycloalkyl, (C0-C6)-Alkylen-Heterocyclus, (C0-C6)-Alkylen-Aryl;
x 0, 1, 2;
R6, R7 unabhängig voneinander H, F, Cl, Br, CN, NO2, =O, =S, =N-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-CO-(C1-C6)-Alkyl, (C1-C0)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, SF5, S(O)x(C1-C6)-Alkyl;
A 5 bis 10 gliedriger Heterocyclus, der in alpha Stellung eine -C=N- Bindung enthält, wobei der Heterocyclus mit einem weiteren 5 bis 10 gliedrigen Ring anneliert sein kann;
B 4 bis 8 gliedriger Cycloalkylring, ein 4 bis 10 gliedriger Heterocyclus oder ein 6 bis 10 gliedriger Arylring;
sowie deren physiologisch verträgliche Salze.Preference is given to compounds of the formula I in which one or more radicals have the following meanings:
R 1 is H, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, CO- (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-O- (C 1 -C 6 ) -alkyl;
R 2 , R 3 independently of one another are H, F, Cl, Br, CN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene O- (C 0 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -Alkylene-phenyl, SCF 3 , SF 5 , SCH 3 ;
R 4 , R 5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, -CO-COO- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O- (C 0 -C 6 ) -alkyl, (C 1 -C 0 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CONH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene CON [(C 0 -C 6 ) -alkyl] 2 , (C 0 -C 6 ) -alkylene-NH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-NH-COO- ( C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -alkyl] -O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -Alkylene-N [(C 0 -C 6 ) -alkyl] 2 , (C 0 -C 6 ) -alkylene-aryl, SF 5 , (C 0 -C 6 ) -alkyl-S (O) x (C C 1 -C 6 ) -alkyl, S (O) x (C 1 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, S (O) x (C 2 -C 6 ) -alkylene O- (C 0 -C 6 ) -alkyl, -SO 2 -NH- (C 0 -C 6 ) -alkyl, -SO 2 -N - [(C 0 -C 6 ) -alkyl] 2 , S (O ) x (C 0 -C 6 ) -alkylene heterocycle, S (O) x (C 1 -C 6 ) -alkylene-CO-heterocycle, -NH-SO 2 - (C 1 -C 6 ) -alkyl, ( C 0 -C 6 ) -alkylene-cycloalkyl, (C 0 -C 6 ) -alkylene heterocycle, (C 0 -C 6 ) -alkylene-aryl;
x 0, 1, 2;
R6, R7 are independently H, F, Cl, Br, CN, NO 2, = O, = S, = NO- (C 0 -C 6) -alkyl, (C 0 -C 6) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O-CO- (C 1 -C 6 ) -alkyl, (C 1 -C 0 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, SF 5 , S (O) x (C 1 -C 6 ) alkyl;
A 5 to 10-membered heterocycle which contains a -C = N bond in the alpha position, where the heterocycle may be fused to another 5 to 10 membered ring;
B is 4 to 8 membered cycloalkyl ring, a 4 to 10 membered heterocycle or a 6 to 10 membered aryl ring;
and their physiologically acceptable salts.

Besonders bevorzugt sind Verbindungen der Formel I, worin ein oder mehrere Reste folgende Bedeutung haben:
R1 H, (C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, CO-(C1-C6)-Alkyl, (C2-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C2-C6)-Alkylen-O-(C1-C6)-Alkyl;
R2, R3 H;
R4, R5 unabhängig voneinander H, F, Cl, Br, CN, SCN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, -CO-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-CONH(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-NH(C0-C6)-Alkyl, (C0-C6)-Alkylen-NH-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-N[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-Aryl, SF5, (C0-C6)-Alkyl-S(O)x(C1-C6)-Alkyl, S(O)x(C1-C6)-Alkylen-COO-(C0-C6)-Alkyl, S(O)x(C2-C6)-Alkylen-O-(C0-C6)-Alkyl, -SO2-NH-(C0-C6)-Alkyl, -SO2-N-[(C0-C6)-Alkyl]2, S(O)x(C0-C6)-Alkylen-Heterocyclus, S(O)x(C1-C0)-Alkylen-CO-Heterocyclus, -NH-SO2-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Cycloalkyl, (C0-C6)-Alkylen-Heterocyclus, (C0-C6)-Alkylen-Aryl;
x 0, 1, 2;
R6, R7 unabhängig voneinander H, F, Cl, Br, CN, NO2, =O, =S, =N-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-CO-(C1-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, SF5, S(O)x-(C1-C6)-Alkyl;
A ein 5 gliedriger Heterocyclus, der in alpha Stellung eine -C=N- Bindung enthält, wobei der Heterocyclus mit einem weiteren 5 bis 10 gliedrigen Ring anneliert sein kann;
B 4 bis 8 gliedriger Cycloalkylring, ein 4 bis 10 gliedriger Heterocyclus oder ein 6 bis 10 gliedriger Arylring;
sowie deren physiologisch verträgliche Salze.Particular preference is given to compounds of the formula I in which one or more radicals have the following meanings:
R 1 is H, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, CO- (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-O- (C 1 -C 6 ) -alkyl;
R2, R3 H;
R4, R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, -CO-COO- (C 0 -C 6 ) alkyl, (C 0 -C 6 ) alkylene-O- (C 0 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CONH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -Alkyl] 2 , (C 0 -C 6 ) -alkylene-NH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-NH-COO- (C 0 -C 6 ) -alkyl , (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -alkyl] -O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-N [(C C 1 -C 6 ) -alkyl] 2 , (C 0 -C 6 ) -alkylene-aryl, SF 5 , (C 0 -C 6 ) -alkyl-S (O) x (C 1 -C 6 ) -alkyl, S (O) x (C 1 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, S (O) x (C 2 -C 6 ) -alkylene-O- (C 0 -C 6 ) -Alkyl, -SO 2 -NH- (C 0 -C 6 ) -alkyl, -SO 2 -N - [(C 0 -C 6 ) -alkyl] 2 , S (O) x (C 0 -C 6 ) -Alkylene heterocycle, S (O) x (C 1 -C 0 ) -alkylene-CO-heterocycle, -NH-SO 2 - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene -Cycloalkyl, (C 0 -C 6 ) -alkylene heterocycle, (C 0 -C 6 ) -alkylene-aryl;
x 0, 1, 2;
R6, R7 are independently H, F, Cl, Br, CN, NO 2, = O, = S, = NO- (C 0 -C 6) -alkyl, (C 0 -C 6) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O-CO- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, SF 5 , S (O) x - (C 1 -C 6 ) alkyl;
A is a 5-membered heterocycle which contains a -C = N bond in the alpha position, where the heterocycle may be fused to another 5 to 10 membered ring;
B is 4 to 8 membered cycloalkyl ring, a 4 to 10 membered heterocycle or a 6 to 10 membered aryl ring;
and their physiologically acceptable salts.

Ganz besonders bevorzugt sind Verbindungen der Formel I, worin ein oder mehrere Reste folgende Bedeutung haben:
R1 H, (C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, CO-(C1-C6)-Alkyl, (C2-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C2-C6)-Alkylen-O-(C1-C6)-Alkyl;
R2, R3 H;
R4, R5 unabhängig voneinander H, F, Cl, Br, CN, SCN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, -CO-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-CONH(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-NH(C0-C6)-Alkyl, (C0-C6)-Alkylen-NH-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-N[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-Aryl, SF5, (C0-C6)-Alkyl-S(O)x(C1-C6)-Alkyl, S(O)x(C1-C6)-Alkylen-COO-(C0-C6)-Alkyl, S(O)x(C2-C6)-Alkylen-O-(C0-C6)-Alkyl, -SO2-NH-(C6-C6)-Alkyl, -SO2-N-[(C0-C6)-Alkyl]2, S(O)x(C0-C6)-Alkylen-Heterocyclus, S(O)x(C1-C6)-Alkylen-CO-Heterocyclus, -NH-SO2-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Cycloalkyl, (C0-C6)-Alkylen-Heterocyclus, (C0-C6)-Alkylen-Aryl;
x 0, 1, 2;
R6, R7 unabhängig voneinander H, F, Cl, Br, CN, NO2, =O, =S, =N-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-CO-(C1-C6)-Alkyl, (C1-C0)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, SF5, S(O)x(C1-C6)-Alkyl;
A Thiazol-2-yl, Pyrazol-3-yl, Pyridin-2-yl, Oxazol-2-yl, Isoxazol-3-yl, Imidazol-2-yl, [1,2,4]Thiadiazol-3-yl, [1,2,4]Thiadiazol-5-yl, [1,3,4]Thiadiazol-3-yl, Pyridin-2-yl, Pyrimidin-2-yl, Pyrimidin-4-yl, Pyrazin-2-yl, Pyridazin-2-yl, [1,2,4]Triazin-3-yl, [1,2,4]Triazin-6-yl, Thiazolo[4,5-b]pyridin-2-yl, Thieno[2,3-d]thiazol-2-yl, Benzothiazol-2-yl, Benzooxazol-2-yl, Benzimidazol-2-yl, Chinolin-2-yl, Isochinolin-3-yl, 4,5,6,7-Tetrahydro-benzothiazol-2-yl, 4,5,6,7-Tetrahydro-benzooxazol-2-yl, 4,5,6,7-Tetrahydro-benzimidazol-2-yl, 4,5,6,7-Tetrahydro-pyrazolo[1,5-a]pyridin-2-yl, 5,6-Dihydro-4H-cyclopentathiazol-2-yl, 4,5-Dihydro-thiazol-2-yl;
B Cyclopentyl, Cyclohexyl, Tetrahydrofuranyl, Tetrahydropyranyl, Tetrahydrothiopyranyl, Piperidinyl, Phenyl, Pyridyl, Furanyl, Thiophenyl, Thiazolyl, Oxazolyl, Pyrazolyl, Isoxazolyl;
sowie deren physiologisch verträgliche Salze.Very particular preference is given to compounds of the formula I in which one or more radicals have the following meanings:
R 1 is H, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, CO- (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-O- (C 1 -C 6 ) -alkyl;
R2, R3 H;
R4, R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, -CO-COO- (C 0 -C 6 ) alkyl, (C 0 -C 6 ) alkylene-O- (C 0 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CONH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -Alkyl] 2 , (C 0 -C 6 ) -alkylene-NH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-NH-COO- (C 0 -C 6 ) -alkyl , (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -alkyl] -O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-N [(C C 1 -C 6 ) -alkyl] 2 , (C 0 -C 6 ) -alkylene-aryl, SF 5 , (C 0 -C 6 ) -alkyl-S (O) x (C 1 -C 6 ) -alkyl, S (O) x (C 1 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, S (O) x (C 2 -C 6 ) -alkylene-O- (C 0 -C 6 ) -Alkyl, -SO 2 -NH- (C 6 -C 6 ) -alkyl, -SO 2 -N - [(C 0 -C 6 ) -alkyl] 2 , S (O) x (C 0 -C 6 ) -Alkylene heterocycle, S (O) x (C 1 -C 6 ) -alkylene-CO-heterocycle, -NH-SO 2 - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene -Cycloalkyl, (C 0 -C 6 ) -alkylene heterocycle, (C 0 -C 6 ) -alkylene-aryl;
x 0, 1, 2;
R6, R7 are independently H, F, Cl, Br, CN, NO 2, = O, = S, = NO- (C0-C6) alkyl, (C 0 -C 6) -alkylene-COO- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O-CO- (C 1 -C 6 ) -Alkyl, (C 1 -C 0 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, SF 5 , S (O) x (C 1 -C 6 ) alkyl;
A thiazol-2-yl, pyrazol-3-yl, pyridin-2-yl, oxazol-2-yl, isoxazol-3-yl, imidazol-2-yl, [1,2,4] thiadiazol-3-yl, [1,2,4] thiadiazol-5-yl, [1,3,4] thiadiazol-3-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazine-2-yl, Pyridazin-2-yl, [1,2,4] triazin-3-yl, [1,2,4] triazin-6-yl, thiazolo [4,5-b] pyridin-2-yl, thieno [2, 3-d] thiazol-2-yl, benzothiazol-2-yl, benzooxazol-2-yl, benzimidazol-2-yl, quinolin-2-yl, isoquinolin-3-yl, 4,5,6,7-tetrahydro benzothiazol-2-yl, 4,5,6,7-tetrahydrobenzooxazol-2-yl, 4,5,6,7-tetrahydrobenzimidazol-2-yl, 4,5,6,7-tetrahydropyra zolo [1,5-a] pyridin-2-yl, 5,6-dihydro-4H-cyclopentathiazol-2-yl, 4,5-dihydro-thiazol-2-yl;
B cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, phenyl, pyridyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyrazolyl, isoxazolyl;
and their physiologically acceptable salts.

Die Erfindung bezieht sich auf Verbindungen der Formel I, in Form ihrer Racemate, racemischen Mischungen und reinen Enantiomere sowie auf ihre Diastereomere und Mischungen davon.The The invention relates to compounds of the formula I, in the form of their Racemates, racemic mixtures and pure enantiomers as well their diastereomers and mixtures thereof.

Können Reste oder Substituenten mehrfach in den Verbindungen der Formel I auftreten, so können sie alle unabhängig voneinander die angegebenen Bedeutungen haben und gleich oder verschieden sein.Can Radicals or substituents multiply in the compounds of the formula I occur so they can all be independent have the meanings given and the same or different.

Unter der Defintion (C0-C6)-Alkylen- wird verstanden, dass entweder eine Bindung oder eine (C1-C6)-Alkylen Gruppe vorhanden sein kann.By the definition (C 0 -C 6 ) -alkylene it is understood that either a bond or a (C 1 -C 6 ) -alkylene group may be present.

Unter der Defintion -(C0-C6)-Alkyl wird verstanden, dass entweder ein Wasserstoff oder eine (C1-C6)-Alkyl Gruppe vorhanden sein kann.By the definition of - (C 0 -C 6 ) -alkyl is meant that either a hydrogen or a (C 1 -C 6 ) -alkyl group may be present.

Unter "Anellierung" oder "anelliert" wird verstanden, dass ein weiteres Ringssystem ankondensiert ist. Das weitere ankondensierte Ringssystem kann aromatisch oder nichtaromatisch und carbocyclisch oder heterocyclisch sein.Under "Anellierung" or "finned" is understood to be another Ring system is condensed. The further fused ring system may be aromatic or non-aromatic and carbocyclic or heterocyclic be.

Pharmazeutisch verträgliche Salze sind aufgrund ihrer höheren Wasserlöslichkeit gegenüber den Ausgangs- bzw. Basisverbindungen besonders geeignet für medizinische Anwendungen. Diese Salze müssen ein pharmazeutisch verträgliches Anion oder Kation aufweisen. Geeignete pharmazeutisch verträgliche Säureadditionssalze der erfindungsgemäßen Verbindungen sind Salze anorganischer Säuren, wie Salzsäure, Bromwasserstoff-, Phosphor-, Metaphosphor-, Salpeter- und Schwefelsäure sowie organischer Säuren, wie z. B. Essigsäure, Benzolsulfon-, Benzoe-, Zitronen-, Ethansulfon-, Fumar-, Glucon-, Glykol-, Isethion-, Milch-, Lactobion-, Malein-, Äpfel-, Methansulfon-, Bernstein-, p-Toluolsulfon- und Weinsäure. Geeignete pharmazeutisch verträgliche basische Salze sind Ammoniumsalze, Alkalimetallsalze (wie Natrium- und Kaliumsalze), Erdalkalisalze (wie Magnesium- und Calciumsalze), Trometamolsalz (2-Amino-2-hydroxymethyl-1,3-propandiol), Diethanolaminsalz, Lysinsalz oder Ethylendiaminsalz.pharmaceutical Compatible salts are due to their higher Solubility in water compared to the starting or Basic compounds particularly suitable for medical applications. These salts must be a pharmaceutically acceptable Anion or cation. Suitable pharmaceutically acceptable Acid addition salts of the invention Compounds are salts of inorganic acids, such as hydrochloric acid, Hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid and organic acids, such as. Acetic acid, Benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, Glycol, isethione, milk, lactobion, malein, apples, Methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable basic salts are Ammonium salts, alkali metal salts (such as sodium and potassium salts), Alkaline earth salts (such as magnesium and calcium salts), trometamol salt (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine salt, lysine salt or ethylenediamine salt.

Salze mit einem nicht pharmazeutisch verträglichen Anion, wie zum Beispiel Trifluoracetat, gehören ebenfalls in den Rahmen der Erfindung als nützliche Zwischenprodukte für die Herstellung oder Reinigung pharmazeutisch verträglicher Salze und/oder für die Verwendung in nicht-therapeutischen, zum Beispiel in-vitro-Anwendungen.salts with a non-pharmaceutically acceptable anion, such as for example, trifluoroacetate, are also included in the scope of the invention as useful intermediates for the preparation or purification pharmaceutically acceptable Salts and / or for use in non-therapeutic, for example, in vitro applications.

Ein weiterer Aspekt der Erfindung sind die physiologisch funktionellen Derivate der Verbindungen der Formel I. Der hier verwendete Begriff "physiologisch funktionelles Derivat" bezeichnet jedes physiologisch verträgliche Derivat einer erfindungsgemäßen Verbindung der Formel I, z. B. einen Ester, der bei Verabreichung an einen Säuger, wie z. B. den Menschen, in der Lage ist, (direkt oder indirekt) eine Verbindung der Formel I oder einen aktiven Metaboliten hiervon zu bilden.One Another aspect of the invention are the physiologically functional Derivatives of the compounds of the formula I. The term used here "physiologically functional derivative" refers to any physiological compatible derivative of a novel Compound of the formula I, for. For example, an ester which is administered when administered a mammal, such as As the human being, is able to (directly or indirectly) a compound of formula I or an active To form metabolites thereof.

Zu den physiologisch funktionellen Derivaten zählen auch Prodrugs der erfindungsgemäßen Verbindungen, wie zum Beispiel in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57–61 beschrieben. Solche Prodrugs können in vivo zu einer erfindungsgemäßen Verbindung metabolisiert werden. Diese Prodrugs können selbst wirksam sein oder nicht.The physiologically functional derivatives also include prodrugs of the compounds of the invention, such as in Chem. Pharm. Bull. 1994, 42, 57-61 described. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.

Die erfindungsgemäßen Verbindungen können auch in verschiedenen polymorphen Formen vorliegen, z. B. als amorphe und kristalline polymorphe Formen. Alle polymorphen Formen der erfindungsgemäßen Verbindungen gehören in den Rahmen der Erfindung und sind ein weiterer Aspekt der Erfindung.The Compounds according to the invention can also exist in various polymorphic forms, for. B. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are another Aspect of the invention.

Nachfolgend beziehen sich alle Verweise auf "Verbindung(en) gemäß Formel I" auf Verbindung(en) der Formel I wie vorstehend beschrieben, sowie ihre Salze, Solvate und physiologisch funktionellen Derivate wie hierin beschrieben.following all references refer to "compound (s) according to formula I "on compound (s) of the formula I as described above, as well as their salts, solvates and physiologically functional derivatives such as described herein.

Unter einem Alkylrest wird eine geradkettige oder verzweigte Kohlenwasserstoffkette mit einem oder mehreren Kohlenstoffen verstanden, wie z. B. Methyl, Ethyl, iso-Propyl, tert.-Butyl, Hexyl.Under an alkyl radical becomes a straight-chain or branched hydrocarbon chain understood with one or more carbons, such as. Methyl, Ethyl, isopropyl, tert -butyl, hexyl.

Die Alkylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z. B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1-C6)Alkyl]2, Cycloalkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)-Alkyl, O-CO-(C1-C6)-Alkyl, O-CO-(C1-C6)-Aryl, O-CO-(C1-C6)-Heterocyclus,;
PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S(CH2)-Aryl, S-(CH2)n-Heterocyclus, SO-(C1-C6)-Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterocyclus, SO2-(C1-C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus, SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N(C1-C6)-Alkyl)(CH2)n-Aryl, SO2-N(C1-C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, SO2-N((CH2)n-(Heterocyclus)2 wobei n = 0–6 sein kann und der Arylrest oder heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2 substituiert sein kann;
C(NH)(NH2), NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C2-C7)-Acyl, NH-CO-(C1-C6)-Alkyl, NH-COO-(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-COO-Aryl, NH-COO-Heterocyclus, NH-CO-NH-(C1-C6)-Alkyl, NH-CO-NH-Aryl, NH-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-COO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-CO-Aryl, N[(C1-C6)-Alkyl]-CO-Heterocyclus, N(C1-C6)-Alkyl-COO-Aryl, N[(C1-C6)-Alkyl]-COO-Heterocyclus, N[(C1-C6)-Alkyl]-CO-NH-(C1-C6)-Alkyl), N[(C1-C6)-Alkyl]-CO-NH-Aryl, N[(C1-C6)-Alkyl]-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-[(C1-C6)-Alkyl]2, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl)]-Aryl, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl]-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-(Aryl)2, N[(C1-C6)-Alkyl]-CO-N-(Heterocyclus)2, N(Aryl)-CO-(C1-C6)-Alkyl, N(Heterocyclus)-CO-(C1-C6)-Alkyl, N(Aryl)- COO-(C1-C6)-Alkyl, N(Heterocyclus)-COO-(C1-C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(C1-C6)-Alkyl), N(Heterocyclus)-CO-NH-(C1-C6)-Alkyl, N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-[(C1-C6)-Alkyl]2, N(Heterocyclus)-CO-N-[(C1-C6)-Alkyl]2, N(Aryl)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Heterocyclus)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N-(Aryl)2, Aryl, O-(CH2)-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0–6 sein kann, wobei der Arylrest oder heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl oder CONH2.The alkyl radicals may be substituted one or more times with suitable groups, such as. For example: 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, O- (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;
PO 3 H 2 , SO 3 H, 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 ) -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n - Aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 , SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical substituted up to two times with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 substituted can be;
C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 2 -C 7 ) acyl, NH -CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle , NH-CO-NH- (C 1 -C 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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 (heterocyclic) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl , N (heterocyclic) -COO- (C 1 -C 6 ) -alkyl, N (A ryl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocyclic) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) Alkyl), N (heterocyclic) -CO-NH- (C 1 -C 6 ) -alkyl, N (aryl) -CO-NH-aryl, N (heterocyclic) -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 (heterocyclic) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocyclic ) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, wherein the aryl radical or heterocyclic radical is one to three -fold may be substituted with 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 or CONH 2 .

Unter einem Alkenylrest wird eine geradkettige oder verzweigte Kohlenwasserstofflkette mit zwei oder mehreren Kohlenstoffen sowie einer oder mehreren Doppelbindungen verstanden, wie z. B. Vinyl, Allyl, Pentenyl.Under an alkenyl radical becomes a straight-chain or branched hydrocarbon chain with two or more carbons and one or more double bonds understood, such. Vinyl, allyl, pentenyl.

Die Alkenylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z. B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1-C6)Alkyl]2, Cycloalkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)-Alkyl, O-CO-(C1-C6)-Alkyl, O-CO-(C1-C6)-Aryl, O-CO-(C1-C6)-Heterocyclus,;
PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)-Aryl, S-(CH2)n-Heterocyclus, SO-(C1-C6)-Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterocyclus, SO2-(C1-C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus, SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N(C1-C6)-Alkyl)(CH2)n-Aryl, SO2-N(C1-C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, SO2-N((CH2)n-(Heterocyclus)2 wobei n = 0–6 sein kann und der Arylrest oder heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2 substituiert sein kann;
C(NH)(NH2), NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C2-C7)-Acyl, NH-CO-(C1-C6)-Alkyl, NH-COO-(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-COO-Aryl, NH-COO-Heterocyclus, NH-CO-NH-(C1-C6)-Alkyl, NH-CO-NH-Aryl, NH-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-COO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-CO-Aryl, N[(C1-C6)-Alkyl]-CO-Heterocyclus, N(C1-C0)-Alkyl-COO-Aryl, N[(C1-C6)-Alkyl]-COO-Heterocyclus, N[(C1-C6)-Alkyl]-CO-NH-(C1-C6)-Alkyl), N[(C1-C6)-Alkyl]-CO-NH-Aryl, N[(C1-C6)-Alkyl]-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-[(C1-C6)-Alkyl]2, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl)]-Aryl, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl]-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-(Aryl)2, N[(C1-C6)-Alkyl]-CO-N- (Heterocyclus)2, N(Aryl)-CO-(C1-C6)-Alkyl, N(Heterocyclus)-CO-(C1-C6)-Alkyl, N(Aryl)-COO-(C1-C6)-Alkyl, N(Heterocyclus)-COO-(C1-C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(C1-C6)-Alkyl), N(Heterocyclus)-CO-NH-(C1-C6)-Alkyl, N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-[(C1-C6)-Alkyl]2, N(Heterocyclus)-CO-N-[(C1-C6)-Alkyl]2, N(Aryl)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Heterocyclus)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N-(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0–6 sein kann, wobei der Arylrest oder heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl oder CONH2.The alkenyl radicals may be substituted one or more times with suitable groups, such as. B, 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, O- (C 1 -C 6 ) alkyl, O-CO- (C C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) -heterocycle;
PO 3 H 2 , SO 3 H, 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 ) -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- ( CH 2 ) n -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) - Alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 , SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the Aryl radical or heterocyclic radical up to two times with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 may be substituted;
C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 2 -C 7 ) acyl, NH -CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle , NH-CO-NH- (C 1 -C 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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 0 ) -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 (heterocyclic) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl , N (heterocyclic) -COO- (C 1 -C 6 ) -alkyl, N (A ryl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocyclic) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) Alkyl), N (heterocyclic) -CO-NH- (C 1 -C 6 ) -alkyl, N (aryl) -CO-NH-aryl, N (heterocyclic) -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 (heterocyclic) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocyclic ) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, wherein the aryl radical or heterocyclic radical is a bis May be substituted 3-fold with 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 or CONH 2 ,

Unter einem Alkinylrest wird eine geradkettige oder verzweigte Kohlenwasserstoffkette mit zwei oder mehreren Kohlenstoffen sowie einer oder mehreren Dreifachbindungen verstanden, wie z. B. Ethinyl, Propinyl, Hexinyl.Under an alkynyl radical becomes a straight-chain or branched hydrocarbon chain with two or more carbons and one or more triple bonds understood, such. Ethynyl, propynyl, hexynyl.

Die Alkinylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z. B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1-C6)Alkyl]2 , Cycloalkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)-Alkyl, O-CO-(C1-C6)-Alkyl, O-CO-(C1-C6)-Aryl, O-CO-(C1-C6)-Heterocyclus;
PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)n-Aryl, S-(CH2)n-Heterocyclus, SO-(C1-C6)-Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterocyclus, SO2-(C1-C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus, SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N(C1-C6)-Alkyl)(CH2)n-Aryl, SO2-N(C1-C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, SO2-N((CH2)n-Heterocyclus)2 wobei n = 0–6 sein kann und der Arylrest oder heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2 substituiert sein kann;
C(NH)(NH2), NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C2-C7)-Acyl, NH-CO-(C1-C6)-Alkyl, NH-COO-(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-COO-Aryl, NH-COO-Heterocyclus, NH-CO-NH-(C1-C6)-Alkyl, NH-CO-NH-Aryl, NH-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-COO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-CO-Aryl, N[(C1-C6)-Alkyl]-CO-Heterocyclus, N(C1-C6)-Alkyl-COO-Aryl, N[(C1-C6)-Alkyl]-COO-Heterocyclus, N[(C1-C6)-Alkyl]-CO-NH-(C1-C6)-Alkyl), N[(C1-C6)-Alkyl]-CO-NH-Aryl, N[(C1-C6)-Alkyl]-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl-CO-N-[(C1-C6)-Alkyl]2, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl)]-Aryl, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)- Alkyl]-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-(Aryl)2, N[(C1-C6)-Alkyl]-CO-N-(Heterocyclus)2, N(Aryl)-CO-(C1-C6)-Alkyl, N(Heterocyclus)-CO-(C1-C6)-Alkyl, N(Aryl)-COO-(C1-C6)-Alkyl, N(Heterocyclus)-COO-(C1-C0)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(C1-C6)-Alkyl), N(Heterocyclus)-CO-NH-(C1-C6)-Alkyl, N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-[(C1-C6)-Alkyl]2, N(Heterocyclus)-CO-N-[(C1-C6)-Alkyl]2, N(Aryl)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Heterocyclus)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N-(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0–6 sein kann, wobei der Arylrest oder heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl oder CONH2.The alkynyl radicals may be substituted one or more times with suitable groups, such as. B, 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, O- (C 1 -C 6 ) alkyl, O-CO- (C C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) -heterocycle;
PO 3 H 2 , SO 3 H, 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 -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -Alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 , SO 2 -N ((CH 2 ) n -heterocycle) 2 where n = 0-6 and the Aryl radical or heterocyclic radical up to two times with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 may be substituted;
C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 2 -C 7 ) acyl, NH -CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle , NH-CO-NH- (C 1 -C 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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 (heterocyclic) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocycle) -COO- (C 1 -C 0 ) -alkyl, N (Ar yl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) Alkyl), N (heterocyclic) -CO-NH- (C 1 -C 6 ) -alkyl, N (aryl) -CO-NH-aryl, N (heterocyclic) -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 (heterocyclic) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocyclic ) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, wherein the aryl radical or heterocyclic radical is a bis May be substituted 3-fold with 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 or CONH 2 ,

Unter einem Arylrest wird ein Phenyl, Naphthyl-, Biphenyl-, Tetrahydronaphthyl-, alpha- oder beta-Tetralon-, Indanyl- oder Indan-1-on-ylrest verstanden.Under an aryl radical is a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonic, indanyl or indan-1-one-yl radical.

Die Arylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z. B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1-C6)Alkyl]2, Cycloalkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)-Alkyl, O-CO-(C1-C6)-Alkyl, O-CO-(C1-C6)-Aryl, O-CO-(C1-C6)-Heterocyclus,;
PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)n-Aryl, S-(CH2)n-Heterocyclus, SO-(C1-C6)-Alkyl, SO-(CH2)n-Aryl, SO-(CH2)-Heterocyclus, SO2-(C1-C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus, SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N((C1-C6)-Alkyl)(CH2)n-Aryl, SO2-N((C1-C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, SO2-N((CH2)n-Heterocyclus)2 wobei n = 0–6 sein kann und der Arylrest oder heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2 substituiert sein kann;
C(NH)(NH2), NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C2-C7)-Acyl, NH-CO-(C1-C6)-Alkyl, NH-COO-(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-COO-Aryl, NH-COO-Heterocyclus, NH-CO-NH-(C1-C6)-Alkyl, NH-CO-NH-Aryl, NH-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-COO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-CO-Aryl, N[(C1-C6)-Alkyl]-CO-Heterocyclus, N(C1-C6)-Alkyl-COO-Aryl, N[(C1-C6)-Alkyl]-COO-Heterocyclus, N[(C1-C6)-Alkyl]-CO-NH-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-CO-NH-Aryl, N[(C1-C6)-Alkyl]-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-[(C1- C6)-Alkyl]2, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl)]-Aryl, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl]-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-(Aryl)2, N[(C1-C6)-Alkyl]-CO-N-(Heterocyclus)2, N(Aryl)-CO-(C1-C6)-Alkyl, N(Heterocyclus)-CO-(C1-C6)-Alkyl, N(Aryl)-COO-(C1-C6)-Alkyl, N(Heterocyclus)-COO-(C1-C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(C1-C6)-Alkyl), N(Heterocyclus)-CO-NH-(C1-C6)-Alkyl, N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-[(C1-C6)-Alkyl]2, N(Heterocyclus)-CO-N-[(C1-C6)-Alkyl]2, N(Aryl)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Heterocyclus)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N-(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0–6 sein kann, wobei der Arylrest oder heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl oder CONH2.The aryl radicals may be substituted one or more times with suitable groups, such as. B, 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, O- (C 1 -C 6 ) alkyl, O-CO- (C C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) -heterocycle;
PO 3 H 2 , SO 3 H, 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 -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N ((C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N ((C 1 -C 6 ) -Alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 , SO 2 -N ((CH 2 ) n -heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical up to twice with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 may be substituted;
C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 2 -C 7 ) acyl, NH -CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle , NH-CO-NH- (C 1 -C 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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 (heterocyclic) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocycle) -COO- (C 1 -C 6 ) -alkyl, N (Ar yl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) Alkyl), N (heterocyclic) -CO-NH- (C 1 -C 6 ) -alkyl, N (aryl) -CO-NH-aryl, N (heterocyclic) -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 (heterocyclic) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocyclic ) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, wherein the aryl radical or heterocyclic radical is a bis May be substituted 3-fold with 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 or CONH 2 ,

Unter einem Cycloalkylrest wird ein einen oder mehrere Ringe enthaltendes Ringssystem, welches gesättigt oder partiell ungesättigt (mit einer oder zwei Doppelbindungen) vorliegt, verstanden, das ausschließlich aus Kohlenstoffatomen aufgebaut ist, wie z. B. Cyclopropyl, Cyclopentyl, Cyclopentenyl, Cyclohexyl oder Adamantyl.A cycloalkyl radical is understood to mean a ring system containing one or more rings which is saturated or partially unsaturated (having one or two double bonds), which is composed exclusively of carbon atoms, such as, for example, Cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or ada mantyl.

Die Cycloalkylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z. B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1-C6)Alkyl]2, Cycloalkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)-Alkyl, O-CO-(C1-C6)-Alkyl, O-CO-(C1-C6)-Aryl, O-CO-(C1-C6)-Heterocyclus,;
PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)n-Aryl, S-(CH2)n-Heterocyclus, SO-(C1-C6)-Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterocyclus, SO2-(C1-C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus, SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N((C1-C6)-Alkyl)(CH2)n-Aryl, SO2-N((C1-C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, SO2-N((CH2)n-Heterocyclus)2 wobei n = 0–6 sein kann und der Arylrest oder heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2 substituiert sein kann;
C(NH)(NH2), NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C2-C7)-Acyl, NH-CO-(C1-C6)-Alkyl, NH-COO-(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-COO-Aryl, NH-COO-Heterocyclus, NH-CO-NH-(C1-C6)-Alkyl, NH-CO-NH-Aryl, NH-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-COO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-CO-Aryl, N[(C1-C6)-Alkyl]-CO-Heterocyclus, N(C1-C6)-Alkyl-COO-Aryl, N[(C1-C6)-Alkyl]-COO-Heterocyclus, N[(C1-C6)-Alkyl]-CO-NH-(C1-C6)-Alkyl), N[(C1-C6)-Alkyl]-CO-NH-Aryl, N[(C1-C6)-Alkyl]-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-[(C1-C6)-Alkyl]2, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl)]-Aryl, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl]-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-(Aryl)2, N[(C1-C6)-Alkyl]-CO-N-(Heterocyclus)2, N(Aryl)-CO-(C1-C6)-Alkyl, N(Heterocyclus)-CO-(C1-C6)-Alkyl, N(Aryl)-COO-(C1-C6)-Alkyl, N(Heterocyclus)-COO-(C1-C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(C1-C6)-Alkyl), N(Heterocyclus)-CO-NH-(C1-C6)-Alkyl, N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-[C1-C6)-Alkyl], N(Heterocyclus)-CO-N-[(C1-C6)-Alkyl]2, N(Aryl)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Heterocyclus)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N-(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0–6 sein kann, wobei der Arylrest oder heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl oder CONH2.The cycloalkyl radicals may be substituted one or more times with suitable groups, such as. B, 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, O- (C 1 -C 6 ) alkyl, O-CO- (C C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) -heterocycle;
PO 3 H 2 , SO 3 H, 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 -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N ((C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N ((C 1 -C 6 ) -alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 , SO 2 -N ((CH 2 ) n -heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical up to two times with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl , NH 2 may be substituted;
C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 2 -C 7 ) acyl, NH -CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle , NH-CO-NH- (C 1 -C 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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 (heterocyclic) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl , N (heterocyclic) -COO- (C 1 -C 6 ) -alkyl, N (Ar yl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) Alkyl), N (heterocyclic) -CO-NH- (C 1 -C 6 ) -alkyl, N (aryl) -CO-NH-aryl, N (heterocyclic) -CO-NH-aryl, N (aryl) - CO-N- [C 1 -C 6 -alkyl], N (heterocycle) -CO-N - [(C 1 -C 6 ) -alkyl] 2 , N (aryl) -CO-N [(C 1 - C 6 ) -alkyl] -aryl, N (heterocyclic) -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 -heterocycle, where n = 0-6, where the aryl radical or heterocyclic radical is one to three may be substituted with 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 or CONH 2 .

Unter Heterocyclus bzw. heterocyclischer Rest werden Ringe und Ringsysteme verstanden, die außer Kohlenstoff noch Heteroatome, wie zum Beispiel Stickstoff, Sauerstoff oder Schwefel enthalten. Ferner gehören auch Ringsysteme zu dieser Definition, worin der Heterocylus bzw. der heterocyclische Rest mit einem weiteren Ringsystem anelliert ist.Under Heterocycle or heterocyclic radical are rings and ring systems understood that except carbon still heteroatoms, such as For example, nitrogen, oxygen or sulfur. Further Ring systems also belong to this definition, in which the Heterocyclic or the heterocyclic radical with a further ring system is finned.

Geeignete "Heterocyclen" bzw. "heterocyclische Reste" sind Acridinyl, Azocinyl, Benzimidazolyl, Benzofuryl, Benzothienyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Benzimidazalinyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Decahydrochinolinyl, 2H,6H-1,5,2-Dithiazinyl, Dihydrofuro[2,3-b]-Tetrahydrofuran, 5,6-Dihydro-4H-cyclopentathiazol-2-yl, 4,5-Dihydro-thiazol-2-yl, Furyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, 1H-Indazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-Indolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolyl, Isoxazolyl, Morpholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1,2,3-Oxadiazolyl, 1,2,4-Oxadiazolyl, 1,2,5- Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pyridooxazole, Pyridoimidazole, Pyridothiazole, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H-Pyrrolyl, Pyrrolyl, 4,5,6,7-Tetrahydro-benzooxazol-2-yl, 4,5,6,7-Tetrahydro-benzothiazol-2-yl, 4,5,6,7-Tetrahydro-benzoimidazol-2-yl, 4,5,6,7-Tetrahydro-pyrazolo[1,5-a]pyridin-2-yl, Tetrahydrofuranyl, Tetrahydropyranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, 6H-1,2,5-Thiadazinyl, Thiazolyl, 1,2,3-Thiadiazolyl, 1,2,4-Thiadiazolyl, 1,2,5-Thiadiazolyl, 1,3,4-Thiadiazolyl, Thienyl, Triazinyl, Triazolyl, Tetrazolyl, Thiazolo[4,5-b]pyridinyl, Thieno[2,3-d]thiazol-2-yl und Xanthenyl.suitable "Heterocycles" or "heterocyclic radicals" are acridinyl, azocinyl, Benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, Benzothiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, Benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, Quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, Chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, Dihydrofuro [2,3-b] tetrahydrofuran, 5,6-dihydro-4H-cyclopentathiazol-2-yl, 4,5-dihydro-thiazol-2-yl, furyl, furazanyl, imidazolidinyl, imidazolinyl, Imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, Isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, Isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, Naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, Oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, Phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, Piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, Pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazoles, Pyridoimidazoles, pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl, Pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, 4,5,6,7-tetrahydro-benzooxazol-2-yl, 4,5,6,7-tetrahydrobenzothiazol-2-yl, 4,5,6,7-tetrahydro-benzoimidazol-2-yl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-yl, tetrahydrofuranyl, Tetrahydropyranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazinyl, triazolyl, Tetrazolyl, thiazolo [4,5-b] pyridinyl, thieno [2,3-d] thiazol-2-yl and xanthenyl.

Pyridyl steht sowohl für 2-, 3- als auch 4-Pyridyl. Thienyl steht sowohl für 2- als auch 3-Thienyl. Furyl steht sowohl für 2- als auch 3-Furyl.pyridyl represents both 2-, 3- and 4-pyridyl. Thienyl stands for both 2- and 3-thienyl. Furyl stands for both 2- and 3-furyl.

Umfasst sind weiterhin die entsprechenden N-Oxide dieser Verbindungen, also z. B. 1-Oxy-2-, 3- oder 4-pyridyl.includes are still the corresponding N-oxides of these compounds, ie z. For example 1-oxy-2-, 3- or 4-pyridyl.

Umfasst sind weiterhin ein oder mehrfach benzoannelierte Derivate dieser Heterocyclen.includes are still one or more benzoannelated derivatives of these Heterocycles.

Die Heterocyclen bzw. heterocyclischen Reste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z. B: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1-C6)Alkyl]2, Cycloalkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)-Alkyl, O-CO-(C1-C6)-Alkyl, O-CO-(C1-C6)-Aryl, O-CO-(C1-C6)-Heterocyclus,;
PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)n-Aryl, S-(CH2)n-Heterocyclus, SO-(C1-C6)-Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterocyclus, SO2-(C1-C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus, SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N(C1-C6)-Alkyl)(CH2)n-Aryl, SO2-N(C1-C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, SO2-N((CH2)n-(Heterocyclus)2 wobei n = 0–6 sein kann und der Arylrest oder heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2 substituiert sein kann;
C(NH)(NH2), NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C2-C7)-Acyl, NH-CO-(C1-C6)-Alkyl, NH-COO-(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-COO-Aryl, NH- COO-Heterocyclus, NH-CO-NH-(C1-C6)-Alkyl, NH-CO-NH-Aryl, NH-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-COO-(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]-CO-Aryl, N[(C1-C6)-Alkyl]-CO-Heterocyclus, N(C1-C6)-Alkyl-COO-Aryl, N[(C1-C6)-Alkyl]-COO-Heterocyclus, N[(C1-C6)-Alkyl]-CO-NH-(C1-C6)-Alkyl), N[(C1-C6)-Alkyl]-CO-NH-Aryl, N[(C1-C6)-Alkyl]-CO-NH-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-[(C1-C6)-Alkyl]2, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl)]-Aryl, N[(C1-C6)-Alkyl]-CO-N[(C1-C6)-Alkyl]-Heterocyclus, N[(C1-C6)-Alkyl]-CO-N-(Aryl)2, N[(C1-C6)-Alkyl]-CO-N-(Heterocyclus)2, N(Aryl)-CO-(C1-C6)-Alkyl, N(Heterocyclus)-CO-(C1-C6)-Alkyl, N(Aryl)-COO-(C1-C6)-Alkyl, N(Heterocyclus)-COO-(C1-C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(C1-C6)-Alkyl), N(Heterocyclus)-CO-NH-(C1-C6)-Alkyl, N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-[(C1-C6)-Alkyl]2, N(Heterocyclus)-CO-N-[(C1-C6)-Alkyl]2, N(Aryl)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Heterocyclus)-CO-N[(C1-C6)-Alkyl]-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N-(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0–6 sein kann, wobei der Arylrest oder heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N[(C1-C6)-Alkyl]2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl oder CONH2.The heterocycles or heterocyclic radicals may be substituted one or more times with suitable groups, such as. B: 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, O- (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;
PO 3 H 2 , SO 3 H, 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 -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -Alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 , SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical up to twice with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 may be substituted;
C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 2 -C 7 ) acyl, NH -CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle , NH-CO-NH- (C 1 -C 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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 (heterocyclic) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl , N (heterocyclic) -COO- (C 1 -C 6 ) -alkyl, N (A ryl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocyclic) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) Alkyl), N (heterocyclic) -CO-NH- (C 1 -C 6 ) -alkyl, N (aryl) -CO-NH-aryl, N (heterocyclic) -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 (heterocyclic) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocyclic ) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, wherein the aryl radical or heterocyclic radical is a bis May be substituted 3-fold with 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 or CONH 2 ,

Verbindungen der Formel I aktivieren den Glucosestoffwechsel in Glucokinaseexprimierenden Zellen. Sie sind daher gut zur Behandlung und Verhinderung erhöhter Blutzuckerspiegel, Obesitas und des metabolischen Syndroms geeignet ( Sagen et al. Diabetes 55, 1713–1722, Levin et al. Diabetes (2006), S122–S130 , Matschinsky et al (2006) 55, 1–12 ).Compounds of the formula I activate the glucose metabolism in glucokinase expressing cells. They are therefore well suited for the treatment and prevention of elevated blood sugar levels, obesity and the metabolic syndrome ( Sagen et al. Diabetes 55, 1713-1722, Levin et al. Diabetes (2006), S122-S130 . Matschinsky et al (2006) 55, 1-12 ).

Aufgrund der Aktivierung von Glucokinase können die Verbindungen der Formel I auch zur Behandlung bzw. Prävention weiterer Krankheiten und Leiden in einem Säugetier, vorzugsweise einem Menschen, geeignet sein, die durch erhöhten Blutzuckerspiegel, Übergewicht oder durch verringerte Aktivität von Glucokinase hervorgerufen werden.by virtue of Activation of glucokinase may be the compounds of the formula I also for the treatment or prevention of further Diseases and conditions in a mammal, preferably a person, who is likely to be affected by elevated blood sugar, obesity or caused by reduced activity of glucokinase become.

Die Verbindungen der vorliegenden Erfindung eignen sich insbesondere zur Behandlung und/oder Prävention von:

  • 1. – Glucoseverwertungsstörungen und Störungen des Fettsäurestoffwechsels – Störungen, bei denen Insulinresistenz eine Rolle spielt Diabetes mellitus, insbesondere Typ-2-Diabetes, einschließlich der Prävention der damit verbundenen Folgeerkrankungen. Besondere Aspekte in diesem Zusammenhang sind – Hyperglykämia, – Verbesserung der Insulinresistenz, – Verbesserung der Glucosetoleranz, – Schutz der β-Zellen der Bauchspeicheldrüse – Prävention makro- und mikrovaskulärer Erkrankungen
  • 2. Übergewicht und dessen Folgen wie beispielsweise Dyslipidemien, Atherosklerose, koronare Herzkrankheit, zerebrovaskuläre Erkrankungen usw., insbesondere (jedoch nicht darauf beschränkt) die, die durch einen oder mehrere der folgenden Faktoren gekennzeichnet sind: – hohe Plasmatriglyceridkonzentrationen, hohe postprandiale Plasmatriglyceridkonzentrationen, – niedrige HDL-Cholesterinkonzentration – niedrige ApoA-Lipoproteinkonzentrationen – hohe LDL-Cholesterinkonzentrationen – kleine dichte LDL-Cholesterinpartikel hohe ApoB-Lipoproteinkonzentrationen
  • 3. Verschiedene andere Leiden, die mit dem metabolischen Syndrom bzw. Syndrom X assoziert sein können, wie – Zunahme des Bauchumfangs – Dyslipidämie (z. B. Hypertriglyceridämie und/oder niedriges HDL) – Insulinresistenz – Hyperkoagulabilität – Hyperurikämie – Mikroalbuminämie – Thrombosen, hyperkoagulabile und prothrombotische Zustände (arteriell und venös) – Bluthochdruck – Herzinsuffizienz, beispielsweise (jedoch nicht darauf beschränkt), nach Herzinfarkt, hypertensiver Herzkrankheit oder Kardiomyopathie
  • 4. Primäre Hypertriglyceridämie oder sekundäre Hypertriglyceridämien nach familiärer Retikulohistiozytose Lipoproteinlipasemangel Hyperlipoproteinämien Apolipoproteinmangel (z. B. ApoCII- oder ApoE-Mangel)
  • 5. Genetisch bedingte verringerte Aktivität von Glucokinase, insbesondere dem so genannten MODY2
  • 6. Krankheiten bzw. Leiden, die mit neurologischen, psychiatrischen oder Immunerkrankungen bzw. -leiden in Zusammenhang stehen
The compounds of the present invention are particularly suitable for the treatment and / or prevention of:
  • 1. - Glucose utilization disorders and disorders of fatty acid metabolism - Disorders in which insulin resistance plays a role Diabetes mellitus, especially type 2 diabetes, including the prevention of associated sequelae. Special aspects in this connection are - hyperglycemia, - improvement of insulin resistance, - improvement of glucose tolerance, - protection of pancreatic β-cells - prevention of macro- and microvascular diseases
  • 2. Obesity and its consequences such as dyslipidemias, atherosclerosis, coronary heart disease, cerebrovascular diseases, etc., particularly those (but not limited to) characterized by one or more of the following factors: high plasma triglyceride concentrations, high postprandial plasma triglyceride concentrations, low levels HDL cholesterol concentration - low apoA lipoprotein concentrations - high LDL cholesterol concentrations - small dense LDL cholesterol particles high apoB lipoprotein concentrations
  • 3. Various other conditions that may be associated with the metabolic syndrome or syndrome X, such as - Increase in abdominal circumference - Dyslipidaemia (eg hypertriglyceridemia and / or low HDL) - Insulin resistance - Hypercoagulability - Hyperuricemia - Microalbuminemia - Thrombosis, hypercoagulable and prothrombotic conditions (arterial and venous) - Hypertension - Heart failure, for example (but not limited to) , after heart attack, hypertensive heart disease or cardiomyopathy
  • 4. Primary hypertriglyceridemia or secondary hypertriglyceridemias after familial reticulohistiocytosis Lipoprotein lipase deficiency Hyperlipoproteinemias Apolipoprotein deficiency (eg ApoCII or ApoE deficiency)
  • 5. Genetically related decreased activity of glucokinase, especially the so-called MODY2
  • 6. Diseases or conditions associated with neurological, psychiatric or immune disorders or disorders

Die Verbindung(en) der Formel I können auch in Kombination mit weiteren Wirkstoffen verabreicht werden.The Compound (s) of formula I may also be used in combination be administered with other active ingredients.

Die Menge einer Verbindung gemäß Formel I, die erforderlich ist, um den gewünschten biologischen Effekt zu erreichen, ist abhängig von einer Reihe von Faktoren, z. B. der gewählten spezifischen Verbindung, der beabsichtigten Verwendung, der Art der Verabreichung und dem klinischen Zustand des Patienten. Im Allgemeinen liegt die Tagesdosis im Bereich von 0,3 mg bis 100 mg (typischerweise von 3 mg und 50 mg) pro Tag pro Kilogramm Körpergewicht, z. B. 3–10 mg/kg/Tag. Eine intravenöse Dosis kann z. B. im Bereich von 0,3 mg bis 1,0 mg/kg liegen, die geeigneterweise als Infusion von 10 ng bis 100 ng pro Kilogramm pro Minute verabreicht werden kann. Geeignete Infusionslösungen für diese Zwecke können z. B. von 0,1 ng bis 10 mg, typischerweise von 1 ng bis 10 mg pro Milliliter, enthalten. Einzeldosen können z. B. von 1 mg bis 10 g des Wirkstoffs enthalten. Somit können Ampullen für Injektionen beispielsweise von 1 mg bis 100 mg, und oral verabreichbare Einzeldosisformulierungen, wie zum Beispiel Tabletten oder Kapseln, können beispielsweise von 1,0 bis 1000 mg, typischerweise von 10 bis 600 mg enthalten. Zur Therapie der oben genannten Zustände können die Verbindungen gemäß Formel I selbst als Verbindung verwendet werden, vorzugsweise liegen sie jedoch mit einem verträglichen Träger in Form einer pharmazeutischen Zusammensetzung vor. Der Träger muss natürlich verträglich sein, in dem Sinne, dass er mit den anderen Bestandteilen der Zusammensetzung kompatibel ist und nicht gesundheitsschädlich für den Patienten ist. Der Träger kann ein Feststoff oder eine Flüssigkeit oder beides sein und wird vorzugsweise mit der Verbindung als Einzeldosis formuliert, beispielsweise als Tablette, die von 0,05% bis 95 Gew.-% des Wirkstoffs enthalten kann. Weitere pharmazeutisch aktive Substanzen können ebenfalls vorhanden sein, einschließlich weiterer Verbindungen gemäß Formel I. Die erfindungsgemäßen pharmazeutischen Zusammensetzungen können nach einer der bekannten pharmazeutischen Methoden hergestellt werden, die im wesentlichen darin bestehen, dass die Bestandteile mit pharmakologisch verträglichen Trägerund/oder Hilfsstoffen gemischt werden.The Amount of a compound of formula I required is to achieve the desired biological effect, depends on a number of factors, such as B. the chosen specific compound, intended use, type the administration and clinical condition of the patient. In general the daily dose is in the range of 0.3 mg to 100 mg (typically of 3 mg and 50 mg) per day per kilogram of body weight, z. B. 3-10 mg / kg / day. An intravenous dose can z. In the range of 0.3 mg to 1.0 mg / kg, suitably administered as an infusion of 10 ng to 100 ng per kilogram per minute can be. Suitable infusion solutions for these Purposes can z. From 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Single doses can z. B. from 1 mg to 10 g of the active ingredient. Thus, you can Ampoules for injections, for example, from 1 mg to 100 mg, and single dose oral formulations such as For example, tablets or capsules may range from 1.0 to 1000 mg, typically from 10 to 600 mg. For therapy The above states can be the connections according to formula I itself used as a compound However, they are preferably compatible with one another Carrier in the form of a pharmaceutical composition. The carrier must of course be tolerated be, in the sense that he is with the other constituents of the composition is compatible and not harmful to health the patient is. The carrier may be a solid or a Be liquid or both and is preferably with the compound is formulated as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Further Pharmaceutically active substances may also be present be, including other compounds according to formula I. The pharmaceutical compositions of the invention can be prepared by any of the known pharmaceutical methods essentially consisting in that the Ingredients with pharmacologically acceptable carrier and / or Adjuvants are mixed.

Erfindungsgemäße pharmazeutische Zusammensetzungen sind solche, die für orale, rektale, topische, perorale (z. B. sublinguale) und parenterale (z. B. subkutane, intramuskuläre, intradermale oder intravenöse) Verabreichung geeignet sind, wenngleich die geeignetste Verabreichungsweise in jedem Einzelfall von der Art und Schwere des zu behandelnden Zustandes und von der Art der jeweils verwendeten Verbindung gemäß Formel I abhängig ist. Auch dragierte Formulierungen und dragierte Retardformulierungen gehören in den Rahmen der Erfindung. Bevorzugt sind säure- und magensaftresistente Formulierungen. Geeignete magensaftresistente Beschichtungen umfassen Celluloseacetatphthalat, Poylvinylacetatphthalat, Hydroxypropylmethylcellulosephthalat und anionische Polymere von Methacrylsäure und Methacrylsäuremethylester.invention Pharmaceutical compositions are those intended for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) Administration, although the most suitable route of administration in each individual case of the nature and severity of the treatment Condition and of the type of compound used in each case according to the formula I is dependent. Also coated formulations and sugar-coated Retard formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, Polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Geeignete pharmazeutische Verbindungen für die orale Verabreichung können in separaten Einheiten vorliegen, wie zum Beispiel Kapseln, Oblatenkapseln, Lutschtabletten oder Tabletten, die jeweils eine bestimmte Menge der Verbindung gemäß Formel I enthalten; als Pulver oder Granulate; als Lösung oder Suspension in einer wässrigen oder nicht-wässrigen Flüssigkeit; oder als eine Öl-in-Wasser- oder Wasser-in-Öl-Emulsion. Diese Zusammensetzungen können, wie bereits erwähnt, nach jeder geeigneten pharmazeutischen Methode zubereitet werden, die einen Schritt umfasst, bei dem der Wirkstoff und der Träger (der aus einem oder mehreren zusätzlichen Bestandteilen bestehen kann) in Kontakt gebracht werden. Im allgemeinen werden die Zusammensetzungen durch gleichmäßiges und homogenes Vermischen des Wirkstoffs mit einem flüssigen und/oder feinverteilten festen Träger hergestellt, wonach das Produkt, falls erforderlich, geformt wird. So kann beispielsweise eine Tablette hergestellt werden, indem ein Pulver oder Granulat der Verbindung verpresst oder geformt wird, gegebenenfalls mit einem oder mehreren zusätzlichen Bestandteilen. Gepresste Tabletten können durch tablettieren der Verbindung in frei fließender Form, wie beispielsweise einem Pulver oder Granulat, gegebenenfalls gemischt mit einem Bindemittel, Gleitmittel, inertem Verdün ner und/oder einem (mehreren) oberflächenaktiven/dispergierenden Mittel in einer geeigneten Maschine hergestellt werden. Geformte Tabletten können durch Formen der pulverförmigen, mit einem inerten flüssigen Verdünnungsmittel befeuchteten Verbindung in einer geeigneten Maschine hergestellt werden.Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula I; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients). In general In other words, the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded, if necessary. For example, a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients. Pressed tablets may be prepared by tableting the compound in free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or a (multiple) surfactant / dispersing agent in a suitable machine. Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.

Pharmazeutische Zusammensetzungen, die für eine perorale (sublinguale) Verabreichung geeignet sind, umfassen Lutschtabletten, die eine Verbindung gemäß Formel I mit einem Geschmacksstoff enthalten, üblicherweise Saccharose und Gummi arabicum oder Tragant, und Pastillen, die die Verbindung in einer inerten Basis wie Gelatine und Glycerin oder Saccharose und Gummi arabicum umfassen.pharmaceutical Compositions suitable for peroral (sublingual) Administration include lozenges containing a A compound according to formula I with a flavor usually containing sucrose and gum arabic or tragacanth, and lozenges that compound in an inert Base like gelatin and glycerine or sucrose and gum arabic include.

Geeignete pharmazeutische Zusammensetzungen für die parenterale Verabreichung umfassen vorzugsweise sterile wässrige Zubereitungen einer Verbindung gemäß Formel I, die vorzugsweise isotonisch mit dem Blut des vorgesehenen Empfängers sind. Diese Zubereitungen werden vorzugsweise intravenös verabreicht, wenngleich die Verabreichung auch subkutan, intramuskulär oder intradermal als Injektion erfolgen kann. Diese Zubereitungen können vorzugsweise hergestellt werden, indem die Verbindung mit Wasser gemischt wird und die erhaltene Lösung steril und mit dem Blut isotonisch gemacht wird. Injizierbare erfindungsgemäße Zusammensetzungen enthalten im Allgemeinen von 0,1 bis 5 Gew.-% der aktiven Verbindung.suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a Compound according to formula I, which is preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, albeit the administration also subcutaneously, intramuscularly or intradermally can be done as an injection. These preparations can preferably prepared by mixing with water is mixed and the resulting solution sterile and with the Blood is made isotonic. Injectable invention Compositions generally contain from 0.1 to 5% by weight the active compound.

Geeignete pharmazeutische Zusammensetzungen für die rektale Verabreichung liegen vorzugsweise als Einzeldosis-Zäpfchen vor. Diese können hergestellt werden, indem man eine Verbindung gemäß Formel I mit einem oder mehreren herkömmlichen festen Trägern, beispielsweise Kakaobutter, mischt und das entstehende Gemisch in Form bringt.suitable pharmaceutical compositions for rectal administration are preferably present as single-dose suppositories. These can be prepared by adding a compound according to formula I with one or more conventional solid supports, For example, cocoa butter, mixes and the resulting mixture in Form brings.

Geeignete pharmazeutische Zusammensetzungen für die topische Anwendung auf der Haut liegen vorzugsweise als Salbe, Creme, Lotion, Paste, Spray, Aerosol oder Öl vor. Als Träger können Vaseline, Lanolin, Polyethylenglykole, Alkohole und Kombinationen von zwei oder mehreren dieser Substanzen verwendet werden. Der Wirkstoff ist im Allgemeinen in einer Konzentration von 0,1 bis 15 Gew.-% der Zusammensetzung vorhanden, beispielsweise von 0,5 bis 2%.suitable pharmaceutical compositions for topical use on the skin are preferably as ointment, cream, lotion, paste, Spray, aerosol or oil. As a carrier can Vaseline, lanolin, polyethylene glycols, alcohols and combinations used by two or more of these substances. The active substance is generally in a concentration of 0.1 to 15 wt .-% of the composition, for example from 0.5 to 2%.

Auch eine transdermale Verabreichung ist möglich. Geeignete pharmazeutische Zusammensetzungen für transdermale Anwendungen können als einzelne Pflaster vorliegen, die für einen langzeitigen engen Kontakt mit der Epidermis des Patienten geeignet sind. Solche Pflaster enthalten geeigneterweise den Wirkstoff in einer gegebenenfalls gepufferten wässrigen Lösung, gelöst und/oder dispergiert in einem Haftmittel oder dispergiert in einem Polymer. Eine geeignete Wirkstoff-Konzentration beträgt ca. 1% bis 35%, vorzugsweise ca. 3% bis 15%. Als eine besondere Möglichkeit kann der Wirkstoff, wie beispielsweise in Pharmaceutical Research, 2(6): 318 (1986) beschrieben, durch Elektrotransport oder Iontophorese freigesetzt werden.Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. As a special possibility, the active ingredient, such as in Pharmaceutical Research, 2 (6): 318 (1986) be released by electrotransport or iontophoresis.

Als weitere Wirkstoffe für die Kombinationspräparate sind geeignet: Alle Antidiabetika, die in der Roten Liste 2006, Kapitel 12 genannt sind; alle Abmagerungsmittel/Appetitzügler, die in der Roten Liste 2006, Kapitel 1 genannt sind; alle Lipidsenker, die in der Roten Liste 2006, Kapitel 58 genannt sind. Sie können mit der erfindungsgemäßen Verbindung der Formel I insbesondere zur synergistischen Wirkungsverbesserung kombiniert werden. Die Verabreichung der Wirkstoffkombination kann entweder durch getrennte Gabe der Wirkstoffe an den Patienten oder in Form von Kombinationspräparaten, worin mehrere Wirkstoffe in einer pharmazeutischen Zubereitung vorliegen, erfolgen. Die meisten der nachfolgend aufgeführten Wirkstoffe sind in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001, offenbart.When other active ingredients for the combination preparations are suitable: all antidiabetics, which in the red list 2006, Chapter 12; all weight loss products / appetite suppressants, which are listed in the Red List 2006, Chapter 1; all lipid-lowering drugs, which are listed in the Red List 2006, chapter 58. You can with the compound of the formula according to the invention I combined in particular for synergistic effect improvement become. The administration of the drug combination can either by separate administration of the active ingredients to the patient or in the form of combination preparations, wherein several active ingredients in a pharmaceutical preparation, take place. Most The following are listed in USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville 2001, disclosed.

Antidiabetika umfassen Insulin und Insulinderivate, wie z. B. Lantus® (siehe www.lantus.com ) oder HMR 1964 oder Levemir® (insulin detemir) oder solche, wie sie in WO2005005477 (Novo Nordisk) beschrieben sind, schnell wirkende Insulin (siehe US 6,221,633 ), inhalierbare Insulin, wie z. B. Exubera® oder orale Insulin, wie z. B. IN-105 (Nobex) oder Oral-lynTM (Generex Biotechnology), GLP-1-Derivate wie z. B. Exenatide, Liraglutide oder diejenigen die in WO 98/08871 , WO2005027978 , WO2006037811 , WO2006037810 von Novo Nordisk A/S, in WO 01/04156 von Zealand oder in WO 00/34331 von Beaufour-Ipsen offenbart wurden, Pramlintide Acetat (Symlin; Amylin Pharmaceuticals), sowie oral wirksame hypoglykämische Wirkstoffe.Antidiabetics include insulin and insulin derivatives, such as. Lantus® (see www.lantus.com ) or HMR 1964 or Levemir ® (insulin detemir) or those as described in WO2005005477 (Novo Nordisk), fast-acting insulin (see US 6,221,633 ), inhalable insulin, such as. B. Exubera ® or oral insulin, such as. B. IN-105 (Nobex) or Oral-lyn ™ (Generex Biotechnology), GLP-1 derivatives such. Exenatide, liraglutide or those in WO 98/08871 . WO2005027978 . WO2006037811 . WO2006037810 from Novo Nordisk A / S, in WO 01/04156 from Zealand or in WO 00/34331 by Beaufour-Ipsen, Pramlintide Acetate (Symlin; Amylin Pharmaceuticals), as well as orally active hypoglycemic agents.

Die oral wirksamen hypoglykämischen Wirkstoffe umfassen vorzugsweise
Sulfonylharnstoffe,
Biguanidine,
Meglitinide,
Oxadiazolidindione,
Thiazolidindione,
Glukosidase-Inhibitoren,
Hemmstoffe der Glykogenphosphorylase,
Glukagon-Antagonisten,
Glukokinaseaktivatoren,
Inhibitoren der Fructose-1,6-bisphosphatase
Modulatoren des Glukosetransporters-4 (GLUT4),
Inhibitoren der Glutamin-Fructose-6-Phosphat-Amidotransferase (GFAT),
GLP-1-Agonisten, Kaliumkanalöffner, wie z. B. diejenigen, die in WO 97/26265 und WO 99/03861 von Novo Nordisk A/S offenbart wurden oder die, die in WO2006045799 beschrieben sind (Solvay),
Inhibitoren der Dipeptidylpeptidase-IV (DPP-IV),
Insulin-Sensitizer,
Inhibitoren von Leberenzymen, die an der Stimulation der Glukoneogenese und/oder Glykogenolyse beteiligt sind,
Modulatoren der Glukoseaufnahme, des Glukosetransports und der Glukoserückresorption,
Hemmstoffe der 11β-HSD1,
Inhibitoren der Protein-Tyrosin-Phosphatase-1B (PTP1B),
Modulatoren des natrium-abhängigen Glukosetransporters 1 oder 2 (SGLT1, SGLT2),
den Fettstoffwechsel verändernde Verbindungen wie antihyperlipidämische Wirkstoffe und antilipidämische Wirkstoffe,
Verbindungen, die die Nahrungsmitteleinnahme verringern,
Verbindungen, die die Thermogenese erhöhen,
PPAR- und RXR-Modulatoren und
Wirkstoffe, die auf den ATP-abhängigen Kaliumkanal der Betazellen wirken.The orally active hypoglycemic agents preferably comprise
sulfonylureas,
biguanides,
meglitinides,
oxadiazolidinediones,
thiazolidinediones,
Glucosidase inhibitors,
Inhibitors of glycogen phosphorylase,
Glucagon antagonists,
glucokinase
Inhibitors of fructose 1,6-bisphosphatase
Glucose Transporter 4 Modulators (GLUT4),
Inhibitors of glutamine-fructose 6-phosphate amidotransferase (GFAT),
GLP-1 agonists, potassium channel openers, such as. B. those in WO 97/26265 and WO 99/03861 disclosed by Novo Nordisk A / S or those published in WO2006045799 are described (Solvay),
Inhibitors of dipeptidyl peptidase-IV (DPP-IV),
Insulin sensitizers,
Inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis,
Modulators of glucose uptake, glucose transport and glucose reabsorption,
Inhibitors of 11β-HSD1,
Inhibitors of protein tyrosine phosphatase-1B (PTP1B),
Modulators of the Sodium-Dependent Glucose Transporter 1 or 2 (SGLT1, SGLT2),
fat metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents,
Compounds that reduce food intake,
Compounds that increase thermogenesis,
PPAR and RXR modulators and
Drugs that act on the ATP-dependent potassium channel of beta cells.

Bei einer Ausführungsform der Erfindung wird die Verbindungen der Formel I in Kombination mit einem HMGCoA-Reduktase Inhibitor wie Simvastatin, Fluvastatin, Pravastatin, Lovastatin, Atorvastatin, Cerivastatin, Rosuvastatin, L-659699 verabreicht.at An embodiment of the invention is the compounds of the formula I in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, Cerivastatin, rosuvastatin, L-659699 administered.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Cholesterinresorptionsinhibitor, wie z. B. Ezetimibe, Tiqueside, Pamaqueside, FM-VP4 (sitostanol/campesterol ascorbyl phosphat; Forbes Medi-rech, WO2005042692 , WO2005005453 ), MD-0727 (Microbia Inc., WO2005021497 , WO2005021495 ) oder mit Verbindungen, wie in WO2002066464 (Kotobuki Pharmaceutical Co. Ltd.) oder WO2005044256 oder WO2005062824 (Merck & Co.) oder WO2005061451 und WO2005061452 (AstraZeneca AB) und WO2006017257 (Phenomix) oder WO2005033100 (Lipideon Biotechnology AG) beschrieben, verabreicht.In one embodiment of the invention, the compound of the formula I in combination with a cholesterol resorption inhibitor, such. Ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate; Forbes Medi-rech, WO2005042692 . WO2005005453 ), MD-0727 (Microbia Inc., WO2005021497 . WO2005021495 ) or with compounds as in WO2002066464 (Kotobuki Pharmaceutical Co. Ltd.) or WO2005044256 or WO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZeneca AB) and WO2006017257 (Phenomix) or WO2005033100 (Lipideon Biotechnology AG).

Bei einer Ausfürungsform der Erfindung wird die Verbindung der Formel I in Kombination mit VytorinTM, einer festen Kombination von Ezetimibe mit Simvastatin, verabreicht. Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einer festen Kombination von Ezetimibe mit Fenofibrat verabreicht.In one embodiment of the invention, the compound of formula I is administered in combination with Vytorin ™ , a fixed combination of ezetimibe with simvastatin. In one embodiment of the invention, the compound of formula I is administered in combination with a fixed combination of ezetimibe with fenofibrate.

Bei einer weiteren Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einer festen Kombination von Fenofibrat mit Rosuvastatin verabreicht.at Another embodiment of the invention is the compound of formula I in combination with a fixed combination of fenofibrate administered with rosuvastatin.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit ISIS-301012, einem Antisense-Oligonukleotid, welches in der Lage ist, das Apolipoprotein B Gen zu regulieren, verabreicht.at An embodiment of the invention is the compound of formula I in combination with ISIS-301012, an antisense oligonucleotide, which is able to regulate the apolipoprotein B gene, administered.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem PPAR gamma Agonisten, wie z. B. Rosiglitazon, Pioglitazon, JTT-501, Gl 262570, R-483, CS-011 (Rivoglitazon) verabreicht.at An embodiment of the invention is the compound of Formula I in combination with a PPAR gamma agonist, such as z. Rosiglitazone, pioglitazone, JTT-501, GI 262570, R-483, CS-011 (Rivoglitazone).

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit CompetactTM, einer festen Kombination von Pioglitazon Hydrochlorid mit Metformin Hydrochlorid, verabreicht.In one embodiment of the invention, the compound of formula I is administered in combination with Competact ™ , a solid combination of pioglitazone hydrochloride with metformin hydrochloride.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit duetactTM, einer festen Kombination von Pioglitazon Hydrochlorid mit Glimepirid, verabreicht.In one embodiment of the invention, the compound of formula I is administered in combination with duetact ™ , a solid combination of pioglitazone hydrochloride with glimepiride.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Avandamet®, einer festen Kombination von Rosiglitazon Maleat mit Metformin Hydrochlorid, verabreicht.In one embodiment of the invention, the compound of formula I in combination with Avandamet ®, a fixed combination of rosiglitazone maleate with metformin hydrochloride is administered.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit PPAR alpha Agonisten, wie z. B. GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945 verabreicht.at An embodiment of the invention is the compound of formula I in combination with PPAR alpha agonists such. B. GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem gemischten PPAR alpha/gamma Agonisten, wie z. B. Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, oder wie in PCT/US 00/11833 , PCT/US 00/11490 , DE10142734.4 oder in J. P. Berger et al., TRENDS in Pharmacological Sciences 28(5), 244–251, 2005 beschrieben, verabreicht.In one embodiment of the invention, the compound of formula I in combination with a mixed PPAR alpha / gamma agonist, such as. Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, or as in PCT / US 00/11833 . PCT / US 00/11490 . DE10142734.4 or in JP Berger et al., TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005 described, administered.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem PPAR delta Agonisten, wie z. B. GW-501516 verabreicht.at An embodiment of the invention is the compound of Formula I in combination with a PPAR delta agonist, such as z. GW-501516.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Metaglidasen oder mit MBX-2044 oder anderen partiellen PPAR gamma Agonisten/Antagonisten verabreichtat In one embodiment, the compound of the formula I in combination with metaglidases or with MBX-2044 or other partial PPAR gamma agonists / antagonists administered

Bei einer weiteren Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Aktivator der AMP-aktivierten Proteinkinase (AMPK), wie z. B. A-769662 oder solchen Verbindungen wie sie in US20050038068 beschrieben sind, verabreicht.In a further embodiment of the invention, the compound of the formula I in combination with an activator of the AMP-activated protein kinase (AMPK), such. B. A-769662 or such compounds as described in US20050038068 described.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Fibrat, wie z. B. Fenofibrat, Clofibrat, Bezafibrat, verabreicht.at An embodiment of the invention is the compound the formula I in combination with a fibrate, such as. Fenofibrate, Clofibrate, bezafibrate.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem MTP-Inhibitor, wie z. B. Implitapide, BMS-201038, R-103757 oder solchen wie in WO2005085226 , WO2005121091 , WO2006010423 beschrieben, verabreicht.In one embodiment of the invention, the compound of the formula I in combination with an MTP inhibitor, such as. Implitapide, BMS-201038, R-103757 or such as in WO2005085226 . WO2005121091 . WO2006010423 described, administered.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem CETP-Inhibitor, wie z. B. Torcetrapib oder JTT-705 oder solchen wie sie in WO2006002342 , WO2006010422 , WO2006012093 beschrieben sind, verabreicht.In one embodiment of the invention, the compound of the formula I in combination with a CETP inhibitor, such as. Torcetrapib or JTT-705 or such as in WO2006002342 . WO2006010422 . WO2006012093 described.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Gallensäureresorptionsinhibitor (siehe z. B. US 6,245,744 , US 6,221,897 oder WO00/61568 ), wie z. B. HMR 1741 oder solchen wie in DE 10 2005 033 099.1 und DE 10 2005 033 100.9 beschrieben, verabreicht.In one embodiment of the invention, the compound of the formula I is used in combination with bile acid resorption inhibitor (see, for example, US Pat. US 6,245,744 . US 6,221,897 or WO00 / 61568 ), such. HMR 1741 or such as in DE 10 2005 033 099.1 and DE 10 2005 033 100.9 described, administered.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem polymeren Gallensäureadsorber, wie z. B. Cholestyramin, Colesevelam, verabreicht.at An embodiment of the invention is the compound of the formula I in combination with a polymeric bile acid adsorber, such as As cholestyramine, colesevelam administered.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem LDL-Rezeptorinducer (siehe US 6,342,512 ), wie z. B. HMR1171, HMR1586, oder solchen wie in WO2005097738 beschrieben, verabreicht.In one embodiment of the invention, the compound of the formula I in combination with an LDL receptor inducers (see US 6,342,512 ), such. HMR1171, HMR1586, or such as in WO2005097738 described, administered.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Omacor® (Omega-3-Fettsäuren; hochkonzentrierte Ethylester der Eicosapentaensäure und der Docosahexaensäure) verabreicht.In one embodiment, the compound of formula I in combination with Omacor ® (Omega-3 fatty acids; highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid) is administered.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem ACAT-Inhibitor, wie z. B. Avasimibe oder SMP-797, verabreicht.at An embodiment of the invention is the compound the formula I in combination with an ACAT inhibitor, such as. B. Avasimibe or SMP-797.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Antioxidans, wie z. B. OPC-14117, Probucol, Tocopherol, Ascorbinsäure, β-Caroten oder Selen verabreicht.at An embodiment of the invention is the compound the formula I in combination with an antioxidant, such as. OPC-14117, Probucol, tocopherol, ascorbic acid, β-carotene or selenium.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Vitamin, wie z. B. Vitamin B6 oder Vitamin B12 verabreicht.at An embodiment of the invention is the compound the formula I in combination with a vitamin, such as. B. Vitamin B6 or vitamin B12 administered.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Lipoprotein-Lipase Modulator, wie z. B. Ibrolipim (NO-1886), verabreicht.In one embodiment of the invention, the compound of the formula I is used in combination with a Lipoprotein lipase modulator, such as. Ibrolipim (NO-1886).

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem ATP-Citrat-Lyase Inhibitor, wie z. B. SB-204990, verabreicht.at An embodiment of the invention is the compound of the formula I in combination with an ATP citrate lyase inhibitor, such as SB-204990.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Squalen Synthetase Inhibitor, wie z. B. BMS-188494 oder wie in WO2005077907 beschrieben, verabreicht.In one embodiment of the invention, the compound of the formula I in combination with a squalene synthetase inhibitor, such as. BMS-188494 or as in WO 2005/077907 described, administered.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Lipoprotein(a) antagonist, wie z. B. Gemcabene (CI-1027) verabreicht.at An embodiment of the invention is the compound of the formula I in combination with a lipoprotein (a) antagonist, such as G., Gemcabene (CI-1027).

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Agonisten des GPR109A (HM74A Rezeptor Agonisten), wie z. B. Nicotinsäure oder „extended release niacin" in Verbindung mit MK-0524A oder solchen Verbindungen, wie sie in WO2006045565 , WO2006045564 , WO2006069242 beschrieben sind, verabreicht.In one embodiment of the invention, the compound of the formula I in combination with an agonist of GPR109A (HM74A receptor agonist), such. As nicotinic acid or "extended release niacin" in conjunction with MK-0524A or such compounds as in WO2006045565 . WO2006045564 . WO2006069242 described.

Bei einer anderen Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Agonisten des GPR116, wie sie z. B. in WO2006067531 , WO200606753 beschrieben sind, verabreicht.In another embodiment of the invention, the compound of formula I in combination with an agonist of GPR116, as described, for. In WO2006067531 . WO200606753 described.

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Lipase Inhibitor, wie z. B. Orlistat oder Cetilistat (ATL-962), verabreicht.at An embodiment of the invention is the compound the formula I in combination with a lipase inhibitor, such as. B. Orlistat or cetilistat (ATL-962).

Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Insulin verabreicht.at An embodiment of the invention is the compound of formula I in combination with insulin.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Sulfonylharnstoff, wie z. B. Tolbutamid, Glibenclamid, Glipizid oder Glimepirid verabreicht.at In one embodiment, the compound of the formula I in combination with a sulfonylurea, such as. Tolbutamide, Glibenclamide, glipizide or glimepiride.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einer die Insulinsekretion verstärkende Substanz, wie z. B. KCP-265 ( WO2003097064 ), verabreicht.In one embodiment, the compound of formula I in combination with an insulin secretion enhancing substance, such as. B. KCP-265 ( WO2003097064 ).

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Agonisten des glucose-abhängigen insulinotropischen Rezeptors (GDIR) wie z. B. APD-668 verabreicht Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Biguanid, wie z. B. Metformin, verabreicht.at In one embodiment, the compound of the formula I in combination with agonists of glucose-dependent insulinotropic Receptor (GDIR) such. B. APD-668 administered In one embodiment the compound of the formula I in combination with a biguanide, such as z. As metformin administered.

Bei wieder einer anderen Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Meglitinid, wie z. B. Repaglinide oder Nateglinid, verabreicht.at Yet another embodiment, the compound the formula I in combination with a meglitinide, such as. B. repaglinide or nateglinide.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Thiazolidindion, wie z. B. Troglitazon, Ciglitazon, Pioglitazon, Rosiglitazon oder den in WO 97/41097 von Dr. Reddy's Research Foundation offenbarten Verbindungen, insbesondere 5-[[4-[(3,4-Dihydro-3-methyl-4-oxo-2-chinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidindion, verabreicht.In one embodiment, the compound of formula I in combination with a thiazolidinedione, such as. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or the in WO 97/41097 from dr. Reddy's Research Foundation disclosed compounds, especially 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem α-Glukosidase-Inhibitor, wie z. B. Miglitol oder Acarbose, verabreicht.at In one embodiment, the compound of the formula I in combination with an α-glucosidase inhibitor, such as. As miglitol or acarbose administered.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Wirkstoff verabreicht, der auf den ATP-abhängigen Kaliumkanal der Betazellen wirkt, wie z. B. Tolbutamid, Glibenclamid, Glipizid, Glimepirid oder Repaglinid.at In one embodiment, the compound of the formula I administered in combination with an active ingredient that is ATP-dependent Potassium channel of the beta cells acts, such. Tolbutamide, glibenclamide, glipizide, Glimepiride or repaglinide.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit mehr als einer der vorstehend genannten Verbindungen, z. B. in Kombination mit einem Sulfonylharnstoff und Metformin, einem Sulfonylharnstoff und Acarbose, Repaglinid und Metformin, Insulin und einem Sulfonylharnstoff, Insulin und Metformin, Insulin und Troglitazon, Insulin und Lovastatin, etc. verabreicht.at In one embodiment, the compound of the formula I in combination with more than one of the aforementioned compounds, z. In combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, Insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Hemmstoff der Glykogenphosphorylase, wie z. B. PSN-357 oder FR-258900 oder solchen wie in WO2003084922 , WO2004007455 , WO2005073229-31 , WO2005067932 beschrieben, verabreicht.In one embodiment, the compound of the formula I in combination with an inhibitor of glycogen phosphorylase, such. B. PSN-357 or FR-258900 or such as in WO2003084922 . WO2004007455 . WO2005073229-31 . WO2005067932 described, administered.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Glukagon-Rezeptor-Antagonisten, wie z. B. A-770077 oder NNC-25-2504 oder wie in WO2004100875 , WO2005065680 , beschrieben, verabreicht.In one embodiment, the compound of the formula I in combination with glucagon Rezep tor antagonists, such as. A-770077 or NNC-25-2504 or as in WO2004100875 . WO2005065680 , described, administered.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Aktivatoren der Glukokinase, wie z. B. LY-2121260 ( WO2004063179 ), PSN-105, PSN-110, GKA-50 oder solchen wie sie z. B. in WO2004072031 , WO2004072066 , WO2005080360 , WO2005044801 , WO2006016194 , WO2006058923 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I in combination with activators of glucokinase, such as. B. LY-2121260 ( WO2004063179 ), PSN-105, PSN-110, GKA-50 or such as those described e.g. In WO2004072031 . WO2004072066 . WO2005080360 . WO2005044801 . WO2006016194 . WO2006058923 described.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Glukoneogenese, wie z. B. FR-225654 , verabreicht. Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der Fructose-1,6-bisphosphatase (FBPase) wie z. B. CS-917 (MB-06322) oder MB-07803 oder solchen wie sie in WO2006023515 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I in combination with an inhibitor of gluconeogenesis, such as. B. FR-225654 administered. In one embodiment, the compound of the formula I in combination with inhibitors of fructose 1,6-bisphosphatase (FBPase) such. CS-917 (MB-06322) or MB-07803 or such as described in U.S. Pat WO2006023515 described.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des Glukosetransporters-4 (GLUT4), wie z. B. KST-48 ( D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004) ), verabreicht.In one embodiment, the compound of the formula I in combination with modulators of the glucose transporter-4 (GLUT4), such as. B. KST-48 ( DO. Lee et al .: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004) ).

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der Glutamin-Fructose-6-Phosphat-Amidotransferase (GFAT), wie sie z. B. in WO2004101528 beschrieben sind, verabreicht.In one embodiment, the compound of formula I is used in combination with inhibitors of glutamine-fructose 6-phosphate amidotransferase (GFAT), as described e.g. In WO2004101528 described.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der Dipeptidylpeptidase-IV (DPP-IV), wie z. B. Vildagliptin (LAF-237), Sitagliptin (MK-0431), Saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X, KRP-104, DP-893 oder wie sie in WO2003074500 , WO2003106456 , WO200450658 , WO2005058901 , WO2005012312 , WO2005/012308 , WO2006039325 , WO2006058064 , PCT/EP2005/007821 , PCT/EP2005/008005 , PCT/EP2005/008002 , PCT/EP2005/008004 , PCT/EP2005/008283 , DE 10 2005 012 874.2 oder DE 10 2005 012 873.4 beschrieben sind, verabreicht.In one embodiment, the compound of formula I in combination with inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as. Vildagliptin (LAF-237), sitagliptin (MK-0431), saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC- 8200, GW-825964X, KRP-104, DP-893 or as in WO2003074500 . WO2003106456 . WO200450658 . WO2005058901 . WO2005012312 . WO2005 / 012308 . WO2006039325 . WO2006058064 . PCT / EP2005 / 007821 . PCT / EP2005 / 008005 . PCT / EP2005 / 008002 . PCT / EP2005 / 008004 . PCT / EP2005 / 008283 . DE 10 2005 012 874.2 or DE 10 2005 012 873.4 described.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit JanuviaTM, einer festen Kombination von Sitagliptin Phosphat mit Metformin hydrochlorid, verabreicht.In one embodiment, the compound of Formula I is administered in combination with Januvia ™ , a solid combination of sitagliptin phosphate with metformin hydrochloride.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Hemmstoffen der 11-beta-Hydroxysteroid-Dehydrogenase-1 (11β-HSDI), wie z. B. BVT-2733, JNJ-25918646, INCB-13739 oder solche, wie sie z. B. in WO200190090-94 , WO200343999 , WO2004112782 , WO200344000 , WO200344009 , WO2004112779 , WO2004113310 , WO2004103980 , WO2004112784 , WO2003065983 , WO2003104207 , WO2003104208 , WO2004106294 , WO2004011410 , WO2004033427 , WO2004041264 , WO2004037251 , WO2004056744 , WO2004058730 , WO2004065351 , WO2004089367 , WO2004089380 , WO2004089470-71 , WO2004089896 , WO2005016877 , WO2005097759 , WO2006010546 , WO2006012227 , WO2006012173 , WO2006017542 , WO2006034804 , WO2006040329 , WO2006051662 , WO2006048750 , WO2006049952 , WO2006048331 , WO2006050908 , WO2006024627 , WO2006040329 , WO2006066109 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I in combination with inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11β-HSDI), such. B. BVT-2733, JNJ-25918646, INCB-13739 or such as z. In WO200190090-94 . WO200343999 . WO2004112782 . WO200344000 . WO200344009 . WO2004112779 . WO2004113310 . WO2004103980 . WO2004112784 . WO2003065983 . WO2003104207 . WO2003104208 . WO2004106294 . WO2004011410 . WO2004033427 . WO2004041264 . WO2004037251 . WO2004056744 . WO2004058730 . WO2004065351 . WO2004089367 . WO2004089380 . WO2004089470-71 . WO2004089896 . WO2005016877 . WO2005097759 . WO2006010546 . WO2006012227 . WO2006012173 . WO2006017542 . WO2006034804 . WO2006040329 . WO2006051662 . WO2006048750 . WO2006049952 . WO2006048331 . WO2006050908 . WO2006024627 . WO2006040329 . WO2006066109 described.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der Protein-Tyrosin-Phosphatase-1B (PTP1B), wie sie z. B. in WO200119830-31 , WO200117516 , WO2004506446 , WO2005012295 , WO2005116003 , PCT/EP2005/005311 , PCT/EP2005/005321 , PCT/EP2005/007151 , PCT/EP2005/01294 oder DE 10 2004 060 542.4 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I in combination with inhibitors of protein tyrosine phosphatase-1B (PTP1B), as z. In WO200119830-31 . WO200117516 . WO2004506446 . WO2005012295 . WO2005116003 . PCT / EP2005 / 005311 . PCT / EP2005 / 005321 . PCT / EP2005 / 007151 . PCT / EP2005 / 01294 or DE 10 2004 060 542.4 described.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des natrium-abhängigen Glukosetransporters 1 oder 2 (SGLT1, SGLT2), wie z. B. KGA-2727, T-1095, SGL-0010, AVE 2268 und SAR 7226 oder wie sie z. B. in WO2004007517 , WO200452903 , WO200452902 , PCT/EP2005/005959 , WO2005085237 , JP2004359630 , WO2005121161 , WO2006018150 , WO2006035796 , WO2006062224 , WO2006058597 oder von A. L. Handlon in Expert Opin. Ther. Patents (2005) 15(11), 1531–1540 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I in combination with modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), such. KGA-2727, T-1095, SGL-0010, AVE 2268 and SAR 7226 or as described e.g. In WO2004007517 . WO200452903 . WO200452902 . PCT / EP2005 / 005959 . WO2005085237 . JP2004359630 . WO2005121161 . WO2006018150 . WO2006035796 . WO2006062224 . WO2006058597 or from AL Handlon in Expert Opinion. Ther. Patents (2005) 15 (11), 1531-1540 described.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des GPR40 verabreicht.at In one embodiment, the compound of the formula I administered in combination with modulators of the GPR40.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des GPR119b, wie sie z. B. in WO2004041274 beschrieben sind, verabreicht.In one embodiment, the compound of formula I is used in combination with modulators of GPR119b, as described e.g. In WO2004041274 described.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des GPR119, wie sie z. B. in WO2005061489 (PSN-632408) beschrieben sind, verabreicht.In one embodiment, the compound of the formula I is used in combination with modulators of the GPR119, as described, for. In WO2005061489 (PSN-632408).

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der hormon-sensitiven Lipase (HSL), wie z. B. in WO2005073199 beschrieben, verabreicht.In one embodiment, the compound of the formula I in combination with inhibitors of hormone-sensitive lipase (HSL), such. In WO2005073199 described, administered.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Hemmstoffen der Acetyl-CoA Carboxylase (ACC) wie z. B. solchen wie in WO199946262 , WO200372197 , WO2003072197 , WO2005044814 , WO2005108370 , JP2006131559 beschrieben, verabreicht.In one embodiment, the compound of the formula I in combination with inhibitors of acetyl-CoA carboxylase (ACC) such. B. such as in WO199946262 . WO200372197 . WO2003072197 . WO2005044814 . WO2005108370 . JP2006131559 described, administered.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Phosphoenolpyruvatcarboxykinase (PEPCK), wie z. B. solchen, wie in WO2004074288 beschrieben, verabreicht.In one embodiment, the compound of formula I in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), such as. B. such as in WO2004074288 described, administered.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Glykogen Synthase Kinase-3 beta (GSK-3 beta), wie z. B. in US2005222220 , WO2005085230 , PCT/EP2005/005346 , WO2003078403 , WO2004022544 , WO2003106410 , WO2005058908 , US2005038023 , WO2005009997 , US2005026984 , WO2005000836 , WO2004106343 , EP1460075 , WO2004014910 , WO2003076442 , WO2005087727 , WO2004046117 beschrieben.In one embodiment, the compound of the formula I in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), such as. In US2005222220 . WO2005085230 . PCT / EP2005 / 005346 . WO2003078403 . WO2004022544 . WO2003106410 . WO2005058908 . US2005038023 . WO2005009997 . US2005026984 . WO2005000836 . WO2004106343 . EP1460075 . WO2004014910 . WO2003076442 . WO2005087727 . WO2004046117 described.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Protein Kinase C beta (PKC beta), wie z. B. Ruboxistaurin, verabreicht.at In one embodiment, the compound of the formula I in combination with an inhibitor of protein kinase C beta (PKC beta), such as. B. Ruboxistaurin administered.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Endothelin-A-Rezeptor Antagonisten, wie z. B. Avosentan (SPP-301), verabreicht.at In one embodiment, the compound of the formula I in combination with an endothelin A receptor antagonist, such as z. B. avosentan (SPP-301).

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der „I-kappaB kinase" (IKK Inhibitoren), wie sie z. B. in WO2001000610 , WO2001030774 , WO2004022553 , WO2005097129 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I is used in combination with inhibitors of "I-kappaB kinase" (IKK inhibitors), as described, for example, in US Pat WO2001000610 . WO2001030774 . WO2004022553 . WO2005097129 described.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des Glucocorticoidrezeptors, wie sie z. B. in WO2005090336 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I in combination with modulators of the glucocorticoid receptor, as described, for. In WO 2005/090336 described.

Bei einer weiteren Ausführungsform wird die Verbindung der Formel I in Kombination mit CART-Modulatoren (siehe "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A. et al.: Hormone and Metabolic Research (2001), 33(9), 554–558 );
NPY-Antagonisten wie z. B. Naphthalin-1-sulfonsäure-{4-[(4-amino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amid Hydrochlorid (CGP 71683A);
NPY-5 Rezeptorantagonisten wie L-152804, S-2367 oder wie sie z. B. in WO2006001318 beschrieben sind;
Peptid YY 3-36 (PYY3-36) oder analoge Verbindungen wie z. B. CJC-1682 (PYY3-36 konjugiert mit humanem Serum Albumin über Cys34) oder CJC-1643 (Derivat des PYY3-36, welches sich in vivo an Serum Albumin konjugiert) oder solche, wie sie in WO2005080424 beschrieben sind;
CB1R (Cannabinoid Rezeptor 1) Antagonisten (wie z. B. Rimonabant, SR147778 oder solche wie sie in z. B. EP 0656354 , WO 00/15609 , WO 02/076949 , WO2005080345 , WO2005080328 , WO2005080343 , WO2005075450 , WO2005080357 , WO200170700 , WO2003026647-48 , WO200302776 , WO2003040107 , WO2003007887 , WO2003027069 , US6,509,367 , WO200132663 , WO2003086288 , WO2003087037 , WO2004048317 , WO2004058145 , WO2003084930 , WO2003084943 , WO2004058744 , WO2004013120 , WO2004029204 , WO2004035566 , WO2004058249 , WO2004058255 , WO2004058727 , WO2004069838 , US20040214837 , US20040214855 , US20040214856 , WO2004096209 , WO2004096763 , WO2004096794 , WO2005000809 , WO2004099157 , US20040266845 , WO2004110453 , WO2004108728 , WO2004000817 , WO2005000820 , US20050009870 , WO200500974 , WO2004111033-34 , WO200411038-39 , WO2005016286 , WO2005007111 , WO2005007628 , US20050054679 , WO2005027837 , WO2005028456 , WO2005063761-62 , WO2005061509 , WO2005077897 , WO2006047516 , WO2006060461 , WO2006067428 , WO2006067443 beschrieben sind);
MC4-Agonisten (z. B. 1-Amino-1,2,3,4-tetrahydro-naphthalin-2-carbonsäure[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(4-chloro-phenyl)-2-oxo-ethyl]-amid; ( WO 01/91752 )) oder LB53280, LB53279, LB53278 oder THIQ, MB243, RY764, CHIR-785, PT-141 oder solche wie sie in WO2005060985 , WO2005009950 , WO2004087159 , WO2004078717 , WO2004078716 , WO2004024720 , US20050124652 , WO2005051391 , WO2004112793 , WOUS20050222014 , US20050176728 , US20050164914 , US20050124636 , US20050130988 , US20040167201 , WO2004005324 , WO2004037797 , WO2005042516 , WO2005040109 , WO2005030797 , US20040224901 , WO200501921 , WO200509184 , WO2005000339 , EP1460069 , WO2005047253 , WO2005047251 , EP1538159 , WO2004072076 , WO2004072077 , WO2006021655-57 beschrieben sind;
Orexin-Rezeptor Antagonisten (z. B. 1-(2-Methyl-benzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl-harnstoff Hydrochlorid (SB-334867-A) oder solche, wie sie z. B. in WO200196302 , WO200185693 , WO2004085403 , WO2005075458 , WO2006067224 beschrieben sind);
Histamin H3 Rezeptor Agonisten (z. B. 3-Cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-propan-1-on Oxalsäuresalz ( WO 00/63208 ) oder solche, wie sie in WO200064884 , WO2005082893 beschrieben sind);
CRF-Antagonisten (z. B. [2-Methyl-9-(2,4,6-timethyl-phenyl)-9H-1,3,9-triaza-fluoren-4-yl]-dipropyl-amin ( WO 00/66585 ));
CRF BP-Antagonisten (z. B. Urocortin);
Urocortin-Agonisten;
Agonisten des beta-3 Adrenoceptors wie z. B. 1-(4-Chloro-3-methanesulfonylmethyl-phenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)-ethylamino]-ethanol Hydrochlorid ( WO 01/83451 ) oder Solabegron (GW-427353) oder N-5984 (KRP-204) oder solche, wie sie in JP2006111553 beschrieben sind;
MSH(Melanocyt-stimulierendes Hormon)-Agonisten;
MCH(melanin-konzentrierendes Hormon) Rezeptor Antagonisten (wie z. B. NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 oder solche Verbindungen, wie sie in WO2003/15769 , WO2005085200 , WO2005019240 , WO2004011438 , WO2004012648 , WO2003015769 , WO2004072025 , WO2005070898 , WO2005070925 , WO2004039780 , WO2003033476 , WO2002006245 , WO2002089729 , WO2002002744 , WO2003004027 , FR2868780 , WO2006010446 , WO2006038680 , WO2006044293 , WO2006044174 beschrieben sind);
CCK-A Agonisten (wie z. B. {2-[4-(4-Chloro-2,5-dimethoxy-phenyl)-5-(2-cyclohexyl-ethyl)-thiazol-2-ylcarbamoyl]-5,7-dimethyl-indol-1-yl}-essigsäure Trifluoressigsäuresalz ( WO 99/15525 ) oder SR-146131 ( WO 0244150 ) oder SSR-125180) oder solchen, wie sie in WO2005116034 beschrieben sind;
Serotonin-Wiederaufnahme-Inhibitoren (z. B. Dexfenfluramine);
gemischte Sertonin- und noradrenerge Verbindungen (z. B. WO 00/71549 );
5-HT-Rezeptor Agonisten z. B. 1-(3-Ethyl-benzofuran-7-yl)-piperazin Oxalsäuresalz ( WO 01/09111 );
5-HT2C Rezeptor Agonisten (wie z. B. Lorcaserin Hydrochlorid (APD-356) oder BVT-933 oder solche, wie sie in WO200077010 , WO20077001-02 , WO2005019180 , WO2003064423 , WO200242304 , WO2005082859 beschrieben sind);
5-HT6 Rezeptor Antagonisten, wie sie z. B. in WO2005058858 beschrieben sind;
Bombesin-Rezeptor Agonisten (BRS-3 Agonisten;
Galanin-Rezeptor Antagonisten;
Wachstumshormon (z. B. humanes Wachstumshormon oder AOD-9604);
Wachstumshormon freisetzende Verbindungen (6-Benzyloxy-1-(2-diisopropylamino-ethylcarbamoyl)-3,4-dihydro-1H-isochinolin-2-carbonsäuretertiärbutylester ( WO 01/85695 )); Growth Hormone Secretagogue Receptor Antagonisten (Ghrelin Antagonisten) wie z. B. A-778193 oder solchen, wie sie in WO2005030734 beschrieben sind;
TRH-Agonisten (siehe z. B. EP 0 462 884 );
entkoppelnde Protein 2- oder 3-Modulatoren;
Leptinagonisten (siehe z. B. 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-Agonisten (Bromocriptin, Doprexin);
Lipase/Amylase-Inhibitoren (z. B. WO 00/40569 );
Inhibitoren der Diacylglycerol O-Acyltransferasen (DGATs) wie z. B. BAY-74-4113 oder wie z. B. in US2004/0224997 , WO2004094618 , WO200058491 , WO2005044250 , WO2005072740 , JP2005206492 , WO2005013907 , WO2006004200 , WO2006019020 , WO2006064189 beschrieben;
Inhibitoren der Fettsäuresynthase (FAS) wie z. B. C75 oder solchen, wie in WO2004005277 beschrieben;
Oxyntomodulin;
Oleoyl-Estron
oder Agonisten des Schilddrüsenhormonrezeptors (thyroid hormone receptor agonists) wie z. B: KB-2115 oder solche, wie in WO20058279 , WO200172692 , WO200194293 , WO2003084915 , WO2004018421 , WO2005092316 beschrieben, verabreicht.In another embodiment, the compound of formula I is used in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript-influencing energy metabolism, anxiety and gastric emptying in mice" Asakawa, A. et al .: Hormone and Metabolic Research (2001), 33 (9), 554-558 );
NPY antagonists such. B. naphthalene-1-sulfonic acid {4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl} -amide hydrochloride (CGP 71683A);
NPY-5 receptor antagonists such as L-152804, S-2367 or as such. In WO2006001318 are described;
Peptide YY 3-36 (PYY3-36) or analogous compounds such. CJC-1682 (PYY3-36 conjugated to human serum albumin via Cys34) or CJC-1643 (derivative of PYY3-36 conjugated to serum albumin in vivo) or those as described in U.S. Pat WO2005080424 are described;
CB1R (cannabinoid receptor 1) antagonists (such as rimonabant, SR147778 or such as in z. B. EP 0656354 . WO 00/15609 . WO 02/076949 . WO2005080345 . WO2005080328 . WO2005080343 . WO2005075450 . WO2005080357 . WO200170700 . WO2003026647-48 . WO200302776 . WO2003040107 . WO2003007887 . WO2003027069 . US6,509,367 . WO200132663 . WO2003086288 . WO2003087037 . WO2004048317 . WO2004058145 . WO2003084930 . WO2003084943 . WO2004058744 . WO2004013120 . WO2004029204 . WO2004035566 . WO2004058249 . WO2004058255 . WO2004058727 . WO2004069838 . US20040214837 . US20040214855 . US20040214856 . WO2004096209 . WO2004096763 . WO2004096794 . WO2005000809 . WO2004099157 . US20040266845 . WO2004110453 . WO2004108728 . WO2004000817 . WO2005000820 . US20050009870 . WO200500974 . WO2004111033-34 . WO200411038-39 . WO2005016286 . WO2005007111 . WO2005007628 . US20050054679 . WO2005027837 . WO2005028456 . WO2005063761-62 . WO2005061509 . WO2005077897 . WO2006047516 . WO2006060461 . WO2006067428 . WO2006067443 described);
MC4 agonists (eg 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4 , 6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chloro-phenyl) -2-oxo-ethyl] -amide; WO 01/91752 )) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141 or those as described in WO2005060985 . WO2005009950 . WO2004087159 . WO2004078717 . WO2004078716 . WO2004024720 . US20050124652 . WO2005051391 . WO2004112793 . WOUS20050222014 . US20050176728 . US20050164914 . US20050124636 . US20050130988 . US20040167201 . WO2004005324 . WO2004037797 . WO2005042516 . WO2005040109 . WO2005030797 . US20040224901 . WO200501921 . WO200509184 . WO2005000339 . EP1460069 . WO2005047253 . WO2005047251 . EP1538159 . WO2004072076 . WO2004072077 . WO2006021655-57 are described;
Orexin receptor antagonists (eg 1- (2-methyl-benzoxazol-6-yl) -3- [1,5] naphthyridin-4-yl-urea hydrochloride (SB-334867-A) or those as they are eg in WO200196302 . WO200185693 . WO2004085403 . WO2005075458 . WO2006067224 described);
Histamine H3 receptor agonists (eg, 3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) -propane-1 -on oxalic acid salt ( WO 00/63208 ) or such as those in WO200064884 . WO2005082893 described);
CRF antagonists (eg, [2-methyl-9- (2,4,6-timethyl-phenyl) -9H-1,3,9-triaza-fluoren-4-yl] -dipropyl-amine ( WO 00/66585 ));
CRF BP antagonists (eg, urocortin);
Urocortin agonists;
Agonists of the beta-3 adrenoceptor such. B. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimethyl-1H-indol-6-yloxy) -ethylamino] -ethanol hydrochloride ( WO 01/83451 ) or Solabegron (GW-427353) or N-5984 (KRP-204) or those as described in JP2006111553 are described;
MSH (melanocyte-stimulating hormone) agonists;
MCH (melanin-concentrating hormone) receptor antagonists (such as NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 or such compounds, as they are in WO2003 / 15769 . WO2005085200 . WO2005019240 . WO2004011438 . WO2004012648 . WO2003015769 . WO2004072025 . WO2005070898 . WO2005070925 . WO2004039780 . WO2003033476 . WO2002006245 . WO2002089729 . WO2002002744 . WO2003004027 . FR2868780 . WO2006010446 . WO2006038680 . WO2006044293 . WO2006044174 described);
CCK-A agonists (such as {2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5,7 -dimethyl-indol-1-yl} -acetic acid trifluoroacetic acid salt ( WO 99/15525 ) or SR-146131 ( WO 0244150 ) or SSR-125180) or those as described in WO2005116034 are described;
Serotonin reuptake inhibitors (eg, dexfenfluramine);
mixed sertonine and noradrenergic compounds (e.g. WO 00/71549 );
5-HT receptor agonists z. B. 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalic acid salt ( WO 01/09111 );
5-HT2C receptor agonists (such as Lorcaserin hydrochloride (APD-356) or BVT-933 or those as described in WO200077010 . WO20077001-02 . WO2005019180 . WO2003064423 . WO200242304 . WO2005082859 described);
5-HT6 receptor antagonists, as they are e.g. In WO2005058858 are described;
Bombesin receptor agonists (BRS-3 agonists;
Galanin receptor antagonists;
Growth hormone (eg, human growth hormone or AOD-9604);
Growth Hormone Releasing Compounds (6-Benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester ( WO 01/85695 )); Growth Hormone Secretagogue Receptor Antagonists (ghrelin antagonists) such as B. A-778193 or those as described in WO2005030734 are described;
TRH agonists (see eg. EP 0 462 884 );
decoupling protein 2- or 3-modulators;
Leptin agonists (see, eg 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 (eg. WO 00/40569 );
Inhibitors of diacylglycerol O-acyltransferases (DGATs) such. B. BAY-74-4113 or such. In US2004 / 0224997 . WO2004094618 . WO200058491 . WO2005044250 . WO2005072740 . JP2005206492 . WO2005013907 . WO2006004200 . WO2006019020 . WO2006064189 described;
Inhibitors of fatty acid synthase (FAS) such. B. C75 or such, as in WO 2004/005277 described;
oxyntomodulin;
Oleoyl-estrone
or thyroid hormone receptor agonists (agonists) such as. B: KB-2115 or such, as in WO20058279 . WO200172692 . WO200194293 . WO2003084915 . WO2004018421 . WO2005092316 described, administered.

Bei einer Ausführungsform ist der weitere Wirkstoff Varenicline Tartrate, ein partieller Agonist des alpha 4-beta 2 nikotinischen Acetylcholinrezeptors.at In one embodiment, the other active substance is varenicline Tartrate, a partial agonist of the alpha 4-beta 2 nicotinic Acetylcholine receptor.

Bei einer Ausführungsform ist der weitere Wirkstoff Trodusquemine.at In one embodiment, the other active ingredient is trodusquemine.

Bei einer Ausführungsform ist der weitere Wirkstoff ein Modulator des Enzyms SIRT1, eines Mitglieds der humanen Sirtuinenzymfamilie.at In one embodiment, the further active ingredient is a modulator the enzyme SIRT1, a member of the human sirtuin enzyme family.

Bei einer Ausführungsform der Erfindung ist der weitere Wirkstoff Leptin;
siehe z. B. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion an Pharmacotherapy (2001), 2(10), 1615–1622 .In one embodiment of the invention, the further active ingredient is leptin;
see, for. B. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622 ,

Bei einer Ausführungsform ist der weitere Wirkstoff Dexamphetamin oder Amphetamin.at In one embodiment, the further active ingredient is dexamphetamine or amphetamine.

Bei einer Ausführungsform ist der weitere Wirkstoff Fenfluramin oder Dexfenfluramin.at In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.

Bei noch einer Ausführungsform ist der weitere Wirkstoff Sibutramin.at In another embodiment, the further active ingredient is sibutramine.

Bei einer Ausführungsform ist der weitere Wirkstoff Mazindol oder Phentermin.at In one embodiment, the further active ingredient is mazindol or phentermine.

Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Ballaststoffen, vorzugsweise unlöslichen Ballaststoffen (siehe z. B. Carob/Caromax® (Zunft H J; et al., Carob pule preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6. ) Caromax ist ein Carob enthaltendes Produkt der Fa. Nutrinova, Nutrition Specialties & Fond Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt/Main)) verabreicht. Die Kombination mit Caromax® kann in einer Zubereitung erfolgen, oder durch getrennte Gabe von Verbindungen der Formel I und Caromax®. Caromax® kann dabei auch in Form von Lebensmitteln, wie z. B. in Backwaren oder Müsliriegeln, verabreicht werden.In one embodiment, the compound of the formula I is used in combination with fibers, preferably insoluble fibers (see, for example, US Pat. Carob / Caromax® (Guild HJ, et al., Carob pule preparation for the treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18 (5), 230-6. ) Caromax is a carob-containing product of the company Nutrinova, Nutrition Specialties & Fond Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt / Main)) administered. Combination with Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®. Caromax ® can also be used in the form of food, such as. B. in baked goods or cereal bars, administered.

Es versteht sich, dass jede geeignete Kombination der erfindungsgemäßen Verbindungen mit einer oder mehreren der vorstehend genannten Verbindungen und wahlweise einer oder mehreren weiteren pharmakologisch wirksamen Substanzen als unter den Schutzbereich der vorliegenden Erfindung fallend angesehen wird.

Figure 00340001
Figure 00350001
Figure 00360001
Figure 00370001
Figure 00380001
Figure 00390001
Figure 00400001
Figure 00410001
Figure 00420001
It is understood that any suitable combination of the compounds of the present invention with one or more of the foregoing compounds and optionally one or more other pharmacologically active substances is considered to fall within the scope of the present invention.
Figure 00340001
Figure 00350001
Figure 00360001
Figure 00370001
Figure 00380001
Figure 00390001
Figure 00400001
Figure 00410001
Figure 00420001

Die Wirksamkeit der Verbindungen wurde wie folgt getestet:The Effectiveness of the compounds was tested as follows:

Enzymatischer Test von Glucokinase-AktivatorenEnzymatic test of glucokinase activators

Humane GlucokinaseHuman glucokinase

Humane Glucokinase wird als Fusionsprotein mit Glutathion-S-Transferase (GST) in E. coli B121 exprimiert und durch eine Affinitätschromatographie aufgereinigt. Durch Verdauung mit Faktor Xa wird GSH abgespalten und das Glucokinase-Polypeptid beginnend mit Ser-6 erhalten. Letzteres wird chromatographisch aufgereinigt. Eine typische Präparation der Glucokinase besitzt bei Raumtemperatur eine spezifische Aktivität von 30 U/mg Protein.humane Glucokinase is used as a fusion protein with glutathione-S-transferase (GST) expressed in E. coli B121 and by affinity chromatography purified. Digestion with Factor Xa cleaves GSH and the glucokinase polypeptide starting with Ser-6. The latter is purified by chromatography. A typical preparation the glucokinase has a specific activity of 30 U / mg protein.

Enyzymatischer TestEnyzymatic test

Die Aktivität von Glucokinase und der Einfluss von Verbindungen auf diese Aktivität werden durch einen gekoppelten optischen Test bei 25°C bestimmt. Das Testvolumen beträgt 100 μl. Die Testzusammensetzung ist: 25 mM HEPES/NaOH (Merck; #110110) pH 7, 25 mM KCl (Merck; #04933), 2 mM MgCl2 (Merck; #05833), 1 mM Dithiothreitol (Merck; #112013), 1 mM NAD (Sigma; #N1511), 5 mM Glucose (Merck; #108337), 1 mM ATP (Sigma; #A2383), 0,1% (w/v) Rinderserumalbumin (Merck; #112018), 0,002 U Glucokinase-Präparation und 3,2 U Glucose-6-Phosphat Dehydrogenase (Sigma; #G8529). Ferner enthält der Ansatz eine Testverbindung. Die Testverbindungen sind jeweils in 10 mM DMSO gelöst und werden bei Endkonzentrationen von 0 μM, 0,1 μM, 0,3 μM, 1 μM, 3 μM, 10 μM, 30 μM und 100 μM getestet. Die Endkonzentration an DMSO im Test beträgt 1% (v/v). Die Reaktion wird durch die Zugabe von ATP gestartet. Die Absorption des Ansatzes bei 340 nm wird unmittelbar nach der Zugabe von ATP und dann 25 min später mit einem Multiwellplattenphotometer (Firma Labsystems, Multiskan Ascent) bestimmt. Die Änderung der Absorption in diesem Zeitraum wird berechnet.The activity of glucokinase and the effect of compounds on this activity are determined by a coupled optical assay at 25 ° C. The test volume is 100 μl. The test composition is: 25mM HEPES / NaOH (Merck, # 110110) pH 7, 25mM KCl (Merck; # 04933), 2mM MgCl 2 (Merck; # 05833), 1mM Dithiothreitol (Merck; # 112013), 1 NAD (Sigma; # N1511), 5mM glucose (Merck; # 108337), 1mM ATP (Sigma; # A2383), 0.1% (w / v) bovine serum albumin (Merck; # 112018), 0.002 U glucokinase Preparation and 3.2 U glucose-6-phosphate dehydrogenase (Sigma; # G8529). Furthermore, the approach contains a test compound. The test compounds are each dissolved in 10 mM DMSO and are tested at final concentrations of 0 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM, 30 μM and 100 μM. The final concentration of DMSO in the test is 1% (v / v). The reaction is started by the addition of ATP. The absorption of the batch at 340 nm is determined immediately after the addition of ATP and then 25 minutes later with a multiwell plate photometer (Labsystems, Multiskan Ascent). The change in absorbance over this period is calculated.

Auswertung:Evaluation:

Die Rohdaten der Extinktionsänderungen werden in ein Microsoft Excel-File transferiert. Der Wert für 0 μM Testverbindung wird als 100% gesetzt. Dosis-Wirkungskurven werden mit dem Programm XL.Fit nach Vorgabe des Herstellers (Firma IDBS) berechnet. Als EC150 wird die Konzentration einer Testverbindung definiert, die eine Steigerung der enzymatischen Aktivität um 50% hervorruft. Die maximal fache Stimulation entspricht dem Verhältnis der größten Extinktionsänderung im Konzentrationsbereich einer Testverbindung zu der Änderung der Absorption ohne Testsubstanz. Tabelle 2: Biologische Aktivität Beispiel Nr EC50 [μM] Fold induction 1 4.2 2.0 5 2.1 4.4 6 15.5 2.1 9 2.2 2.8 The raw data of the extinction changes are transferred to a Microsoft Excel file. The value for 0 μM test compound is set as 100%. Dose-response curves are calculated using the XL.Fit program as specified by the manufacturer (IDBS company). EC150 defines the concentration of a test compound that causes an increase in enzymatic activity by 50%. The maximum stimulation corresponds to the ratio of the greatest change in extinction in the concentration range of a test compound to the change in the absorption without test substance. Table 2: Biological activity Example no EC 50 [μM] Fold induction 1 4.2 2.0 5 2.1 4.4 6 15.5 2.1 9 2.2 2.8

Aus den Messdaten der Tabelle ist abzulesen, dass die erfindungsgemäßen Verbindungen eine Aktivierung von Glukokinase bewirken. Diese Verbindungen eignen sich damit insbesondere zur Senkung des Blutzuckerspiegel und zur Behandlung von Diabetes.Out The measured data of the table can be read that the inventive Connections cause activation of glucokinase. These connections are thus particularly suitable for lowering the blood sugar level and for the treatment of diabetes.

Verfahrenmethod

Die erfindungsgemäßen Verbindungen der Formel I können entsprechend dem folgenden Reaktionsschema hergestellt werden: Verfahren A:

Figure 00450001
The compounds of the formula I according to the invention can be prepared according to the following reaction scheme: Method A:
Figure 00450001

Ein 1-(Phenothiazin-2-yl)-ethanon der allgemeinen Formel A-1, wobei R1, R2 und R3 die oben genannten Bedeutungen haben, wird mit Schwefel und Morpholin bei erhöhter Temperatur (120–180°C) zum Morpholin-4-yl-ethanthion der allgemeinen Formel A-2 umgesetzt. Dieses wird mit einer Base wie zum Beispiel Kaliumhydroxid in einem polaren Lösungsmittel wie zum Beispiel Wasser und Ethanol zur Carbonsäure der allgemeinen Formel A-3 hydrolisiert. Die Carbonsäure wird zum Ester der allgemeinen Formel A-4 umgesetzt, indem die Carbonsäure in einem Alkohol, wie zum Beispiel Ethanol, in Gegenwart eines Säurekatalysators, wie zum Beispiel Schwefelsäure, unter wasserentziehenden Bedingungen, wie zum Beispiel durch Kochen an einem Wasserabscheider in einem Lösungsmittel wie beispielsweise Toluol, azeotrop erhitzt wird. Die Verbindung der allgemeinen Formel A-4 wird mit einem Oxidationsmittel wie zum Beispiel meta-Chlorperbenzoesäure in einem inerten Lösungsmittel wie zum Beispiel Dichlormethan zum Phenothiazin der allgemeinen Formel A-5 umgesetzt. Die Verbindung der allgemeinen Formel A-5 wird mit einer Base wie zum Beispiel Kaliumhexamethyldisilazid in einem polar aprotischen Lösungsmittel wie Tetrahydrofuran, deprotoniert und mit einer Verbindung der allgemeinen Formel A-6 alkyliert, wobei B, R6 und R7 die oben genannten Bedeutungen haben und LG eine Abgangsgruppe wie beispielsweise ein Iodid, Bromid, Mesylat oder Tosylat bedeutet. Die dadurch erhaltene Verbindung der allgemeinen Formel A-7 wird mittels einer Base wie zum Beispiel Natronlauge in einem polar erotischen Lösungsmittelgemisch wie Methanol/Wasser zur Carbonsäure der allgemeinen Formel A-8 hydrolysiert. Unter Einwirkung eines Kupplungsreagenzes, wie zum Beispiel O-[Cyan(ethoxycarbonyl)methylenamino]-1,1,3,3-tetramethyluronium-tetrafluoroborat (TOTU) in Gegenwart einer Base, wie zum Beispiel Diisopropylethylamin in einem polar aprotischen Lösungsmittel wie N,N-Diemethylformamid wird die Carbonsäure der allgemeinen Formel A-8 mit dem Amin der allgemeinen Formel A-9, worin A, R4 und R5 die oben beschriebenen Bedeutungen haben, zum Amid der allgemeinen Formel A-10 umgesetzt. Die racemischen Verbindungen der allgemeinen Formel A-10 können durch Chromatographie an chiraler Phase in die Enantiomere getrennt werden.A 1- (phenothiazin-2-yl) -ethanone of the general formula A-1, wherein R 1, R 2 and R 3 have the abovementioned meanings, is reacted with sulfur and morpholine at elevated temperature (120-180 ° C.) to give morpholine-4 -yl-ethanthion of the general formula A-2 implemented. This is hydrolyzed with a base such as potassium hydroxide in a polar solvent such as water and ethanol to the carboxylic acid of general formula A-3. The carboxylic acid is converted to the ester of general formula A-4 by reacting the carboxylic acid in an alcohol such as ethanol in the presence of an acid catalyst such as sulfuric acid under dehydrating conditions such as by boiling on a water separator in a solvent such as toluene, azeotropically heated. The compound of the general formula A-4 is reacted with an oxidizing agent such as meta-chloroperbenzoic acid in an inert solvent such as dichloromethane to the phenothiazine of the general formula A-5. The compound of general formula A-5 is deprotonated with a base such as potassium hexamethyldisilazide in a polar aprotic solvent such as tetrahydrofuran and alkylated with a compound of general formula A-6, wherein B, R6 and R7 have the meanings given above and LG represents a leaving group such as an iodide, bromide, mesylate or tosylate. The resulting compound of general formula A-7 is hydrolyzed by means of a base such as sodium hydroxide in a polar erotic solvent mixture such as methanol / water to the carboxylic acid of general formula A-8. By the action of a coupling reagent such as O- [cyano (ethoxycarbonyl) methyleneamino] -1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) in the presence of a base such as diisopropylethylamine in a polar aprotic solvent such as N, N -Diemethylformamid the carboxylic acid of the general formula A-8 with the amine of the general formula A-9, wherein A, R4 and R5 have the meanings described above, to the amide of general formula A-10 implemented. The racemic compounds of general formula A-10 can be separated into the enantiomers by chromatography on a chiral phase.

Die Beispiele 1–13 wurden nach Verfahren A hergestellt.The Examples 1-13 were prepared by Method A.

Die verwendeten Abkürzungen stehen für: Ac Acetyl Bn Benzyl iBu Isobutyl tBu tert-Butyl BuLi n-Butyllithium DC Dünnschichtchromatographie DCI direkte chemische Ionisation (bei MS) DCM Dichlormethan DMAP 4-N,N-Dimethylaminopyridin DMF N,N-Dimethylformamid DMSO Dimethylsulfoxid EE Ethylacetat ent Enantiomer/enantiomerenrein EI Elektronenstoß-Ionisation (bei MS) eq Äquivalent ESI Elektronenspray-Ionisation (bei MS) Et Ethyl HPLC Hochdruck-, Hochleistungsflüssigchromatographie KHMDS Kaliumhexamethyldisilazid LC-MS Flüssigchromatographie-gekoppelte Massenspektroskopie m meta mCPBA meta-Chlorperbenzoesäure Me Methyl MeCN Acetonitril MS Massenspektroskopie NMR Kernresonanzspektroskopie o ortho p para Pd/C Palladium auf Kohle iPr Isopropyl nPr n-Propyl rac racemisch/racemisches Gemisch Rf Retentionszeit (bei DC) RP Reversed Phase TOTU O-[Cyan(ethoxycarbonyl)methylenamino]-1,1,3,3-tetramethyluroniumtetrafluoroborat The abbreviations used stand for: Ac acetyl Bn benzyl Bu isobutyl Bu tert-butyl BuLi n-butyllithium DC TLC DCI direct chemical ionization (in MS) DCM dichloromethane DMAP 4-N, N-dimethylaminopyridine DMF N, N-dimethylformamide DMSO dimethyl sulfoxide EE ethyl acetate ent Enantiomer / enantiomerically EGG Electron impact ionization (in MS) eq equivalent to IT I Electron spray ionization (in MS) et ethyl HPLC High pressure, high performance liquid chromatography KHMDS potassium hexamethyldisilazide LC-MS Liquid chromatography-coupled mass spectroscopy m meta mCPBA meta-chloroperbenzoic me methyl MeCN acetonitrile MS mass spectroscopy NMR Nuclear Magnetic Resonance Spectroscopy O ortho p para Pd / C Palladium on charcoal iPr isopropyl nPr n-propyl rac racemic / racemic mixture Rf Retention time (at DC) RP Reversed phase TOTU O- [cyano (ethoxycarbonyl) methyleneamino] -1,1,3,3-tetramethyluronium tetrafluoroborate

Beispielsynthesen nach Verfahren AExample syntheses according to method A

Beispiel 1example 1

2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-N- thiazol-2-yl-propionamid

Figure 00490001
2- (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -N-thiazol-2-yl-propionamide
Figure 00490001

22.7 g 1-(10-Methyl-10H-phenothiazin-2-yl)-ethanon werden mit 7.08 g Schwefel und 15.57 ml Morpholin versetzt. Das Reaktionsgemisch wird zweieinhalb Stunden bei 150°C gerührt.22.7 g 1- (10-methyl-10H-phenothiazin-2-yl) -ethanone is 7.08 g Sulfur and 15.57 ml morpholine added. The reaction mixture is stirred at 150 ° C for two and a half hours.

Das Reaktionsgemisch wird in einem Eisbad abgekühlt und mit Ethylacetat und Ethanol verrührt. Der ausgefallene Niederschlag wird abgesaugt und das Filtrat im Vakuum eingeengt bis sich erneut ein Niederschlag abscheidet. Dieser wird ebenfalls abgesaugt. Die Niederschläge werden vereinigt und im Vakuum getrocknet. Man erhält 30.2 g 2-(10-Methyl-10H-phenothiazin-2-yl)-1-morpholin-4-yl-ethanthion als orangefarbenen Feststoff. C19H20N2OS2 (356.51), LCMS(ESI): 357.1 (M + H+), Rf(n-Heptan:Ethylacetat = 3:1) = 0.12. (10-Methyl-10H-phenothiazin-2-yl)-essigsäure

Figure 00500001
The reaction mixture is cooled in an ice-bath and stirred with ethyl acetate and ethanol. The precipitate is filtered off with suction and the filtrate is concentrated in vacuo until a precipitate separates again. This is also sucked off. The precipitates are combined and dried in vacuo. 30.2 g of 2- (10-methyl-10H-phenothiazin-2-yl) -1-morpholin-4-yl-ethanthione are obtained as orange solid. C19H20N2OS2 (356.51), LCMS (ESI): 357.1 (M + H + ), Rf (n-heptane: ethyl acetate = 3: 1) = 0.12. (10-methyl-10H-phenothiazine-2-yl) acetic acid
Figure 00500001

30.2 g 2-(10-Methyl-10H-phenothiazin-2-yl)-1-morpholin-4-yl-ethanthion werden in einer Lösung aus 50 ml 50%iger wässriger Kalilauge und 100 ml Ethanol zwölf Stunden unter Rückfluss zum Sieden erhitzt. Das Reaktionsgemisch wird im Eisbad abgekühlt und mit konzentrierter Salzsäure auf pH 3 angesäuert. Anschließend wird das Produkt dreimal mit je 250 ml Ethylacetat extrahiert. Die vereinigten organischen Phasen werden über MgSO4 getrocknet und anschließend im Vakuum eingeengt. Man erhält 18.0 g (10-Methyl-10H-phenothiazin-2-yl)-essigsäure als gelbes Öl.
C15H13NO2S (271.34), LCMS(ESI): 271.95 (M + H+), Rf(n-Heptan:Ethylacetat = 1:1) = 0.26. (10-Methyl-10H-phenothiazin-2-yl)-essigsäureethylester

Figure 00500002
30.2 g of 2- (10-methyl-10H-phenothiazin-2-yl) -1-morpholin-4-yl-ethanthion are refluxed for 12 hours in a solution of 50 ml of 50% aqueous potassium hydroxide solution and 100 ml of ethanol , The reaction mixture is cooled in an ice bath and acidified to pH 3 with concentrated hydrochloric acid. The product is then extracted three times with 250 ml of ethyl acetate each time. The combined organic phases are dried over MgSO 4 and then concentrated in vacuo. This gives 18.0 g of (10-methyl-10H-phenothiazin-2-yl) acetic acid as a yellow oil.
C15H13NO2S (271.34), LCMS (ESI): 271.95 (M + H + ), Rf (n-heptane: ethyl acetate = 1: 1) = 0.26. (10-methyl-10H-phenothiazine-2-yl) -acetic acid ethyl ester
Figure 00500002

18.0 g (10-Methyl-10H-phenothiazin-2-yl)-essigsäure werden in einer Mischung aus 400 ml Toluol und 200 ml Ethanol gelöst und mit 5 ml konzentrierter Schwefelsäure versetzt. Das Reaktionsgemisch wird an einem mit Molsieb gefüllten Wasserabscheider zwölf Stunden unter Rückfluss zum Sieden erhitzt. Danach wird das Reaktionsgemisch im Eisbad abgekühlt und mit 200 ml Wasser versetzt. Die Mischung wird durch Zugabe von festem Natriumkarbonat neutralisiert. Anschließend wird das Produkt fünfmal mit je 250 ml Ethylacetat extrahiert. Die vereinigten organischen Phasen werden über MgSO4 getrocknet und anschließend im Vakuum eingeengt. Der Rückstand wird an Kieselgel mit dem Eluens n-Heptan => n-Heptan:Ethylacetat = 10:1 gereinigt. Man erhält 17.0 g (10-Methyl-10H-phenothiazin-2-yl)-essigsäureethylester als gelbes Öl.
C17H17NO2S (299.39), LCMS(ESI): 300.1 (M + H+), Rf(n-Heptan:Ethylacetat = 3:1) = 0.34. (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-essigsäureethylester

Figure 00510001
18.0 g (10-methyl-10H-phenothiazin-2-yl) -acetic acid are dissolved in a mixture of 400 ml of toluene and 200 ml of ethanol and treated with 5 ml of concentrated sulfuric acid. The reaction mixture is refluxed on a molecular sieve-filled water separator for 12 hours under reflux. Thereafter, the reaction mixture is cooled in an ice bath and treated with 200 ml of water. The mixture is neutralized by adding solid sodium carbonate. The product is then extracted five times with 250 ml of ethyl acetate each time. The combined organic phases are dried over MgSO 4 and then concentrated in vacuo. The residue is purified on silica gel with the eluent n-heptane => n-heptane: ethyl acetate = 10: 1. This gives 17.0 g of (10-methyl-10H-phenothiazin-2-yl) acetic acid ethyl ester as a yellow oil.
C17H17NO2S (299.39), LCMS (ESI): 300.1 (M + H + ), Rf (n-heptane: ethyl acetate = 3: 1) = 0.34. (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -acetic acid ethyl ester
Figure 00510001

17.0 g (10-Methyl-10H-phenothiazin-2-yl)-essigsäureethylester werden in 300 ml Dichlormethan gelöst und portionsweise mit mCPBA versetzt. Das Reaktionsgemisch wird eine Stunde bei Raumtemperatur gerührt. Danach wird das Reaktionsgemisch mit 100 ml ges. NaHCO3-Lösung, 5× mit je 100 ml 2 M NaOH und einmal mit 100 ml ges. NaCl-Lösung gewaschen, über MgSO4 getrocknet und anschließend das Lösungsmittel im Vakuum entfernt. Man erhält 6.7 g (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-essigsäureethylester als gelbes Öl, welches beim Stehenlassen langsam durchkristallisiert.
C17H17NO4S (331.39), LCMS(ESI): 332.1 (M + H+), Rf(n-Heptan:EE = 1:1) = 0.49. 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäureethylester

Figure 00510002
17.0 g of (10-methyl-10H-phenothiazin-2-yl) -acetic acid ethyl ester are dissolved in 300 ml of dichloromethane and mixed in portions with mCPBA. The reaction mixture is stirred for one hour at room temperature. Thereafter, the reaction mixture with 100 ml of sat. NaHCO 3 solution, 5 times with 100 ml of 2 M NaOH and once with 100 ml of sat. NaCl solution, dried over MgSO 4 and then the solvent removed in vacuo. This gives 6.7 g (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -acetic acid ethyl ester as a yellow oil, which crystallizes slowly on standing.
C17H17NO4S (331.39), LCMS (ESI): 332.1 (M + H + ), Rf (n-heptane: EE = 1: 1) = 0.49. 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-pyran-4-yl) -propionic acid ethyl ester
Figure 00510002

1.66 ml 1,1,1,3,3,3-Hexamethyldisilazan werden in 20 ml Tetrahydrofuran unter Argon gelöst. Unter Eiskühlung werden 2.90 ml n-Buthyllithium (2.5 M in n-Hexan) zugetropft und 30 Minuten bei 0°C nachgerührt. Anschließend wird diese Lösung zu einer gerührten Lösung von 2.0 g (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-essigsäureethylester in 100 ml Tetrahydrofuran bei –78°C zugetropft. Das Reaktionsgemisch wird 20 Minuten bei –78°C gerührt, dann werden 2.0 g 4-(Iodomethyl)tetrahydro-2H-pyran zugetropft. Das Kühlbad wird entfernt und man lässt langsam auf Raumtemperatur erwärmen. Der Reaktionsansatz wird über Nacht bei Raumtemperatur gerührt. Dann werden 10 ml Wasser zugegeben, das Tetrahydrofuran im Vakuum entfernt und der Rückstand dreimal mit je 100 ml Ethylacetat extrahiert. Die vereinigten organischen Phasen werden über MgSO4 getrocknet und anschließend im Vakuum eingeengt. Der Rückstand wird an Kieselgel mit dem Eluens n- Heptan:Ethylacetat (100%:0%) => n-Heptan:Ethylacetat (0%:100%) gereinigt. Man erhält 2.0 g 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäureethylester als farblosen Feststoff.
C23H27NO5S (429.54), LCMS(ESI): 430.2 (M + H+). 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäure

Figure 00520001
1.66 ml of 1,1,1,3,3,3-hexamethyldisilazane are dissolved in 20 ml of tetrahydrofuran under argon. Under ice-cooling, 2.90 ml of n-butyllithium (2.5 M in n-hexane) are added dropwise and stirred at 0 ° C for 30 minutes. Subsequently, this solution is added dropwise to a stirred solution of 2.0 g (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -acetic acid ethyl ester in 100 ml of tetrahydrofuran at -78 ° C. The reaction mixture is stirred for 20 minutes at -78 ° C, then 2.0 g of 4- (iodomethyl) tetrahydro-2H-pyran are added dropwise. The cooling bath is removed and allowed to warm slowly to room temperature. The reaction mixture is stirred overnight at room temperature. Then 10 ml of water are added, the tetrahydrofuran is removed in vacuo and the residue is extracted three times with 100 ml of ethyl acetate. The combined organic phases are dried over MgSO 4 and then concentrated in vacuo. The residue is purified on silica gel with the eluent n-heptane: ethyl acetate (100%: 0%) => n-heptane: ethyl acetate (0%: 100%). This gives 2.0 g of 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -propionic acid ethyl ester as a colorless solid.
C23H27NO5S (429.54), LCMS (ESI): 430.2 (M + H + ). 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-pyran-4-yl) propionic acid
Figure 00520001

2.0 g 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäureethylester werden in 100 ml Methanol suspendiert und mit 32.1 ml 2 M NaOH Lösung versetzt. Das Reaktionsgemisch wird eine Stunde bei 80°C gerührt. Das Methanol wird im Vakuum entfernt und das Reaktionsgemisch durch Zugabe konzentrierter Salzsäure auf pH 4 eingestellt. Man extrahiert dreimal mit je 100 ml Ethylacetat. Die vereinigten organischen Phasen werden über MgSO4 getrocknet und anschließend im Vakuum eingeengt. Man erhält 1.85 g 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäure als Feststoff.
C21H23NO5S (401.49), LCMS(ESI): 402.2 (M + H+). 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-N-thiazol-2-yl-propionamid

Figure 00520002
2.0 g of 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -propionic acid ethyl ester are suspended in 100 ml of methanol and washed with 32.1 ml of 2 M NaOH solution. The reaction mixture is stirred for one hour at 80.degree. The methanol is removed in vacuo and the reaction mixture is adjusted to pH 4 by addition of concentrated hydrochloric acid. It is extracted three times with 100 ml of ethyl acetate each time. The combined organic phases are dried over MgSO 4 and then concentrated in vacuo. This gives 1.85 g of 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -propionic acid as a solid.
C21H23NO5S (401.49), LCMS (ESI): 402.2 (M + H + ). 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-pyran-4-yl) -N-thiazol-2-yl-propionamide
Figure 00520002

200 mg 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäure, 74.8 mg kommerziell erhältliches 2-Amino-thiazol und 220 μl N,N-Diisopropylethylamin werden in 10 ml Dimethylformamid gelöst. Man gibt 212 mg TOTU hinzu und rührt bei Raumtemperatur über Nacht. Danach wird das Reaktionsgemisch durch Zugabe von 50 ml Ethylacetat verdünnt und fünfmal mit je 30 ml gesättigter Natriumhydrogencarbonatlösung gewaschen. Die organische Phase wird über MgSO4 getrocknet und anschließend das Lösungsmittel im Vakuum entfernt. Der Rückstand wird mittels RP-HPLC gereinigt. Man erhält 141 mg 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-N-thiazol-2-yl-propionamid als farbloses Lyophilisat.
C24H25N3O4S2 (483.61), LCMS(ESI): 484.1 (M + H+).200 mg of 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -propionic acid, 74.8 mg of commercially available 2-amino thiazole and 220 .mu.l of N, N-diisopropylethylamine are dissolved in 10 ml of dimethylformamide. Add 212 mg TOTU and stir at room temperature overnight. Thereafter, the reaction mixture is diluted by addition of 50 ml of ethyl acetate and washed five times with 30 ml of saturated sodium bicarbonate solution. The organic phase is dried over MgSO 4 and then Finally, the solvent is removed in vacuo. The residue is purified by RP-HPLC. 141 mg of 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -N-thiazol-2-yl are obtained. propionamide as a colorless lyophilisate.
C24H25N3O4S2 (483.61), LCMS (ESI): 484.1 (M + H + ).

Beispiel 2Example 2

2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-(5-methyl-thiazol-2-yl)-3-(tetrahydro-pyran-4-yl)-propionamide

Figure 00530001
2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -N- (5-methyl-thiazol-2-yl) -3- (tetrahydro-pyran-4-yl ) -propionamide
Figure 00530001

Analog zu Beispiel 1 erhält man aus 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäure und kommerziell erhältlichem 2-Amino-5-methyl-thiazol 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-(5-methyl-thiazol-2-yl)-3-(tetrahydro-pyran-4-yl)-propionamide.
C25H27N3O4S2 (497.64), LCMS(ESI): 498.1 (M + H+).Analogously to Example 1, 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -propionic acid and commercially available 2 are obtained -Amino-5-methyl-thiazole 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -N- (5-methylthiazol-2-yl) -3- (tetrahydro-pyran-4-yl) -propionamide.
C25H27N3O4S2 (497.64), LCMS (ESI): 498.1 (M + H + ).

Beispiel 3Example 3

N-(5-Chloro-thiazol-2-yl)-2-(10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionamide

Figure 00530002
N- (5-Chloro-thiazol-2-yl) -2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-pyran-4-yl ) -propionamide
Figure 00530002

Analog zu Beispiel 1 erhält man aus 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäure und kommerziell erhältlichem 2-Amino-5-chloro-thiazol Hydrochlorid N-(5-Chloro-thiazol-2-yl)-2-(10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionamide.
C24H24ClN3O4S2 (518.06), LCMS(ESI): 518.1 (M + H+).Analogously to Example 1, 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -propionic acid and commercially available 2 are obtained -Amino-5-chloro-thiazole hydrochloride N- (5-chloro-thiazol-2-yl) -2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3 - (tetrahydro-pyran-4-yl) -propionamide.
C24H24ClN3O4S2 (518.06), LCMS (ESI): 518.1 (M + H + ).

Beispiel 4Example 4

2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-3-(tetrahydro-pyran-4-yl)-propionamide

Figure 00540001
2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -N- (3-methyl- [1,2,4] thiadiazol-5-yl) -3- ( tetrahydro-pyran-4-yl) -propionamide
Figure 00540001

Analog zu Beispiel 1 erhält man aus 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäure und kommerziell erhältlichem 3-Methyl-[1,2,4]thiadiazol-5-ylamin 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-3-(tetrahydro-pyran-4-yl)-propionamide.
C24H26N4O4S2 (498.63), LCMS(ESI): 499.2 (M + H+).Analogously to Example 1, 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydropyran-4-yl) -propionic acid and commercially available 3 are obtained -Methyl [1,2,4] thiadiazol-5-ylamine 2- (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -N- (3-methyl- [1 , 2,4] thiadiazol-5-yl) -3- (tetrahydro-pyran-4-yl) -propionamide.
C24H26N4O4S2 (498.63), LCMS (ESI): 499.2 (M + H + ).

Beispiel 5Example 5

2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-pyran-4-yl)-propionamide

Figure 00540002
2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -N- (1-methyl-1H-pyrazol-3-yl) -3- (tetrahydro-pyran-4 yl) -propionamide
Figure 00540002

Analog zu Beispiel 1 erhält man aus 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäure und kommerziell erhältlichem 1-Methyl-1H-pyrazol-3-amin 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-pyran-4-yl)-propionamide.
C25H28N4O4S (480.59), LCMS(ESI): 481.2 (M + H+).Analogously to Example 1, 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -propionic acid and commercially available 1 are obtained -Methyl-1H-pyrazol-3-amine 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -N- (1-methyl-1H-pyrazol-3-yl ) -3- (tetrahydro-pyran-4-yl) -propionamide.
C25H28N4O4S (480.59), LCMS (ESI): 481.2 (M + H + ).

Beispiel 6Example 6

2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-(6-methyl-pyridazin-3-yl)-3-(tetrahydro-pyran-4-yl)-propionamide

Figure 00540003
2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -N- (6-methyl-pyridazin-3-yl) -3- (tetrahydro-pyran-4-yl ) -propionamide
Figure 00540003

Analog zu Beispiel 1 erhält man aus 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäure und kommerziell erhältlichem 6-Methyl-3- pyridazinamin 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-(6-meth-pyridazin-3-yl)-3-(tetrahydro-pyran-4-yl)-propionamide.
C26H28N4O4S (492.60), LCMS(ESI): 493.2 (M + H+).Analogously to Example 1, 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydropyran-4-yl) -propionic acid and commercially available 6 are obtained -Methyl-3-pyridazinamine 2- (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -N- (6-meth-pyridazin-3-yl) -3- (tetrahydro -pyran-4-yl) -propionamide.
C26H28N4O4S (492.60), LCMS (ESI): 493.2 (M + H + ).

Beispiel 7Example 7

2-[2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionylamino]-thiazole-4-carbonsäureethylester

Figure 00550001
2- [2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-pyran-4-yl) propionylamino] -thiazoles-4-carboxylic acid ethyl ester
Figure 00550001

Analog zu Beispiel 1 erhält man aus 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäure und kommerziell erhältlichem 2-Aminothiazole-4-carbonsäureethylester 2-[2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionylamino]-thiazole-4-carbonsäureethylester.
C27H29N3O6S2 (555.68), LCMS(ESI): 597.20 (M + MeCN + H+).Analogously to Example 1, 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -propionic acid and commercially available 2 are obtained -Aminothiazole-4-carboxylic Acid Ethyl Ester 2- [2- (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -propionylamino] - thiazole-4-carboxylic acid ethyl ester.
C27H29N3O6S2 (555.68), LCMS (ESI): 597.20 (M + MeCN + H + ).

Beispiel 8Example 8

{2-[2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionylamino]-thiazol-4-yl}-essigsäureethylester

Figure 00550002
{2- [2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-pyran-4-yl) -propionylamino] -thiazol-4-yl } acetic acid ethyl ester
Figure 00550002

Analog zu Beispiel 1 erhält man aus 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionsäure und kommerziell erhältlichem 2-Aminothiazol-4-essigsäureethylester {2-[2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionylamino]-thiazol-4-yl}-essigsäureethylester.
C28H31N3O6S2 (569.70), LCMS(ESI): 570.20 (M + H+).Analogously to Example 1, 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydro-pyran-4-yl) -propionic acid and commercially available 2 are obtained -Aminothiazole-4-acetic Acid Ethyl Ester {2- [2- (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydropyran-4-yl) -propionylamino] -thiazol-4-yl} -acetic acid ethyl ester.
C28H31N3O6S2 (569.70), LCMS (ESI): 570.20 (M + H + ).

Beispiel 9Example 9

3-Cyclopentyl-2-(10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-thiazol-2-yl-propionamid

Figure 00560001
3-cyclopentyl-2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -N-thiazol-2-yl-propionamide
Figure 00560001

Analog zu Beispiel 1 erhält man aus (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-essigsäureethylester, kommerziell erhältlichem Iodmethyl-cyclopentan und, kommerziell erhältlichem 2-Amino-thiazol 3-Cyclopentyl-2-(10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-thiazol-2-yl-propionamid.
C24H25N3O3S2 (467.61), LCMS(ESI): 468.2 (M + H+), 509.3 (M + MeCN + H+)Analogously to Example 1 is obtained from (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) acetic acid ethyl ester, commercially available iodomethyl-cyclopentane and, commercially available 2-amino-thiazole 3-cyclopentyl -2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -N-thiazol-2-yl-propionamide.
C24H25N3O3S2 (467.61), LCMS (ESI): 468.2 (M + H + ), 509.3 (M + MeCN + H + )

Beispiel 10Example 10

{2-[2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionylamino]-thiazol-4-yl}-essigsäure

Figure 00560002
{2- [2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-pyran-4-yl) -propionylamino] -thiazol-4-yl }-acetic acid
Figure 00560002

Zu einer Suspension aus 25.0 mg {2-[2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydropyran-4-yl)-propionylamino]-thiazol-4-yl}-essigsäureethylester in 5 ml Tetrahydrofuran und 2 ml Wasser wird bei Raumtemperatur unter Rühren 0.25 ml 2 M NaOH gegeben und 12 Stunden bei Raumtemperatur gerührt. Dann wird das Reaktionsgemisch durch Zugabe von 1 M HCl neutralisiert. Die Lösungsmittel werden im Vakuum entfernt, der Rückstand in 20 ml Ethylacetat aufgenommen und dreimal mit je 10 ml Wasser gewaschen. Die organische Phase wird mit MgSO4 getrocknet und im Vakuum eingeengt. Der Rückstand wird mittels RP-HPLC gereinigt. Man erhält 22.5 mg {2-[2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydropyran-4-yl)-propionylamino]-thiazol-4-yl}-essigsäure als Lyophilisat.
C26H27N3O6S2 (541.65), LCMS(ESI): 542.2 (M + H+).To a suspension of 25.0 mg of {2- [2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydropyran-4-yl) -propionylamino] -thiazole -4-yl} -acetic acid ethyl ester in 5 ml of tetrahydrofuran and 2 ml of water is added at room temperature with stirring 0.25 ml of 2 M NaOH and stirred for 12 hours at room temperature. Then the reaction mixture is neutralized by addition of 1 M HCl. The solvents are removed in vacuo, the residue taken up in 20 ml of ethyl acetate and washed three times with 10 ml of water. The organic phase is dried with MgSO 4 and concentrated in vacuo. The residue is purified by RP-HPLC. This gives 22.5 mg of {2- [2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydropyran-4-yl) -propionylamino] -thiazole-4 -yl} -acetic acid as a lyophilisate.
C26H27N3O6S2 (541.65), LCMS (ESI): 542.2 (M + H + ).

Beispiel 11Example 11

2-[2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionylamino]-thiazole-4-carbonsäure

Figure 00570001
2- [2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-pyran-4-yl) propionylamino] -thiazoles-4-carboxylic acid
Figure 00570001

Analog zu Beispiel 10 erhält man aus 2-[2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydropyran-4-yl)-propionylamino]-thiazole-4-carbonsäureethylester 2-[2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydropyran-4-yl)-propionylamino]-thiazole-4-carbonsäure.
C25H25N3O6S2 (527.62), LCMS(ESI): 528.2 (M + H+), 569.2 (M + MeCN + H+),Analogously to Example 10, 2- [2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydropyran-4-yl) -propionylamino] thiazoles are obtained Ethyl 4-carboxylate 2- [2- (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -3- (tetrahydropyran-4-yl) -propionylamino] -thiazole-4- carboxylic acid.
C25H25N3O6S2 (527.62), LCMS (ESI): 528.2 (M + H + ), 569.2 (M + MeCN + H + ),

Beispiel 12Example 12

2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-furan-3-yl)-propionamid

Figure 00570002
2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -N- (1-methyl-1H-pyrazol-3-yl) -3- (tetrahydro-furan-3 yl) propionamide
Figure 00570002

Analog zu Beispiel 1 erhält man aus (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-essigsäureethylester, kommerziell erhältlichem 3-Iodmethyl-tetrahydrofuran und kommerziell erhältlichem 1-Methyl-1H-pyrazol-3-amin 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-furan-3-yl)-propionamid.
C24H26N4O4S (466.56), LCMS(ESI): 467.2 (M + H+).Analogously to Example 1 is obtained from (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) acetic acid ethyl ester, commercially available 3-iodomethyl-tetrahydrofuran and commercially available 1-methyl-1H-pyrazole 3-Amine 2- (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -N- (1-methyl-1H-pyrazol-3-yl) -3- (tetrahydro furan-3-yl) -propionamide.
C24H26N4O4S (466.56), LCMS (ESI): 467.2 (M + H + ).

Beispiel 13Example 13

2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-furan-3-yl)-N-thiazol-2-yl-propionamid

Figure 00570003
2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-furan-3-yl) -N-thiazol-2-yl-propionamide
Figure 00570003

Analog zu Beispiel 1 erhält man aus (10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-essigsäureethylester, kommerziell erhältlichem 3-Iodmethyl-tetrahydrofuran und kommerziell erhältlichem 2-Amino-thiazol 2-(10-Methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl)-3-(tetrahydro-furan-3-yl)-N-thiazol-2-yl-propionamid.
C23H23N3O4S2 (469.59), LCMS(ESI): 470.1 (M + H+).Analogously to Example 1, ethyl (10-methyl-5,5-dioxo-5,10-dihydro-2-phenothiazin-2-yl) acetate, commercially available 3-iodomethyl-tetrahydrofuran and commercially available 2-amino-thiazole 2 are obtained. (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-furan-3-yl) -N-thiazol-2-yl-propionamide.
C23H23N3O4S2 (469.59), LCMS (ESI): 470.1 (M + H + ).

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Claims (17)

Verbindungen der Formel I,
Figure 00590001
worin bedeuten R1 H, (C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, CO-(C1-C6)-Alkyl, (C2-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C2-C6)-Alkylen-O-(C1-C6)-Alkyl; R2, R3 unabhängig voneinander H, F, Cl, Br, CN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Phenyl, SCF3, SF5, SCH3; R4, R5 unabhängig voneinander H, F, Cl, Br, CN, SCN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, -CO-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-CONH(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-NH(C0-C6)-Alkyl, (C0-C6)-Alkylen-NH-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-N[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-Aryl, SF5, (C0-C6)-Alkyl-S(O)x(C1-C6)-Alkyl, S(O)x(C1-C6)-Alkylen-COO-(C0-C6)-Alkyl, S(O)x(C2-C6)-Alkylen-O-(C0-C6)-Alkyl, -SO2-NH-(C0-C6)-Alkyl, -SO2-N-[(C0-C6)-Alkyl]2, S(O)x(C0-C0)-Alkylen-Heterocyclus, S(O)x(C1-C6)-Alkylen-CO-Heterocyclus, -NH-SO2-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Cycloalkyl, (C0-C6)-Alkylen-Heterocyclus, (C0-C6)-Alkylen-Aryl; x 0, 1, 2; R6, R7 unabhängig voneinander H, F, Cl, Br, CN, NO2, =O, =S, =N-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-CO-(C1-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, SF5, S(O)x-(C1-C0)-Alkyl; A 5 bis 10 gliedriger Heterocyclus, wobei der Heterocyclus mit einem weiteren 5 bis 10 gliedrigen Ring anneliert sein kann; B 4 bis 8 gliedriger Cycloalkylring, ein 4 bis 10 gliedriger Heterocyclus oder ein 6 bis 10 gliedriger Arylring; sowie deren physiologisch verträgliche Salze.Compounds of the formula I,
Figure 00590001
wherein R 1 is H, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, CO- (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-COO - (C 0 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-O- (C 1 -C 6 ) -alkyl; R 2 , R 3 independently of one another are H, F, Cl, Br, CN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene O- (C 0 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -Alkylene-phenyl, SCF 3 , SF 5 , SCH 3 ; R4, R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, -CO-COO- (C 0 -C 6 ) alkyl, (C 0 -C 6 ) alkylene-O- (C 0 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CONH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -Alkyl] 2 , (C 0 -C 6 ) -alkylene-NH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-NH-COO- (C 0 -C 6 ) -alkyl , (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -alkyl] -O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-N [(C C 1 -C 6 ) -alkyl] 2 , (C 0 -C 6 ) -alkylene-aryl, SF 5 , (C 0 -C 6 ) -alkyl-S (O) x (C 1 -C 6 ) -alkyl, S (O) x (C 1 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, S (O) x (C 2 -C 6 ) -alkylene-O- (C 0 -C 6 ) -Alkyl, -SO 2 -NH- (C 0 -C 6 ) -alkyl, -SO 2 -N - [(C 0 -C 6 ) -alkyl] 2 , S (O) x (C 0 -C 0 ) -Alkylene heterocycle, S (O) x (C 1 -C 6 ) -alkylene-CO-heterocycle, -NH-SO 2 - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene -Cycloalkyl, (C 0 -C 6 ) -alkylene heterocycle, (C 0 -C 6 ) -alkylene-aryl; x 0, 1, 2; R6, R7 are independently H, F, Cl, Br, CN, NO 2, = O, = S, = NO- (C 0 -C 6) -alkyl, (C 0 -C 6) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O-CO- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, SF 5 , S (O) x - (C 1 -C 0 ) -alkyl; A is 5 to 10 membered heterocycle, which heterocycle may be fused to another 5 to 10 membered ring; B is 4 to 8 membered cycloalkyl ring, a 4 to 10 membered heterocycle or a 6 to 10 membered aryl ring; and their physiologically acceptable salts. Verbindungen der Formel I, gemäß Anspruch 1, dadurch gekennzeichnet, dass darin bedeuten R1 H, (C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, CO-(C1-C6)-Alkyl, (C2-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C2-C6)-Alkylen-O-(C1-C6)-Alkyl; R2, R3 unabhängig voneinander H, F, Cl, Br, CN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C0)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Phenyl, SCF3, SF5, SCH3; R4, R5 unabhängig voneinander H, F, Cl, Br, CN, SCN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, -CO-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-CONH(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-NH(C0-C6)-Alkyl, (C0-C6)-Alkylen-NH-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-N[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-Aryl, SF5, (C0-C6)-Alkyl-S(O)x(C1-C6)-Alkyl, S(O)x(C1-C6)-Alkylen-COO-(C0-C6)-Alkyl, S(O)x(C2-C6)-Alkylen-O-(C0-C6)-Alkyl, -SO2-NH-(C0-C6)-Alkyl, -SO2-N-[(C0-C6)-Alkyl]2, S(O)x(C0-C6)-Alkylen-Heterocyclus, S(O)x(C1-C6)-Alkylen-CO-Heterocyclus, -NH-SO2-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Cycloalkyl, (C0-C6)-Alkylen-Heterocyclus, (C0-C6)-Alkylen-Aryl; x 0, 1, 2; R6, R7 unabhängig voneinander H, F, Cl, Br, CN, NO2, =O, =S, =N-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-CO-(C1-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, SF5, S(O)x-(C1-C6)-Alkyl; A 5 bis 10 gliedriger Heterocyclus, der in alpha Stellung eine -C=N- Bindung enthält, wobei der Heterocyclus mit einem weiteren 5 bis 10 gliedrigen Ring anneliert sein kann; B 4 bis 8 gliedriger Cycloalkylring, ein 4 bis 10 gliedriger Heterocyclus oder ein 6 bis 10 gliedriger Arylring; sowie deren physiologisch verträgliche Salze.Compounds of the formula I according to Claim 1, characterized in that R1 is H, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, CO- (C 1 -C 6 ) - Alkyl, (C 2 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-O- (C 1 -C 6 ) -alkyl; R 2 , R 3 independently of one another are H, F, Cl, Br, CN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene O- (C 0 -C 6 ) -alkyl, (C 1 -C 0 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -Alkylene-phenyl, SCF 3 , SF 5 , SCH 3 ; R4, R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, -CO-COO- (C 0 -C 6 ) alkyl, (C 0 -C 6 ) alkylene-O- (C 0 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CONH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -Alkyl] 2 , (C 0 -C 6 ) -alkylene-NH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-NH-COO- (C 0 -C 6 ) -alkyl , (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -alkyl] -O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-N [(C C 1 -C 6 ) -alkyl] 2 , (C 0 -C 6 ) -alkylene-aryl, SF 5 , (C 0 -C 6 ) -alkyl-S (O) x (C 1 -C 6 ) -alkyl, S (O) x (C 1 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, S (O) x (C 2 -C 6 ) -alkylene-O- (C 0 -C 6 ) -Alkyl, -SO 2 -NH- (C 0 -C 6 ) -alkyl, -SO 2 -N - [(C 0 -C 6 ) -alkyl] 2 , S (O) x (C 0 -C 6 ) -Alkylene heterocycle, S (O) x (C 1 -C 6 ) alkylene-CO heterocycle, -NH-SO 2 - (C 1 -C 6 ) alkyl, (C 0 -C 6 ) -Al kylene-cycloalkyl, (C 0 -C 6 ) -alkylene heterocycle, (C 0 -C 6 ) -alkylene-aryl; x 0, 1, 2; R6, R7 are independently H, F, Cl, Br, CN, NO 2, = O, = S, = NO- (C 0 -C 6) -alkyl, (C 0 -C 6) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O-CO- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, SF 5 , S (O) x - (C 1 -C 6 ) alkyl; A 5 to 10-membered heterocycle which contains a -C = N bond in the alpha position, where the heterocycle may be fused to another 5 to 10 membered ring; B is 4 to 8 membered cycloalkyl ring, a 4 to 10 membered heterocycle or a 6 to 10 membered aryl ring; and their physiologically acceptable salts. Verbindungen der Formel I, gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, dass darin bedeuten R1 H, (C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, CO-(C1-C6)-Alkyl, (C2-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C2-C6)-Alkylen-O-(C1-C6)-Alkyl; R2, R3 H; R4, R5 unabhängig voneinander H, F, Cl, Br, CN, SCN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, -CO-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-CONH(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-NH(C0-C6)-Alkyl, (C0-C6)-Alkylen-NH-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-N[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-Aryl, SF5, (C0-C6)-Alkyl-S(O)x(C1-C6)-Alkyl, S(O)x(C1-C6)-Alkylen-COO-(C0-C6)-Alkyl, S(O)x(C2-C6)-Alkylen-O-(C0-C6)-Alkyl, -SO2-NH-(C0-C6)-Alkyl, -SO2-N-[(C0-C6)-Alkyl]2, S(O)x(C0-C6)-Alkylen-Heterocyclus, S(O)x(C1-C0)-Alkylen-CO-Heterocyclus, -NH-SO2-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Cycloalkyl, (C0-C6)-Alkylen-Heterocyclus, (C0-C6)-Alkylen-Aryl; x 0, 1, 2; R6, R7 unabhängig voneinander H, F, Cl, Br, CN, NO2, =O, =S, =N-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-CO-(C1-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, SF5, S(O)x-(C1-C6)-Alkyl; A ein 5 gliedriger Heterocyclus, der in alpha Stellung eine -C=N- Bindung enthält, wobei der Heterocyclus mit einem weiteren 5 bis 10 gliedrigen Ring anneliert sein kann; B 4 bis 8 gliedriger Cycloalkyiring, ein 4 bis 10 gliedriger Heterocyclus oder ein 6 bis 10 gliedriger Arylring; sowie deren physiologisch verträgliche Salze.Compounds of formula I, according to claim 1 or 2, characterized in that R1 is H, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, CO- (C 1 -C 6 ) -Alkyl, (C 2 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-O- (C 1 -C 6 ) -alkyl; R2, R3 H; R4, R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, -CO-COO- (C 0 -C 6 ) alkyl, (C 0 -C 6 ) alkylene-O- (C 0 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CONH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -Alkyl] 2 , (C 0 -C 6 ) -alkylene-NH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-NH-COO- (C 0 -C 6 ) -alkyl , (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -alkyl] -O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-N [(C C 1 -C 6 ) -alkyl] 2 , (C 0 -C 6 ) -alkylene-aryl, SF 5 , (C 0 -C 6 ) -alkyl-S (O) x (C 1 -C 6 ) -alkyl, S (O) x (C 1 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, S (O) x (C 2 -C 6 ) -alkylene-O- (C 0 -C 6 ) -Alkyl, -SO 2 -NH- (C 0 -C 6 ) -alkyl, -SO 2 -N - [(C 0 -C 6 ) -alkyl] 2 , S (O) x (C 0 -C 6 ) -Alkylene heterocycle, S (O) x (C 1 -C 0 ) -alkylene-CO-heterocycle, -NH-SO 2 - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene -Cycloalkyl, (C 0 -C 6 ) -alkylene heterocycle, (C 0 -C 6 ) -alkylene-aryl; x 0, 1, 2; R6, R7 are independently H, F, Cl, Br, CN, NO 2, = O, = S, = NO- (C 0 -C 6) -alkyl, (C 0 -C 6) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O-CO- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, SF 5 , S (O) x - (C 1 -C 6 ) alkyl; A is a 5-membered heterocycle which contains a -C = N bond in the alpha position, where the heterocycle may be fused to another 5 to 10 membered ring; B is 4 to 8 membered cycloalkyl ring, a 4 to 10 membered heterocycle or a 6 to 10 membered aryl ring; and their physiologically acceptable salts. Verbindungen der Formel I, gemäß einem oder mehreren der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass darin bedeuten R1 H, (C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, CO-(C1-C6)-Alkyl, (C2-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C2-C6)-Alkylen-O-(C1-C6)-Alkyl; R2, R3 H; R4, R5 unabhängig voneinander H, F, Cl, Br, CN, SCN, NO2, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, -CO-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C1-C0)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-CONH(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-NH(C0-C6)-Alkyl, (C0-C6)-Alkylen-NH-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-CON[(C0-C6)-Alkyl]-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-N[(C0-C6)-Alkyl]2, (C0-C6)-Alkylen-Aryl, SF5, (C0-C6)-Alkyl-S(O)x(C1-C6)-Alkyl, S(O)x(C1-C6)-Alkylen-COO-(C0-C6)-Alkyl, S(O)x(C2-C6)-Alkylen-O-(C0-C6)-Alkyl, -SO2-NH-(C0-C6)-Alkyl, -SO2-N-[(C0-C6)-Alkyl]2, S(O)x(C0-C6)-Alkylen-Heterocyclus, S(O)x(C1-C6)-Alkylen-CO-Heterocyclus, -NH-SO2-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Cycloalkyl, (C0-C6)-Alkylen-Heterocyclus, (C0-C6)-Alkylen-Aryl; x 0, 1, 2; R6, R7 unabhängig voneinander H, F, Cl, Br, CN, NO2, =O, =S, =N-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-COO-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-(C0-C6)-Alkyl, (C0-C6)-Alkylen-O-CO-(C1-C6)-Alkyl, (C1-C6)-Alkyl, (C0-C6)-Alkylen-CO-(C1-C6)-Alkyl, (C0-C6)-Alkylen-Aryl, SF5, S(O)x-(C1-C6)-Alkyl; A Thiazol-2-yl, Pyrazol-3-yl, Pyridin-2-yl, Oxazol-2-yl, Isoxazol-3-yl, Imidazol-2-yl, [1,2,4]Thiadiazol-3-yl, [1,2,4]Thiadiazol-5-yl, [1,3,4]Thiadiazol-3-yl, Pyridin-2-yl, Pyrimidin-2-yl, Pyrimidin-4-yl, Pyrazin-2-yl, Pyridazin-2-yl, [1,2,4]Triazin-3-yl, [1,2,4]Triazin-6-yl, Thiazolo[4,5-b]pyridin-2-yl, Thieno[2,3-d]thiazol-2-yl, Benzothiazol-2-yl, Benzooxazol-2-yl, Benzimidazol- 2-yl, Chinolin-2-yl, Isochinolin-3-yl, 4,5,6,7-Tetrahydro-benzothiazol-2-yl, 4,5,6,7-Tetrahydro-benzooxazol-2-yl, 4,5,6,7-Tetrahydro-benzoimidazol-2-yl, 4,5,6,7-Tetrahydro-pyrazolo[1,5-a]pyridin-2-yl, 5,6-Dihydro-4H-cyclopentathiazol-2-yl, 4,5-Dihydro-thiazol-2-yl; B Cyclopentyl, Cyclohexyl, Tetrahydrofuranyl, Tetrahydropyranyl, Tetrahydrothiopyranyl, Piperidinyl, Phenyl, Pyridyl, Furanyl, Thiophenyl, Thiazolyl, Oxazolyl, Pyrazolyl, Isoxazolyl; sowie deren physiologisch verträgliche Salze.Compounds of formula I, according to one or more of claims 1 to 3, characterized in that R1 is H, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, CO- (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, (C 2 -C 6 ) -alkylene-O- (C 1 -C 6 ) - alkyl; R2, R3 H; R4, R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, -CO-COO- (C 0 -C 6 ) alkyl, (C 0 -C 6 ) alkylene-O- (C 0 -C 6 ) -alkyl, (C 1 -C 0 ) -alkyl, (C 0 -C 6 ) -alkylene-CO - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CONH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -Alkyl] 2 , (C 0 -C 6 ) -alkylene-NH (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-NH-COO- (C 0 -C 6 ) -alkyl , (C 0 -C 6 ) -alkylene-CON [(C 0 -C 6 ) -alkyl] -O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-N [(C C 1 -C 6 ) -alkyl] 2 , (C 0 -C 6 ) -alkylene-aryl, SF 5 , (C 0 -C 6 ) -alkyl-S (O) x (C 1 -C 6 ) -alkyl, S (O) x (C 1 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -alkyl, S (O) x (C 2 -C 6 ) -alkylene-O- (C 0 -C 6 ) -Alkyl, -SO 2 -NH- (C 0 -C 6 ) -alkyl, -SO 2 -N - [(C 0 -C 6 ) -alkyl] 2 , S (O) x (C 0 -C 6 ) -Alkylene heterocycle, S (O) x (C 1 -C 6 ) -alkylene-CO-heterocycle, -NH-SO 2 - (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene -Cycloalkyl, (C 0 -C 6 ) -alkylene heterocycle, (C 0 -C 6 ) -alkylene-aryl; x 0, 1, 2; R6, R7 are independently H, F, Cl, Br, CN, NO 2, = O, = S, = NO- (C 0 -C 6) -alkyl, (C 0 -C 6) -alkylene-COO- ( C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O- (C 0 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-O-CO- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-CO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -alkylene-aryl, SF 5 , S (O) x - (C 1 -C 6 ) alkyl; A thiazol-2-yl, pyrazol-3-yl, pyridin-2-yl, oxazol-2-yl, isoxazol-3-yl, imidazol-2-yl, [1,2,4] thiadiazol-3-yl, [1,2,4] thiadiazol-5-yl, [1,3,4] thiadiazol-3-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazine-2-yl, Pyridazin-2-yl, [1,2,4] triazin-3-yl, [1,2,4] triazin-6-yl, thiazolo [4,5-b] pyridin-2-yl, thieno [2, 3-d] thiazol-2-yl, benzothiazol-2-yl, benzooxazol-2-yl, benzimidazol-2-yl, quinolin-2-yl, isoquinolin-3-yl, 4,5,6,7-tetrahydro benzothiazol-2-yl, 4,5,6,7-tetrahydrobenzooxazol-2-yl, 4,5,6,7-tetrahydro-benzoimidazol-2-yl, 4,5,6,7-tetrahydropyrazolo [ 1,5-a] pyridin-2-yl, 5,6-dihydro-4H-cyclopentathiazol-2-yl, 4,5-dihydro-thiazol-2-yl; B cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, phenyl, pyridyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyrazolyl, isoxazolyl; and their physiologically acceptable salts. Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4, zur Anwendung als Arzneimittel.Compounds according to one or more of claims 1 to 4, for use as a medicament. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4.A medicament containing one or more of the compounds according to one or more of the claims che 1 to 4. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4 und mindestens einen weiteren Wirkstoff.Medicament containing one or more of the compounds according to one or more of the claims 1 to 4 and at least one further active ingredient. Arzneimittel, gemäß Anspruch 7, dadurch gekennzeichnet, dass es als weiteren Wirkstoff eine oder mehrere Antidiabetika, hypoglykämischen Wirkstoffe, HMGCoA-Reduktase Inhibitoren, Cholesterinresorptionsinhibitoren, PPAR gamma Agonisten, PPAR alpha Agonisten, PPAR alpha/gamma Agonisten, PPAR delta Agonisten, Fibrate, MTP-Inhibitoren, Gallensäureresorptionsinhibitoren, MTP-Inhibitoren, CETP-Inhibitoren, polymere Gallensäureadsorber, LDL-Rezeptorinducer, ACAT-Inhibitoren, Antioxidantien, Lipoprotein-Lipase Inhibitoren, ATP-Citrat-Lyase Inhibitoren, Squalen Synthetase Inhibitoren, Lipoprotein(a) Antagonisten, HM74A Rezeptor Agonisten, Lipase Inhibitoren, Insulin, Sulfonylharnstoffe, Biguanide, Meglitinide, Thiazolidindione, α-Glukosidase-Inhibitoren, auf den ATP-abhängigen Kaliumkanal der Betazellen wirkende Wirkstoffe, Glykogen Phosphorylase Inhibitoren, Glukagon-Rezeptor-Antagonisten, Aktivatoren der Glukokinase, Inhibitoren der Glukoneogenese, Inhibitoren der Fructose-1,6-biphosphatase, Modulatoren des Glukosetransporters-4, Inhibitoren der Glutamin-Fructose-6-Phosphat- Amidotransferase, Inhibitoren der Dipeptidylpeptidase-IV, Hemmstoffe der 11-beta-Hydroxysteroid-Dehydrogenase-1, Inhibitoren der Protein-Tyrosin-Phosphatase-1B, Modulatoren des natrium-abhängigen Glukosetransporters 1 oder 2, Modulatoren des GPR40, Inhibitoren der hormon-sensitiven Lipase, Hemmstoffe der Acetyl-CoA Carboxylase, Inhibitoren der Phosphoenolpyruvatcarboxykinase, Inhibitoren der Glykogen Synthase Kinase-3 beta, Inhibitoren der Protein Kinase C beta, Endothelin-A-Rezeptor Antagonisten, Inhibitoren der I kappaB Kinase, Modulatoren des Glukocorticoidrezeptors, CART-Agonisten, NPY-Agonisten, MC4-Agonisten, Orexin-Agonisten, H3-Agonisten, TNF-Agonisten, CRF-Agonisten, CRF BP-Antagonisten, Urocortin-Agonisten, β3-Agonisten,, CB1-Rezeptor Antagonisten, MSH(Melanocyt-stimulierendes Hormon)-Agonisten, CCK-Agonisten, Serotonin-Wiederaufnahme-Inhibitoren, gemischte Sertonin- und noradrenerge Verbindungen, 5HT-Agonisten, Bombesin-Agonisten, Galanin-Antagonisten, Wachstumshormone, Wachstumshormon freisetzende Verbindungen, TRH-Agonisten, entkoppelnde Protein 2- oder 3-Modulatoren, Leptinagonisten, DA-Agonisten (Bromocriptin, Doprexin), Lipase/Amylase-Inhibitoren, PPAR-Modulatoren, RXR-Modulatoren oder TR-β-Agonisten oder Amphetamine enthält.Medicament, according to claim 7, characterized in that it as one further active ingredient one or more Antidiabetics, hypoglycemic agents, HMGCoA reductase Inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha / gamma agonists, PPAR delta agonists, Fibrates, MTP inhibitors, bile acid resorption inhibitors, MTP inhibitors, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein (a) Antagonists, HM74A receptor agonists, lipase inhibitors, insulin, Sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, acting on the ATP-dependent potassium channel of beta cells Active ingredients, glycogen phosphorylase inhibitors, glucagon receptor antagonists, Activators of glucokinase, inhibitors of gluconeogenesis, inhibitors fructose-1,6-biphosphatase, modulators of glucose transporter-4, Inhibitors of glutamine-fructose 6-phosphate amidotransferase, inhibitors dipeptidyl peptidase IV, inhibitors of 11-beta-hydroxysteroid dehydrogenase-1, Inhibitors of protein tyrosine phosphatase-1B, modulators of the sodium-dependent glucose transporter 1 or 2, modulators GPR40, inhibitors of hormone-sensitive lipase, inhibitors acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase, Inhibitors of glycogen synthase kinase-3 beta, inhibitors of Protein kinase C beta, endothelin A receptor antagonists, inhibitors I kappaB kinase, modulators of the glucocorticoid receptor, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptor antagonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed sertonin and noradrenergic compounds, 5HT agonists, bombesin agonists, Galanin antagonists, growth hormones, growth hormone releasing Compounds, TRH agonists, decoupling protein 2 or 3 modulators, Leptin agonists, DA agonists (bromocriptine, doprexine), lipase / amylase inhibitors, PPAR modulators, RXR modulators or TR-β agonists or Contains amphetamines. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4 zur Herstellung eines Medikamentes zur Behandlung des Diabetes.Use of the compounds according to one or more of claims 1 to 4 for producing a Drug for the treatment of diabetes. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprache 1 bis 4 zur Herstellung eines Medikamentes zur Blutzuckersenkung.Use of the compounds according to one or more of the addresses 1 to 4 for the preparation of a medicament for lowering blood sugar. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4 zur Herstellung eines Medikamentes zur Behandlung des metabolischen Syndroms.Use of the compounds according to one or more of claims 1 to 4 for producing a Drug for the treatment of metabolic syndrome. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4 zur Herstellung eines Medikamentes zur Behandlung von Nikotinabhängigkeit.Use of the compounds according to one or more of claims 1 to 4 for producing a Drug for the treatment of nicotine addiction. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4 zur Herstellung eines Medikamentes zur Behandlung von Alkoholabhängigkeit.Use of the compounds according to one or more of claims 1 to 4 for producing a Drug for the treatment of alcohol dependence. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4 zur Herstellung eines Medikamentes zur Behandlung von ZNS-Erkrankungen.Use of the compounds according to one or more of claims 1 to 4 for producing a Drug for the treatment of CNS diseases. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4 zur Herstellung eines Medikamentes zur Behandlung von Schizophrenie.Use of the compounds according to one or more of claims 1 to 4 for producing a Drug for the treatment of schizophrenia. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4 zur Herstellung eines Medikamentes zur Behandlung von Alzheimer.Use of the compounds according to one or more of claims 1 to 4 for producing a Drug for the treatment of Alzheimer's. Verfahren zur Herstellung eines Arzneimittels enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass der Wirkstoff mit einem pharmazeutisch geeigneten Träger vermischt wird und diese Mischung in eine für die Verabreichung geeignete Form gebracht wird.A process for the preparation of a medicament containing one or more of the compounds according to one or more of claims 1 to 4, characterized that the active ingredient with a pharmaceutically suitable carrier is mixed and this mixture in one for administration suitable shape is brought.
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