DE102007005045B4 - Phenothiazine derivatives, process for their preparation and their use as medicines - Google Patents

Phenothiazine derivatives, process for their preparation and their use as medicines

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Publication number
DE102007005045B4
DE102007005045B4 DE200710005045 DE102007005045A DE102007005045B4 DE 102007005045 B4 DE102007005045 B4 DE 102007005045B4 DE 200710005045 DE200710005045 DE 200710005045 DE 102007005045 A DE102007005045 A DE 102007005045A DE 102007005045 B4 DE102007005045 B4 DE 102007005045B4
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alkyl
yl
alkylene
aryl
nh
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DE102007005045A1 (en
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Elisabeth Dr. Defossa
Stefanie Dr. Keil
Dieter Dr. Schmoll
Karl Dr. Schönafinger
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Sanofi SA
Sanofi Aventis France
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Sanofi Aventis France
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/02Heterocyclic 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
    • C07D417/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/14Heterocyclic 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

Compounds of the formula I,
Figure 00000001
in which mean
R1 H, (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 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 heterocyclyl, S (O) x (C 1 -C 6 ) alkylene-CO-heterocyclyl, -NH-SO 2 - (C 1 -C 6 ) alkyl, (C 0 -C 6 ) -alkyl cycloalkyl, (C 0 -C 6 ) -alkylene heterocyclyl, (C 0 -C 6 ) alkylene aryl;
x 0, 1, 2;
R6, R7 independently of one another are 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, 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] thiazole 2-yl, benzothiazol-2-yl, benzooxazol-2-yl, benzimidazol-2-yl, quinolin-2-yl, isoquinolin-3-yl, 4,5,6,7-tetrahydrobenzothiazol-2-yl, 4,5,6,7-Tetrahydrobenzooxazol-2-yl, 4,5,6,7-tetrahydrobenzoimidazol-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.

Description

  • phenothiazine Derivatives, process for their preparation and their use as The invention relates to substituted phenothiazines as well as their physiologically compatible Salts.
  • 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.
  • WO 98/52934 A1 discloses azolidinediones as well as their antidiabetic activity. WO 2006/002441 A1 discloses phenothiazine derivatives and their antidiabetic activity.
  • Of the Invention was the object of compounds for treatment to develop from diabetes. These compounds should in particular Lower the blood sugar level.
  • The invention therefore relates to compounds of the formula I,
    Figure 00010001
    in which mean
    R1 H, (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 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 heterocyclyl, S (O) x (C 1 -C 6 ) alkylene-CO-heterocyclyl, -NH-SO 2 - (C 1 -C 6 ) alkyl, (C 0 -C 6 ) -alkyl cycloalkyl, (C 0 -C 6 ) -alkylene heterocyclyl, (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, 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] thiazole 2-yl, benzothiazol-2-yl, benzooxazol-2-yl, benzimidazol-2-yl, quinolin-2-yl, isoquinolin-3-yl, 4,5,6,7-tetrahydrobenzothiazol-2-yl, 4,5,6,7-Tetrahydrobenzooxazol-2-yl, 4,5,6,7-tetrahydrobenzoimidazol-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.
  • 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.
  • Can leftovers or substituents occur several times in the compounds of formula I, they can do that all independent have the meanings given to each other and the same or different be.
  • 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. 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.
  • By "annulation" or "annealed" is meant that a further ring system is condensed. The further condensed Ring system can be aromatic or non-aromatic and carbocyclic or heterocyclic.
  • pharmaceutical compatible Salts are due to their higher Water across from the starting or basic compounds particularly suitable for medical Applications. These salts need a pharmaceutically acceptable Anion or cation. Suitable pharmaceutically acceptable acid addition salts the compounds of the invention are salts of inorganic acids, like hydrochloric acid, Hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid as well organic acids, such as Acetic acid, Benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, Glycol, Isethione, Milk, Lactobion, Malein, Apples, Methanesulfone, Succinic, p-toluenesulfonic and tartaric acid. 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.
  • salts with a non-pharmaceutically acceptable anion, such as Trifluoroacetate, also belong in the context of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.
  • One Another aspect of the invention are the physiologically functional Derivatives of the compounds of the formula I. The term "physiologically functional Derivative " each physiologically acceptable Derivative of a compound of the invention the formula I, z. Example, an ester when administered to a Mammal, such as Humans, is able to (directly or indirectly) a compound of formula I or an active metabolite thereof to build.
  • To The physiologically functional derivatives also pay for prodrugs compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61 described. Such prodrugs can in vivo to a compound of the invention be metabolized. These prodrugs can be effective themselves or Not.
  • The Compounds of 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 belong within the scope of the invention and are a further aspect of the invention.
  • following all references to "compound (s) according to formula I "on connection (s) of the Formula I as described above, and their salts, solvates and physiologically functional derivatives as described herein.
  • Under an alkyl radical becomes a straight-chain or branched hydrocarbon chain understood with one or more carbons, such as. Methyl, Ethyl, iso-propyl, tert-butyl, Hexyl.
  • The alkyl 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 may be 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 (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 ,
  • 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.
  • 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 ) 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 (heterocycle) -COO- (C 1 -C 6 ) -alkyl, N (Ary l) -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 ,
  • 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.
  • 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 (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] 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 can be 3-fold substituted by 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 ,
  • Under an aryl radical is a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha or beta tetralone, Indanyl or indan-1-one-yl understood.
  • 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 ) 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 6 ) -alkyl, N (Ary l) -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 ,
  • Under a cycloalkyl radical is a ring containing one or more Ring system, which saturated or partially unsaturated (with one or two double bonds), understood that exclusively Carbon atoms is built up, such as. Cyclopropyl, cyclopentyl, Cyclopentenyl, cyclohexyl or adamantyl.
  • 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 ) -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 (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 ,
  • Under Heterocycle or heterocyclic radical are rings and ring systems understood that except carbon still heteroatoms, such as nitrogen, oxygen or sulfur contain. Furthermore belong also ring systems to this definition, wherein the heterocycle or the heterocyclic radical fused with another ring system is.
  • Suitable "heterocycles" or "heterocyclic radicals" are acridinyl, Azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, Benzoxazolyl, benzthiazolyl, 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 stands for both 2-, 3- and 4-pyridyl. Thienyl stands for both 2- and also 3-thienyl. Furyl stands for both 2- and 3-furyl.
  • includes are still the corresponding N-oxides of these compounds, ie z. For example 1-oxy-2-, 3- or 4-pyridyl.
  • includes are still one or more benzoannelated derivatives of these Heterocycles.
  • 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 ) -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 6 ) -alkyl, N ( Aryl) -CO-aryl, N (heterocycle) -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 ,
  • links of formula I activate the glucose metabolism in glucokinase expressing Cells. They are therefore good for treating and preventing elevated blood sugar levels, Obesity and metabolic syndrome (Sagen et al., Diabetes 55, 1713-1722, Levin et al. Diabetes (2006), S122-S130, Matschinsky et al (2006) 55, 1-12).
  • by virtue of The activation of glucokinase may be the compounds of formula I also for treatment or prevention other diseases and conditions in a mammal, preferably one People, be eligible, by elevated blood sugar, obesity or by reduced activity of glucokinase.
  • 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 context are
    • - hyperglycemia,
    • - improvement of insulin resistance,
    • - improvement of glucose tolerance,
    • - Protection of pancreatic β-cells
    • - Prevention of macrovascular and microvascular diseases
    • 2. Overweight and its consequences such as dyslipidemias, atherosclerosis, coronary heart disease, cerebrovascular diseases, etc., particularly, but not limited to, those characterized by one or more of the following factors:
    • High plasma triglyceride concentrations, high postprandial plasma triglyceride concentrations,
    • - low 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
    • Dyslipidemia (eg hypertriglyceridemia and / or low HDL)
    • - insulin resistance
    • - hypercoagulability
    • - hyperuricemia
    • - Microalbuminemia
    • Thromboses, hypercoagulable and prothrombotic states (arterial and venous)
    • - High blood pressure
    • Cardiac insufficiency, 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 ApoB 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
  • The Compound (s) of the formula I can also be administered in combination with other active ingredients.
  • The Quantity of a compound according to formula I, which is required to achieve the desired biological effect to reach is dependent from a number of factors, such as B. the selected specific compound, the intended use, route of administration and clinical use Condition of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically 3 mg and 50 mg) per day per kilogram of body weight, z. B. 3-10 mg / kg / day. An intravenous Dose can be z. B. in the range of 0.3 mg to 1.0 mg / kg, the suitably as an infusion from 10 ng to 100 ng per kilogram can be administered per minute. Suitable infusion solutions for these Purposes can z. From 0.1 ng to 10 mg, typically from 1 ng to 10 mg per Milliliters, included. Single doses can z. From 1 mg to 10 g of the active ingredient. Thus, ampoules for injections for example from 1 mg to 100 mg, and orally administrable single dose formulations, such as tablets or capsules, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For therapy the above states can they Compounds according to formula I myself are used as a compound, preferably they are but with a tolerable carrier in the form of a pharmaceutical composition. The carrier must Naturally compatible be, in the sense that he is with the other constituents of the composition is compatible and is not harmful to the patient. The carrier can a solid or a liquid or be both and preferably with the compound as a single dose formulated, for example as a tablet, from 0.05% to 95% by weight. may contain the active ingredient. Other pharmaceutically active substances can also be present, including other compounds according to formula I. The pharmaceutical according to the invention Compositions can produced according to one of the known pharmaceutical methods, which consist essentially in that the ingredients with pharmacologically acceptable Carrier and / or auxiliaries be mixed.
  • Inventive pharmaceutical Compositions are those suitable for oral, rectal, topical, peroral (e.g., sublingual) and parenteral (e.g., 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 dependent is. Also coated formulations and coated slow release formulations belong within the scope of the invention. Preference is given to acid and gastric juice-resistant Formulations. Suitable enteric coatings include Cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
  • Suitable pharmaceutical compounds for oral administration may be in 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, 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.
  • pharmaceutical Compositions for peroral (sublingual) administration Lozenges containing a compound of formula I with a flavor usually Sucrose and gum arabic or tragacanth, and lozenges containing the Compound in an inert base such as gelatin and glycerin or Sucrose and gum arabic.
  • suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous Preparations of a compound according to formula I, preferably isotonic with the blood of the intended recipient. These preparations are preferably intravenous although administered also subcutaneously, intramuscularly or intradermally can be done as an injection. These preparations may preferably can be prepared by mixing the compound with water and the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.
  • suitable pharmaceutical compositions for rectal administration are preferably present as single-dose suppositories. These can be made be prepared by adding a compound according to formula I with one or more usual solid straps, For example, cocoa butter, mixes and the resulting mixture in Form brings.
  • suitable pharmaceutical compositions for topical application the skin are preferably as ointment, cream, lotion, paste, spray, Aerosol or oil in front. 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%.
  • Also transdermal administration is possible. Suitable pharmaceutical Compositions for transdermal applications can as single patches exist, for a long-term close contact are suitable with the epidermis of the patient. Such patches contain suitably the active ingredient in an optionally buffered aqueous Solution, solved and / or dispersed in an adhesive or dispersed in one Polymer. A suitable drug concentration is about 1% to 35%, preferably about 3% to 15%. As a special possibility For example, the active ingredient, such as in Pharmaceutical Research, 2 (6): 318 (1986), by electrotransport or iontophoresis be released.
  • When further active ingredients for the combination preparations are suitable: all antidiabetics, which in the red list 2006, Chapter 12; all weight loss products / appetite suppressants 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 invention of the formula I in particular for the synergistic effect improvement be combined. 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 are present in a pharmaceutical preparation, respectively. Most of the drugs listed below are in USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville 2001, revealed.
  • Antidiabetics include insulin and insulin derivatives, such as. B. Lantus ® (see www.lantus.com) or HMR 1964 or Levemir ® (insulin detemir) or those described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221,633 ), inhalable insulins, such as. B. Exubera ® or oral insulins 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.
  • 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.
  • at an embodiment The invention relates to 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.
  • 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-Tech, 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).
  • 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.
  • at a further embodiment The invention relates to the compound of the formula I in combination with a fixed combination of fenofibrate with rosuvastatin.
  • at an embodiment The invention relates to the compound of the formula I in combination with ISIS-301012, an antisense oligonucleotide capable of producing the apolipoprotein B gene to be administered.
  • at an embodiment the invention, the compound of formula I in combination with a PPAR gamma agonist such. Rosiglitazone, pioglitazone, JTT-501, GI 262570, R-483, CS-011 (rivoglitazone).
  • 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.
  • 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.
  • 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.
  • at an embodiment the invention, the compound of formula I in combination with PPAR alpha agonists, such as. GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945 administered.
  • 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.
  • at an embodiment the invention, the compound of formula I in combination with a PPAR delta agonist such. GW-501516.
  • at an embodiment is the compound of the formula I in combination with metaglidases or with MBX-2044 or other partial PPAR gamma agonist / antagonist administered
  • 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.
  • at an embodiment the invention, the compound of formula I in combination with a fibrate, such. Fenofibrate, clofibrate, bezafibrate.
  • 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.
  • 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.
  • 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.
  • at an embodiment the invention, the compound of formula I in combination with a polymeric bile acid adsorber, such as As cholestyramine, colesevelam administered.
  • 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. HR1171, HMR1586, or those as in WO2005097738 described, administered.
  • 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.
  • at an embodiment the invention, the compound of formula I in combination with an ACAT inhibitor, such as. Avasimibe or SMP-797.
  • at an embodiment the invention, the compound of formula I in combination with an antioxidant, such as. OPC-14117, probucol, tocopherol, ascorbic acid, β-carotene or selenium administered.
  • at an embodiment the invention, the compound of formula I in combination with a vitamin, such as. As vitamin B6 or vitamin B12 administered.
  • at an embodiment the invention, the compound of formula I in combination with a lipoprotein-lipase modulator, such. Ibrolipim (NO-1886), administered.
  • at an embodiment the invention, the compound of formula I in combination with an ATP citrate lyase inhibitor, such as. SB-204990.
  • In one embodiment of the invention, the compound of the formula I is used in combination with a Squalene synthetase inhibitor, such as. BMS-188494 or as in WO 2005/077907 described, administered.
  • at an embodiment the invention, the compound of formula I in combination with a lipoprotein (a) antagonist, such as. G., Gemcabene (CI-1027).
  • In one embodiment of the invention, the compound of the formula I in combination with an Aqonisten 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.
  • In another embodiment of the invention, the compound of formula I in combination with an Aqonisten of GPR116, as described, for. In WO2006067531 . WO2006067532 described.
  • at an embodiment the invention, the compound of formula I in combination with a lipase inhibitor, such as. Orlistat or cetilistat (ATL-962), administered.
  • at an embodiment the invention, the compound of formula I in combination with Insulin administered.
  • at an embodiment is the compound of the formula I in combination with a sulfonylurea, such as As tolbutamide, glibenclamide, glipizide or glimepiride administered.
  • In one embodiment, the compound of formula I in combination with an insulin secretion enhancing substance, such as. B. KCP-265 ( WO2003097064 ).
  • at an embodiment is 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.
  • at again another embodiment is the compound of the formula I in combination with a meglitinide, such as Repaglinide or nateglinide.
  • 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.
  • at an embodiment is the compound of the formula I in combination with an α-glucosidase inhibitor, such as As miglitol or acarbose administered.
  • at an embodiment is the compound of formula I in combination with an active ingredient administered on the ATP-dependent Potassium channel of the beta cells acts, such. Tolbutamide, glibenclamide, glipizide, Glimepiride or repaglinide.
  • at an embodiment is the compound of formula I in combination with more than one the aforementioned compounds, for. B. 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. administered.
  • 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.
  • In one embodiment, the compound of formula I in combination with glucagon receptor antagonists, such as. A-770077 or NNC-25-2504 or as in WO2004100875 . WO2005065680 , described, administered.
  • 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.
  • 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.
  • at an embodiment is the compound of formula I in combination with modulators of glucose transporter-4 (GLUT4), such as. KST-48 (D.O. Lee et al .: Arzneimittel.-Forsch. Drug Res. 54 (12), 835 (2004)).
  • 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.
  • 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.
  • In one embodiment, the compound of Formula I is administered in combination with Januvia , a solid combination of sitagliptin phosphate with metformin hydrochloride.
  • 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 060542.4 described.
  • 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 by AL Handlon in Expert Opinion. Ther. Patents (2005) 15 (11), 1531-1540.
  • at an embodiment is the compound of formula I in combination with modulators administered by the GPR40.
  • In one embodiment, the compound of formula I is used in combination with modulators of GPR119b, as described e.g. In WO2004041274 described.
  • 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). In one embodiment, the compound of the formula I in combination with inhibitors of hormone-sensitive lipase (HSL), such. In WO2005073199 described, administered.
  • 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.
  • 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.
  • 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.
  • at an embodiment is the compound of formula I in combination with an inhibitor the protein kinase C beta (PKC beta), such as. B. Ruboxistaurin administered.
  • at an embodiment is the compound of the formula I in combination with an endothelin A receptor Antagonists, such as B. avosentan (SPP-301).
  • 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.
  • 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.
  • In a further embodiment, the compound of the formula I is administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcriptinfluenza-specific 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 those as described in, for example, US Pat. 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-trimethyl-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, for example, 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.
  • at an embodiment is the other active substance Varenicline Tartrate, a partial agonist of the alpha 4-beta 2 nicotinic acetylcholine receptor.
  • at an embodiment is the other active ingredient Trodusquemine.
  • at an embodiment the other active substance is a modulator of the enzyme SIRT1, one Member of the human sirtuin enzyme family.
  • 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.
  • at an embodiment is the other active ingredient dexamphetamine or amphetamine.
  • at an embodiment is the other active ingredient fenfluramine or dexfenfluramine.
  • at yet another embodiment is the other active substance sibutramine.
  • at an embodiment is the other ingredient mazindol or phentermine.
  • In one embodiment, the compound of formula I in combination with bulking agents, preferably insoluble bulking agents (see for example, carob / Caromax ® (Zunft HJ; et al., Carob pule preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-. Oct), 18 (5), 230-6.) Caromax is a carob-containing product from the company Nutrinova, Nutrition Specialties & Food 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.
  • It it is understood that any suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active Substances than within the scope of the present invention is considered falling.
  • Figure 00310001
  • Figure 00320001
  • Figure 00330001
  • Figure 00340001
  • Figure 00350001
  • Figure 00360001
  • Figure 00370001
  • Figure 00380001
  • Figure 00390001
  • The Effectiveness of the compounds was tested as follows:
  • Enzymatic test of glucokinase activators
  • Human glucokinase
  • humane Glucokinase is used as a fusion protein with glutathione-S-transferase (GST) expressed in E. coli Bl21 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 glucokinase has a specific activity of 30 at room temperature U / mg protein.
  • Enyzymatic test
  • 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.
  • Evaluation:
  • 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 150 [μM] Fold induction 1 4.2 2.0 5 2.1 4.4 6 15.5 2.1 9 2.2 2.8
  • Out The measured data of the table can be read that the compounds of the invention cause activation of glucokinase. These compounds are suitable thus especially for lowering the blood sugar level and for Treatment of diabetes.
  • method
  • The compounds of the formula I according to the invention can be prepared according to the following reaction scheme: Method A:
    Figure 00420001
  • 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 protic 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.
  • The Examples 1-13 were prepared by Method A.
  • 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 Kaliumbexamethyldisilazid 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
  • Example syntheses according to method A
  • example 1
  • 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-pyran-4-yl) -N-thiazol-2-yl-propionamide
    Figure 00460001
  • 2- (10-methyl-10H-phenothiazine-2-yl) -1-morpholin-4-yl-ethanthion
    Figure 00460002
  • 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 two and a half hours at 150 ° C touched.
  • 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. This gives 30.2 g of 2- (10-methyl-10H-phenothiazin-2-yl) -1-morpholin-4-yl-ethanthion as an orange solid.
    C 19 H 20 N 2 OS 2 (356.51), LCMS (EST): 357.1 (M + H +), Rf (n-heptane: ethyl acetate = 3: 1) = 0:12. (10-methyl-10H-phenothiazine-2-yl) acetic acid
    Figure 00470001
  • 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.
    C 15 H 13 NO 2 S (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 00470002
  • 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.
    C 17 H 17 NO 2 S (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 00480001
  • 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.
    C 17 H 17 NO 4 S (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 00480002
  • 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.
    C 23 H 27 NO 5 S (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 00490001
  • 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.
    C 21 H 23 NO 5 S (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 00490002
  • 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 five times with 30 ml of saturated Na washed triumhydrogencarbonatlösung. The organic phase is dried over MgSO 4 and then 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.
    C 24 H 25 N 3 O 4 S 2 (483.61), LCMS (ESI): 484.1 (M + H +).
  • Example 2
  • 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 00500001
  • 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.
    C 25 H 27 N 3 O 4 S 2 (497.64), LCMS (ESI): 498.1 (M + H +).
  • Example 3
  • 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 00500002
  • 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.
    C 24 H 24 C 1 N 3 O 4 S 2 (518.06), LCMS (ESI): 518.1 (M + H + ).
  • Example 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 00510001
  • 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.
    C 24 H 26 N 4 O 4 S 2 (498.63), LCMS (ESI): 499.2 (M + H +).
  • Example 5
  • 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 00510002
  • 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.
    C 25 H 28 N 4 O 4 S (480.59), LCMS (ESI): 481.2 (M + H +).
  • Example 6
  • 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 00510003
  • 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-methyl-pyridazin-3-yl) -3- (tetrahydro -pyran-4-yl) -propionamide.
    C 26 H 28 N 4 O 4 S (492.60), LCMS (ESI): 493.2 (M + H +).
  • Example 7
  • 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 00520001
  • 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.
    C 27 H 29 N 3 O 6 S 2 (555.68), LCMS (ESI): 597.20 (M + MeCN + H +).
  • Example 8
  • {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 00520002
  • 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.
    C 28 H 31 N 3 O 6 S 2 (569.70), LCMS (ESI): 570.20 (M + H +).
  • Example 9
  • 3-cyclopentyl-2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazin-2-yl) -N-thiazol-2-yl-propionamide
    Figure 00530001
  • 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.
    C 24 H 25 N 3 O 3 S 2 (467.61), LCMS (ESI): 468.2 (M + H +), 509.3 (M + MeCN + H +).
  • Example 10
  • {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 00530002
  • 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.
    C 26 H 27 N 3 O 6 S 2 (541.65), LCMS (ESI): 542.2 (M + H +).
  • Example 11
  • 2- [2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-pyran-4-yl) propionylamino] -thiazoles-4-carboxylic acid
    Figure 00540001
  • 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.
    C 25 H 25 N 3 O 6 S 2 (527.62), LCMS (ESI): 528.2 (M + H +), 569.2 (M + MeCN + H +).
  • Example 12
  • 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 00540002
  • 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.
    C 24 H 26 N 4 O 4 S (466.56), LCMS (ESI): 467.2 (M + H +).
  • Example 13
  • 2- (10-methyl-5,5-dioxo-5,10-dihydro-phenothiazine-2-yl) -3- (tetrahydro-furan-3-yl) -N-thiazol-2-yl-propionamide
    Figure 00540003
  • 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.
    C 23 H 23 N 3 O 4 S 2 (469.59), LCMS (ESI): 470.1 (M + H +).

Claims (13)

  1. Compounds of the formula I,
    Figure 00560001
    wherein R 1 is H, (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 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 heterocyclyl, S (O) x (C 1 -C 6 ) alkylene-CO-heterocyclyl, -NH-SO 2 - (C 1 -C 6 ) alkyl, (C 0 -C 6 ) -alkyl cycloalkyl, (C 0 -C 6 ) -alkylene heterocyclyl, (C 0 -C 6 ) alkylene aryl; x 0, 1, 2; R6, R7 independently of one another are 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, 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] thiazole 2-yl, benzothiazol-2-yl, benzooxazol-2-yl, benzimidazol-2-yl, quinolin-2-yl, isoquinolin-3-yl, 4,5,6,7-tetrahydrobenzothiazol-2-yl, 4,5,6,7-Tetrahydrobenzooxazol-2-yl, 4,5,6,7-tetrahydrobenzoimidazol-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.
  2. Medicament containing one or more of the compounds according to claim 1.
  3. Medicament containing one or more of the compounds according to claim 1 and at least one further active ingredient.
  4. Medicament according to claim 3, characterized in that it contains as further active ingredient one or more antidiabetics, hypoglycemic agents, HMGCoA reductase inhibitors, cholesterol resorption 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, insulins, sulfonylureas, biguanides, meglitinides, thiazoles diones, α-glucosidase inhibitors, beta-cell ATP-dependent potassium channel drugs, glycogen phosphorylase inhibitors, glucagon receptor antagonists, glucokinase activators, gluconeogenesis inhibitors, fructose 1,6 biphosphatase inhibitors, modulators of the glucose transporter -4, glutamine-fructose-6-phosphate amidotransferase inhibitors, dipeptidyl-peptidase-IV inhibitors, 11-beta-hydroxysteroid dehydrogenase-1 inhibitors, protein tyrosine phosphatase-1B inhibitors, sodium-dependent glucose transporter modulators 1 or 2, modulators of GPR40, inhibitors of hormone-sensitive lipase, inhibitors of 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 of I kappaB kinase, modulators of the glucocorticoid receptor, CART agonists, NPY agonists, MC4 agonists, Orexin-Ag onists, 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 sertonine 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, doprexin) , Lipase / amylase inhibitors, PPAR modulators, RXR modulators or TR-β agonists or amphetamines.
  5. Use of the compounds according to claim 1 for the preparation a drug for the treatment of diabetes.
  6. Use of the compounds according to claim 1 for the preparation a drug for lowering blood sugar.
  7. Use of the compounds according to claim 1 for the preparation a drug to treat the metabolic syndrome.
  8. Use of the compounds according to claim 1 for the preparation a drug for the treatment of nicotine addiction.
  9. Use of the compounds according to claim 1 for the preparation a drug for the treatment of alcohol dependence.
  10. Use of the compounds according to claim 1 for the preparation a drug for the treatment of CNS disorders.
  11. Use of the compounds according to claim 1 for the preparation a drug for the treatment of schizophrenia.
  12. Use of the compounds according to claim 1 for the preparation a drug for the treatment of Alzheimer's.
  13. A process for the preparation of a medicament containing one or more of the compounds according to claim 1, characterized in that that the active ingredient is mixed with a pharmaceutically suitable carrier and this mixture in a suitable for administration Shape is brought.
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