DE102004038269A1 - Substituted bicyclic 8-piperidino-xanthines, process for their preparation and their use as pharmaceuticals - Google Patents

Substituted bicyclic 8-piperidino-xanthines, process for their preparation and their use as pharmaceuticals

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Publication number
DE102004038269A1
DE102004038269A1 DE200410038269 DE102004038269A DE102004038269A1 DE 102004038269 A1 DE102004038269 A1 DE 102004038269A1 DE 200410038269 DE200410038269 DE 200410038269 DE 102004038269 A DE102004038269 A DE 102004038269A DE 102004038269 A1 DE102004038269 A1 DE 102004038269A1
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Prior art keywords
alkylene
alkyl
aryl
nh
cycloalkyl
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German (de)
Inventor
Christian Dr. Buning
Elisabeth Dr. Defossa
Gerhard Dr. Jaehne
Karl Dr. Schoenafinger
Lothar Dr. Schwink
Georg Dr. Tschank
Holger Dr. Wagner
Ulrich Dr. Werner
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Sanofi Aventis Deutschland GmbH
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Sanofi Aventis Deutschland GmbH
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Priority to DE200410038269 priority Critical patent/DE102004038269A1/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention relates to substituted, bicyclic 8-piperidino-xanthines and their physiologically acceptable salts and physiologically functional derivatives. DOLLAR A The invention relates to compounds of the formula I, DOLLAR F1 wherein the radicals have the meanings indicated, and their physiologically acceptable salts. The compounds are suitable for. As drugs for the prevention and treatment of type 2 diabetes.

Description

  • The The invention relates to substituted, bicyclic 8-piperidino-xanthines and their physiologically acceptable Salts and physiologically functional derivatives.
  • Structure-like compounds are already described in the prior art (see EP 1338595 ).
  • Of the Invention was the object of the compounds available provide a therapeutically useful blood sugar lowering Unfold their effect.
  • The invention therefore relates to compounds of the formula I,
    Figure 00010001
    in which mean
    R 1, R 2, R 3 independently of one another are H, (C 1 -C 10 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10 ) -alkenyl, (C 2 -C 10 ) -alkynyl, ( C 6 -C 10 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH, OH, (C 1 -C 6 ) alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, OR 7, OP (O) (OR7) 2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (C 1 -C 6) -alkylene-OR7, (C 1 -C 6) -alkylene-NR7R8, (C 1 - C 6) -alkylene-NR7SO 2 R7, (C 1 -C 6) -alkylene-SR7, alkylene-S (O) R7, alkylene-S (O) 2 R7, alkylene-S (O) 2 NR7R8, (C 1 -C 6) -alkylene-COR7, (C 1 -C 6) -alkylene-COOR7, (C 1 -C 6) -alkylene-CONR7R8, SR7, SOR7, SO2 R7, SO 2 NR7R8, NR7SO 2 R 7, (C 1 -C 6 ) -alkylene- (C 3 -C 10 ) -cycloalkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) - Alkylene-heterocyclyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl or heterocyclyl;
    R 7, R 8 independently of one another are H, (C 1 -C 6 ) -alkyl, -CF 3 , (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) Alkylene-CONR9R10, CONR9R10, (C 1 -C 6 ) alkylene-COOR 9, COOR 9, COR 9, (C 1 -C 6 ) alkylene-COR 9, (C 1 -C 6 ) alkylene-OR 9, (C 1 -C 6 ) -alkylene-NR9R10, (C 1 -C 6 ) -alkylene-SR 9, (C 1 -C 6 ) -alkylene-S (O) R 9, (C 1 -C 6 ) -alkylene-S (O ) 2 R 9, S (O) R 9, S (O) 2 R 9, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
    R9, R10 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, - (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) -alkylene heterocyclyl;
    R4 and R5 together form a 3-5-membered alkylene chain in which a CH 2 group is replaced by NR11 where R6 is H or is equal to R12, or
    R5 and R6 together form a 3 to 5-membered alkylene chain in which a CH 2 group is replaced by NR11 where R4 is H or R12; wherein the 3 to 5-membered alkylene chain may each be mono- or polysubstituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH (C C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, where the alkyl groups are or may be substituted several times with F, Cl, Br, I;
    R 11 is hydrogen, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
    R 12 is F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -Cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, where the alkyl groups may be mono- or polysubstituted by F, Cl, Br, I;
    n 0, 1, 2, 3, 4;
    and their physiologically acceptable salts.
  • Preference is given to compounds of the formula I in which one or more radicals have the following meaning:
    R 1, R 2, R 3 independently of one another are H, (C 1 -C 10 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10 ) -alkenyl, (C 2 -C 10 ) -alkynyl, ( C 6 -C 10 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH, OH, (C 1 -C 6 ) alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, OR 7, OP (O) (OR 7) 2 , NR 7 R 8, NR 7CON R 7 R 8, COR 7, OCOR 7, OCOOR 7, COOR 7, CONR 7 R 8, OCONR 7 R 8, (C 1 -C 6 ) alkylene-OR7, (C 1 -C 6) -alkylene-NR7R8, (C 1 -C 6) -alkylene-NR7SO 2 R7, (C 1 -C 6) -alkylene-SR7, alkylene-S (O) R7, Alkylene S (O) 2 R 7, Alkylene S (O) 2 NR 7 R 8, (C 1 -C 6 ) Alkylene COR 7, (C 1 -C 6 ) Alkylene COOR 7, (C 1 -C 6 ) alkylene-CONR7R8, SR7, SOR7, SO2 R7, SO 2 NR7R8, NR7SO 2 R7, (C 1 -C 6) alkylene- (C 3 -C 10) cycloalkyl, (C 1 -C 6) alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene-heterocyclyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl or heterocyclyl;
    R7, R8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) -alkylene-CONR 9 R 10 , (C 1 -C 6 ) -alkylene-COOR 9, (C 1 -C 6 ) -alkylene-COR 9, (C 1 -C 6 ) -alkylene-OR 9, (C 1 -C 6 ) -alkylene-NR 9 R 10, (C 1 -C 6 ) -alkylene-SR 9, (C 1 -C 6 ) -alkylene-S (O) R 9, (C 1 -C 6 ) -alkylene-S (O) 2 R 9 ,,, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
    R9, R10 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene heterocyclyl;
    the rest A
    Figure 00040001
    one of the following has the structures A1 to A10
    Figure 00040002
    where the carbon atoms in the structures A1 to A10 can be monosubstituted to tetra-substituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, where the alkyl groups may be mono- or polysubstituted by F, Cl, Br, I;
    R 11 is hydrogen, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
    and their physiologically acceptable salts.
  • Particular preference is given to compounds of the formula I in which one or more radicals have the following meaning:
    R 1, R 2, R 3 independently of one another are H, (C 1 -C 10 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10 ) -alkenyl, (C 2 -C 10 ) -alkenyl, ( C 6 -C 10 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be monosubstituted or polysubstituted by F, Cl, Br, CN ,, OH, ( C 1 -C 6 ) alkyl, - CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, OR 7, NR 7 R 8, NR 7 CONR 7 R 8, COR 7, COOR 7 , CONR7R8, (C 1 -C 6) -alkylene-OR7, (C 1 -C 6) -alkylene-NR7R8, (C 1 -C 6) -alkylene-NR7SO 2 R7, (C 1 -C 6) alkylene -SR7, alkylene-S (O) R7, alkylene-S (O) 2 R7, alkylene-S (O) 2 NR7R8, (C 1 -C 6 ) alkylene-COR7, (C 1 -C 6 ) alkylene -COOR 7, (C 1 -C 6) -alkylene-CONR7R8, SR7, SOR7, SO2 R7, SO 2 NR7R8, NR7SO 2 R7, (C 1 -C 6) alkylene- (C 3 -C 10) cycloalkyl , (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene-heterocyclyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -Aryl or heterocyclyl;
    R7, R8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) -alkylene-CONR 9 R 10 , (C 1 -C 6 ) -alkylene-COOR 9, (C 1 -C 6 ) -alkylene-COR 9, (C 1 -C 6 ) -alkylene-OR 9, (C 1 -C 6 ) -alkylene-NR 9 R 10, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
    R9, R10 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene heterocyclyl;
    the rest A
    Figure 00060001
    one of the following has the structures A1 to A6
    Figure 00060002
    it being possible for the carbon atoms in structures A1 to A6 to be monosubstituted to tetra-substituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH ( C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, wherein the alkyl groups include - or may be substituted several times with F, Cl, Br, I;
    R11 is hydrogen;
    and their physiologically acceptable salts.
  • Very particular preference is given to compounds of the formula I in which one or more radicals have the following meaning:
    R 1, R 2, R 3 are independently (C 1 -C 10 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10 ) -alkenyl, (C 2 -C 10 ) -alkynyl, (C 6 -C 10 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, CN ,, OH, (C 1 -C 6 ) -alkyl, - CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, OR 7, NR 7 R 8, NR 7CONR 7 R 8, COR 7, COOR7, CONR7R8, (C 1 -C 6 ) -alkylene-OR7, (C 1 -C 6 ) -alkylene-NR 7 R 8, (C 1 -C 6 ) -alkylene-NR 7 SO 2 R 7, (C 1 -C 6 ) - Alkylene-SR7, Alkylene-S (O) R7, Alkylene-S (O) 2 R7, Alkylene-S (O) 2 NR7R8, (C 1 -C 6 ) -alkylene-COR7, (C 1 -C 6 ) - alkylene-COOR7, (C 1 -C 6) -alkylene-CONR7R8, SR7, SOR7, SO2 R7, SO 2 NR7R8, NR7SO 2 R7, (C 1 -C 6) alkylene- (C 3 -C 10) - Cycloalkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene-heterocyclyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -Aryl or heterocyclyl;
    R7, R8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) -alkylene-CONR 9 R 10 , (C 1 -C 6 ) -alkylene-COOR 9, (C 1 -C 6 ) -alkylene-COR 9, (C 1 -C 6 ) -alkylene-OR 9, (C 1 -C 6 ) -alkylene-NR 9 R 10, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
    R9, R10 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene heterocyclyl;
    the rest A
    Figure 00070001
    one of the following has the structures A1 to A6
    Figure 00080001
    it being possible for the carbon atoms in structures A1 to A6 to be monosubstituted to tetra-substituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH ( C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, wherein the alkyl groups include - or may be substituted several times with F, Cl, Br, I;
    R11 is hydrogen;
    and their physiologically acceptable salts.
  • The symbol "*" indicates the point of attachment of the remainder A, A1, A2, A3, A4, A5 or A6
    Figure 00080002
    the xanthine.
  • The The invention relates to compounds of the formula I, in the form of their Razemate, racemic mixtures and pure enantiomers and on 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.
  • 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, Amber, 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 (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, Lysine, or ethylenediamine.
  • 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.
  • Of the term used herein "physiological functional derivative " each physiologically acceptable Derivative of a compound of the invention of the formula I, e.g. an ester which, when administered to a mammal, such as e.g. the human being, who is able (directly or indirectly) one Compound of formula I or an active metabolite thereof form.
  • To the physiologically functional derivatives also include prodrugs of the compounds according to the invention. 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 in different polymorphic forms, e.g. 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 with one or more carbons, e.g. Methyl, Ethyl, iso-propyl, tert-butyl, Hexyl.
  • The alkyl radicals may be mono- or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C 1 - C 6 ) alkyl O-CO- (C 1 -C 6 ) alkyl, O-CO- (C 1 -C 6 ) aryl, O-CO- (C 1 -C 6 ) heterocycle; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1 -C 6 ) -alkyl] 2 , S- (C 1 - C 6 ) -alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -Alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 , SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical up to 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 , C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C 1 - C 7 ) acyl, NH-CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, 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 ) -Al kyl) -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 (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 (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C 1 -C 6 ) alkyl) 2 , N (heterocyclic) -CO-N- (C 1 -C 6 ) alkyl) 2 , N (aryl) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (heterocycle) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocyclic) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, where the aryl or heterocyclic May be substituted one to three times 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 , 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 as e.g. Vinyl, allyl, pentenyl, 2-methylbut-2-en-4-yl.
  • The alkenyl radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , cycloalkyl, (C 1 -C 10 ) -alkyl, (C 2 -C 6 ) -alkynyl, O- (C 1 - C 6 ) -alkyl O-CO- (C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) -heterocycle; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1 -C 6 ) -alkyl] 2 , S- (C 1 - C 6 ) -alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -Alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical up to 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 , C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C 1 - C 7 ) acyl, NH-CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, 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 (heterocycle) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocycle) -COO - (C 1 -C 6 ) alkyl, N (aryl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl ) -CO-NH- (C 1 -C 6 ) -alkyl), N (heterocycle) -CO-NH- (C 1 -C 6 ) -alkyl), N (aryl) -CO-NH-aryl, N ( Heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C 1 -C 6 ) -alkyl) 2 , N (heterocycle) -CO-N- (C 1 -C 6 ) -alkyl) 2 , N (aryl) -C O-N ((C 1 -C 6 ) alkyl) aryl, N (heterocycle) -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, where the aryl radical or Heterocyclic radical may be monosubstituted to trisubstituted 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, 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 as e.g. Ethynyl, propynyl, butynyl, hexynyl.
  • The alkynyl radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , cycloalkyl, (C 2 -C 6 ) alkenyl, (C 1 -C 10 ) alkyl, O- (C 1 -) C 6 ) -alkyl O-CO- (C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) -heterocycle; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1 -C 6 ) -alkyl] 2 , S- (C 1 - C 6 ) -alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -Alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical up to 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 , C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C 1 - C 7 ) acyl, NH-CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, 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 ) -Al kyl) -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 (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 (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C 1 -C 6 ) alkyl) 2 , N (heterocyclic) -CO-N- (C 1 -C 6 ) alkyl) 2 , N (aryl) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (heterocycle) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocyclic) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, where the aryl or heterocyclic May be substituted one to three times 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 , 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 monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , cycloalkyl, (C 1 -C 10 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) Alkynyl, O- (C 1 -C 6 ) -alkyl O-CO- (C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) heterocycle ,; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1 -C 6 ) -alkyl] 2 , S- (C 1 - C 6 ) -alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n heterocycle, SO 2 - (C 1 -C 6 ) alkyl, SO 2 - (CH 2 ) n aryl, SO 2 - (CH 2 ) n heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) - Alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical up to twice with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C 1 -C 7 ) acyl, NH-CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, 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 (heterocycle) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocycle) -COO - (C 1 -C 6 ) alkyl, N (aryl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl ) -CO-NH- (C 1 -C 6 ) -alkyl), N (heterocycle) -CO-NH- (C 1 -C 6 ) -alkyl), N (aryl) -CO-NH-aryl, N ( Heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C 1 -C 6 ) -alkyl) 2 , N (heterocycle) -CO-N- (C 1 -C 6 ) -alkyl) 2 , N (aryl) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (heterocycle) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocyclic) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, where the aryl or heterocyclic May be substituted one to three times 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 , 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 constructed, such. Cyclopropyl, cyclopentyl, Cyclopentenyl, cyclohexyl or adamantyl.
  • The Cycloalkylrestereste may be substituted one or more times by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C 1 -C 6) alkyl, CONH 2, CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , cycloalkyl, (C 1 -C 10 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) Alkynyl, O- (C 1 -C 6 ) -alkyl O-CO- (C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) heterocycle ,; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1 -C 6 ) -alkyl] 2 , S- (C 1 - C 6 ) -alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2) n heterocycle, SO 2 -N (C 1 -C 6) alkyl) (CH 2) n -aryl, SO2-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 (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C 1 -C 7 ) acyl, NH-CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, 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 ) -Al kyl) -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 (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 (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C 1 -C 6 ) alkyl) 2 , N (heterocyclic) -CO-N- (C 1 -C 6 ) alkyl) 2 , N (aryl) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (heterocycle) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocyclic) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, where the aryl or heterocyclic May be substituted one to three times 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 , CONH 2 .
  • Under Heterocyclyl, heterocycle or heterocyclic radical become rings and ring systems understood which except carbon still heteroatoms, such as nitrogen, oxygen or sulfur. Further belong also ring systems to this definition, wherein the heterocycle or the heterocyclic radical is fused with benzene nuclei. The heterocycle or the heterocyclic radical can be aromatic, saturated aliphatic or partially unsaturated be aliphatic.
  • suitable Heterocyclyl radicals, 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, 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, tetrahydrofuranyl, 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, triazolyl, tetrazolyl 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 e.g. 1-Oxy-2-, 3- or 4-pyridyl.
  • includes are still one or more benzoannelated derivatives of these Heterocycles.
  • The heterocyclic rings or heterocyclic radicals may be mono- or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl , CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , cycloalkyl, (C 1 -C 10 ) -alkyl, (C 2 -C 6 ) -alkenyl, ( C 2 -C 6 ) alkynyl, O- (C 1 -C 6 ) -alkyl O-CO- (C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O- CO (C 1 -C 6 ) heterocycle; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1 -C 6 ) -alkyl] 2 , S- (C 1 - C 6 ) -alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n -heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n-aryl, SO 2 -N (C 1 -C 6 ) -Alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical up to 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 , C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C 1 - C 7 ) acyl, NH-CO- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, 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 (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) -alkyl), N (heterocycle) -CO-NH- (C 1 -C 6 ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle ) -CO-NH-aryl, N (aryl) -CO-N- (C 1 -C 6 ) -alkyl) 2 , N (heterocycle) -CO-N- (C 1 -C 6 ) -alkyl) 2 , N (aryl) -CO-N ((C 1 -C 6 ) alkyl) aryl, N (heterocyclic) -CO-N ((C 1 -C 6 ) alkyl) aryl, N (aryl) -CO -N- (aryl) 2 , N (heterocycle) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6 wherein the aryl radical or heterocyclic radical can be monosubstituted to trisubstituted 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, CONH 2 .
  • The Compound (s) of formula (I) may 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, e.g. the chosen 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, e.g. 3-10 mg / kg / day. An intravenous dose may e.g. in the area from 0.3 mg to 1.0 mg / kg, suitably as an infusion from 10 ng to 100 ng per kilogram per minute can. Suitable infusion solutions for this Purposes can e.g. from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per Milliliters, included. Single doses may e.g. 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 adjuvants are 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 in separate units, such as capsules, cachets, Lozenges or tablets, each containing a certain amount the compound according to formula I included; as a powder or granules; as a solution or suspension in one aqueous or non-aqueous Liquid; or as an oil-in-water or water-in-oil emulsion. These compositions can, As already mentioned, prepared according to any suitable pharmaceutical method, which comprises a step in which the active ingredient and the carrier (the one or more additional ones Constituents can be) brought into contact. In general the compositions become uniform and homogeneous of the active ingredient with a liquid and / or finely divided solid support, after which the Product is molded if necessary. So, for example A tablet can be prepared by adding a powder or granules the compound is pressed or molded, optionally with a or several additional ones Ingredients. Pressed tablets can be made by tableting Connection in free-flowing Mold, such as a powder or granules, optionally mixed with a binder, lubricant, inert thinner and / or one (several) surface-active / dispersing Means be made in a suitable machine. molded Tablets can by molding the powdery, with an inert liquid thinner moistened connection made in a suitable machine become.
  • Pharmaceutical compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in one 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 before 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 listed in the Red List 2004, Chapter 12 are called. You can with the compounds 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 the USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville 2001, disclosed.
  • Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 fast-acting insulins (see US 6,221,633 ), GLP-1 derivatives such as those disclosed in WO 98/08871 by Novo Nordisk A / S, as well as orally active hypoglycemic agents.
  • The orally effective hypoglycemic Active ingredients preferably include sulphonylfharnates, biguanidines, Meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, Glucagon antagonists, GLP-1 agonists, potassium channel openers, such as e.g. those described in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, inhibitors of liver enzymes, those involved in the stimulation of gluconeogenesis and / or glycogenolysis involved, modulators of glucose uptake, lipid metabolism changing Compounds such as antihyperlipidemic Active ingredients and antilipidemic Active ingredients, compounds that reduce food intake, PPAR and PXR agonists and agents acting on the ATP-dependent potassium channel the beta cells act.
  • 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 administered.
  • In one embodiment of the invention, the compounds of the formula I are used in combination with a cholesterol absorption inhibitor, such as ezetimibe, tiqueside, pamaqueside, or with a compound as described in PCT / EP 2004/00269, PCT / EP 2003/05815, PCT / EP 2003 / 05814, PCT / EP 2003/05816, EP 0114531 . US 6,498,156 described, administered.
  • In one embodiment of the invention, the compounds of the formula I are used in combination with a PPAR gamma agonist, such as rosiglitazone, pioglitazone, JTT-501, Gl 262570.
  • at an embodiment The invention relates to the compounds of the formula I in combination with PPAR alpha agonist, e.g. GW 9578, GW 7647.
  • In one embodiment of the invention, the compounds of formula I are used in combination with a mixed PPAR alpha / gamma agonist such as GW 1536, AVE 8042, AVE 8134, AVE 0847 or as in PCT / US 11833, PCT / US 11490, DE10142734.4 described administered.
  • at an embodiment The invention relates to the compounds of the formula I in combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.
  • at an embodiment The invention relates to the compounds of the formula I in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757, administered.
  • In one embodiment of the invention, the compounds of the formula I are used in combination with bile acid resorption inhibitor (see, for example, US Pat US 6,245,744 or US 6,221,897 ), such as HMR 1741.
  • at an embodiment The invention relates to the compounds of the formula I in combination with a CETP inhibitor, e.g. JTT-705.
  • at an embodiment The invention relates to the compounds of the formula I in combination with a polymeric bile acid adsorber, such as. Cholestyramine, colesevelam.
  • In one embodiment of the invention, the compounds of the formula I in combination with an LDL receptor inducers (see US 6,342,512 ), such as HMR1171, HMR1586.
  • at an embodiment The invention relates to the compounds of the formula I in combination with an ACAT inhibitor, e.g. Avasimibe, administered.
  • at an embodiment The invention relates to the compounds of the formula I in combination with an antioxidant, e.g. OPC-14117 administered.
  • at an embodiment The invention relates to the compounds of the formula I in combination with a lipoprotein lipase inhibitor, e.g. NO-1886, administered.
  • at an embodiment The invention relates to the compounds of the formula I in combination with an ATP citrate lyase inhibitor, e.g. SB-204990 administered.
  • at an embodiment The invention relates to the compounds of the formula I in combination with a squalene synthetase inhibitor, e.g. BMS-188494.
  • at an embodiment The invention relates to the compounds of the formula I in combination with a lipoprotein (a) antagonist, e.g. CI-1027 or nicotinic acid.
  • at an embodiment The invention relates to the compounds of the formula I in combination with a lipase inhibitor, e.g. Orlistat, administered.
  • at an embodiment The invention relates to the compounds of the formula I in combination administered with insulin.
  • at an embodiment the compounds of the formula I in combination with a sulphonylurea, such as. Tolbutamide, glibenclamide, glipizide or glimepiride.
  • at an embodiment are the compounds of formula I in combination with a biguanide, such as e.g. Metformin, administered.
  • at again an embodiment are the compounds of the formula I in combination with a meglitinide, such as. Repaglinide, administered.
  • at an embodiment are the compounds of the formula I in combination with a thiazolidinedione, such as. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or in WO 97/41097 by Dr. med. Reddy's Research Disclosed compounds, in particular 5- [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione, administered.
  • at an embodiment are the compounds of the formula I in combination with an α-glucosidase inhibitor, such as. Miglitol or acarbose, administered.
  • In one embodiment, the compounds of formula I in combination with adenosine A1 agonists, such as. B. those in EP 0912520 or PCT / EP06749.
  • at an embodiment the compounds of the formula I are administered in combination with an active substance, on the ATP-dependent Potassium channel of the beta cells acts, e.g. Tolbutamide, glibenclamide, glipizide, Glimepiride or repaglinide.
  • at an embodiment the compounds of the formula I in combination with more than one of the aforementioned compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, Insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. administered.
  • In a further embodiment, the compounds of the formula I are used in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript-influenced transient influenza energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M .: Hormone and Metabolic Research (2001), 33 (9), 554-558), NPY antagonists eg naphthalene-1-sulfonic acid {4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl} -amide hydrochloride ( CGP 71683A)), 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)) , Orexin antagonists (eg, 1- (2-methyl-benzoxazol-6-yl) -3- [1,5] -naphthyridin-4-yl-urea hydrochloride (SB-334867-A)), H3 agonists (3) Cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) -propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (eg, [2-methyl-9- (2,4,6-timethyl-phenyl) -9H-1,3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585)), CRF BP antagonists (eg, urocortin), urocortin agonists, β3 agonists (eg, 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3-dimethyl- 1H-indol-6-yloxy) -ethylamino] -ethanol hydrochloride (WO 01/83451)), CB1 (cannabinoid receptor 1) receptor antagonists (eg rimonabant or the active ingredients mentioned in WO 02/28346, MSH (melanocyte-stimulating hormone ) Agonists, CCK-A agonists (eg {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)), serotonin reuptake inhibitors (eg dexfenfluramine), mixed sertonine and noradrenergic compounds (eg WO 00/71549), 5HT agonists eg 1- (3-ethyl-benzofuran-7-yl) piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (eg human growth hormone), growth hormone free Substituting compounds (6-benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see, for example EP 0 462 884 ) decoupling protein 2- or 3-modulators, leptin agonists (see, eg, Lee, Daniel W., Leinung, Matthew C .; Rozhavskaya-Arena, Marina; Grasso, Patricia.) Leptin agonists as a potential approach to the treatment of obesity the Future (2001), 26 (9), 873-881), DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors (eg WO 00/40569), PPAR modulators (eg WO 00/78312), RXR Modulators or TR-β agonists.
  • at an embodiment the invention is the further active ingredient leptin; see, e.g. "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 dexamphatamine 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 active substance orlistat.
  • at an embodiment is the other ingredient mazindol or phentermine.
  • at a further embodiment is the other active ingredient rimonabant.
  • In one embodiment, the compounds of formula I in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob / Caromax ® (Zunft HJ; et al, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct). 18 (5), 230-6.) Caromax is a carob-containing product of 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 administered in the form of food, such as in baked goods or muesli bars.
  • 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 00270001
  • The compounds of the formula I can be prepared by using suitable starting materials of formula II, wherein X is a leaving group such as chlorine, bromine, iodine, sulfonyloxy, sulfinyl, sulfoxyl, with a compound of formula IV optionally in the presence of suitable bases and in suitable solvents.
  • Figure 00280001
  • In the cases where R11 is hydrogen, it may be convenient to add the rest N in the nitrogen function more protected Use form and the protective group after the reaction with II split off again. Such suitable protecting groups and the methods the introduction and splitting are known (See: Theodors W. Greene and Peter G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc., New York, 1999).
  • The Halogen compounds of the formula II can be prepared by known processes such as by halogenation of the corresponding H or Hydroxi compound (formula II, X = H) can be obtained. Suitable halogenating agents can for example, halogens such as chlorine and bromine, N-bromosuccinimide, phosphorus pentachloride or phosphorus oxychloride.
  • The Synthesis of compounds of formula II is described in the literature (See: Houben Weyl E9b / 2, p. 331 ff and references cited therein). You can for example, starting from Diaminopyrimidinderivaten or Aminoimidazolcarbonsäureamiden obtained by reaction with suitable reagents and by targeted chemical modifications such as hydrolysis, suitable reagents obtained and by targeted chemical modifications such as hydrolysis, alkylation, Halogenation or acylation into the desired starting compounds of formula II.
  • The Residues R1 to R3 can be prepared by methods known per se Produce alkylation of corresponding known precursors, wherein the order can be varied. But you can also by the appropriate Selection of suitable precursors in the preparation of the Xanthingerüstes be introduced.
  • The Synthesis of the bicyclic amines IV can according to literature See, for example: Armarego, W.L. F J. Chem. Soc (Section C): (1967), (5), 377-83).
  • Octahydro-pyrrolo [3,4-b] pyridine (A4, A5) and octahydro-pynolo [3,4-c] pyridine (A6, A7) are commercial available.
  • To This method can be the following examples produce. They serve for explanation of the invention, but without limiting it.
  • Figure 00300001
  • The compounds of the formula I have favorable effects on the lipid and carbohydrate metabolism, in particular they lower the blood sugar level and are suitable for the treatment of type 2 diabetes, insulin resistance, dyslipidaemias and the metabolic syndrome / syndrome X. Wei terhin, the compounds are suitable for the prophylaxis and treatment of arteriosclerotic phenomena. The compounds may be used alone or in combination with other blood sugar lowering agents. The compounds act as DPP-IV (dipeptidyl peptidase IV) inhibitors and are also useful in the treatment of disorders of sensation and other psychiatric indications such as depression, anxiety, anxiety disorders, schizophrenia, and the treatment of disorders associated with the circadian rhythm Weight reduction in mammals, for the treatment of immune disorders, and for the treatment of substance abuse.
  • Farther are they suitable for the treatment of cancer, arthritis, osteoarthritis, Osteoporosis, sleep disorders, Sleep apnea, female and male Sexual disorders, inflammation, Acne, pigmentation of the skin, disorders of steroid metabolism, skin diseases, psoriasis, mycoses, neurodegenerative Diseases, multiple sclerosis and Alzheimer's disease.

Claims (14)

  1. Compounds of the formula I,
    Figure 00320001
    in which R1, R2, R3 independently of one another are H, (C 1 -C 10 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10 ) -alkenyl, (C 2 -C 10 ) - Alkynyl, (C 6 -C 10 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN , NO 2 , SH, OH, (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, OR7, OP (O) (OR7) 2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (C 1 -C 6) -alkylene-OR7, (C 1 -C 6) -alkylene-NR7R8 , (C 1 -C 6 ) -alkylene-NR 7 SO 2 R 7, (C 1 -C 6 ) -alkylene-SR 7, alkylene-S (O) R 7, alkylene-S (O) 2 R 7, alkylene-S (O) 2 NR7R8, (C 1 -C 6) -alkylene-COR7, (C 1 -C 6) -alkylene-COOR7, (C 1 -C 6) -alkylene-CONR7R8, SR7, SOR7, SO2 R7, SO 2 NR7R8 , NR7SO 2 R7, (C 1 -C 6) alkylene- (C 3 -C 10) cycloalkyl, (C 1 -C 6) alkylene- (C 6 -C 10) -aryl, (C 1 -C 6 ) -alkylene-heterocyclyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl or heterocyclyl; R 7, R 8 independently of one another are H, (C 1 -C 6 ) -alkyl, -CF 3 , (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) Alkylene-CONR9R10, CONR9R10, (C 1 -C 6 ) alkylene-COOR 9, COOR 9, COR 9, (C 1 -C 6 ) alkylene-COR 9, (C 1 -C 6 ) alkylene-OR 9, (C 1 -C 6 ) -alkylene-NR9R10, (C 1 -C 6 ) -alkylene-SR 9, (C 1 -C 6 ) -alkylene-S (O) R 9, (C 1 -C 6 ) -alkylene-S (O ) 2 R 9, S (O) R 9, S (O) 2 R 9, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl; R9, R10 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, - (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) -alkylene heterocyclyl; R4 and R5 together form a 3-5-membered alkylene chain in which a CH 2 group is replaced by NR11 where R6 is H or is equal to R12, or R5 and R6 together form a 3 to 5-membered alkylene chain in which a CH 2 group is replaced by NR11, wherein R4 is H or R12; wherein the 3 to 5-membered alkylene chain may each be mono- or polysubstituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH (C C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, where the alkyl groups are or may be substituted several times with F, Cl, Br, I; R 11 is hydrogen, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-aryl or (C 1 -C 4 ) -alkylene heterocyclyl; R 12 is F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -Cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, where the alkyl groups may be mono- or polysubstituted by F, Cl, Br, I; n 0, 1, 2, 3, 4; and their physiologically acceptable salts.
  2. Compounds of formula I, according to claim 1, characterized in that: R1, R2, R3 independently of one another are H, (C 1 -C 10 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10) alkenyl, (C 2 -C 10) -alkynyl, (C 6 -C 10) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH, OH, (C 1 -C 6 ) alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, OR 7, OP (O) (OR 7) 2 , NR 7 R 8, NR 7CON R 7 R 8, COR 7, OCOR 7, OCOOR 7, COOR 7, CONR 7 R 8, OCONR 7 R 8, (C 1 -C 6 ) alkylene-OR7, (C 1 -C 6) -alkylene-NR7R8, (C 1 -C 6) -alkylene-NR7SO 2 R7, (C 1 -C 6) -alkylene-SR7, alkylene-S (O) R7, Alkylene S (O) 2 R 7, Alkylene S (O) 2 NR 7 R 8, (C 1 -C 6 ) Alkylene COR 7, (C 1 -C 6 ) Alkylene COOR 7, (C 1 -C 6 ) alkylene-CONR7R8, SR7, SOR7, SO2 R7, SO 2 NR7R8, NR7SO 2 R7, (C 1 -C 6) alkylene- (C 3 -C 10) cycloalkyl, (C 1 -C 6) alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene-heterocyclyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl or heterocyclyl; R7, R8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) -alkylene-CONR 9 R 10 , (C 1 -C 6 ) -alkylene-COOR 9, (C 1 -C 6 ) -alkylene-COR 9, (C 1 -C 6 ) -alkylene-OR 9, (C 1 -C 6 ) -alkylene-NR 9 R 10, (C 1 -C 6 ) -alkylene-SR 9, (C 1 -C 6 ) -alkylene-S (O) R 9, (C 1 -C 6 ) -alkylene-S (O) 2 R 9 ,,, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl; R9, R10 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene heterocyclyl; the rest A
    Figure 00340001
    one of the following has the structures A1 to A10
    Figure 00350001
    where the carbon atoms in the structures A1 to A10 can be monosubstituted to tetra-substituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, where the alkyl groups may be mono- or polysubstituted by F, Cl, Br, I; R 11 is hydrogen, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-aryl or (C 1 -C 4 ) -alkylene heterocyclyl; and their physiologically acceptable salts.
  3. Compounds of formula I, according to claim 1 or 2, characterized in that: R1, R2, R3 independently of one another are H, (C 1 -C 10 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10 ) -alkenyl, (C 2 -C 10 ) -alkynyl, (C 6 -C 10 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals are or polysubstituted by F, Cl, Br, CN ,, OH, (C 1 -C 6 ) -alkyl, - CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) -alkenyl, ( C 2 -C 6 ) alkynyl, OR 7, NR 7 R 8, NR 7 CONR 7 R 8, COR 7, COOR 7, CONR 7 R 8, (C 1 -C 6 ) alkylene-OR 7, (C 1 -C 6 ) alkylene-NR 7 R 8, (C 1 -C 6) -alkylene-NR7SO 2 R7, (C 1 -C 6) -alkylene-SR7, alkylene-S (O) R7, alkylene-S (O) 2 R7, alkylene-S (O) 2 NR7R8, (C 1 -C 6) -alkylene-COR7, (C 1 -C 6) -alkylene-COOR7, (C 1 -C 6) -alkylene-CONR7R8, SR7, SOR7, SO2 R7, SO 2 NR7R8, NR7SO 2 R7, ( C 1 -C 6 ) -alkylene- (C 3 -C 10 ) -cycloalkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene-heterocyclyl , (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl or the like r heterocyclyl; R7, R8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) -alkylene-CONR 9 R 10 , (C 1 -C 6 ) -alkylene-COOR 9, (C 1 -C 6 ) -alkylene-COR 9, (C 1 -C 6 ) -alkylene-OR 9, (C 1 -C 6 ) -alkylene-NR 9 R 10, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl; R9, R10 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene heterocyclyl; the rest A
    Figure 00360001
    one of the following has the structures A1 to A6
    Figure 00370001
    it being possible for the carbon atoms in structures A1 to A6 to be monosubstituted to tetra-substituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH ( C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, wherein the alkyl groups include - or may be substituted several times with F, Cl, Br, I; R11 is hydrogen; and their physiologically acceptable salts.
  4. Compounds according to one or more of claims 1 to 3, characterized in that R1, R2, R3 independently of one another are (C 1 -C 10 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10 ) -Alkenyl, (C 2 -C 10 ) -alkynyl, (C 6 -C 10 ) -aryl, heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals mono- or polysubstituted with F, Cl, Br, CN ,, OH, (C 1 -C 6 ) -alkyl, - CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) -alkenyl, (C 2 -) C 6) alkynyl, OR7, NR7R8, NR7CONR7R8, COR7, COOR7, CONR7R8, (C 1 -C 6) -alkylene-OR7, (C 1 -C 6) -alkylene-NR7R8, (C 1 -C 6) -alkylene-NR7SO 2 R7, (C 1 -C 6) -alkylene-SR7, alkylene-S (O) R7, alkylene-S ( O) 2 R 7, alkylene-S (O) 2 NR 7 R 8, (C 1 -C 6 ) -alkylene-COR 7, (C 1 -C 6 ) -alkylene-COOR 7, (C 1 -C 6 ) -alkylene-CONR 7 R 8, SR7, SOR7, SO2 R7, SO 2 NR7R8, NR7SO 2 R7, (C 1 -C 6) alkylene- (C 3 -C 10) cycloalkyl, (C 1 -C 6) alkylene- (C 6 - C 10 ) -aryl, (C 1 -C 6 ) -alkylene-heterocyclyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl or heterocyclyl; R7, R8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) -alkylene-CONR 9 R 10 , (C 1 -C 6 ) -alkylene-COOR 9, (C 1 -C 6 ) -alkylene-COR 9, (C 1 -C 6 ) -alkylene-OR 9, (C 1 -C 6 ) -alkylene-NR 9 R 10, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl; R9, R10 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl, (C 1 -C 6 ) -alkylene heterocyclyl; the rest A
    Figure 00380001
    one of the following has the structures A1 to A6
    Figure 00380002
    it being possible for the carbon atoms in structures A1 to A6 to be monosubstituted to tetra-substituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH ( C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, wherein the alkyl groups include - or may be substituted several times with F, Cl, Br, I; R11 is hydrogen; and their physiologically acceptable salts.
  5. Compounds according to a or more of the claims 1 to 4 for use as a medicament.
  6. Medicament containing one or more of the compounds according to one or more of the claims 1 to 4
  7. Medicament containing one or more of the compounds according to one or more of the claims 1 to 4 and at least one further active ingredient.
  8. Medicament according to claim 7, 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, fibrates, MTP inhibitors, bile acid resorption 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, lipase inhibitors, insulins, sulphonylureas, biguanides, meglitinides, Thiazolidinediones, α-glucosidase inhibitors, beta-cell ATP-dependent potassium channel drugs, CART agonists, NPY agonists, CB-1 receptor antagonists, MCH Anta gonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists; CRF BP antagonists, urocortin agonists, β3 agonists, MSH (melanocyte stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed sertonine and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, Growth hormone, 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 Contains amphetamines.
  9. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament for lowering blood sugar.
  10. Use of the compounds according to one or more of claims 1 to 4 for the preparation of a medicament for the treatment of type II diabetes.
  11. Use of the compounds according to one or more of claims 1 to 4 for the preparation of a medicament for the treatment of lipid and Carbohydrate metabolism disorders.
  12. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament for the treatment of arteriosclerotic Diseases.
  13. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament for the treatment of insulin resistance.
  14. A process for the preparation of a medicament containing one or more of the compounds according to one or more of claims 1 to 4, characterized in that the active ingredient with a pharmaceutically suitable carrier is mixed and this mixture in a suitable for administration Shape is brought.
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