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HK1091825B - Substituted thiazole-benzoisothiazole dioxide derivatives, method for the production thereof and use of the same - Google Patents

Substituted thiazole-benzoisothiazole dioxide derivatives, method for the production thereof and use of the same Download PDF

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Publication number
HK1091825B
HK1091825B HK06112382.5A HK06112382A HK1091825B HK 1091825 B HK1091825 B HK 1091825B HK 06112382 A HK06112382 A HK 06112382A HK 1091825 B HK1091825 B HK 1091825B
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alkyl
aryl
heterocycle
coo
compounds
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HK06112382.5A
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HK1091825A1 (en
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Stefan Petry
Karl-Heinz Baringhaus
Norbert Tennagels
Guenter Mueller
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Sanofi-Aventis Deutschland Gmbh
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Priority claimed from DE10334309A external-priority patent/DE10334309A1/en
Application filed by Sanofi-Aventis Deutschland Gmbh filed Critical Sanofi-Aventis Deutschland Gmbh
Publication of HK1091825A1 publication Critical patent/HK1091825A1/en
Publication of HK1091825B publication Critical patent/HK1091825B/en

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Substituted thiazole-benzisothiazole dioxide derivatives, method for the production thereof and use thereof
The invention relates to substituted thiazole-benzisothiazole dioxide derivatives and to their physiologically tolerated salts and physiologically functional derivatives.
Benzisothiazole dioxide derivatives of similar structure and their use for the treatment of diabetes have been described in the prior art (WO 02/11722).
It is an object of the present invention to provide compounds useful for the prevention and treatment of diabetes. The compounds used for this purpose exhibit a therapeutically utilizable hypoglycemic effect. In particular, these compounds have an improved action or improved ADME properties (absorption, distribution, metabolism and excretion) compared to the compounds of WO 02/11722.
The invention therefore relates to compounds of the formula I and to their physiologically tolerated salts,
the meaning is as follows:
r1, R2 independently of one another are H, aryl, COOH, (C)1-C6) alkylene-COOH, -COO (C)1-C6) Alkyl radicals, (C)1-C6) -alkylene-COO (C)1-C6) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)1-C6) Alkylene-aryl, heterocycle, (C)1-C6) Alkylene-heterocycles, CF3、OCF3、CN、(CH2)1-6-OH、O-(C1-C6) Alkyl, CO- (C)1-C6) -alkyl, -C (O) O-alkyl, COOH, CON (R9) (R10), wherein said aryl and heterocyclyl may be substituted by F, Cl, Br, (CH)2)0-2OH、(C1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, CF3、OCF3N (R9) (R10), piperidone, piperazine, piperazinone, N- (C)1-C6Alkylene) piperazines, N- (C)1-C6Alkylene) piperazinones, morpholines, thiomorpholines (thiomorpholine), NO2、CN、O-(C1-C6) Alkyl, S (O)0-2-(C1-C6) Alkyl, SO2-N(R9)(R10)、CO-(C1-C6) -alkyl, -COOH, (C)1-C6) alkylene-COOH, COO (C)1-C6) Alkyl radicals, (C)1-C6) -alkylene-COO (C)1-C6) Alkyl radicals, (C)3-C10) Cycloalkyl, phenyl substituted one or more times, wherein these piperidones, piperazinones, N- (C)1-C6Alkylene) piperazines, N- (C)1-C6The-alkylene) piperazinones, morpholines, thiomorpholines and phenyl rings may be substituted by F, Cl, Br, (CH)2)0-2OH、COOH、CN、NO2、-O-(C1-C6) -alkyl, -NH-O- (C)1-C6) -alkyl, - (CO) -NH-O- (C)1-C6) alkylene-N (R9) (R10), - (CO) - (C)1-C6) Alkyl, - (C)1-C6) -alkyl, CF3、OCF3N (R9) (R10) one or more times;
r3 is H, (C)1-C6) Alkyl radicals, (C)1-C6) Alkylene aryl radical, C (O) -aryl radical, (C)1-C6) Alkylene-heterocyclic, CO- (C)1-C6) Alkyl, where the aryl and heterocyclyl radicals may be substituted by F, Cl, Br, (C)1-C6) Alkyl, COOH, COO- (C)1-C6) -alkyl, CF3Or OCF3One or more substitutions;
r4, R5 independently of one another are H, F, Cl, Br, (C)1-C6) -alkyl, CF3、OCF3、NO2、N(R9)(R10)、CN、O-(C1-C6) Alkyl, CO- (C)1-C6) Alkyl, COOH, (C)1-C6) alkylene-COOH, CON (R9) (R10), (C)1-C6) alkylene-CON (R9) (R10), COO (C)1-C6) Alkyl radicals, (C)1-C6) -alkylene-COO (C)1-C6) Alkyl, S (O)0-2-(C1-C6) Alkyl, S (O)2-N(R9)(R10)、CH2OH、CH2OCH3；
R6, R7 independently of one another are H, F, Cl, Br, (C)1-C6) -alkyl, cyclopropyl, tetrafluorocyclopropyl, difluorocyclopropyl; or
R6 and R7 together form the group ═ CH2；
R8 is H, CH3、CF3、CH2OH；
R9 is H, (C)1-C4) -an alkyl group;
r10 is H, (C)1-C4) -an alkyl group; or
R9 and R10 form together with the N atom to which they are bound a 3-to 9-membered ring system.
Preference is given to compounds of the formula I in which one or more radicals have the following meanings:
r1 is aryl, (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)1-C6) Alkylene-aryl, heterocycle, (C)1-C6) Alkylene-heterocycles, CF3、OCF3、CN、(CH2)1-6-OH、O-(C1-C6) Alkyl, CO- (C)1-C6) -alkyl, C (O) O-alkyl, COOH, CON (R9) (R10), wherein said aryl and heterocyclyl may be substituted by F, Cl, Br, (CH)2)0-2OH、(C1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, CF3、OCF3N (R9) (R10), piperidone, piperazine, piperazinone, N- (C)1-C6-alkylene) -piperazine, N- (C)1-C6Alkylene) piperazinones, morpholines, thiomorpholines, NO2、CN、O-(C1-C6) Alkyl, S (O)0-2-(C1-C6) Alkyl, SO2-N(R9)(R10)、CO-(C1-C6) -alkyl, -COOH, (C)1-C6) alkylene-COOH, -COO (C)1-C6) Alkyl radicals, (C)0-C6) -alkylene-COO (C)1-C6) Alkyl radical, C3-C10Cycloalkyl, phenyl substituted one or more times, wherein these piperidones, piperazinones, N- (C)1-C6-alkylene) -piperazine, N- (C)1-C6The-alkylene) piperazinones, morpholines, thiomorpholines and phenyl rings may be substituted by F, Cl, Br, (CH)2)0-2OH、COOH、CN、NO2、-O-(C1-C6) -alkyl, -NH-O- (C)1-C6) -alkyl, - (CO) -NH-O- (C)1-C6) alkylene-N (R9) (R10), - (CO) - (C)1-C6) Alkyl, - (C)1-C6) -alkyl, CF3、OCF3N (R9) (R10) one or more times;
r2 is H, aryl, COOH, (C)1-C6) alkylene-COOH, -COO (C)1-C6) Alkyl radicals, (C)1-C6) -alkylene-COO (C)1-C6) -an alkyl group; (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)1-C6) Alkylene-aryl, heterocycle, (C)1-C6) Alkylene-heterocycles, CF3、OCF3、CN、-(CH2)1-6-OH、O-(C1-C6) Alkyl, CO- (C)1-C6) -alkyl, C (O) O-alkyl, COOH, CON (R9) (R10), wherein said aryl and heterocyclyl may be substituted by F, Cl, Br, (CH)2)0-2OH、(C1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, CF3、OCF3N (R9) (R10), piperidone, piperazine, piperazinone, N- (C)1-C6Alkylene) piperazines, N- (C)1-C6Alkylene) piperazinones, morpholines, thiomorpholines, NO2、CN、O-(C1-C6) Alkyl, S (O)0-2-(C1-C6) Alkyl, SO2-N(R9)(R10)、CO-(C1-C6) -alkyl, -COOH, (C)1-C6) alkylene-COOH, -COO (C)1-C6) Alkyl radicals, (C)1-C6) -alkylene-COO (C)1-C6) Alkyl radical, C3-C10-cycloalkyl, phenyl substituted one or more times;
r3 is H, (C)1-C6) Alkyl radicals, (C)1-C6) Alkylene-aryl, -C (O) -aryl, (C)1-C6) Alkylene-heterocyclic, CO- (C)1-C6) -an alkyl group;
r4, R5 are each independently H, F, Cl,Br、(C1-C6) -alkyl, CF3、OCF3、NO2、N(R9)(R10)、CN、O-(C1-C6) Alkyl, CO- (C)1-C6) Alkyl, COOH, (C)1-C6) alkylene-COOH, -CON (R9) (R10), (C)1-C6) alkylene-CON (R9) (R10), COO (C)1-C6) Alkyl radicals, (C)1-C6) -alkylene-COO (C)1-C6) Alkyl, S (O)0-2-(C1-C6) Alkyl, S (O)2-N(R9)(R10)、CH2OH、CH2OCH3；
R6, R7 independently of one another are H, F, Cl, Br, (C)1-C6) -alkyl, cyclopropyl, tetrafluorocyclopropyl, difluorocyclopropyl; or
R6 and R7 together form the group ═ CH2；
R8 is H, CH3、CF3、CH2OH；
R9 is H, (C)1-C4) -an alkyl group;
r10 is H, (C)1-C4) -an alkyl group; or
R9 and R10 form together with the N atom to which they are bound a 3-to 9-membered ring system.
Particular preference is given to compounds of the formula I in which one or more radicals have the following meanings and to their physiologically tolerated salts:
r1 is phenyl, naphthyl, thionaphthyl, pyridyl, wherein said phenyl, naphthyl, thionaphthyl and pyridyl may be substituted by F, Cl, Br, (CH)2)0-2OH、(C1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, CF3、OCF3N (R9) (R10), piperidone, piperazine, piperazinone, N- (C)1-C6Alkylene) piperazines, N- (C)1-C6-alkylene) piperazinones, morpholines, piperazinones, and piperazinones,Thiomorpholine, NO2、CN、O-(C1-C6) Alkyl, S (O)0-2-(C1-C6) Alkyl, SO2-N(R9)(R10)、CO-(C1-C6) Alkyl, COOH, (C)1-C6) alkylene-COOH, COO (C)1-C6) Alkyl radicals, (C)1-C6) -alkylene-COO (C)1-C6) Alkyl radical, C3-C10Cycloalkyl, phenyl substituted one or more times, wherein these piperidones, piperazinones, N- (C)1-C6-alkylene) -piperazine, N- (C)1-C6The-alkylene) piperazinones, morpholines, thiomorpholines and phenyl rings may be substituted by F, Cl, Br, (CH)2)0-2OH、COOH、CN、NO2、-O-(C1-C6) -alkyl, -NH-O- (C)1-C6) -alkyl, - (CO) -NH-O- (C)1-C6) alkylene-N (R9) (R10), - (CO) - (C)1-C6) Alkyl, - (C)1-C6) -alkyl, CF3、OCF3N (R9) (R10) one or more times;
r2 is H, (C)1-C6) Alkyl, COOH, (C)1-C6) alkylene-COOH, -COO (C)1-C6) Alkyl radicals, (C)1-C6) -alkylene-COO (C)1-C6) -an alkyl group;
r3 is H, (C)1-C6) Alkyl radicals, (C)1-C6) Alkylene-aryl, -C (O) -aryl, (C)1-C6) Alkylene-heterocyclic, CO- (C)1-C6) -an alkyl group;
r4, R5 is H;
r6, R7 is H;
r8 is H;
r9 is H, (C)1-C4) -an alkyl group;
r10 is H, (C)1-C4) -an alkyl group.
Very particular preference is given to compounds of the formula I in which one or more radicals have the following meanings and their physiologically tolerated salts:
r1 is phenyl, where the phenyl group may be substituted by F, Cl, Br, (CH)2)0-2OH、(C1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, CF3、OCF3N (R9) (R10), piperidone, piperazine, piperazinone, N- (C)1-C6Alkylene) piperazines, N- (C)1-C6Alkylene) piperazinones, morpholines, thiomorpholines, NO2、CN、O-(C1-C6) Alkyl, S (O)0-2-(C1-C6) Alkyl, SO2-N(R9)(R10)、CO-(C1-C6) Alkyl, COOH, (C)1-C6) alkylene-COOH, COO (C)1-C6) Alkyl radicals, (C)1-C6) -alkylene-COO (C)1-C6) Alkyl radical, C3-C10Cycloalkyl, phenyl substituted one or more times, wherein these piperidones, piperazinones, N- (C)1-C6Alkylene) piperazines, N- (C)1-C6The-alkylene) piperazinones, morpholines, thiomorpholines and phenyl rings may be substituted by F, Cl, Br, (CH)2)0-2OH、COOH、CN、NO2、-O-(C1-C6) -alkyl, -NH-O- (C)1-C6) -alkyl, - (CO) -NH-O- (C)1-C6) alkylene-N (R9) (R10), - (CO) - (C)1-C6) Alkyl, - (C)1-C6) -alkyl, CF3、OCF3N (R9) (R10) one or more times;
r2 is H, (C)1-C6) Alkyl, -C (O) O- (C)1-C6) Alkyl, - (C)1-C6) alkylene-C (O) O- (C)1-C6) -alkyl, -COOH, - (C)1-C6) -alkylene-COOH;
r3 is H, (C)1-C6) Alkyl radicals, (C)1-C6) Alkylene-aryl, -C (O) -arylBase, (C)1-C6) Alkylene-heterocyclic, CO- (C)1-C6) -an alkyl group;
r4, R5 is H;
r6, R7 is H;
r8 is H;
r9 is H;
r10 is H.
The present invention relates to compounds of formula I in the form of racemates, racemic mixtures and pure enantiomers as well as to their diastereomers and mixtures thereof.
If a group or substituent is present more than once in a compound of the formula I, they can each have the stated meaning independently of one another and can be identical or different.
Pharmaceutically acceptable salts are particularly suitable for medical applications because they have a higher solubility in water than the original or base compound. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and salts of organic acids such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically acceptable base salts are ammonium salts, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. magnesium and calcium salts), tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine salts.
Salts formed with non-pharmaceutically acceptable anions, such as trifluoroacetate, are also included within the scope of the invention, which are useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or which are useful in non-therapeutic applications, such as in vitro uses.
The term "physiologically functional derivative" as used herein means any physiologically tolerated derivative of a compound of the formula I according to the invention, for example an ester, which on administration to a mammal, such as for example a human, is capable of forming (directly or indirectly) a compound of the formula I or an active metabolite thereof.
Physiologically functional derivatives include prodrugs of the compounds of the invention, such as, for example, those described in H.Okada et al, chem.pharm.Bull.1994, 42, 57-61. Such prodrugs can be metabolized in vivo to the compounds of the invention. These prodrugs may be active or inactive themselves.
The compounds of the invention may also exist in various polymorphic forms, for example, in amorphous and crystalline polymorphic forms. All polymorphic forms of the present invention are included within the scope of the present invention and are a further aspect of the present invention.
All references hereinafter to "compounds of formula (I)" are intended to refer to the compounds of formula I as defined above, as well as their salts, solvates and physiologically functional derivatives as described herein.
Alkyl means a straight or branched hydrocarbon chain having one or more carbons, such as, for example, methyl, ethyl, isopropyl, t-butyl, hexyl.
The alkyl group may be substituted one or more times by suitable groups such as, for example:
F、Cl、Br、I、CF3、NO2、N3、CN、COOH、COO(C1-C6) Alkyl, CONH2，CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2Cycloalkyl group, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, O- (C)1-C6) Alkyl O-CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Aryl, O-CO- (C)1-C6) -a heterocycle;
PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)nAryl, S- (CH)2)n-heterocycle, SO- (C)1-C6) Alkyl, SO- (CH)2)nAryl, SO- (CH)2)n-heterocyclic ring, SO2-(C1-C6) Alkyl, SO2-(CH2)nAryl, SO2-(CH2)n-heterocyclic ring, SO2-NH(CH2)nAryl, SO2-NH(CH2)n-heterocyclic ring, SO2-N(C1-C6) -alkyl) (CH2)nAryl, SO2-N(C1-C6) -alkyl) (CH2)n-heterocyclic ring, SO2-N((CH2)n-aryl radicals)2、SO2-N((CH2)n- (heterocycle)2Wherein n may be 0 to 6, and said aryl or heterocyclyl group may be substituted by F, Cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2Up to 2 substitutions;
C(NH)(NH2)、NH2、NH-(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、NH(C1-C7) -acyl group, NH-CO- (C)1-C6) -alkyl, NH-COO- (C)1-C6) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (C)1-C6) Alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N (C)1-C6) -alkyl-CO- (C)1-C6) Alkyl, N (C)1-C6) -alkyl-COO- (C)1-C6) Alkyl, N (C)1-C6) alkyl-CO-aryl, N (C)1-C6) -alkyl-CO-heterocycle, N (C)1-C6) -alkyl-COO-aryl, N (C)1-C6) -alkyl-COO-heterocycle, N (C)1-C6) -alkyl-CO-NH- (C)1-C6) Alkyl), N (C)1-C6) alkyl-CO-NH-aryl, N (C)1-C6) -alkyl-CO-NH-heterocycle, N ((C)1-C6) -alkyl) -CO-N- (C)1-C6) -alkyl groups)2、N((C1-C6) -alkyl) -CO-N ((C)1-C6) Alkyl-aryl, N ((C)1-C6) -alkyl) -CO-N ((C)1-C6) -alkyl) -heterocycle, N ((C)1-C6) -alkyl) -CO-N- (aryl)2、N((C1-C6) -alkyl) -CO-N- (heterocycle)2N (aryl) -CO- (C)1-C6) Alkyl, N (heterocycle) -CO- (C)1-C6) -alkyl, N (aryl) -COO- (C)1-C6) -alkyl, N (heterocycle) -COO- (C)1-C6) Alkyl, N (aryl) -CO-aryl, N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C)1-C6) -alkyl), N (heterocycle) -CO-NH- (C1-C6) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C)1-C6) -alkyl groups)2N (heterocyclic) -CO-N- (C)1-C6) -alkyl groups)2N (aryl) -CO-N ((C)1-C6) Alkyl-aryl, N (heterocycle) -CO-N ((C)1-C6) -alkyl) -aryl, N (aryl) -CO-N- (aryl)2N (heterocyclic) -CO-N- (aryl)2Aryl, O- (CH)2)nAryl, O- (CH)2)n-heterocycle, wherein n may be 0-6, wherein said aryl or heterocyclyl may be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH2And 1 to 3 times of substitution.
Alkenyl means a straight or branched hydrocarbon chain having two or more carbons and one or more double bonds, such as for example vinyl, allyl, pentenyl.
The alkenyl group may be substituted one or more times by suitable groups such as, for example: F. cl, Br, I, CF3、NO2、N3、CN、COOH、COO(C1-C6) Alkyl, CONH2，CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2Cycloalkyl group, (C)1-C10) Alkyl radicals, (C)2-C6) -alkynyl, O- (C)1-C6) Alkyl O-CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Aryl, O-CO- (C)1-C6) -a heterocycle;
PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)nAryl, S- (CH)2)n-heterocycle, SO- (C)1-C6) Alkyl, SO- (CH)2)nAryl, SO- (CH)2)n-heterocyclic ring, SO2-(C1-C6) Alkyl, SO2-(CH2)nAryl, SO2-(CH2)n-heterocyclic ring, SO2-NH(CH2)nAryl, SO2-NH(CH2)n-heterocyclic ring, SO2-N(C1-C6) -alkyl) (CH2)nAryl, SO2-N(C1-C6) -alkyl) (CH2)n-heterocyclic ring, SO2-N((CH2)n-aryl radicals)2、SO2-N((CH2)n- (heterocycle)2Wherein n may be 0 to 6, and said aryl or heterocyclyl group may be substituted by F, Cl, Br, OH, CF3，NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2Up to 2 substitutions;
C(NH)(NH2)、NH2、NH-(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、NH(C1-C7) -acyl group, NH-CO- (C)1-C6) -alkyl, NH-COO- (C)1-C6) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (C)1-C6) Alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N (C)1-C6) -alkyl-CO- (C)1-C6) Alkyl, N (C)1-C6) -alkyl-COO- (C)1-C6) Alkyl, N (C)1-C6) alkyl-CO-aryl, N (C)1-C6) -alkyl-CO-heterocycle, N (C)1-C6) -alkyl-COO-aryl, N (C)1-C6) -alkyl-COO-heterocycle, N (C)1-C6) -alkyl-CO-NH- (C)1-C6) Alkyl), N (C)1-C6) alkyl-CO-NH-aryl, N (C)1-C6) -alkyl-CO-NH-heterocycle, N ((C)1-C6) -alkyl) -CO-N- (C)1-C6) -alkyl groups)2、N((C1-C6) -alkyl) -CO-N ((C)1-C6) Alkyl-aryl, N ((C)1-C6) -alkyl) -CO-N ((C)1-C6) -alkyl) -heterocycle, N ((C)1-C6) -alkyl) -CO-N- (aryl)2、N((C1-C6) -alkyl) -CO-N- (heterocycle)2N (aryl) -CO- (C)1-C6) Alkyl, N (heterocycle) -CO- (C)1-C6) -alkyl, N (aryl) -COO- (C)1-C6) -alkyl, N (heterocycle) -COO- (C)1-C6) Alkyl, N (aryl) -CO-aryl, N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C)1-C6) -alkyl), N (heterocycle) -CO-NH- (C1-C6) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C)1-C6) -alkyl groups)2N (heterocyclic) -CO-N- (C)1-C6) -alkanesBase)2N (aryl) -CO-N ((C)1-C6) Alkyl-aryl, N (heterocycle) -CO-N ((C)1-C6) -alkyl) -aryl, N (aryl) -CO-N- (aryl)2N (heterocyclic) -CO-N- (aryl)2Aryl, O- (CH)2)nAryl, O- (CH)2)n-heterocycle, wherein n may be 0-6, wherein said aryl or heterocyclyl may be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH2And 1 to 3 times of substitution.
Alkynyl means a straight or branched hydrocarbon chain having two or more carbons and one or more triple bonds, such as for example ethynyl, propynyl, hexynyl.
The alkynyl group may be substituted one or more times by suitable groups such as, for example: F. cl, Br, I, CF3、NO2、N3、CN、COOH、COO(C1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2Cycloalkyl group, (C)2-C6) -alkenyl, (C)1-C10) Alkyl, O- (C)1-C6) Alkyl O-CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Aryl, O-CO- (C)1-C6) -a heterocycle;
PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)nAryl, S- (CH)2)n-heterocycle, SO- (C)1-C6) Alkyl, SO- (CH)2)nAryl, SO- (CH)2)n-heterocyclic ring, SO2-(C1-C6) Alkyl, SO2-(CH2)nAryl, SO2-(CH2)n-heterocyclic ring, SO2-NH(CH2)nAryl, SO2-NH(CH2)n-heterocyclic ring, SO2-N(C1-C6) -alkyl) (CH2)nAryl, SO2-N(C1-C6) -alkyl) (CH2)n-heterocyclic ring, SO2-N((CH2)n-aryl radicals)2、SO2-N((CH2)n- (heterocycle) 2, wherein n may be 0-6, and said aryl or heterocyclyl may be substituted by F, Cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2Up to 2 substitutions;
C(NH)(NH2)、NH2、NH-(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、NH(C1-C7) -acyl group, NH-CO- (C)1-C6) -alkyl, NH-COO- (C)1-C6) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (C)1-C6) Alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N (C)1-C6) -alkyl-CO- (C)1-C6) Alkyl, N (C)1-C6) -alkyl-COO- (C)1-C6) Alkyl, N (C)1-C6) alkyl-CO-aryl, N (C)1-C6) -alkyl-CO-heterocycle, N (C)1-C6) -alkyl-COO-aryl, N (C)1-C6) -alkyl-COO-heterocycle, N (C)1-C6) -alkyl-CO-NH- (C)1-C6) Alkyl), N (C)1-C6) alkyl-CO-NH-aryl, N (C)1-C6) -alkyl-CO-NH-heterocycle, N ((C)1-C6) -alkyl) -CO-N- (C)1-C6) -alkyl groups)2、N((C1-C6) -alkyl groups)-CO-N((C1-C6) Alkyl-aryl, N ((C)1-C6) -alkyl) -CO-N ((C)1-C6) -alkyl) -heterocycle, N ((C)1-C6) -alkyl) -CO-N- (aryl)2、N((C1-C6) -alkyl) -CO-N- (heterocycle)2N (aryl) -CO- (C)1-C6) Alkyl, N (heterocycle) -CO- (C)1-C6) -alkyl, N (aryl) -COO- (C)1-C6) -alkyl, N (heterocycle) -COO- (C)1-C6) Alkyl, N (aryl) -CO-aryl, N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C)1-C6) -alkyl), N (heterocycle) -CO-NH- (C1-C6) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C)1-C6) -alkyl groups)2N (heterocyclic) -CO-N- (C)1-C6) -alkyl groups)2N (aryl) -CO-N ((C)1-C6) Alkyl-aryl, N (heterocycle) -CO-N ((C)1-C6) -alkyl) -aryl, N (aryl) -CO-N- (aryl)2N (heterocyclic) -CO-N- (aryl)2Aryl, O- (CH)2)nAryl, O- (CH)2)n-heterocycle, wherein n may be 0-6, wherein said aryl or heterocyclyl may be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH2And 1 to 3 times of substitution.
Aryl means phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha-or beta-tetrahydronaphthalenonyl, indanyl or indan-1-one-yl.
The aryl group may be substituted one or more times with suitable groups such as, for example: F. cl, Br, I, CF3、NO2、N3、CN、COOH、COO(C1-C6) Alkyl, CONH2，CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2Cycloalkyl group, (C)1-C10) Alkyl radicals, (C)2-C6) Alkyl radicals, (C)2-C6) -alkynyl, O- (C)1-C6) Alkyl O-CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Aryl, O-CO- (C)1-C6) -a heterocycle;
PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)nAryl, S- (CH)2)n-heterocycle, SO- (C)1-C6) Alkyl, SO- (CH)2)nAryl, SO- (CH)2)n-heterocyclic ring, SO2-(C1-C6) Alkyl, SO2-(CH2)nAryl, SO2-(CH2)n-heterocyclic ring, SO2-NH(CH2)nAryl, SO2-NH(CH2)n-heterocyclic ring, SO2-N(C1-C6) -alkyl) (CH2)nAryl, SO2-N(C1-C6) -alkyl) (CH2)n-heterocyclic ring, SO2-N((CH2)n-aryl radicals)2、SO2-N((CH2)n- (heterocycle)2Wherein n may be 0 to 6, and said aryl or heterocyclyl group may be substituted by F, Cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2Up to 2 substitutions;
C(NH)(NH2)、NH2、NH-(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、NH(C1-C7) -acyl group, NH-CO- (C)1-C6)-Alkyl, NH-COO- (C)1-C6) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (C)1-C6) Alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N (C)1-C6) -alkyl-CO- (C)1-C6) Alkyl, N (C)1-C6) -alkyl-COO- (C)1-C6) Alkyl, N (C)1-C6) alkyl-CO-aryl, N (C)1-C6) -alkyl-CO-heterocycle, N (C)1-C6) -alkyl-COO-aryl, N (C)1-C6) -alkyl-COO-heterocycle, N (C)1-C6) -alkyl-CO-NH- (C)1-C6) Alkyl), N (C)1-C6) alkyl-CO-NH-aryl, N (C)1-C6) -alkyl-CO-NH-heterocycle, N ((C)1-C6) -alkyl) -CO-N- (C)1-C6) -alkyl groups)2、N((C1-C6) -alkyl) -CO-N ((C)1-C6) Alkyl-aryl, N ((C)1-C6) -alkyl) -CO-N ((C)1-C6) -alkyl) -heterocycle, N ((C)1-C6) -alkyl) -CO-N- (aryl)2、N((C1-C6) -alkyl) -CO-N- (heterocycle)2N (aryl) -CO- (C)1-C6) Alkyl, N (heterocycle) -CO- (C)1-C6) -alkyl, N (aryl) -COO- (C)1-C6) -alkyl, N (heterocycle) -COO- (C)1-C6) Alkyl, N (aryl) -CO-aryl, N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C)1-C6) -alkyl), N (heterocycle) -CO-NH- (C1-C6) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C)1-C6) -alkyl groups)2N (heterocyclic) -CO-N- (C)1-C6) -alkyl groups)2N (aryl) -CO-N ((C)1-C6) Alkyl-aryl, N (heterocycle) -CO-N ((C)1-C6) -alkyl) -aryl, N (aryl) -CO-N- (aryl)2N (heterocyclic) -CO-N- (aryl) 2, aryl, O- (CH)2)nAryl, O- (CH)2)n-heterocycles, whichWherein n may be 0-6, wherein said aryl or heterocyclyl may be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH2And 1 to 3 times of substitution.
Cycloalkyl means a ring system consisting solely of carbon atoms, in saturated or partially unsaturated (with one or two double bonds) form, containing one or more rings, such as, for example, cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
The cycloalkyl group may be substituted one or more times by suitable groups such as, for example: F. cl, Br, I, CF3、NO2、N3、CN、COOH、COO(C1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2Cycloalkyl group, (C)1-C10) Alkyl radicals, (C)2-C6) Alkenyl, (C2-C6) -alkynyl, O- (C)1-C6) Alkyl O-CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Aryl, O-CO- (C)1-C6) -a heterocycle;
PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)nAryl, S- (CH)2)n-heterocycle, SO- (C)1-C6) Alkyl, SO- (CH)2)nAryl, SO- (CH)2)n-heterocyclic ring, SO2-(C1-C6) Alkyl, SO2-(CH2)nAryl, SO2-(CH2)n-heteroRing, SO2-NH(CH2)nAryl, SO2-NH(CH2)n-heterocyclic ring, SO2-N(C1-C6) -alkyl) (CH2)nAryl, SO2-N(C1-C6) -alkyl) (CH2)n-heterocyclic ring, SO2-N((CH2)n-aryl radicals)2、SO2-N((CH2)n- (heterocycle)2Wherein n may be 0 to 6, and said aryl or heterocyclyl group may be substituted by F, Cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2Up to 2 substitutions;
C(NH)(NH2)、NH2、NH-(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、NH(C1-C7) -acyl group, NH-CO- (C)1-C6) -alkyl, NH-COO- (C)1-C6) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (C)1-C6) Alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N (C)1-C6) -alkyl-CO- (C)1-C6) Alkyl, N (C)1-C6) -alkyl-COO- (C)1-C6) Alkyl, N (C)1-C6) alkyl-CO-aryl, N (C)1-C6) -alkyl-CO-heterocycle, N (C)1-C6) -alkyl-COO-aryl, N (C)1-C6) -alkyl-COO-heterocycle, N (C)1-C6) -alkyl-CO-NH- (C)1-C6) Alkyl), N (C)1-C6) alkyl-CO-NH-aryl, N (C)1-C6) -alkyl-CO-NH-heterocycle, N ((C)1-C6) -alkyl) -CO-N- (C)1-C6) -alkyl groups)2、N((C1-C6) -alkyl) -CO-N ((C)1-C6) Alkyl-aryl, N ((C)1-C6) -alkyl) -CO-N ((C)1-C6) -alkyl) -heterocycle, N ((C)1-C6) -alkyl) -CO-N- (aryl)2、N((C1-C6) -alkyl) -CO-N- (heterocycle)2N (aryl) -CO- (C)1-C6) Alkyl, N (heterocycle) -CO- (C)1-C6) -alkyl, N (aryl) -COO- (C)1-C6) -alkyl, N (heterocycle) -COO- (C)1-C6) Alkyl, N (aryl) -CO-aryl, N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C)1-C6) -alkyl), N (heterocycle) -CO-NH- (C1-C6) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C)1-C6) -alkyl groups)2N (heterocyclic) -CO-N- (C)1-C6) -alkyl groups)2N (aryl) -CO-N ((C)1-C6) Alkyl-aryl, N (heterocycle) -CO-N ((C)1-C6) -alkyl) -aryl, N (aryl) -CO-N- (aryl)2N (heterocyclic) -CO-N- (aryl)2Aryl, O- (CH)2)nAryl, O- (CH)2)n-heterocycle, wherein n may be 0-6, wherein said aryl or heterocyclyl may be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH2And 1 to 3 times of substitution.
Heterocycle or heterocyclyl means rings and ring systems which, in addition to carbon, contain heteroatoms such as, for example, nitrogen, oxygen or sulfur. Also included in this definition are ring systems in which the heterocycle or heterocyclic group is fused to a benzene nucleus.
Suitable "heterocyclic" or "heterocyclic" groups are acridinyl, azocinyl (azocinyl), benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl (benzimidazalinyl), carbazolyl, 4 aH-carbazolyl, carbolinyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, benzopyranyl, cinnolinyl, decahydroquinolyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b ] -tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolizinyl, indolyl, 3H-indolyl, Isobenzofuranyl, isobenzodihydropyranyl, isoindolyl, isoindolinyl, isoindolyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, 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, purinyl (purynyl), pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyridinyl, and the like, 2H-pyrrolyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1, 2, 5-thiadiazinyl (thiadazinyl), thiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thienyl, triazolyl, tetrazolyl, and xanthenyl.
Pyridyl represents 2-, 3-and 4-pyridyl. Thienyl represents 2-and 3-thienyl. Furyl means 2-and 3-furyl.
Also included are the corresponding N-oxides of these compounds, i.e., for example, 1-oxo-2-, 3-, or 4-pyridyl.
Also included are derivatives of these heterocycles which are benzofused one or more times.
The heterocyclic or heterocyclic group may be substituted one or more times by suitable groups such as, for example: F. cl, Br, I, CF3、NO2、N3、CN、COOH、COO(C1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2Cycloalkyl group, (C)1-C10) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, O- (C)1-C6) Alkyl O-CO- (C)1-C6) Alkyl, O-CO- (C)1-C6) Aryl, O-CO- (C)1-C6) -a heterocycle;
PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)nAryl, S- (CH)2)n-heterocycle, SO- (C)1-C6) Alkyl, SO- (CH)2)nAryl, SO- (CH)2)n-heterocyclic ring, SO2-(C1-C6) Alkyl, SO2-(CH2)nAryl, SO2-(CH2)n-heterocyclic ring, SO2-NH(CH2)nAryl, SO2-NH(CH2)n-heterocyclic ring, SO2-N(C1-C6) -alkyl) (CH2)nAryl, SO2-N(C1-C6) -alkyl) (CH2)n-heterocyclic ring, SO2-N((CH2)n-aryl radicals)2、SO2-N((CH2)n- (heterocycle)2Wherein n may be 0 to 6, and said aryl or heterocyclyl group may be substituted by F, Cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2Up to 2 substitutions;
C(NH)(NH2)、NH2、NH-(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、NH(C1-C7) -acyl group, NH-CO-(C1-C6) -alkyl, NH-COO- (C)1-C6) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (C)1-C6) Alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N (C)1-C6) -alkyl-CO- (C)1-C6) Alkyl, N (C)1-C6) -alkyl-COO- (C)1-C6) Alkyl, N (C)1-C6) alkyl-CO-aryl, N (C)1-C6) -alkyl-CO-heterocycle, N (C)1-C6) -alkyl-COO-aryl, N (C)1-C6) -alkyl-COO-heterocycle, N (C)1-C6) -alkyl-CO-NH- (C)1-C6) Alkyl), N (C)1-C6) alkyl-CO-NH-aryl, N (C)1-C6) -alkyl-CO-NH-heterocycle, N ((C)1-C6) -alkyl) -CO-N- (C)1-C6) -alkyl groups)2、N((C1-C6) -alkyl) -CO-N ((C)1-C6) Alkyl-aryl, N ((C)1-C6) -alkyl) -CO-N ((C)1-C6) -alkyl) -heterocycle, N ((C)1-C6) -alkyl) -CO-N- (aryl)2、N((C1-C6) -alkyl) -CO-N- (heterocycle)2N (aryl) -CO- (C)1-C6) Alkyl, N (heterocycle) -CO- (C)1-C6) -alkyl, N (aryl) -COO- (C)1-C6) -alkyl, N (heterocycle) -COO- (C)1-C6) Alkyl, N (aryl) -CO-aryl, N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C)1-C6) -alkyl), N (heterocycle) -CO-NH- (C1-C6) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C)1-C6) -alkyl groups)2N (heterocyclic) -CO-N- (C)1-C6) -alkyl groups)2N (aryl) -CO-N ((C)1-C6) Alkyl-aryl, N (heterocycle) -CO-N ((C)1-C6) -alkyl) -aryl, N (aryl) -CO-N- (aryl)2N (heterocyclic) -CO-N- (aryl)2Aryl, O- (CH)2)n-an aryl group,O-(CH2)n-heterocycle, wherein n may be 0-6, wherein said aryl or heterocyclyl may be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH(C1-C6) Alkyl, N ((C)1-C6) -alkyl groups)2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH2And 1 to 3 times of substitution.
The amount of a compound of formula I required to achieve the desired biological effect will depend on a variety of factors, such as the particular compound selected, the intended use, the mode of administration, and the clinical condition of the patient. The daily dose is generally in the range 0.3mg to 100mg (usually 3mg to 50mg) per day per kilogram body weight, for example 3-10 mg/kg/day. The intravenous dose may be, for example, from 0.3mg to 1.0mg/kg, which may suitably be administered as an infusion of from 10ng to 100 ng/kg/min. Suitable infusions for these purposes may contain, for example, 0.1ng to 10mg/ml, usually 1ng to 10 mg/ml. Single doses may contain, for example, from 1mg to 10g of active ingredient. Thus, ampoules for injection may contain, for example, from 1mg to 100mg of active ingredient, single-dose preparations which can be administered orally, such as capsules or tablets, may contain, for example, from 1.0 to 1000mg, usually from 10 to 600 mg. For the treatment of the above conditions, the compounds of formula I may be used as such, but they are preferably in the form of a pharmaceutical composition containing an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and not deleterious to the health of the patient. The carrier may be a solid or a liquid or both, and is preferably formulated with the compound as a single dose, e.g. a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances, including other compounds of formula I, may also be present. The pharmaceutical compositions of the present invention may be prepared by any of the known pharmaceutical methods which essentially comprise admixing the components with a pharmacologically acceptable carrier and/or excipient.
The pharmaceutical compositions of the invention 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 mode of administration in each case depends on the nature and severity of the condition being treated and on the nature of the compound of formula I used in each case. Coated formulations and coated sustained release formulations are also included within the scope of the invention. Acid-and gastric juice-resistant formulations are preferred. Suitable coatings resistant to gastric juices include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compositions for oral administration may be in the form of individual units such as capsules, cachets, lozenges or tablets, which in each case contain a specific amount of a compound of formula I; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical process which includes the step of bringing into contact the active ingredient with the carrier (which may contain one or more additional ingredients). In general, the compositions may be prepared by the following method: the active ingredient is mixed homogeneously and homogeneously with the liquid and/or finely divided solid carrier, after which the product is shaped, if necessary. Thus, tablets may be prepared, for example, by compressing or shaping a powder or granules of the compound, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, glidant, inert diluent, and/or one or more surfactants/dispersants. Shaped tablets may be prepared by shaping in a suitable machine a powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for oral (sublingual) administration include suckable tablets containing a compound of formula I in combination with a flavoring agent, usually sucrose and acacia or tragacanth, and pastilles (pastilles) containing the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, but may also be administered by subcutaneous, intramuscular or intradermal injection. These formulations can preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with blood. The injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.
Pharmaceutical compositions suitable for rectal administration are preferably in the form of single dose suppositories. These formulations may be prepared by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Pharmaceutical compositions suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Carriers which may be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is typically present at a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2% by weight.
Transdermal administration may also be used. Pharmaceutical compositions suitable for transdermal use may be in the form of a single plaster suitable for prolonged intimate contact with the epidermis of a patient. Such plasters suitably contain the active ingredient dissolved and/or dispersed in an adhesive or dispersed in a polymer in an aqueous solution, buffered as appropriate. Suitable active ingredient concentrations are about 1% to 35%, preferably about 3% to 15%. One particular possibility is a method as described, for example, in Pharmaceutical Research, 2 (6): 318(1986), the active ingredient is released by electrotransport or iontophoresis.
One or more compounds of formula (I) may also be administered in combination with other active ingredients.
Other active ingredients suitable for use in the combination product are:
all antidiabetic agents mentioned in chapter 12 of Roten Liste 2003. They may be used in combination with the compounds of formula I according to the invention, in particular for synergistic purposes. The active compound combinations can be administered by administering the active ingredients to the patient separately or in the form of a combined preparation in which a plurality of active ingredients are present in one pharmaceutical preparation. Most of the active ingredients listed below are disclosed in the USP compatibility of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
Antidiabetic agents include insulin and insulin derivatives, such as, for example, Lantus(see www.lantus.com) or HMR 1964, fast acting insulin (see US6,221,633), GLP-1 derivatives such as for example those disclosed in WO 97/26265, WO 99/03861, WO 01/04156, WO00/34331, WO 00/34332, WO 91/11457 and US6,380,357 and orally active hypoglycemic active ingredients.
Orally active hypoglycemic active ingredients preferably include sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers such as those disclosed, for example, in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, inhibitors of liver enzymes associated with the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds that alter lipid metabolism such as antihyperlipidemic active compounds and antilipidemic active compounds, compounds that reduce food intake, PPAR and PXR agonists, and active ingredients that act on the ATP-dependent potassium channels of the beta cells.
In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with cholesterol absorption inhibitors such as, for example, ezetimibe, tiquinan, pamabrin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR γ agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.
In one embodiment of the invention, the compounds of the formula I are administered in combination with PPAR α agonists such as, for example, GW9578, GW 7647.
In one embodiment of the invention, the compounds of the formula I are administered in combination with mixed PPAR α/γ agonists such as, for example, those described in GW 1536, AVE 8042, AVE 8134, AVE 0847 or PCT/US0011833, PCT/US 11490, DE 10142734.4.
In one embodiment of the invention, the compounds of the formula I are administered in combination with fibrates such as, for example, fenofibrate, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, Enptapi, BMS-201038, R-103757.
In one embodiment of the invention, the compounds of formula I are administered in combination with a bile acid absorption inhibitor (see e.g. US6,245,744 or US6,221,897) such as e.g. HMR 1741.
In one embodiment of the invention, the compound of formula I is administered in combination with a CETP inhibitor such as, for example, JTT-705.
In one embodiment of the invention, the compounds of the formula I are administered in combination with polymeric bile acid adsorbents such as, for example, cholestyramine, colesevelam.
In one embodiment of the invention, the compounds of formula I are administered in combination with an LDL receptor inducing agent (see US6,342,512) such as, for example, HMR1171 or HMR 1586.
In one embodiment of the invention, the compounds of the formula I are administered in combination with ACAT inhibitors such as, for example, avasimibe.
In one embodiment of the invention, the compounds of the formula I are applied in combination with antioxidants, such as, for example, OPC-14117.
In one embodiment of the invention, the compounds of the formula I are administered in combination with lipoprotein lipase inhibitors such as, for example, NO-1886.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP-citrate lyase inhibitor such as, for example, SB-204990.
In one embodiment of the invention, the compound of formula I is administered in combination with a squalene synthetase inhibitor such as, for example, BMS-188494.
In one embodiment of the invention, the compounds of the formula I are administered in combination with lipoprotein (a) antagonists such as, for example, CI-1027 or nicotinic acid.
In one embodiment of the invention, the compounds of the formula I are administered in combination with lipase inhibitors such as, for example, orlistat.
In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
In one embodiment, the compounds of the formula I are administered in combination with sulfonylureas, such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.
In one embodiment, the compounds of formula I are administered in combination with a biguanide such as, for example, metformin.
In another embodiment, the compounds of the formula I are administered in combination with meglitinides, such as, for example, repaglinide.
In one embodiment, the compounds of formula I are administered in combination with thiazolidinediones such as, for example, compounds disclosed in WO97/41097 to troglitazone, ciglitazone, pioglitazone, rosiglitazone or dr. reddy's Research Foundation, in particular 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxo-2-quinazolinyl) methoxy ] phenyl ] methyl ] -2, 4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in combination with an α -glucosidase inhibitor, such as, for example, miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glyburide, glipizide, glimepiride or repaglinide.
In one embodiment, the compounds of formula I are administered in combination with one or more of the above-mentioned compounds, for example with sulfonylureas and metformin, sulfonylureas and acarbose, repaglinide and metformin, insulin and sulfonylureas, insulin and metformin, insulin and troglitazone, insulin and lovastatin, and the like.
In another embodiment, the compounds of formula I are administered in combination with: CART modulators (see "cocaine-amphetamine regulated transcription affecting energy metabolism, anxiety and gastric emptying in mice" Asakawa, A et al, M.: Hormone and Metabolic Research (2001), 33(9), 554-), NPY antagonists such as naphthalene-1-sulfonic acid {4- [ (4-aminoquinazolin-2-ylamino) methyl ] cyclohexylmethyl } amide hydrochloride (CGP 71683A)), MC4 agonists such as 1-amino-1, 2, 3, 4-tetrahydronaphthalene-2-carboxylic acid [2- (3A-benzyl-2-methyl-3-oxo-2, 3, 3A, 4, 6, 7-hexahydropyrazolo [4, 3-c ] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoethyl ] amide (WO 01/91752)), ", and, Orexin antagonists (e.g., 1- (2-methylbenzoxazol-6-yl) -3- [1, 5] naphthyridin-4-ylurea hydrochloride (SB-334867-A)), H3 agonists (3-cyclohexyl-1- (4, 4-dimethyl-1, 4, 6, 7-tetrahydroimidazo [4, 5-c ] pyridin-5-yl) propan-1-one oxalate (WO 00/63208)), TNF agonists, CRF antagonists (e.g., [ 2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-1, 3, 9-triazafluoren-4-yl ] dipropylamine (WO 00/66585)), CRF BP antagonists (e.g., urocortin (urocortin)),) and, Urocortin agonists, beta 3-agonists (e.g. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2, 3-dimethyl-1H-indol-6-yloxy) ethylamino ] ethanol hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2- [4- (4-chloro-2, 5-dimethoxyphenyl) -5- (2-cyclohexylethyl) thiazol-2-ylcarbamoyl ] -5, 7-dimethylindol-1-yl } acetic acid trifluoroacetate (WO99/15525), 5-hydroxytryptamine reuptake inhibitors (e.g. dextrofenfluramine), Mixed 5-hydroxytryptamine and noradrenergic compounds (e.g., WO 00/71549), 5HT agonists such as 1- (3-ethylbenzofuran-7-yl) piperazine oxalate (WO 01/09111), bombesin agonists, somatostatin neuropeptide antagonists, growth hormones (e.g., human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see, e.g., EP 0462884), uncoupling protein 2 or protein 3 modulators, leptin agonists (see, e.g., Lee, Daniel w.; leingung, Matthew.; Rozhavskaya-Arena, marina; drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptine, dopexin), lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR- β agonists.
In one embodiment of the invention, the other active ingredient is leptin; see, e.g., "therapeutic application prospect for leptin", Salvador, Javier; Gomez-Ambrosi, Javier; fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-.
In one embodiment, the other active ingredient is dextroamphetamine or amphetamine.
In one embodiment, the other active ingredient is an antihypertensive, such as, for example, an ACE inhibitor.
In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.
In another embodiment, the other active ingredient is sibutramine.
In one embodiment, the other active ingredient is orlistat.
In one embodiment, the other active ingredient is mazindol or phentermine.
In one embodiment, the compounds of formula I are administered in combination with a bulking agent, preferably an insoluble bulking agent (see, e.g., carob/Caromax)(Zunft H J et al, carob pulp preparations for the treatment of hypercholesterolemia, ADVANCES IN THERAPY (20019 months-10 months), 18(5), 230-6). Caromax is a peptide derived from Nutrinova, Nutrition Specialties&FoodIngredients GmbH，Industiepark65926 the carob-containing product supplied by Frankfur/Main). The compound of formula I and Caromax may be administered in one formulation or by separate administrationTo implement with CaromaxCombinations of (a) and (b). CaromaxIt can also be administered in the form of a food product, for example in the form of a bakery or breakfast bar.
It is to be understood that each suitable combination of a compound of the invention with one or more of the above-mentioned compounds and, if desired, one or more other pharmaceutically active substances is to be regarded as falling within the scope of the present invention.
The examples described in detail below are intended to illustrate the invention, but not to limit it.
The activity of the compounds was tested as follows:
enzyme assay for detecting phosphatase inhibition
The compounds of formula I were tested for their phosphatase inhibiting effect in an in vitro assay. The preparation of the enzyme and the implementation of the assay were carried out as follows.
Obtaining an enzyme preparation
A) Cell culture:
sf9 cells (Spodoptera frugiperda type cells; available from invitrogen) were cultured in spinner flasks at 28 ℃ with Grace supplemented medium (Gibco-BRL) containing 10% heat-inactivated fetal bovine serum (Gibco-BRL) according to the protocol of Summers and Smith (A Manual for Methods for bacterial vectors and Induction Culture Processes [ Bulletin No.15555]. Texas A & Munichity, Texas Agricultural Experiment Station, College Station, TX, 1987).
Construction of recombinant baculovirus transfer vectors: a cDNA encoding the regulatory and catalytic domain of human PTP1B, but not having a carboxy-terminal hydrophobic region (equivalent to 1-299aa), was obtained by polymerase chain reaction with the attached cloning site and an appropriate cDNA template (available from invitrogen, for example) via primers, and then cloned into a baculovirus expression vector (amersham pharmacia Biotech.). Recombinant baculoviruses were prepared with the aid of the Bac-to-Bac baculovirus expression system (available from Gibco-BRL). The gene was cloned into the pFASTBA AC donor plasmid (available from Life Technologies). The resulting plasmid was transferred into competent DH10BAC E.coli (Escherichia coli) cells (available from Life Technologies). After transposition and antibiotic selection, the recombinant plasmid DNA was isolated from the selected E.coli colonies and then used for transfection of Sf9 insect cells. The virus particles in the upper medium were amplified three times until a virus reservoir volume of 500ml was reached.
B) Preparation of recombinant protein:
baculovirus infection of 500ml spinner cultured Sf9 cells was performed essentially as described by Summers and Smith (supra). Sf9 cells were pelleted at 1-3X 10 by centrifugation at 300g for 5 min6Individual cellPrecipitating at a density of 1X 10/ml, removing the supernatant, and isolating the cells7The density of individual cells/ml was resuspended in a suitable recombinant virus stock solution (MOI 10). After careful shaking at room temperature for 1.5 hours, fresh medium was added to achieve a cell density of 1X 106Individual cells/ml. Then, after infection, the cells were cultured in this suspension at 28 ℃ for a suitable time.
C) Cell fractionation and whole cell extracts of infected Sf9 cells:
after infection, aliquots were analyzed for protein expression by SDS-PAGE and Western blot analysis. Cell fractionation was carried out as described (Cromlish, W. and Kennedy, B.biochem. Pharmacol.52: 1777-1785, 1996). Whole cell extracts were obtained from 1ml aliquots of infected Sf9 cells at a time post infection. The pelleted cells (300 Xg, 5 min) were washed once with phosphate-buffered saline (4 ℃), resuspended in 50. mu.l water and disrupted by repeated freeze/thaw. The protein concentration was determined by means of the Bradford method and using bovine serum albumin as standard.
The operation method of the determination method comprises the following steps:
A) dephosphorylation of phosphopeptides:
the assay is based on phosphate release of a consensus substrate peptide, which is detected at nanomolar concentrations by the malachite green/ammonium molybdate method (Lanzetta, P.A., Alvarez, L.J., Reinach, P.S., Candia, O.A. anal biochem.100: 95-97, 1979) adapted to microtiter plate format. The dedecasphinpeptide TRDIYETDYRK (Biotrend, Cologne) corresponds to amino acid 1142-1153 of the catalytic domain of the insulin receptor, which is (auto-) phosphorylated on tyrosine residues 1146, 1150 and 1151. The recombinant hPTP1B was diluted with assay buffer (40mM Tris/HCl, pH7.4, 1mM EDTA, 20mM DTT), corresponding to an activity of 1000-1500nmol/min/mg protein, and then (20. mu.l aliquots) were subjected to a total volume of 90. mu.l (assay buffer) in the absence or presence of test substance (5. mu.l) at the desired concentration (final DMSO concentration 2% maximum)Preincubation (15 min, 30 ℃). To start the dephosphorylation reaction, the peptide substrate (10. mu.l, prewarmed to 30 ℃) was added to the pre-incubated enzyme preparation with or without test substance (final concentration 0.2-200. mu.M) and incubation was continued for 1 hour. The reaction was stopped by adding 100 μ l of malachite green hydrochloride (0.45%, 3 parts), ammonium molybdate tetrahydrate (4.2%, in 4N HCl, 1 part) and 0.5% tween 20 as stop solution. After incubation at 22 ℃ for 30 minutes to develop the color, the absorbance at 650nm was measured with a microtiter plate reader (molecular apparatus). Samples and blanks were measured in triplicate. PTP1B activity was calculated as the number of nanomoles of phosphate released per minute per milligram of protein using potassium phosphate as a standard. The inhibition of recombinant hPTP1B by the test substance was calculated as a percentage of the phosphatase control. IC (integrated circuit)50The values are in clear agreement with the four-parameter nonlinear logistic regression curve.
B) Cleavage of p-nitrophenyl phosphate:
the assay is based on the alteration of the uptake of the non-physiological substrate p-nitrophenyl phosphate during cleavage under standard conditions to produce nitrophenols (Tonks, N.K., Diltz, C.D:, Fischer, E.H.J.biol.chem.263: 6731-. An appropriate dilution of the inhibitor was pipetted into the reaction mixture containing 0.5-5mM p-nitrophenyl phosphate. The following buffers (total volume 100. mu.l) were used: (a)100mM sodium acetate (pH5.5), 50mM NaCl, 0.1% (w/v) bovine serum albumin, 5mM glutathione, 5mM DTT, 0.4mM EGTA and 1mM EDTA; (b)50mM Hepes/KOH (pH7.4), 100mM NaCl, 0.1% (w/v) bovine serum albumin, 5mM glutathione, 5mM DTT and 1mM EDTA. The reaction was started by adding the enzyme and allowed to react in a microtiter plate at 25 ℃ for 1 hour. The reaction was stopped by adding 100. mu.l of 0.2N NaOH. The enzyme activity was determined by measuring the absorbance at 405nm, with appropriate calibration of the absorbance of the test substance and p-nitrophenyl phosphate. The results are expressed as a percentage of the control by comparing the amount of p-nitrophenol formed in the sample treated with the test substance (nmol/min/mg protein) with the amount of p-nitrophenol formed in the untreated sample. The mean and standard deviation were calculated and IC50 values were determined by regression analysis of the linear portion of the inhibition curve.
Table 2: biological activity
Examples IC-50(μM)
1 ＞80
2 27.8
3 8.8
4 6.2
5 15.9
6 48.0
7 7.9
8 5.9
9 6.3
10 5.3
11 6.2
12 ＞80
13 ＞80
14 2.77
As can be seen from the table, the compounds of formula I inhibit the activity of phosphotyrosine phosphatase 1B (PTP1B) and are therefore highly suitable for lowering blood glucose levels. They are therefore particularly suitable for the treatment of type I and type II diabetes, insulin resistance, dyslipidemia (dyslipemia), metabolic syndrome/syndrome X, morbid obesity and for reducing body weight in mammals. Because it inhibits PTP1B, the compounds of formula I are also suitable for the treatment of hypertriglyceridemia, hypertension, atherosclerosis, immune system dysfunction, autoimmune diseases, allergic diseases such as, for example, asthma, arthritis, osteoarthritis, osteoporosis, proliferative disorders such as cancer and psoriasis, diseases associated with a reduction or an increase in the production of growth factors, hormones or cytokines which induce the release of growth hormone. These compounds are also useful in the treatment of neurological disorders such as, for example, alzheimer's disease or multiple sclerosis. These compounds are also useful in the treatment of health disorders and other psychiatric indications such as, for example, depression, anxiety states, anxiety neurosis, schizophrenia, as well as in the treatment of circadian rhythm-related disorders and drug abuse. They are also suitable for the treatment of sleep disorders, sleep apnoea, female and male sexual dysfunction, inflammation, acne, skin pigmentation, disorders of steroid metabolism, skin diseases and mycoses.
The preparation of some examples is described in detail below, and other compounds of formula I can be obtained analogously:
experimental part:
a solution of 2-fluoro-5-nitrobenzyl bromide (30g, 0.128mol) in acetonitrile (250ml) was added to Na2SO3(27.36g, 0.128mol) in H2To a solution in O (375ml), the mixture was stirred at room temperature for 24 hours. The solvent is distilled off in vacuo, the residue is stirred with 100ml of isopropanol, the solid is filtered off and washed with a little isopropanol and diethyl ether.
Yield: 28.15g
Sodium salt of sulfonic acid 1(35.19g, 0.1368mol) was added to POCl3(430ml) and then PCl was added5(28.78g, 0.137 mol). The mixture was heated at reflux for 5 hours. For work-up, it was concentrated under vacuum and the residue was poured into ice/water. The reaction product was isolated as a pale yellow solid which was filtered off.
Yield: 30.3g
Sulfonyl chloride 1(30.3g, 0.12mol) in CH at room temperature2Cl2The solution in (125ml) was added dropwise to concentrated ammonia (90ml, 1.2 mol). The mixture was stirred at room temperature for 20 hours and then acidified to pH1 with HCl (1N). The organic phase was distilled off under reduced pressure, during which the reaction product was isolated as a pale yellow solid. The reaction product was then filtered off.
Yield 25.01g (89.4%).
Diazabicycloundecene (34.1g, 33.42ml, 0.22mol) was added to a solution of compound 1(25g, 0.107mol) in DMF (1L) at room temperature and the reaction mixture was stirred at 130 ℃ for 2 hours. The solvent was then distilled off in vacuo, the residue was mixed with water (400ml), HCl (2N, 400ml) was added and the product was extracted several times with dichloromethane. The combined organic phases were dried (Na)2SO4) And the solvent was distilled off under reduced pressure. The residue remaining was stirred with a small amount of cold isopropanol and the reaction product was filtered off.
Yield: 20.8g (91.3%).
535mg of nitro compound are dissolved in 100ml of a methanol/THF mixture (1: 1), to which 5 mol% Pd (10% on activated carbon) are added. Hydrogenation was carried out with hydrogen in a hydrogenation apparatus at room temperature until absorption of hydrogen ceased (reaction time: 1 hour). For the working-up, Celite was usedThe catalyst was filtered off with a filter aid and the filtrate was concentrated under reduced pressure. The oily residue is stirred with a small amount of diethyl ether, filtered off, washed with n-pentane and dried in vacuo.
Yield: 397mg (86% of theory)
368mg (2mmol) of the amine prepared above was dissolved in 30ml of anhydrous THF, and 250. mu.l of ethoxycarbonyl isothiocyanate was added thereto while stirring at room temperature. Then, the mixture was stirred at room temperature for 4 hours.
For working up, the solvent is removed under reduced pressure, the oily residue is stirred with diethyl ether and the reaction product is filtered off.
Yield 613mg (97% of theory) beige crystals
504mg (1.6mmol) of carbamate were suspended in 10ml of THF/water (1: 1), and 3.2ml of 3.2(mmol)1M aqueous NaOH solution was added thereto while stirring at room temperature. The reaction mixture was stirred at room temperature for 5 hours.
For work-up, its volume was concentrated under reduced pressure to about 1/3 of the initial volume and the reaction mixture was adjusted to pH6 by addition of 2N aqueous HCl, so that the resulting thiourea slowly isolated as pale beige crystals. The reaction product was filtered off and washed with water.
Yield 300mg (77% of theory)
Example 1:
73mg (0.3mmol) of thiourea were dissolved in 5ml of absolute ethanol, and 85mg (0.3mmol) of 4- (trifluoromethoxy) phenacyl bromide was added. The reaction mixture was heated under reflux of the solvent for 5 hours.
For working up, the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (15-25 μ; from Merck) using ethyl acetate/n-heptane (mixing ratio 1: 1) as mobile phase.
Yield 79mg (61% of theory)

Claims (10)

1. A compound of the formula I or a physiologically tolerated salt thereof,
the meaning is as follows:
r1 is aryl selected from phenyl and naphthyl, COOH, heterocycle selected from benzothienyl and pyridyl, wherein said aryl and heterocycle may be substituted by F, Cl, Br, OH, (C)1-C6) Alkyl, OCF3N (R9) (R10) one or more times;
r2 is H, (C)1-C6) -an alkyl group;
r3 is H;
r4, R5 is H;
r6, R7 is H;
r8 is H;
r9 and R10 form together with the N atom to which they are bound a 3-to 9-membered ring system.
2. A compound of the formula I as claimed in claim 1, in which the meanings are:
r1 is phenyl, where the phenyl group may be substituted by F, Cl, Br, OH, (C)1-C6) Alkyl radical, OCF3N (R9) (R10) one or more times;
r2 is H, (C)1-C6) -an alkyl group;
r3 is H;
r4, R5 is H;
r6, R7 is H;
r8 is H;
r9 and R10 form together with the N atom to which they are bound a 3-to 9-membered ring system.
3. A pharmaceutical composition comprising one or more compounds of claim 1 or 2.
4. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment or prophylaxis of diabetes.
5. The use according to claim 4, wherein the medicament is for the treatment of type II diabetes.
6. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for lowering blood glucose.
7. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment of disorders of lipid and carbohydrate metabolism.
8. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment of the manifestations of arteriosclerosis.
9. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of insulin resistance.
10. A process for the preparation of a medicament containing one or more compounds as claimed in claim 1 or 2, which comprises mixing the compounds with a suitable pharmaceutically acceptable carrier and converting the mixture into a form suitable for administration.
HK06112382.5A 2003-07-28 2004-07-15 Substituted thiazole-benzoisothiazole dioxide derivatives, method for the production thereof and use of the same HK1091825B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10334309.1 2003-07-28
DE10334309A DE10334309A1 (en) 2003-07-28 2003-07-28 Substituted thiazole-Benzoisothiazoldioxidderivate, processes for their preparation and their use
PCT/EP2004/007847 WO2005012295A1 (en) 2003-07-28 2004-07-15 Substituted thiazole-benzoisothiazole dioxide derivatives, method for the production thereof and use of the same

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HK1091825A1 HK1091825A1 (en) 2007-01-26
HK1091825B true HK1091825B (en) 2009-03-20

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