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US 2019/0055226 A1Published application
5-fluoro-c-(aryl or heterocyclyl)-glycoside derivatives useful as dual sglt1 / sglt2 modulators
AssigneeJanssen Pharmaceutica NV
InventorsGuozhang Xu, Gee-Hong Kuo, Micheal Gaul
Life of this patent
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Abstract
The present invention is directed to 5-fluoro-C-(aryl or hetercyclyl)-glycoside derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by SGLT activity, more particularly dual SGLT1/2 activity.
Claims26
A compound of formula (I)
- wherein
- R1 is selected from the group consisting of —C1-4alkyl, hydroxy substituted C1-4alkyl, —CH2—R10, C3-6cycloalkyl, hydroxy substituted C3-6cycloalkyl, —C(O)OH and —C(O)O—(C1-4alkyl);
- wherein R10 is selected from the group consisting of fluoro, C1-2alkoxy, cyano and NRARB;
- wherein RA and RB are each independently selected from the group consisting of hydrogen and C1-2alkyl;
- R2 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-4alkyl, —(C1-4alkyl)-OH, C1-4alkoxy, cyano substituted C1-4alkoxy, C2-4alkenyl, C2-4alkenyl-oxy, benzyloxy and carboxy;
- R3 is selected from the group consisting of hydrogen, halogen, C1-4alkyl and C2-4alkenyl;
- R4 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, cyano substituted C1-4alkoxy, and C3-6cycloalkyl;
- alternatively, R2 and R3 or R3 and R4 are taken together with the carbon atoms to which they are bound to form a ring structure selected from the group consisting of 2,3-dihydro-furanyl and 3,4-dihydro-2H-pyranyl;
- wherein the 2,3-dihyfro-furanyl or 3,4-dihydro-2H-pyranyl is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, methyl, ethyl, hydroxy-methyl- and hydroxyethyl-;
- R5 and R6 are the same and are hydrogen;
- is selected from the group consisting of C5-12cycloalkyl, C5-12cycloalkenyl, phenyl, heteroaryl and heterocyclyl;
- wherein the phenyl, heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo (i.e. ═O), C1-4alkyl, C1-4alkoxy, fluorinated C1-2alkyl, fluorinated C1-2alkoxy, cyano, 2,5-dimethyl-thien-3-yl, 5-methyl-thiazol-2-yl and —C(O)—R11;
- wherein R11 is selected from the group consisting of C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl and thiazol-2-yl;
- provided that when is bicyclo[4.2.0]octa-1 (6),2,4-trien-3-yl or bicyclo[4.2.0]octan-3-yl, then R2 and R3 or R3 and R4 are taken together with the carbon atoms to which they are bound to form a ring structure selected from the group consisting of 4,5-dihydro-furanyl and tetrahydropyranyl;
- wherein 4,5-dihyfro-furanyl or tetrahydropyranyl is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, methyl, ethyl, hydroxy-methyl- and hydroxyethyl-;
- provided further that when is phenyl, wherein the phenyl is optionally substituted, then R2 and R3 or R3 and R4 are taken together with the carbon atoms to which they are bound to form a ring structure selected from the group consisting of 2,3-dihydro-furanyl and 3,4-dihydro-2H-pyranyl
- provided further that when is thienyl or pyridyl, then R2 and R3 or R3 and R4 are taken together with the carbon atoms to which they are bound to form a ring structure selected from the group consisting of 2,3-dihydro-furanyl and 3,4-dihydro-2H-pyranyl;
- provided further that when R1 is —CH2OH, R2 is H, R3 is H, R4 is H or Cl, R5 is H and R6 is H, then is other than benzothien-2-yl;
- or an isotopologue or pharmaceutically acceptable salt thereof.
16 more elements
A compound of formula (V-S)
- wherein A1, A2 and A3 are each an independently selected from the group consisting of C1-8alkyl, C3-6cycloalkyl, bicyclo[2.2.1]heptan-2-yl, phenyl and 3,5-di(trifluoromethyl)phenyl.
A process for the preparation of a compound of formula (V-S)
- wherein A1, A2 and A3 are each an independently selected from the group consisting of C1-8alkyl, C3-6cycloalkyl, bicyclo[2.2.1]heptan-2-yl, phenyl and 3,5-di(trifluoromethyl)phenyl;
- comprising
- reacting (2S,3R,4S,5R,6R)-2-(allyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, with an acylating agent;
- in the presence of an inorganic or organic base;
- neat, when in the presence of an organic base or when in the presence of an inorganic base, in an organic solvent;
- at a temperature in the range of from about −50° C. to about room temperature;
- to yield the corresponding compound of formula (A-1), wherein W is the corresponding acyl group, preferably —C(O)-methyl, —C(O)-ethyl, —C(O)-benzyl, more preferably —C(O)-benzyl (benzoyl);
- reacting the compound of formula (A-1) with a fluorinating agent;
- in an organic solvent or mixture of organic solvents;
- at a temperature in the range of from about −50° C. to about room temperature;
- to yield the corresponding compound of formula (A-2);
- de-protecting the compound of formula (A-2) to yield (2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol;
- reacting (2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol with a trialkyl silyl reagent;
- in the presence of an organic base;
- in an organic solvent or mixture of organic solvents;
- at a temperature in the range of from about 0° C. to about 50° C.;
- to yield the corresponding compound of formula (A-3) wherein A1, A2 and A3 are the corresponding alkyl groups;
- reacting the compound of formula (A-3) with allyl isomerization catalyst in an organic solvent or mixture of water and a water miscible organic solvent;
- at a temperature of in the range of from about 75° C. to about 105° C.;
- to yield the corresponding compound of formula (A-4), wherein the compound of formula (A-4) is not isolated;
- reacting the compound of formula (A-4) with an co-oxidant;
- in the presence of an oxidizing reagent;
- in an organic solvent or mixture of water and a water miscible organic solvent;
- at a temperature in the range of from about 0° C. to about 50° C.;
- to yield the corresponding compound o formula (A-5);
- reacting the compound of formula (A-5) under SWERN oxidation conditions;
- to yield the corresponding compound of formula (V-S).
24 more elements
Dependencies are inferred from the claim text.