US 8,940,927 B2 · Activators of glucokinase

Abstract

The present invention provides for novel compounds of Formulas I and II and pharmaceutically acceptable salts and co-crystals thereof which have glucokinase activator activity. The present invention further provides for pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucokinase activator is indicated, including Type 1 and 2 diabetes, impaired glucose tolerance, insulin resistance and hyperglycemia. The present invention also provides for processes of making the compounds of Formulas I and II, including salts and co-crystals thereof, and pharmaceutical compositions comprising the same.

A compound of Formula (II),

wherein:
X is selected from the group consisting of aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy, and arylalkyloxy, and
G2 is CR4;
R2 is optionally substituted arylene-O—;
G1 is CR4;
G3 is CR4;
R4 is H, halogen, or optionally substituted alkyl;
D is selected from a group consisting of heteroaryl, aryl, optionally substituted heteroaryl, and optionally substituted aryl;
R50 is —P(O)(XY2R51)R1 or —P(O)(YR51)Y1R51;
R1 is selected from the group consisting of hydrogen, optionally substituted —C1-C6-alkyl, —CF3, —CHF2, —CH2F, —CH2OH, optionally substituted —C2-C6 alkenyl, optionally substituted —C2-C6 alkynyl, optionally substituted —(CR522)ncycloalkyl, optionally substituted (CR522)nheterocycloalkyl, —(CR522)k S(=0)R53, and —(CR522)kS(═O)2R53;
Y, Y1, and Y2 are each independently selected from —O— or —NR60;
wherein,
when Y2 is —O— or when Y and Y1 are both —O—, R51 attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted —CH2-heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R52)2OC(O)NR522, —NR52—C(O)—R53, —C(R52)2—OC(O)R53, —C(R52)2—O—C(O)OR53, —C(R52)2OC(O)SR53, -alkyl-S—C(O)R53, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy;
or
when Y2 is —NR60— or when Y and Y1 are both —NR60—, then R51 attached to —NR60— is independently selected from —H, —[C(R52)2]r—COOR53, —C(R54)2COOR53, —[C(R52)2]r—C(O)SR53, and -cycloalkylene-COOR53;
or
when Y is —O— and Y1 is NR60, then R51 attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R52)2OC(O)NR522, —NR52—C(O)—R53, —C(R52)2—OC(O)R53, —C(R52)2—O—C(O)OR53, —C(R52)2OC(O)SR53, -alkyl-S—C(O)R53, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy, and R51 attached to —NR60— is independently selected from —H, —[C(R52)2]r—COOR53, —C(R54)2COOR53, —[C(R52)2]r—C(O)SR53, and -cycloalkylene-COOR53, wherein if both R51 are alkyl, at least one is higher alkyl;
or
when Y and Y1 are independently selected from —O— and —NR60—, then R51 and R51 together form a cyclic group comprising -alkyl-S—S-alkyl-, or R51 and R51 together are the group
wherein,
V, W, and W′ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl;
and
Z is —CHR52OH, —CHR52OC(O)R53, —CHR52OC(S)R53, —CHR52OC(S)OR53, —CHR52OC(O)SR53, —CHR52OCO2R53, —OR52, —SR52, —CHR52N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR522)OH, —CH(C═CR52)OH, —R52, —NR522, —OCOR53, —OCO2R53, —SCOR53, —SCO2R53, —NHCOR52, —NHCO2R53, —CH2NHaryl, —(CH2)r—OR52 or —(CH2)r—SR52;
or
W and W′ are as defined above and together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon;
or
W′ and Z are as defined above and together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms or carbon substituted by hydrogen and substituted with one substituent selected from hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy which is attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
or
V and W′ are as defined above and together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
or
V and Z are as defined above and together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, where V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R52 is R53 or —H;
R53 is alkyl, aryl, heterocycloalkyl or aralkyl;
R54 is independently selected from —H or alkyl, or together R54 and R54 form a cycloalkylene group;
R60 is —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, lower acyl, C1-6-perfluoroalkyl or NH(CR55R55)fCH3;
r is an integer 2 or 3;
f is an integer 0, 1, or 2;
wherein, V, Z, W, W′ are not all —H, and when Z is —R52, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl;
and
pharmaceutically acceptable salts thereof.

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Activators of glucokinase

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Activators of glucokinase

Life of this patent

Abstract

Claims31