CRYSTAL STRUCTURES OF SGLT2 INHIBITORS AND PROCESSES FOR PREPARING SAME
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Abstract
The present invention relates to physical crystal structures of compound of the formula (I):
which is an H-1 form, H-2 form or S-PG form, pharmaceutical compositions containing structures of compound I and methods of treating diseases using compound I.
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Citations
28 Claims
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1. A crystal structure of
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5. The crystal structure of the (S)-propylene glycol ((S)—
- PG) Ia
- View Dependent Claims (11, 12, 13, 14, 15, 16, 26)
which comprises: reacting a compound of Formula I
in an organic solvent with (S)-propylene glycol to yield the compound of Formula Ia.
- PG) Ia
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12. The process as defined in claim 11 including the step of adding seeds of compound Ia ((S)—
- PG) to the reaction mixture containing compound I and (S)-propylene glycol.
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13. The process as defined in claim 11 wherein the organic solvent is an alkyl acetate or methyl t-butyl ether.
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14. A process for preparing a crystalline compound Ia as defined in claim 5, which comprises reacting a compound of the structure
with a reducing agent in the presence of an activating group to form compound I of the structure reacting compound I with (S)-propylene glycol in the presence of an organic solvent, optionally adding seeds of compound Ia ((S)— - PG) to the reaction mixture, to form crystalline compound Ia
- PG) to the reaction mixture, to form crystalline compound Ia
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15. The process as defined in claim 14 wherein the reducing agent is an alkylsulfyl halide and the activating group is a Lewis acid.
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16. The process as defined in claim 15 wherein the reducing agent is triethylsilane, the activating group is BF3OEt2 or BF3.2CH3COOH, and in the organic solvent is methyl t-butyl ether.
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26. A method of treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, dyslipidemia, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels in a mammal comprising administering to the mammal a therapeutically-effective amount of the crystal structure according to claim 5.
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6. The crystal structure of the L-phenylalanine (L-Phe) (form H-1) Ib
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7. The crystal structure of the L-phenylalanine (L-Phe) (form H-2) Ic
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17. A process for preparing the L-phenylalanine of the structure of formula Ic form H-2
which comprises a) providing compound A of the structure b) dissolving compound A in an alcohol solvent; -
c) treating the resulting solution with strong base; d) heating the resulting mixture at a temperature within the range from about 45 to about 55°
C.;e) cooling the resulting mixture to a temperature within the range from about 15 to about 30°
C.;f) adding strong mineral acid to the cooled mixture to neutralize the mixture; g) adding L-phenylalanine in an organic solvent and water to the mixture; h) heating the mixture to obtain a solution; i) optionally adding seeds of compound Ic form H-2, in a slurry with water and solvent, to the solution; and j) cooling the resulting solution to form crystals of compound Ic form H-2. - View Dependent Claims (18, 19)
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Specification