N-(indole-2-carbonyl)-b-alaninamide crystal forms
AssigneePfizer Inc.
InventorsDouglas J. M. Allen, Frank R. Busch, Joseph F. Krzyzaniak, Zheng Jane Li, Susan L. Orrill, Peter R. Rose, Derek L. Tickner, Harry O. Tobiassen
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Abstract
The instant invention provides crystal forms of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (I) 1 processes for the production of such crystal forms; pharmaceutical compositions comprising such crystal forms; and methods of treating glycogen phosphorylase dependent diseases, or conditions with such crystal forms, or such pharmaceutical compositions.
Claims27
Amorphous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide.
A crystal form of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form A), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) of about 12.73, 16.82, 17.67, 20.24, 20.56, 20.96, 21.41, 25.61 and 25.85, and X-ray diffraction d-spacings (Å) of about 6.95, 5.27, 5.02, 4.38, 4.32, 4.23, 4.15, 3.48, and 3.44, respectively.
A crystal form of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form B), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) of about 10.08, 11.49, 17.59, 19.42, 19.75, 21.65, 22.91, 24.66 and 26.42, and X-ray diffraction d-spacings of about 8.77, 7.70, 5.04, 4.57, 4.49, 4.10, 3.88, 3.61, and 3.37, respectively.
A crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, mono-ethanolate (Form C), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) of about 6.26, 8.70, 18.46, 19.22, 21.24, 23.27, 23.62, 23.87, and X-ray diffraction d-spacings of about 14.12, 10.16, 4.80, 4.61, 4.18, 3.82, 3.76, and 3.72, respectively.
A crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate (Form D), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) at about 4.90, 8.53, 14.38, 18.13, 21.74, 22.23, 22.46, 22.97 and 23.45, and X-ray diffraction d-spacings of about 18.02, 10.36, 6.15, 4.89, 4.08, 4.00, 3.96, 3.87, and 3.79, respectively.
A crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, hemi-ethanolate (Form E), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) at about 11.97, 16.80, 20.07, 21.06, 22.00, 23.89, and 26.27, and X-ray diffraction d-spacings of about 7.39, 5.27, 4.42, 4.22, 4.04, 3.72, and 3.39, respectively.
A crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, monohydrate (Form F), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) at about 4.30, 6.07, 9.67, 13.66, 17.88, 20.09, 10 and 21.88, and X-ray diffraction d-spacings of about 20.54, 14.54, 9.14, 6.48, 4.96, 4.42, and 4.06, respectively.
A crystal form of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form G), crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) at about 18.2, 20.1, 24.3, 25.2, and 26.3, and X-ray diffraction d-spacings, expressed in Å, of about 4.9, 4.4, 3.7, 3.5, and 3.4, respectively.
A process for preparing anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form A), which process comprises azetropically distilling a solution prepared from 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate (Form D), in an aprotic solvent to substantially remove said water of hydration and crystallize said Form A crystal form.
A process for preparing anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form B), which process comprises the steps of:
- (a) adding water to a suspension of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form A), or 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate (Form D) crystal forms, in an aprotic solvent such that a water content of between about 0.5% and about 5.0% is achieved, and said Form A or said Form D crystal form is substantially dissolved to form a solution;
- and
- (b) allowing said Form B crystal form to crystallize from said solution.
A process for purifying anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form B), which process comprises the steps of:
- (a) heating a suspension of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form B) in an aqueous solvent system comprising:
- (i) tetrahydrofuran and an aprotic, substantially tetrahydrofuran-miscible co-solvent;
- and
- (ii) about 3% to about 8% water;
- such that said Form B crystal form is substantially dissolved to form a solution;
- and
- (b) heating said solution to substantially remove aqueous tetrahydrofuran and crystallize said Form B crystal form.
A process for preparing 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate (Form D), which process comprises the steps of:
- (a) adding water to a suspension of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form A), or anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form B) (Form B) crystal forms in an aprotic solvent such that a water content of between about 5% and about 10% is achieved;
- (b) heating said suspension to substantially dissolve said Form A or said Form B crystal form to form a solution;
- and
- (c) diluting said solution with a non-polar, anti-solvent to crystallize said Form D crystal form.
A pharmaceutical composition comprising a Form A or Form B crystal form of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, or a Form D crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate, and a pharmaceutically acceptable carrier, vehicle, or diluent.
A method of treating a glycogen phosphorylase dependent disease or condition which method comprises administering to a mammal in need of such treatment a Form A or Form B crystal form of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, a Form D crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate, or a pharmaceutical composition comprising such Form A, Form B, or Form D crystal forms.
Dependencies are inferred from the claim text.