POLYMORPHS, SOLVATES, AND HYDRATE OF 5-(4'-FLUORO-2'-OXO-1',2'-DIHYDROSPIRO[CYCLOPROPANE-1,3'-INDOL]-5'-YL)-1--METHYL-1H-PYRROLE-2-CARBONITRILE
First Claim
1. A form of 5-(4′
- -fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile selected from the group consisting of;
(i) polymorph Form II of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising;
(a) an X-ray diffraction peak pattern comprising a peak at 2θ
of about 12.5°
at greater than about 95% relative intensity; and
(b) a differential scanning calorimetry thermogram having an endothermic peak with a Tonset of about 223°
C.;
(ii) polymorph Form III of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising;
(c) an X-ray diffraction peak pattern comprising a peak at 2θ
of about 18.7°
at greater than about 95% relative intensity; and
(d) a differential scanning calorimetry thermogram having an endothermic peak with a Tonset of about 220.5°
C.;
(iii) solvate Form I of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising an X-ray diffraction peak pattern comprising a peak at 2θ
of about 14.8°
at greater than about 95% relative intensity;
(iv) solvate Form II of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising;
(e) an X-ray diffraction peak pattern comprising a peak at 2θ
of about 9.5°
at greater than about 95% relative intensity; and
(f) a differential scanning calorimetry thermogram having an endothermic peak with a Tonset of about 221.5°
C., 95.3°
C., or a combination thereof;
(v) solvate Form III of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising;
(g) an X-ray diffraction peak pattern comprising a peak at 2θ
of about 11.9°
at greater than about 95% relative intensity; and
(h) a differential scanning calorimetry thermogram having an endothermic peak with a Tonset of about 224.6°
C., 103.2°
C., or a combination thereof;
(vi) solvate Form IV of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising an X-ray diffraction peak pattern comprising a peak at 2θ
of about 22.3°
at greater than about 95% relative intensity; and
(vii) hydrate of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising;
(j) an X-ray diffraction peak pattern comprising a peak at 2θ
of about 8.4°
at greater than about 95% relative intensity; and
(k) a differential scanning calorimetry thermogram having one endothermic peak with a Tonset of about 223°
C. and a second endothermic peak with a Tonset of about 111°
C.
1 Assignment
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Accused Products
Abstract
Novel polymorph Form II and III, solvate Forms I, II, III, and IV, and the hydrate of 5-(4′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-5′-yl)-1-methyl-1H-pyrrole-2-carbonitrile are provided, as are methods for preparing the same. Pharmaceutical compositions and kits containing these novel polymorphs, solvates, and hydrate, and combinations thereof are further provided, as are methods of contraception; treating or preventing fibroids, uterine leiomyomata, endometriosis, dysfunctional bleeding, polycystic ovary syndrome, hormone-dependent carcinomas; treating symptoms of premenstrual syndrome and premenstrual dysphoric disorder; providing hormone replacement therapy; stimulating food intake; synchronizing estrus; or treating symptoms of premenstrual syndrome using one or more of these polymorphs, solvates, or hydrate.
12 Citations
37 Claims
-
1. A form of 5-(4′
- -fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile selected from the group consisting of;(i) polymorph Form II of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising;(a) an X-ray diffraction peak pattern comprising a peak at 2θ
of about 12.5°
at greater than about 95% relative intensity; and(b) a differential scanning calorimetry thermogram having an endothermic peak with a Tonset of about 223°
C.;(ii) polymorph Form III of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising;(c) an X-ray diffraction peak pattern comprising a peak at 2θ
of about 18.7°
at greater than about 95% relative intensity; and(d) a differential scanning calorimetry thermogram having an endothermic peak with a Tonset of about 220.5°
C.;(iii) solvate Form I of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising an X-ray diffraction peak pattern comprising a peak at 2θ
of about 14.8°
at greater than about 95% relative intensity;(iv) solvate Form II of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising;(e) an X-ray diffraction peak pattern comprising a peak at 2θ
of about 9.5°
at greater than about 95% relative intensity; and(f) a differential scanning calorimetry thermogram having an endothermic peak with a Tonset of about 221.5°
C., 95.3°
C., or a combination thereof;(v) solvate Form III of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising;(g) an X-ray diffraction peak pattern comprising a peak at 2θ
of about 11.9°
at greater than about 95% relative intensity; and(h) a differential scanning calorimetry thermogram having an endothermic peak with a Tonset of about 224.6°
C., 103.2°
C., or a combination thereof;(vi) solvate Form IV of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising an X-ray diffraction peak pattern comprising a peak at 2θ
of about 22.3°
at greater than about 95% relative intensity; and(vii) hydrate of 5-(4′
-fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile comprising;(j) an X-ray diffraction peak pattern comprising a peak at 2θ
of about 8.4°
at greater than about 95% relative intensity; and(k) a differential scanning calorimetry thermogram having one endothermic peak with a Tonset of about 223°
C. and a second endothermic peak with a Tonset of about 111°
C. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)
- -fluoro-2′
-
17. A micronized hydrate of 5-(4′
- -fluoro-2′
-oxo-1′
,2′
-dihydrospiro[cyclopropane-1,3′
-indol]-5′
-yl)-1-methyl-1H-pyrrole-2-carbonitrile which has a median particle size less than about 10 μ
m.
- -fluoro-2′
Specification