Solid forms of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) and method for preparing the same

Patent metadata

Field	Value
Publication number	US-10717715-B2
Application number	US-201716330909-A
Country	US
Kind code	B2
Filing date	Aug 29, 2017
Priority date	Sep 6, 2016
Publication date	Jul 21, 2020
Grant date	Jul 21, 2020

Abstract

Disclosed are solid forms of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) selected from an amorphous form or a crystalline anhydrous form. Also disclosed are solid solvates of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) selected from an acetone solvate, a dimethylcarbonate solvate, an isopropyl ether solvate, an acetonitrile solvate, a toluene solvate, a mesitylene solvate, a nitromethane solvate, a dichloromethane/heptane solvate and an ethyl acetate solvate, for use as intermediates.

First claim

The invention claimed is:

1. A solid form of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) selected from the group consisting of an amorphous form and a crystalline anhydrous form;
wherein the amorphous form is characterized by a XRPD pattern showing absence of diffraction peaks, a FTIR spectrum having peaks at about 2940-1708-1597-1444-1380-1288-1188-1105-1033-959-880-803-678±4 cm −1 and by a Glass Transition (Tg) approximately between 60° C. and 110° C. with a maximum at about 76° C.; and
wherein the crystalline anhydrous form is characterized by a XRPD pattern showing peaks at about 6.0-9.4-11.9-13.2-13.8-15.3-19.1-20.1-24.0-28.1±0.2 degrees two theta, a FTIR pattern with peaks at about 3582-3416-2979-2940-1709-1594-1442-1380-1288-1103-1030-959-881-794-686±4 cm −1 and by a TG/DTA thermogram showing an endothermic signal with maximum at about 100.5° C. and a melting peak with maximum at about 134.4° C.

2. The solid form of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 1 , which is said amorphous form.

3. The solid form of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 1 , which is said crystalline anhydrous form.

4. A solid solvate of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) selected from the group consisting of an acetone solvate, a dimethylcarbonate solvate, an isopropyl ether solvate, an acetonitrile solvate, a toluene solvate, a mesitylene solvate, a nitromethane solvate, a dichloromethane/heptane solvate and an ethyl acetate solvate;
wherein the acetone solvate characterized by a XRPD pattern showing peaks at about 5.7-8.5-11.4-12.1-13.1-15.4-19.1-20.6-21.6-24.0±0.2 degrees two theta, by a FTIR pattern with peaks at about 3579-3478-3364-2940-1711-1695-1595-1442-1358-1217-1105-1033-959-880-793-684±4 cm −1 and by a TG/DTA thermogram showing an endothermic signal with maximum at about 123.1° C. associated with a weight loss of about 5% and a melting peak with maximum at about 134.3° C.;
wherein the dimethylcarbonate solvate is characterized by a XRPD pattern showing peaks at about 5.7-8.4-10.1-11.6-13.0-14.0-15.4-19.3-21.7-23.4±0.2 degrees two theta, by a FTIR pattern with peaks at about 3581-3473-2939-1754-1709-1696-1594-1441-1287-1151-1105-1030-959-880-794-685±4 cm −1 and by a TG/DTA thermogram showing an endothermic signal with maximum at about 137.0° C. associated with a weight loss of about 6-7%;
wherein the isopropyl ether solvate is characterized by a XRPD pattern showing peaks at about 5.9-9.2-10.4-11.8-11.9-13.1-13.6-15.1-17.9-22.2-24.1-30.3±0.2 degrees two theta, by a FTIR pattern with peaks at about 3581-3463-2940-1705-1644-1595-1456-1442-1288-1152-1105-1029-959-881-837-794-686±4 cm −1 and by a TG/DTA thermogram showing a weak endothermic signal below 100° C. and an endothermic peak with a maximum at about 135.7° C. associated with a weight loss of about 11.0% at 133° C.;
wherein the acetonitrile solvate is characterized by FTIR spectrum with peaks at 3581-3474-3378-2940-1706-1644-1596-1456-1312-1288-1152-1104-1076-1049-1030-959-880-794-685±4 cm −1 and by a TG/DTA thermogram showing a weak endothermic signal with maximum at about 124.4° C. associated with a weight loss of about 1.3% at 126° C.;
wherein the toluene solvate is characterized by a XRPD pattern showing peaks at about 5.6-5.7-8.4-8.5-10.3-11.4-11.5-12.1-13.1-14.1-15.4-19.3-21.6-23.2±0.2 degrees two theta, by a FTIR pattern with peaks at about 3576-3481-2874-1706-1693-1640-1597-1497-1455-1309-1295-1106-1074-1049-1003-958-880-837-794-730-696-684-649±4 cm −1 and by a weak endothermic signal at a maximum at about 123.4 associated with a weight loss of about 8.4% at 129° C.;
wherein the nitromethane solvate is characterized by a XRPD pattern showing peaks at about 5.8-8.6-9.0-10.4-11.7-13.2-14.1-15.6-21.9-23.6-24.2±0.2 degrees two theta, by a FTIR pattern with peaks at about 3579-3476-2876-1710-1643-1596-1560-1442-1358-1336-1288-1218-1105-1030-959-880-837-794-685±4 cm −1 and by a TG/DTA thermogram showing a double endothermic peak with maxima at about 125.4 and 133.9 associated with a weight loss of about 5.8% at 140° C.;
wherein the mesitylene solvate is characterized by a XRPD pattern showing peaks at about 5.3-6.0-9.1-10.5-12.1-13.0-14.8-18.2-22.3-24.3-25.8-28.6-30.6-34.7±0.2 degrees two theta, a FTIR spectrum with peaks at about 3580-3479-2876-1705-1642-1595-1560-1455-1441-1381-1311-1288-1150-1105-1074-1029-1003-958-880-836-794-685±4 cm −1 and by a TG/DTA thermogram showing an endothermic peak with maximum at about 133.2° C. associated with a weight loss of about 2.0% at 131° C.;
wherein the dichloromethane/heptane solvate is characterized by a XRPD pattern showing peaks at about 5.7-8.6-9.0-10.4-11.6-12.2-12.9-14.4-15.5-17.5-19.9-21.7-22.4-28.1-29.4±0.2 degrees two theta, by a FTIR spectrum with peaks at about 3578-3474-2876-1705-1652-1596-1454-1442-1288-1217-1152-1105-1075-1050-1030-1003-958-880-837-794-770-739-700-685±4 cm −1 and by an endothermic signal with maximum at about 130.7° C. associated with a weight loss of about 4.1% between 130 and 135° C.; and
wherein the ethyl acetate solvate is characterized by a XRPD pattern showing peaks at about 5.8-8.6-10.0-11.6-12.7-13.1-14.0-15.6-16.0-19.1-20.2-22.0-23.2±0.2 degrees two theta and by a TG/DTA thermogram showing an endothermic signal with maximum at about 123.8° C. associated with a weight loss of about 5.4% at about 130° C.

5. The solid solvate of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 4 , which is said acetone solvate.

6. The solid solvate of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 4 , which is said dimethylcarbonate solvate.

7. The solid solvate of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 4 , which is said isopropyl ether solvate.

8. The solid solvate of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 4 , which is said acetonitrile solvate.

9. The solid solvate of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 4 , which is said toluene solvate.

10. The solid solvate of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 4 , which is said nitromethane solvate.

11. The solid solvate of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 4 , which is said mesitylene solvate.

12. The solid solvate of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 4 , which is said dichloromethane/heptane solvate.

13. The solid solvate of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) according to claim 4 , which is said ethyl acetate solvate.

Assignees

• Indena Spa

Inventors

• Allegrini Pietro
• Peterlongo Federico
• Gambini Andrea
• Ciceri Daniele
• Sardone Nicola
• Ricotti Maurizio

Classifications

• C07D261/18 Primary

  Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title