Processes for preparing isoquinolinones and solid forms of isoquinolinones
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-473/34
A61K-031/52
A61P-035/00
출원번호
US-0347423
(2012-01-10)
등록번호
US-8809349
(2014-08-19)
발명자
/ 주소
Ren, Pingda
Martin, Michael
Isbester, Paul
Lane, Benjamin S.
Kropp, Jason
출원인 / 주소
Infinity Pharmaceuticals, Inc.
대리인 / 주소
Jones Day
인용정보
피인용 횟수 :
14인용 특허 :
264
초록▼
Polymorphs of chemical compounds that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including P13 kinase activity, are described herein. Also provided herein ar
Polymorphs of chemical compounds that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including P13 kinase activity, are described herein. Also provided herein are processes for preparing compounds, polymorphs thereof, and pharmaceutical compositions thereof.
대표청구항▼
1. A compound of Formula (I): wherein the compound is polymorph Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, or Form J of a compound of Formula (I), or a salt, solvate, or hydrate thereof; or a mixture of two or more thereof, wherein polymorph Form A has the following cha
1. A compound of Formula (I): wherein the compound is polymorph Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, or Form J of a compound of Formula (I), or a salt, solvate, or hydrate thereof; or a mixture of two or more thereof, wherein polymorph Form A has the following characteristic X-ray Powder Diffraction (XRPD) peaks: 2θ=9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°);polymorph Form B has the following characteristic XRPD peaks: 2θ=7.9° (±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°);polymorph Form C has the following characteristic XRPD peaks: 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°);polymorph Form D has the following characteristic XRPD peaks: 2θ=11.4° (±0.2°), 17.4° (±0.2°), and 22.9° (±0.2°);polymorph Form E has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.3° (±0.2°), and 24.4° (±0.2°);polymorph Form F has the following characteristic XRPD peaks: 2θ=9.6° (±0.2°), 17.3° (±0.2°), and 24.6° (±0.2°);polymorph Form G has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.5° (±0.2°), and 19.0° (±0.2°);polymorph Form H has the following characteristic XRPD peaks: 2θ=8.9° (±0.2°), 9.2° (±0.2°), and 14.1° (±0.2°);polymorph Form I has the following characteristic XRPD peaks: 2θ=9.7° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°); andpolymorph Form J has the following characteristic XRPD peaks: 2θ=9.1° (±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°). 2. A mixture of two or more compounds of Formula (I): wherein the compounds of Formula (I) are selected from: i) polymorph Form C, or a salt, solvate, or hydrate thereof; andii) at least one non-Form C polymorph selected from Form A, Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form of a compound of Formula (I), or a salt, solvate, or hydrate thereof, whereinpolymorph Form A has the following characteristic X-ray Powder Diffraction (XRPD) peaks: 2θ=9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°);polymorph Form B has the following characteristic XRPD peaks: 2θ=7.9° (±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°);polymorph Form C has the following characteristic XRPD peaks: 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°);polymorph Form D has the following characteristic XRPD peaks: 2θ=11.4° (±0.2°), 17.4° (±0.2°), and 22.9° (±0.2°);polymorph Form E has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.3° (±0.2°), and 24.4° (±0.2°);polymorph Form F has the following characteristic XRPD peaks: 2θ=9.6° (±0.2°), 17.3° (±0.2°), and 24.6° (±0.2°);polymorph Form G has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.5° (±0.2°), and 19.0° (±0.2°);polymorph Form H has the following characteristic XRPD peaks: 2θ=8.9° (±0.2°), 9.2° (±0.2°), and 14.1° (±0.2°);polymorph Form I has the following characteristic XRPD peaks: 2θ=9.7° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°); andpolymorph Form J has the following characteristic XRPD peaks: 2θ=9.1° (±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°). 3. A mixture of two or more compounds of Formula (I): wherein the compounds of Formula (I) are selected from: i) polymorph Form A, or a salt, solvate, or hydrate thereof; andii) at least one non-Form A polymorph selected from Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form of a compound of Formula (I), or a salt, solvate, or hydrate thereof, whereinpolymorph Form A has the following characteristic X-ray Powder Diffraction (XRPD) peaks: 2θ=9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°);polymorph Form B has the following characteristic XRPD peaks: 2θ=7.9° (±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°);polymorph Form C has the following characteristic XRPD peaks: 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°);polymorph Form D has the following characteristic XRPD peaks: 2θ=11.4° (±0.2°), 17.4° (±0.2°), and 22.9° (±0.2°);polymorph Form E has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.3° (±0.2°), and 24.4° (±0.2°);polymorph Form F has the following characteristic XRPD peaks: 2θ=9.6° (±0.2°), 17.3° (±0.2°), and 24.6° (±0.2°);polymorph Form G has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.5° (±0.2°), and 19.0° (±0.2°);polymorph Form H has the following characteristic XRPD peaks: 2θ=8.9° (±0.2°), 9.2° (±0.2°), and 14.1° (±0.2°);polymorph Form I has the following characteristic XRPD peaks: 2θ=9.7° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°); andpolymorph Form J has the following characteristic XRPD peaks: 2θ=9.1° (±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°). 4. A mixture according to claim 2, wherein the mixture is at least 50% by weight polymorph Form C, or a salt, solvate, or hydrate thereof. 5. Polymorph Form C of a compound of Formula (I): or a salt, solvate, or hydrate thereof, wherein the polymorph has the following characteristic X-ray Powder Diffraction (XRPD) peaks: 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°). 6. The polymorph according to claim 5, further comprising at least one characteristic XRPD peak selected from 2θ=6.6° (±0.2°) and 12.5° (±0.2°). 7. The polymorph according to claim 5, wherein the polymorph has the following characteristic XRPD peaks: 2θ=6.6° (±0.2°), 10.4° (±0.2°), 12.5° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°), in combination with at least one XRPD peak selected from 2θ=8.8° (±0.2°), 9.9° (±0.2°), 13.4° (±0.2°), 15.5° (±0.2°), 16.9° (±0.2°), 19.8° (±0.2°), 21.3° (±0.2°), 23.6° (±0.2°), 25.3° (±0.2°), and 27.9° (±0.2°). 8. The polymorph according to claim 5, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 3. 9. Polymorph Form B of a compound of Formula (I): or a salt, solvate, or hydrate thereof, wherein the polymorph has the following characteristic XRPD peaks: 2θ=7.9° (±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°). 10. The polymorph according to claim 9, further comprising at least one characteristic XRPD peak selected from 2θ=14.0° (±0.2°) and 15.0° (±0.2°). 11. The polymorph according to claim 9, wherein the polymorph has the following characteristic XRPD peaks: 2θ=7.9° (±0.2°), 13.4° (±0.2°), 14.0° (±0.2°), 15.0° (±0.2°), and 23.4° (±0.2°), in combination with at least one XRPD peak selected from 2θ=9.5° (±0.2°), 12.7° (±0.2°), 13.6° (±0.2°), 14.2° (±0.2°), 15.7° (±0.2°), 19.0° (±0.2°), 22.3° (±0.2°), 24.2° (±0.2°), 24.8° (±0.2°), and 26.9° (±0.2°). 12. The polymorph according to claim 9, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 2. 13. Polymorph Form D of a compound of Formula (I): or a salt, solvate, or hydrate thereof, wherein the polymorph has the following characteristic XRPD peaks: 2θ=11.4° (±0.2°), 17.4° (±0.2°), and 22.9° (±0.2°). 14. The polymorph according to claim 13, further comprising at least one characteristic XRPD peak selected from 2θ=9.2° (±0.2°) and 18.3° (±0.2°). 15. The polymorph according to claim 13, wherein the polymorph has the following characteristic XRPD peaks: 2θ=9.2° (±0.2°), 11.4° (±0.2°), 17.4° (±0.2°), 18.3° (±0.2°), and 22.9° (±0.2°), in combination with at least one XRPD peak selected from 2θ=9.8° (±0.2°), 12.2° (±0.2°), 15.8° (±0.2°), 16.2° (±0.2°), 16.8° (±0.2°), 18.9° (±0.2°), 19.9° (±0.2°), 20.0° (±0.2°), 24.9° (±0.2°), and 29.3° (±0.2°). 16. The polymorph according to claim 13, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 4. 17. Polymorph Form E of a compound of Formula (I): or a salt, solvate, or hydrate thereof, wherein the polymorph has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.3° (±0.2°), and 24.4° (±0.2°). 18. The polymorph according to claim 17, further comprising at least one characteristic XRPD peak selected from 2θ=12.7° (±0.2°) and 13.9° (±0.2°). 19. The polymorph according to claim 17, wherein the polymorph has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.3° (±0.2°), 12.7° (±0.2°), 13.9° (±0.2°), and 24.4° (±0.2°), in combination with at least one XRPD peak selected from 2θ=12.4° (±0.2°), 13.3° (±0.2°), 14.3° (±0.2°), 15.5° (±0.2°), 17.4° (±0.2°), 18.5° (±0.2°), 22.0° (±0.2°), 23.9° (±0.2°), 24.1° (±0.2°), and 26.4° (±0.2°). 20. The polymorph according to claim 17, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 5. 21. Polymorph Form F of a compound of Formula (I): or a salt, solvate, or hydrate thereof, wherein the polymorph has the following characteristic XRPD peaks: 2θ=9.6° (±0.2°), 17.3° (±0.2°), and 24.6° (±0.2°). 22. The polymorph according to claim 21, further comprising at least one characteristic XRPD peak selected from 2θ=14.0° (±0.2°) and 19.2° (±0.2°). 23. The polymorph according to claim 21, wherein the polymorph has the following characteristic XRPD peaks: 2θ=9.6° (±0.2°), 14.0° (±0.2°), 17.3° (±0.2°), 19.2° (±0.2°), and 24.6° (±0.2°), in combination with at least one XRPD peak selected from 2θ=12.4° (±0.2°), 16.1° (±0.2°), 16.6° (±0.2°), 17.1° (±0.2°), 20.8° (±0.2°), 21.5° (±0.2°), 22.0° (±0.2°), 24.3° (±0.2°), 25.2° (±0.2°), and 25.4° (±0.2°). 24. The polymorph according to claim 21, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 6. 25. Polymorph Form G of a compound of Formula (I): or a salt, solvate, or hydrate thereof, wherein the polymorph has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.5° (±0.2°), and 19.0° (±0.2°). 26. The polymorph according to claim 25, further comprising at least one characteristic XRPD peak selected from 2θ=10.6° (±0.2°) and 19.6° (±0.2°). 27. The polymorph according to claim 25, wherein the polymorph has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.5° (±0.2°), 10.6° (±0.2°), 19.0° (±0.2°), and 19.6° (±0.2°), in combination with at least one XRPD peak selected from 2θ=13.4° (±0.2°), 15.0° (±0.2°), 15.8° (±0.2°), 17.8° (±0.2°), 20.7° (±0.2°), 21.2° (±0.2°), 22.8° (±0.2°), 23.8° (±0.2°), 24.3° (±0.2°), and 25.6° (±0.2°). 28. The polymorph according to claim 25, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 7. 29. Polymorph Form H of a compound of Formula (I): or a salt, solvate, or hydrate thereof, wherein the polymorph has the following characteristic XRPD peaks: 2θ=8.9° (±0.2), 9.2° (±0.2°), and 14.1° (±0.2°). 30. The polymorph according to claim 29, further comprising at least one characteristic XRPD peak selected from 2θ=17.3° (±0.2°) and 18.5° (±0.2°). 31. The polymorph according to claim 29, wherein the polymorph has the following characteristic XRPD peaks: 2θ=8.9° (±0.2°), 9.2° (±0.2°), 14.1° (±0.2°), 17.3° (±0.2°), and 18.5° (±0.2°), in combination with at least one XRPD peak selected from 2θ=7.1° (±0.2°), 10.6° (±0.2°), 11.3° (±0.2°), 11.6° (±0.2°), 16.2° (±0.2°), 18.3° (±0.2°), 18.8° (±0.2°), 20.3° (±0.2°), 21.7° (±0.2°), and 24.7° (±0.2°). 32. The polymorph according to claim 29, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 8. 33. Polymorph Form I of a compound of Formula (I): or a salt, solvate, or hydrate thereof, wherein the polymorph has the following characteristic XRPD peaks: 2θ=9.7° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°). 34. The polymorph according to claim 33, further comprising at least one characteristic XRPD peak selected from 2θ=11.4° (±0.2°) and 14.2° (±0.2°). 35. The polymorph according to claim 33, wherein the polymorph has the following characteristic XRPD peaks: 2θ=9.7° (±0.2°), 11.4° (±0.2°), 14.2° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°), in combination with at least one XRPD peak selected from 2θ=9.2° (±0.2°), 14.7° (±0.2°), 15.5° (±0.2°), 16.7° (±0.2°), 17.3° (±0.2°), 18.4° (±0.2°), 21.4° (±0.2°), 22.9° (±0.2°), 29.1° (±0.2°), and 34.1° (±0.2°). 36. The polymorph according to claim 33, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 9. 37. Polymorph Form J of a compound of Formula (I): or a salt, solvate, or hydrate thereof, wherein the polymorph has the following characteristic XRPD peaks: 2θ=9.1° (±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°). 38. The polymorph according to claim 37, further comprising at least one characteristic XRPD peak selected from 2θ=16.4° (±0.2°) and 17.9° (±0.2°). 39. The polymorph according to claim 37, wherein the polymorph has the following characteristic XRPD peaks: 2θ=9.1° (±0.2°), 16.4° (±0.2°), 17.3° (+0.2°), 17.9° (±0.2°), and 18.3° (±0.2°), in combination with at least one XRPD peak selected from 2θ=9.4° (±0.2°), 10.1° (±10.2°), 10.7° (±0.2°), 14.0° (±0.2°), 14.3° (±0.2°), 15.5° (±0.2°), 16.9° (±0.2°), 19.9° (±0.2°), 24.0° (±0.2°), and 24.7° (10.2°). 40. The polymorph according to claim 37, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 10. 41. A pharmaceutical composition comprising a compound according to claim 1, and one or more pharmaceutically acceptable excipients. 42. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I): wherein the pharmaceutical composition comprises polymorph Form C of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and one or more pharmaceutically acceptable excipients wherein the polymorph has the following characteristic X-ray Powder Diffraction (XRPD) peaks: 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°). 43. The pharmaceutical composition according to claim 42, wherein the pharmaceutical composition further comprises at least one non-Form C polymorph selected from Form A, Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form of a compound of Formula (I), or a salt, solvate, or hydrate thereof, wherein polymorph Form A has the following characteristic X-ray Powder Diffraction (XRPD) peaks: 2θ=9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.21;polymorph Form B has the following characteristic XRPD peaks: 2θ=7.9° (±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°);polymorph Form D has the following characteristic XRPD peaks: 2θ=11.4°(±0.2°), 17.4° (±0.2°), and 22.9° (±0.2°);polymorph Form E has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.3° (±0.2°), and 24.4° (±0.2°);polymorph Form F has the following characteristic XRPD peaks: 2θ=9.6° (±0.2°), 17.3° (±0.2°), and 24.6° (±0.2°);polymorph Form G has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.5° (±0.2°), and 19.0° (±0.2°);polymorph Form H has the following characteristic XRPD peaks: 2θ=8.9° (±0.2°), 9.2° (±0.2°), and 14.1° (±0.2°);polymorph Form I has the following characteristic XRPD peaks: 2θ=9.7° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°); andpolymorph Form J has the following characteristic XRPD peaks: 2θ=9.1° (±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°). 44. The pharmaceutical composition according to claim 43, wherein the pharmaceutical composition comprises polymorph Form C and polymorph Form A in a ratio of greater than about 9:1 Form C:Form A. 45. The pharmaceutical composition according to claim 42, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients selected from silicified microcrystalline cellulose, lactose, mannitol, starch, sorbitol, sucrose, dicalcium phosphate, microcrystalline cellulose, crospovidone, croscarmellose sodium, and sodium starch glycolate, silicon dioxide, silicon dioxide, magnesium silicate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid, sodium lauryl sulphate, sodium dodecyl sulphate, Tween® 80, and Lutrol®. 46. The pharmaceutical composition of claim 41, further comprising an amorphous form of a compound of Formula (I). 47. Polymorph Form A of a compound of Formula (I): or a salt, solvate, or hydrate thereof, wherein the polymorph has the following characteristic XRPD peaks: 2θ=9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°). 48. The polymorph according to claim 47, further comprising at least one characteristic XRPD peak selected from 2θ=15.6° (±0.2°) and 19.2° (±0.2°). 49. The polymorph according to claim 47, wherein the polymorph has the following characteristic XRPD peaks: 2θ=9.6° (±0.2°), 12.2° (±0.2°), 15.6° (±0.2°), 18.3° (±0.2°), and 19.2° (±0.2° in combination with at least one XRPD peak selected from 2θ=9.1° (±0.2°), 9.4° (±0.2°), 12.4° (±0.2°), (14.8° (±0.2°), 16.3° (±0.2°), 17.7° (±0.2°), 21.1° (±0.2°), 21.9° (±0.2°), 24.0° (±0.2°), and 26.9° (±0.2°). 50. The polymorph according to claim 47, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 1. 51. The polymorph of claim 47, wherein Form A has an endothermic peak at about 238° C. or about 239° C. 52. The polymorph of claim 5, wherein Form C has an endothermic peak at about 203° C. 53. The polymorph of claim 5, wherein Form C has an endothermic peak at about 206° C. or about 208° C. 54. The polymorph of claim 5, wherein Form C has an endothermic peak in the range of about 203° C. to about 208° C., and at least one peak selected from an exothermic peak in the range of about 251° C. to about 254° C., and an endothermic peak in the range of about 281° C. to about 283° C. 55. The polymorph of claim 5, wherein Form C has an endothermic peak at about 208° C., an exothermic peak at about 254° C., and an endothermic peak at about 283° C. 56. The mixture of claim 2, wherein the mixture comprises polymorph Form C and an amorphous form of a compound of Formula (I). 57. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 1:1. 58. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 2:1. 59. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 3:1. 60. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 4:1. 61. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 5:1. 62. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 6:1. 63. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 7:1. 64. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 8:1. 65. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 9:1.
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Goulet, Joung L.; Cubbon, Rose M.; Cummings, Richard T.; Hong, Xingfang; Sinclair, Peter J.; Thompson, James E., Benzimisazo[4,5-f]isoquinolinone derivatives.
Alexander James Bridges ; William Alexander Denny NZ; David Fry ; Alan Kraker ; Robert Frederick Meyer ; Gordon William Rewcastle NZ; Andrew Mark Thompson NZ, Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family.
Bridges Alexander James (Saline MI) Denny William Alexander (Pakuranga NZX) Fry David (Ypsilanti MI) Kraker Alan (Ann Arbor MI) Meyer Robert Frederick (Ann Arbor MI) Rewcastle Gordon William (Manurew, Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family.
Bridges Alexander James ; Denny William Alexander,NZX ; Fry David ; Kraker Alan ; Meyer Robert Frederick ; Rewcastle Gordon William,NZX ; Thompson Andrew Mark,NZX, Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family.
Bridges, Alexander James; Denny, William Alexander; Fry, David; Rewcastle, Gordon William, Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family.
Bridges, Alexander James; Denny, William Alexander; Fry, David; Rewcastle, Gordon William, Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family.
Spada Alfred P. (Lansdale PA) Maquire Martin P. (King of Prussia PA) Persons Paul E. (King of Prussia PA) Myers Michael R. (Reading PA), Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase.
Spada Alfred P. (Lansdale PA) Myers Michael R. (Reading PA) Maguire Martin P. (Mont Clare PA) Persons Paul E. (King of Prussia PA), Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase.
Spada Alfred P. (Lansdale PA) Myers Michael R. (Reading PA) Maguire Martin P. (Mont Clare PA) Persons Paul E. (King of Prussia PA), Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase.
Spada Alfred P. ; Myers Michael R. ; Maguire Martin P. ; Persons Paul E., Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase.
Spada Alfred P. (Lansdale PA) Maguire Martin P. (King of Prussia PA) Persons Paul E. (King of Prussia PA) Myers Michael R. (Reading PA), Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase.
Spada Alfred P. ; Myers Michael R. ; Maguire Martin P. ; Persons Paul E., Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase.
Wood R. Andrew (Bloomington MN), Camera for producing video output signal, infrared focal plane array package for such camera, and method and apparatus f.
Charles Petrie ; Mark W. Orme ; Nand Baindur ; Kirk G. Robbins ; Maria Kontoyianni ; Gregory R. Mundy, Compositions and methods for treating bone deficit conditions.
Orme, Mark W.; Baindur, Nand; Robbins, Kirk G.; Harris, Scott M.; Kontoyianni, Maria; Hurley, Laurence H.; Kerwin, Sean M.; Mundy, Gregory; Petrie, Charles, Compositions and methods for treating bone deficit conditions.
Petrie Charles ; Orme Mark W. ; Baindur Nand ; Robbins Kirk G. ; Harris Scott M. ; Mundy Gregory R., Compositions and methods for treating bone deficit conditions.
Petrie Charles ; Orme Mark W. ; Baindur Nand ; Robbins Kirk G. ; Kontoyianni Maria ; Mundy Gregory R., Compositions and methods for treating bone deficit conditions.
Petrie Charles ; Orme Mark W. ; Baindur Nand ; Robbins Kirk G. ; Kontoyianni Maria ; Mundy Gregory R., Compositions and methods for treating bone deficit conditions.
Petrie Charles ; Orme Mark W. ; Baindur Nand ; Robbins Kirk G. ; Kontoyianni Maria ; Mundy Gregory R., Compositions and methods for treating bone deficit conditions.
Spada Alfred P. (Lansdale PA) Fink Cynthia A. (Doylestown PA) Myers Michael R. (Reading PA), Compounds having antihypertensive and anti-ischemic properties.
Spada Alfred P. (Lansdale PA) Fink Cynthia A. (Lebanon NJ) Myers Michael R. (Reading PA), Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties.
Oh, Jong Eun; Lee, Keon Hyoung; Park, Tae Gwan; Nam, Yoon Sung, Controlled drug delivery system using the conjugation of drug to biodegradable polyester.
Oshlack Benjamin (New York NY) Chasin Mark (Manalapan NJ) Pedi ; Jr. Frank (Yorktown Heights NY), Controlled release formulations coated with aqueous dispersions of acrylic polymers.
Marshall Lucia G. I. (St. Charles MO) Patel Kanaiyalal R. (St. Louis MO) Roufa Dikla G. (St. Louis MO), Controlled release formulations of trophic factors in ganglioside-lipsome vehicle.
Adams,Julian; Castro,Alfredo C.; Foley,Michael A.; Janardanan Nair,Somarajan Nair; Nevalainen,Marta; Porter,James R.; Tremblay,Martin R., Cyclopamine analogues and methods of use thereof.
Spada Alfred P. (Lansdale PA) Fink Cynthia A. (Lebanon PA) Myers Michael R. (Reading PA) Reilly Laurence W. (Doylestown PA) Vanasse Benoit J. (Collegeville PA), DI (1R)-(-)camphosulfonic acid) salt, preparation thereof and use thereof.
Alexander, John C.; Schuh, Joseph R.; Gorczynski, Richard J., Epoxy-steroidal aldosterone antagonist and angiotensin II antagonist combination therapy.
Tapolsky, Gilles; Chand, Pooran; Trent, John O.; Telang, Sucheta; Clem, Brian F.; Chesney, Jason A., Family of PFKFB3 inhibitors with anti-neoplastic activities.
Freyne, Eddy Jean Edgard; Buijnsters, Peter Jacobus Johannes Antonius; Willems, Marc; Embrechts, Werner Constant Johan; Love, Christopher John; Janssen, Paul Adriaan Jan; Lewi, Paulus Joannes; Heeres, Jan; de Jonge, Marc René; Koymans, Lucien Maria Henricus; Vinkers, Hendrik Maarten; Van Aken, Koen Jeanne Alfons; Diels, Gaston Stanislas Marcella, Heteroaryl amines as glycogen synthase kinase 3β inhibitors (GSK3 inhibitors).
Hedgpeth Joel ; Afonina Irina A. ; Kutyavin Igor V. ; Lukhtanov Eugeny A. ; Belousov Evgeniy S. ; Meyer ; Jr. Rich B., Hybridization and mismatch discrimination using oligonucleotides conjugated to minor groove binders.
Joel Hedgpeth ; Irina A. Afonina ; Igor V. Kutyavin ; Eugeny A. Lukhtanov ; Evgeniy S. Belousov ; Rich B. Meyer, Jr., Hybridization and mismatch discrimination using oligonucleotides conjugated to minor groove binders.
Adams Jerry Leroy (Wayne PA) Gallagher Timothy Francis (Harleysville PA) Lee John C. (Radnor PA) White John Richard (Coatesville PA), Imidazole derivatives and their use as cytokine inhibitors.
Kania, Robert Steven; Bender, Steven Lee; Borchardt, Allen J.; Cripps, Stephan James; Hua, Ye; Johnson, Michael David; Johnson, Jr., Theodore Otto; Luu, Hiep The; Palmer, Cynthia Louise; Reich, Siegf, Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use.
Kania, Robert Steven; Bender, Steven Lee; Borchardt, Allen J.; Cripps, Stephan James; Palmer, Cynthia Louise; Tempczyk-Russell, Anna Maria; Varney, Michael David; Collins, Michael Raymond, Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use.
Bonjouklian Rosanne (Zionsville IN) Dodge Jeffrey A. (Indianapolis IN) Vlahos Chris J. (Carmel IN), Inhibition of phosphatidylinositol 3-kinase with 17 b
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Anthony Neville J. ; Gomez Robert P. ; Tran Lekhanh O. ; Young Steven D., Inhibitors of farnesyl-protein transferase.
Sadhu, Chanchal; Dick, Ken; Treiberg, Jennifer; Sowell, C. Gregory; Kesicki, Edward A.; Oliver, Amy, Inhibitors of human phosphatidyl-inositol 3-kinase delta.
Sadhu, Chanchal; Dick, Ken; Treiberg, Jennifer; Sowell, C. Gregory; Kesicki, Edward A.; Oliver, Amy, Inhibitors of human phosphatidylinositol 3-kinase delta.
Sadhu, Chanchal; Dick, Ken; Treiberg, Jennifer; Sowell, C. Gregory; Kesicki, Edward A.; Oliver, Amy, Inhibitors of human phosphatidylinositol 3-kinase delta.
Sadhu, Chanchal; Dick, Ken; Treiberg, Jennifer; Sowell, C. Gregory; Kesicki, Edward A.; Oliver, Amy, Inhibitors of human phosphatidylinositol 3-kinase delta.
Julian M. C. Golec GB; David J. Lauffer ; David J. Livingston ; Michael D. Mullican ; Philip L. Nyce ; Andrea L. C. Robidoux ; Marion W. Wannamaker, Inhibitors of interleukin-1.beta. converting enzyme.
Mohr Judy M. (Menlo Park CA) Baker Richard W. (Palo Alto CA) Nakaji Lisa A. (San Jose CA), Liquid reservoir transdermal patch for the administration of ketorolac.
Baxter, Anthony David; Boyd, Edward Andrew; Guicherit, Oivin M.; Price, Stephen; Rubin, Lee D., Mediators of hedgehog signaling pathways, compositions and uses related thereto.
Lilley Stephen J. (Sawston GBX) Taylor Hugh F. (Sawston GBX) Theobald David R. (Huntingdon GBX) Carlson Craig J. (Andover MA) Rosen David I. (Arlington MA) Johnson Thomas R. (Milford NH), Medical injection system and method, gas spring thereof and launching device using gas spring.
Hefner ; Jr. Robert E. (Lake Jackson TX) Earls Jimmy D. (Lake Jackson TX) Puckett Paul M. (Lake Jackson TX), Mesogenic polycyanates and thermosets thereof.
Hefner ; Jr. Robert E. (Lake Jackson TX) Earls Jimmy D. (Lake Jackson TX) Puckett Paul M. (Lake Jackson TX), Mesogenic polycyanates and thermosets thereof.
Delapierre, Guillaume; Duclairoir, Florence; Marchon, Jean-Claude, Method for grafting molecules of interest on inorganic surfaces, resulting surfaces and uses thereof.
Kerwin, Sean M.; Hurley, Laurence H.; DeLuca, Mark R.; Moore, III, Bob M.; Mundy, Gregory R., Methods and compositions for stimulating osteoblast proliferation or treating malignant cell proliferation and methods for selecting osteoblast proliferation stimulants.
Firestein Gary S. (Del Mar CA) Ugarkar Bheemarao G. (Escondido CA) Miller Leonard P. (Carlsbad CA) Gruber Harry E. (Rancho Santa Fe CA) Bullough David A. (San Diego CA) Erion Mark D. (Del Mar CA) Cas, Methods for treating adenosine kinase related conditions.
Petrie Charles ; Orme Mark W. ; Baindur Nand ; Robbins Kirk G. ; Hurley Laurence H. ; Kerwin Sean M. ; Mundy Gregory R., Methods for treating bone deficit conditions with benzothiazole.
Olsson Ray A. (Odessa FL) Thompson Robert D. (Irvine CA), N-6 substituted-5′-(N-substitutedcarboxamido)adenosines as cardiac vasodilators and antihypertensive agents.
Otmar Klingler DE; Gerhard Zoller DE; Elisabeth Defossa DE; Fahad A. Al-Obeidi ; Armin Walser ; James Ostrem, N-guanidinoalkylamides, their preparation, their use, and pharmaceutical preparations comprising them.
McKinnon ; Jr. Charles N. (Laguna Niguel CA) Peterson Steven F. (West Linn OR) Smith Paul E. (Tualatin OR) Nakagawa Takaaki (Tigard OR) Bartholomew Victor L. (Tigard OR), Needleless hypodermic injection device.
Peterson Steven F. (West Linn OR) McKinnon ; Jr. Charles N. (Laguna Niguel CA) Smith Paul E. (Tualatin OR) Nakagawa Takaaki (Tigard OR) Bartholomew Victor L. (Tigard OR), Needleless hypodermic injection methods and device.
Gall, Alexander A.; Kutyavin, Igor V.; Vermeulen, Nicolaas M. J.; Dempcy, Robert O., Non-aggregating, non-quenching oligomers comprising nucleotide analogues; methods of synthesis and use thereof.
Meyer ; Jr. Rich B. ; Afonina Irina A. ; Kutyavin Igor V., Oligonucleotides containing pyrazolo[3,4-D]pyrimidines for hybridization and mismatch discrimination.
Rich B. Meyer, Jr. ; Irina A. Afonina ; Igor V. Kutyavin, Oligonucleotides containing pyrazolo[3,4-d]pyrimidines for hybridization and mismatch discrimination.
Santus Giancarlo (Milan ITX) Bilato Ettore (Padua ITX) Lazzarini Gabriele (Pero ITX), Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension.
Le Grazie Cristina (Milan ITX), Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutic.
Zilch Harald (Mannheim DEX) Leinert Herbert (Heppenheim DEX) Mertens Alfred (Schriesheim DEX) Herrmann Dieter (Heidelberg DEX), Phospholipid derivatives of nucleosides.
Zilch Harald,DEX ; Leinert Herbert,DEX ; Mertens Alfred,DEX ; Herrmann Dieter,DEX, Phospholipid derivatives of nucleosides and their use as anti-viral medicaments.
Myers Michael R. ; Spada Alfred P. ; Maguire Martin P. ; Persons Paul E., Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylati.
Tanaka, Toshihiko; Iwashita, Eiichirou; Tarao, Akiko; Amenomori, Akira; Ono, Yuya, Purine derivatives and medicaments comprising the same as active ingredient.
Allen, Daniel Rees; Buckley, George Martin; Bürli, Roland; Davenport, John Richard; Kinsella, Natasha; Lock, Christopher James; Lowe, Christopher; Mack, Stephen Robert; Pitt, William Ross; Ratcliffe, Andrew James; Richard, Marianna Dilani; Sabin, Verity Margaret; Sharpe, Andrew; Tait, Laura Jane; Warrellow, Graham John; Williams, Sophie Caroline, Quinoxaline and quinoline derivatives as kinase inhibitors.
Farid Samir Y. ; Lenhard Jerome R. ; Chen Chin H. ; Muenter Annabel A. ; Gould Ian R. ; Godleski Stephen A. ; Zielinski Paul A., Silver halide light sensitive emulsion layer having enhanced photographic sensitivity.
Porter, Jeffrey; Guicherit, Oivin M.; Rubin, Lee; Baxter, Anthony David; Boyd, Edward Andrew; Price, Stephen, Small organic molecule regulators of cell proliferation.
Bridges Alexander James ; Denny William Alexander,NZX ; Fry David ; Kraker Alan ; Meyer Robert Frederick ; Rewcastle Gordon William,NZX ; Thompson Andrew Mark,NZX, Substituted pyrido[3,2-d]pyrimidines capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family.
Chen, Yi; Cushing, Timothy D.; Hao, Xiaolin; He, Xiao; Reichelt, Andreas; Rzasa, Robert M.; Seganish, Jennifer; Shin, Youngsook; Zhang, Dawei, Substituted quinolines and their uses in treatment of inflammatory and related conditions.
Bodmer David (Klingnau CHX) Fong Jones W. (Parsippany NJ) Kissel Thomas (Staufen DEX) Maulding Hawkins V. (Mendham NJ) Nagele Oskar (Sissach CHX) Pearson Jane E. (Ogendensburg NJ), Sustained release formulations of water soluble peptides.
Fisher Abraham (Holon PA ILX) Hanin Israel (Pittsburgh PA) Abraham Donald J. (Murrysville PA), Tritium labelled N-mustard type compounds and a process for their production.
Schaumann Wolfgang (Heidelberg DEX) Wilhelms Otto-Henning (Weinheim-Rittenweier DEX) Roesch Androniki (Mannheim DEX) Kampe Wolfgang (Heddesheim DEX), Use of adenosine derivatives as anti-allergic compounds and pharmaceutical compositions containing them.
Ren, Pingda; Martin, Michael; Isbester, Paul; Lane, Benjamin S.; Kropp, Jason, Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1 (2H)-one and methods of use thereof.
Grenier, Louis; Lescarbeau, Andre; Sharma, Praveen; Genov, Daniel G., Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same.
Palombella, Vito J.; Winkler, David G., Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors.
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