Claims for Patent: 9,980,947

Summary for Patent: 9,980,947

Title:	Tetrahydro-pyrido[3,4-b]indole estrogen receptor modulators and uses thereof
Abstract:	Described herein are tetrahydro-pyrido[3,4-b]indol-1-yl compounds with estrogen receptor modulation activity or function having the Formula I structure: ##STR00001## and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such estrogen receptor modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.
Inventor(s):	Labadie; Sharada (Sunnyvale, CA), Liang; Jun (Los Altos Hills, CA), Ortwine; Daniel Fred (San Ramon, CA), Wang; Xiaojing (Foster City, CA), Zbieg; Jason (South San Francisco, CA), Zhang; Birong (Union City, CA), Goodacre; Simon Charles (Harlow, GB), Ray; Nicholas Charles (Harlow, GB), Li; Jun (Foster City, CA)
Assignee:	Genentech, Inc. (South San Francisco, CA)
Application Number:	14/972,326
Patent Claims:	1. A compound having formula (Ih): ##STR00406## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: Y.sup.2 is --(CH.sub.2); R.sup.a is independently selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.8 alkenyl, propargyl, C.sub.3-C.sub.6 cycloalkyl, and C.sub.3-C.sub.6 heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, OH, OCH.sub.3, and SO.sub.2CH.sub.3; R.sup.b is independently selected from the group consisting of H, --O(C.sub.1-C.sub.3 alkyl), C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.8 alkenyl, and propargyl, each optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, --CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2CHF.sub.2, --CH.sub.2CH.sub.2F, OH, OCH.sub.3, and SO.sub.2CH.sub.3, R.sup.c is H; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of H, --CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2OH, --CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH, --CH(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3, --CH.sub.2OP(O)(OH).sub.2, --CH.sub.2F, --CHF.sub.2, --CH.sub.2NH.sub.2, --CH.sub.2NHSO.sub.2CH.sub.3, --CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2, --CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2CHF.sub.2, --CH(CH.sub.3)CN, --C(CH.sub.3).sub.2CN, and --CH.sub.2CN; R.sup.5 is selected from the group consisting of C.sub.1-C.sub.9 alkyl, C.sub.3-C.sub.9 cycloalkyl, C.sub.3-C.sub.9 heterocycle, C.sub.6-C.sub.9 aryl, C.sub.6-C.sub.9 heteroaryl, --(C.sub.1-C.sub.6 alkyldiyl)-(C.sub.3-C.sub.9 cycloalkyl), --(C.sub.1-C.sub.6 alkyldiyl)-(C.sub.3-C.sub.9 heterocycle), C(O)NR.sup.a, SO.sub.2R.sup.a, and SO.sub.2NR.sup.a, each optionally substituted with one or more of halogen, CN, OR.sup.a, N(R.sup.a).sub.2, C.sub.1-C.sub.9 alkyl, C.sub.3-C.sub.9 cycloalkyl, C.sub.3-C.sub.9 heterocycle, C.sub.6-C.sub.9 aryl, C.sub.6-C.sub.9 heteroaryl, C(O)R.sup.b, C(O)NR.sup.a, SO.sub.2R.sup.a, and SO.sub.2NR.sup.a; R.sup.6 is independently F or Cl; m is 0, 1, 2, 3, or 4; R.sup.7 is independently halogen; and n is 0, 1 or 2. 2. The compound of claim 1 having Formula Ii: ##STR00407## 3. The compound of claim 2 having Formula Ij: ##STR00408## 4. The compound of claim 3 having Formula Ik: ##STR00409## 5. The compound of claim 1 wherein R.sup.7 is F. 6. The compound of claim 1 wherein R.sup.1 and R.sup.2 are H. 7. The compound of claim 1 wherein R.sup.3 is H, and R.sup.4 is --CH.sub.3. 8. The compound of claim 1 wherein R.sup.5 is C.sub.1-C.sub.6 fluoroalkyl. 9. The compound of claim 1 wherein m is 0. 10. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1 and at least one pharmaceutically acceptable excipient. 11. The pharmaceutical composition according to claim 10, further comprising an additional therapeutic agent. 12. A method of treating breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer in a patient having said cancer, the method comprising administering to said patient a therapeutically effective amount of a compound of formula (Ih) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof ##STR00410## wherein: Y.sup.2 is --(CH.sub.2); R.sup.a is independently selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.8 alkenyl, propargyl, C.sub.3-C.sub.6 cycloalkyl, and C.sub.3-C.sub.6 heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, OH, OCH.sub.3, and SO.sub.2CH.sub.3; R.sup.b is selected from the group consisting of H, --O(C.sub.1-C.sub.3 alkyl), C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.8 alkenyl, and propargyl, each optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, --CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2CHF.sub.2, --CH.sub.2CH.sub.2F, OH, OCH.sub.3 and SO.sub.2CH.sub.3; R.sup.c is H; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of H, --CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2OH, --CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH, --CH(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3, --CH.sub.2OP(O)(OH).sub.2, --CH.sub.2F, --CHF.sub.2, --CH.sub.2NH.sub.2, --CH.sub.2NHSO.sub.2CH.sub.3, --CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2, --CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2CHF.sub.2, --CH(CH.sub.3)CN, --C(CH.sub.3).sub.2CN, and --CH.sub.2CN; R.sup.5 is selected from the group consisting of C.sub.1-C.sub.9 alkyl, C.sub.3-C.sub.9 cycloalkyl, C.sub.3-C.sub.9 heterocycle, C.sub.6-C.sub.9 aryl, C.sub.6-C.sub.9 heteroaryl, --(C.sub.1-C.sub.6 alkyldiyl)-(C.sub.3-C.sub.9 cycloalkyl), --(C.sub.1-C.sub.6 alkyldiyl)-(C.sub.3-C.sub.9 heterocycle), C(O)NR.sup.a, SO.sub.2R.sup.a, and SO.sub.2NR.sup.a, each optionally substituted with one or more of halogen, CN, OR.sup.a, N(R.sup.a).sub.2, C.sub.1-C.sub.9 alkyl, C.sub.3-C.sub.9 cycloalkyl, C.sub.3-C.sub.9 heterocycle, C.sub.6-C.sub.9 aryl, C.sub.6-C.sub.9 heteroaryl, C(O)R.sup.b, C(O)NR.sup.a, SO.sub.2R.sup.a, and SO.sub.2NR.sup.a; R.sup.6 is independently F or Cl; m is 0, 1, 2, 3, or 4; R.sup.7 is independently halogen; and n is 0, 1 or 2. 13. The method of claim 12, wherein the cancer is breast cancer. 14. The method of claim 12, further comprising administering to the patient an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulatory agent, chemotherapeutic agent, an apoptosis-enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders, or a combination thereof. 15. The method of claim 12, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutic agent selected from the group consisting of paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab, trastuzumab emtansine, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, and ixabepilone, or a combination thereof. 16. The method of claim 12, wherein the compound or pharmaceutically acceptable salt thereof is administered in combination with a CDK 4/6 inhibitor. 17. The method of claim 16, wherein the CDK 4/6 inhibitor is selected from the group consisting of palbociclib, ribociclib and LY283519, or a pharmaceutically acceptable salt thereof. 18. A kit for treating breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer, the kit comprising: a) a pharmaceutical composition of claim 10; and b) instructions for use. 19. The compound of claim 1 comprising one or more deuterium. 20. The compound 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phen- yl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propa- n-1-ol, or a pharmaceutically acceptable salt thereof. 21. The compound 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phen- yl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-d- ifluoropropan-1-ol, or a pharmaceutically acceptable salt thereof. 22. The compound of claim 1 having the formula: ##STR00411## or a pharmaceutically acceptable salt thereof. 23. The method of claim 12, wherein the compound or pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition. 24. The method of claim 12, wherein the cancer is hormone receptor positive metastatic breast cancer. 25. The method of claim 12, wherein the cancer is hormone dependent breast cancer. 26. The method of claim 13, wherein the compound or pharmaceutically acceptable salt thereof is administered prior to the patient having received surgery. 27. The method of claim 13, wherein the compound or pharmaceutically acceptable salt thereof is administered after the patient has received surgery. 28. The method of claim 12 or 13, wherein the patient is chemotherapy-naive. 29. The method of claim 13, wherein the breast cancer is a hormone refractory breast cancer. 30. The method of claim 14, wherein the compound or a pharmaceutically acceptable salt thereof is administered prior to administration of the additional therapeutic agent to the patient. 31. The method of claim 14, wherein the compound or a pharmaceutically acceptable salt thereof is administered after the administration of the additional therapeutic agent to the patient. 32. A method of treating breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer, the method comprising administering to a patient having said cancer a compound of formula: ##STR00412## ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429## or a pharmaceutically acceptable salt thereof. 33. The method of claim 32, wherein the compound is: ##STR00430## 34. The method of claim 32, wherein the compound is a pharmaceutically acceptable salt of the compound: ##STR00431## 35. A method of treating breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer, the method comprising administering to a patient having said cancer a compound of formula: ##STR00432## or a pharmaceutically acceptable salt thereof. 36. The method of claim 35, wherein the compound is: ##STR00433## 37. The method of claim 35, wherein the compound is a pharmaceutically acceptable salt of the compound: ##STR00434## 38. The method of claim 32, wherein the cancer is breast cancer. 39. The method of claim 35, wherein the cancer is breast cancer. 40. A method of treating breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer, the method comprising administering to a patient having said cancer a compound of formula: ##STR00435## or a pharmaceutically acceptable salt thereof. 41. The method of claim 40, wherein the compound is: ##STR00436## 42. The method of claim 40, wherein the compound is a pharmaceutically acceptable salt of: ##STR00437## 43. A method of treating breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer, the method comprising administering to a patient having said cancer a compound of formula: ##STR00438## or a pharmaceutically acceptable salt thereof. 44. The method of claim 43, wherein the compound is: ##STR00439## 45. The method of claim 43, wherein the compound is a pharmaceutically acceptable salt of: ##STR00440## 46. A method of treating breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer, the method comprising administering to a patient having said cancer a compound of formula: ##STR00441## or a pharmaceutically acceptable salt thereof. 47. The method of claim 46, wherein the compound is: ##STR00442## 48. The method of claim 46, wherein the compound is a pharmaceutically acceptable salt of: ##STR00443## 49. The method of claim 12, wherein the compound comprises a compound of Formula Ii: ##STR00444## or a pharmaceutically acceptable salt thereof. 50. The method of claim 12, wherein the compound comprises a compound of Formula Ij: ##STR00445## or a pharmaceutically acceptable salt thereof. 51. The method of claim 12, wherein the compound comprises a compound of Formula Ik: ##STR00446## or a pharmaceutically acceptable salt thereof. 52. The method of claim 12, wherein R.sup.7 is F. 53. The method of claim 12, wherein R.sup.1 and R.sup.2 are H. 54. The method of claim 12, wherein R.sup.3 is H, and R.sup.4 is --CH.sub.3. 55. The method of claim 12, wherein R.sup.5 is C.sub.1-C.sub.6 fluoroalkyl. 56. The method of claim 12, wherein m is 0. 57. The method of claim 12, wherein the patient has been treated at least once with one or more therapeutic agents selected from the group consisting of paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab, trastuzumab emtansine, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, and ixabepilone, or a combination thereof. 58. The method of claim 12, wherein the patient has been treated at least once with a hormone blocking therapy, a chemotherapeutic agent, radiation therapy, monoclonal antibody, or a combination thereof. 59. The method of claim 58, wherein the patient has been previously treated with at least one of chemotherapy and radiation therapy. 60. The method of claim 58, wherein the compound is administered in combination with a hormone blocking therapy, a chemotherapeutic agent, radiation therapy, a monoclonal antibody, or a combination thereof. 61. The method of claim 58, wherein the chemotherapeutic agent comprises a therapeutic antibody selected from the group consisting of alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, pertuzumab, trastuzumab, trastuzumab emtansine, and tositumomab, or a combination thereof. 62. The method of claim 61, wherein the chemotherapeutic agent comprises a therapeutic antibody selected from the group consisting of bevacizumab, rituximab, pertuzumab, trastuzumab, and trastuzumab emtansine, or a combination thereof. 63. The method of claim 58, wherein the chemotherapeutic agent comprises one or more of: (i) anti-estrogens; (ii) selective estrogen receptor modulators; (iii) selective estrogen receptor modulators; or (iv) anti-androgens, or a pharmaceutically acceptable salt thereof. 64. The method of claim 63, wherein the selective estrogen receptor modulator comprises tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, or toremifene citrate. 65. The method of claim 63, wherein the selective estrogen receptor modulator comprises fulvestrant. 66. The method of claim 63, wherein aromatase inhibitor comprises 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane, formestanie, fadrozole, vorozole, letrozole, or anastrozole. 67. The method of claim 63, wherein the anti-androgen comprises flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine. 68. The method of claim 14, wherein the compound is administered in combination with cobimetinib. 69. The method of claim 14, wherein the compound is administered in combination with taselisib or ipatasertib. 70. The method of claim 17, wherein the compound is administered in combination with palbociclib. 71. The method of claim 17, wherein the compound is administered in combination with ribociclib. 72. The compound N-(3,5-difluoro-4-((1R,3R)-7-fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3- ,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azeti- din-3-amine or a pharmaceutically acceptable salt thereof. 73. The compound N-(3,5-difluoro-4-((1R,3R)-7-fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3- ,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azeti- din-3-amine. 74. A pharmaceutically acceptable salt of the compound N-(3,5-difluoro-4-((1R,3R)-7-fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3- ,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azeti- din-3-amine. 75. The compound N-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetr- ahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-ami- ne or a pharmaceutically acceptable salt thereof. 76. The compound N-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetr- ahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-ami- ne. 77. A pharmaceutically acceptable salt of the compound N-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetr- ahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-ami- ne. 78. The compound N-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-t- etrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-- amine or a pharmaceutically acceptable salt thereof. 79. The compound N-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-t- etrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-- amine. 80. A pharmaceutically acceptable salt of the compound N-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-t- etrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-- amine. 81. The compound 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phen- yl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propa- n-1-ol. 82. A pharmaceutically acceptable salt of the compound 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phen- yl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propa- n-1-ol, or a pharmaceutically acceptable salt thereof. 83. The compound 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phen- yl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-d- ifluoropropan-1-ol. 84. A pharmaceutically acceptable salt of the compound 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phen- yl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-d- ifluoropropan-1-ol. 85. A process for preparing a compound of formula (Ih) of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, the process comprising: cyclizing a compound of formula (3) ##STR00447## with a compound of formula ##STR00448## thereby forming a compound of formula (Ih) ##STR00449## 86. The process of claim 85, wherein the compound of formula (3) is prepared by reacting a compound of formula (11) ##STR00450## (i) with X--R.sup.5 wherein X is I, Br, or --OTf; (ii) with an acyl chloride having formula ##STR00451## or (iii) with a sulfonyl chloride having formula ##STR00452## or (iv) by reductive amination with an aldehyde or ketone. 87. A process for preparing a compound of formula (Ih) of claim 1, the process comprising: (a) reacting a compound of formula (11) ##STR00453## (i) with a compound of formula X--R.sup.5, wherein X is I, Br, or --OTf; (ii) with an acyl chloride having formula ##STR00454## or (iii) with a sulfonyl chloride having formula ##STR00455## or (iv) by reductive amination with an aldehyde or ketone, to yield a compound having formula (3) ##STR00456## (b) cyclizing the compound of formula (3) with a compound of formula ##STR00457## to yield a compound having formula (13) ##STR00458## wherein X.sup.1 is I or Br; and (c) reacting the compound of formula (13) with a compound having formula ##STR00459## to yield a compound having formula (Ih) ##STR00460##

Details for Patent 9,980,947

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	02/20/1991		2039-02-26
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	06/28/2000		2039-02-26
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2039-02-26
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2039-02-26