Claims for Patent: 7,902,354

Summary for Patent: 7,902,354

Title:	Lapachone compounds and methods of use thereof
Abstract:	The present invention provides novel tricyclic spiro-oxathiine naphthoquinone derivatives, a synthetic method for making the derivatives, and the use of the derivatives to induce cell death and/or to inhibit proliferation of cancer or precancerous cells. The naphthoquinone derivatives of the present invention are related to the compound known as .beta.-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho(1,2-b)pyran-5,6-dione).
Inventor(s):	Ashwell; Mark A. (Carlisle, MA), Tandon; Manish (Framingham, MA), Lapierre; Jean-Marc (Pelham, NH), Ali; Syed (North Andover, MA), Vensel; David (Somerville, MA), Li; Chiang J. (Cambridge, MA)
Assignee:	ArQule, Inc. (Woburn, MA)
Application Number:	11/894,900
Patent Claims:	1. A compound of Formula I: ##STR00355## or a pharmaceutically acceptable salt and/or an individual diastereomer thereof, wherein: X=N-J.sub.1, ##STR00356## O, or S; p=1 or 2; q=p or p+1; R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each, independently, H, OH, F, Cl, Br, I, CH.sub.3, CF.sub.3, C.sub.2-C.sub.6 straight chain alkyl, substituted C.sub.1-C.sub.6 straight chain alkyl, C.sub.3-C.sub.6 branched alkyl, C.sub.3-C.sub.8 cycloalkyl, allyl, C.sub.2-C.sub.6 straight chain alkenyl, substituted C.sub.2-C.sub.6 straight chain alkenyl, C.sub.3-C.sub.6 branched alkenyl, C.sub.5-C.sub.8 cycloalkenyl, C.sub.2-C.sub.6 alkynyl, NO.sub.2, CN, NH.sub.2, alkylamine, substituted alkylamine, dialkylamine, arylamine, C(O)NHR.sub.14, NHC(O)R.sub.15, carbamoyl, aminesulfoxide, sulfonamide, sulfamoyl, sulfonic acid, phenyl, C.sub.5-C.sub.8 aryl, heteroaryl, heterocyclyl, OCH.sub.3, OCF.sub.3, C.sub.2-C.sub.6 alkoxy, alkoxycarbonyl, carboxyacid, carbonylalkoxy, SH, thioalkyl, thioaryl, alkylthioaryl, or C.sub.1-C.sub.6 hydroxyl alkyl; J.sub.1 is -(CR.sub.5R.sub.6).sub.n-(CR.sub.7R.sub.8).sub.m--Y, --S(O).sub.O--Z, amidine, substituted amidine, heterocyclyl, substituted heterocyclyl, 3,4-dioxo-3,4-dihydronaphthalenyl, heteroaryl, substituted heteroaryl, or ##STR00357## m=0, 1, 2, 3, 4, or 5; n=0, 1, 2, 3, 4, or 5; o=1 or 2; t=1 or 2; R.sub.5 and R.sub.6 are each, independently, H, OH, CH.sub.3, CF.sub.3, C.sub.2-C.sub.6 straight chain alkyl, C.sub.3-C.sub.6 branched alkyl, C.sub.3-C.sub.8 cycloalkyl, allyl, C.sub.2-C.sub.6 straight chain alkenyl, C.sub.3-C.sub.6 branched alkenyl, C.sub.5-C .sub.8 cycloalkenyl, C.sub.2-C.sub.6 alkynyl, phenyl, C.sub.5-C.sub.8 aryl, heteroaryl, heterocyclyl, carboxylate, or carbonylalkoxy; when R.sub.5=R.sub.6, R.sub.5 is not OH; R.sub.7 and R.sub.8 are each, independently, H, F, Cl, Br, I, OH, CH.sub.3, C.sub.2-C.sub.6 straight chain alkyl, CF.sub.3, C.sub.3-C.sub.6 branched alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.6 alkoxy, allyl, C.sub.2-C.sub.6 straight chain alkenyl, C.sub.3-C.sub.6 branched alkenyl, C.sub.5-C.sub.8 cycloalkenyl, C.sub.2-C.sub.6 alkynyl, NO.sub.2, CN, amine, alkylamine, dialkylamine, arylamine, carbamoyl, aminesulfoxide, sulfonamide, sulfonic acid, phenyl, C.sub.5-C.sub.8 aryl, heteroaryl, heterocyclyl, OCH.sub.3, OCF.sub.3, alkoxycarbonyl, carboxyacid, carbonylalkoxy, SH, thioalkyl, thioaryl, or alkylthioaryl; when R.sub.7=R.sub.8, R.sub.7 is not OH, NH.sub.2, SH, or NO.sub.2; Y is H, F, Cl, Br, I, CR.sub.10.dbd.CHR.sub.11, CF.sub.3, CH.sub.3, C.sub.2-C.sub.6 straight chain alkyl, substituted C.sub.2-C.sub.6 straight chain alkyl, C.sub.3-C.sub.6 branched alkyl, CH.sub.2OR.sub.16, phenyl, substituted phenyl, C.sub.5-C.sub.8 aryl, substituted C.sub.5-C.sub.8 aryl, C.sub.3-C.sub.8 cycloalkyl, substituted C.sub.3-C.sub.8 cycloalkyl, CH.sub.2-heterocycle, C.sub.5-C.sub.8 cycloalkenyl, aryloxy, substituted aryloxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, benzyl, alkylamine, substituted alkylamine, benzylamine, OH, OCR.sub.12.dbd.CHR.sub.13, C.sub.2-C.sub.6 alkynyl, amine, dialkylamine, arylamine, amide, carbamoyl, aminesulfoxide, sulfamide, sulfamoyl, sulfonic acid, heteroaryloxy, OCH.sub.3, OCF.sub.3, C.sub.2-C.sub.6 alkoxy, alkenoxy, phenoxy, benzyloxy, alkoxycarbonyl, carboxyacid, carboxyalkoxy, carbonylalkyl, thio, alkylthio, thioalkyl, arylthio, thioaryl, alkylthioaryl, or ##STR00358## provided that, when n=0 and m=0, Y is H, heterocyclyl, heteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.5-C.sub.8 cycloalkenyl, aryl, or ##STR00359## each of which may be substituted; W is C.sub.2-C.sub.6 straight chain alkyl, substituted C.sub.1-C.sub.6 straight chain alkyl, OCH.sub.3, C.sub.2-C.sub.6 alkoxy, alkylthioalkyl, substituted alkylthioalkyl, C.sub.3-C.sub.8 cycloalkyl, substituted C.sub.3-C.sub.8 cycloalkyl, C.sub.5-C.sub.8 aryl, substituted aryl, phenyl, substituted phenyl, CR.sub.10.dbd.CHR.sub.11, alkylthio, benzyl, substituted benzyl, heterocyclyl, substituted heterocyclyl, phenoxy, aryloxy, substituted aryloxy, OCR.sub.12.dbd.CHR.sub.13, benzyloxy, heteroaryloxy, substituted heteroaryloxy, amine, substituted amine, arylamine, substituted arylamine, phenylamine, substituted phenylamine, CH.sub.3, CF.sub.3, C.sub.3-C.sub.6 branched alkyl, C.sub.5-C.sub.8 cycloalkenyl, C.sub.2-C.sub.6 alkynyl, alkylamine, dialkylamine, heteroaryl, CH.sub.2-heterocyclyl, CH.sub.2-substituted heterocyclyl, OCF.sub.3, alkenoxy, CH.sub.2OR.sub.16, thioalkyl, arylthio, thioaryl, alkylthioaryl, alkylcarboxy, phenyl sulfonylamide, substituted aryl sulfonylamide, or chlorophenylacetyl; Z is CH.sub.3, CF.sub.3, C.sub.2-C.sub.6 straight chain alkyl, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl, C.sub.5-C.sub.8 aryl, substituted C.sub.5-C.sub.8 aryl, C.sub.3-C.sub.6 branched alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.5-C.sub.8 cycloalkenyl, C.sub.2-C.sub.6 alkynyl, amine, alkylamine, dialkylamine, arylamine, benzyl, heteroaryloxy, heterocyclyl, CH.sub.2-heterocycle, OCH.sub.3, OCF.sub.3, C.sub.2-C.sub.6 alkoxy, alkenoxy, phenoxy, aryloxy or benzyloxy; R.sub.9 is H, CH.sub.3, C.sub.2-C.sub.6 straight chain alkyl, or C.sub.3-C.sub.6 branched alkyl; R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are each, independently, H, phenyl, C.sub.5-C.sub.8 aryl, CH.sub.3, CF.sub.3, C.sub.2-C.sub.6 straight chain alkyl, C.sub.3-C.sub.8 cycloalkyl, heteroaryl, or heterocyclyl; R.sub.14 and R.sub.15 are each, independently H, C.sub.2-C.sub.6 straight alkyl, C.sub.3-C.sub.6 branched alkyl, C.sub.3-C.sub.8 cycloalkyl, allyl, C.sub.2-C.sub.6 straight alkenyl, branched alkenyl, C.sub.5-C.sub.8 cycloalkenyl, phenyl, C.sub.5-C.sub.8 aryl, benzyl, CH.sub.2C(OCH.sub.3).sub.2, heteroaryl, or heterocyclyl; R.sub.16 is C.sub.3-C.sub.6 branched alkyl, C.sub.5-C.sub.8 aryl, substituted C.sub.5-C.sub.8 aryl, heteroaryl, phenyl, substituted phenyl, CH.sub.2-aryl, benzyl, H, CH.sub.3, CF.sub.3, C.sub.2-C.sub.6 straight chain alkyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, or CH.sub.2-heteroaryl, J.sub.2 and J.sub.3 are each, independently, H, F, Cl, Br, I, CR.sub.17.dbd.CHR.sub.18, CF.sub.3, CH.sub.3, C.sub.2-C.sub.6 straight chain alkyl, substituted C.sub.1-C.sub.6 straight chain alkyl, C.sub.3-C.sub.6 branched alkyl, CH.sub.2OR.sub.21, phenyl, C.sub.5-C .sub.8 aryl, substituted C.sub.5-C.sub.8 aryl, C.sub.3-C.sub.8 cycloalkyl, substituted C.sub.3-C.sub.8 cycloalkyl, CH.sub.2-heterocycle, C.sub.5-C.sub.8 cycloalkenyl, aryloxy, substituted aryloxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, benzyl, alkylamine, substituted alkylamine, benzylamine, OH, OCR.sub.19.dbd.CHR.sub.20, C.sub.2-C.sub.6 alkynyl, amine, dialkylamine, arylamine, amide, carbamoyl, aminesulfoxide, sulfamide, sulfamoyl, sulfonic acid, heteroaryloxy, OCH.sub.3,OCF.sub.3, C.sub.2-C.sub.6 alkoxy, alkenoxy, phenoxy, benzyloxy, alkoxycarbonyl, carboxyacid, carboxyalkoxy, carbonylalkyl, thio, alkylthio, thioalkyl, arylthio, thioaryl, alkylthioaryl, or ##STR00360## when J.sub.2 .dbd.J.sub.3, J.sub.2 is not OH, NH.sub.2, or SH; or J.sub.2 and J.sub.3 can form a 4, 5, 6, 7, or 8 membered spiro ring containing 0, 1, or 2 heteroatoms selected from O, N, and S; R.sub.17, R.sub.18, R.sub.19, and R.sub.20 are each, independently, H, phenyl, C.sub.5-C.sub.8 aryl, CH.sub.3, CF.sub.3, C.sub.2-C.sub.6 straight chain alkyl, C.sub.3-C.sub.8 cycloalkyl, heteroaryl, or heterocyclyl; and R.sub.21 is H, C.sub.2-C.sub.6 straight alkyl, C.sub.3-C.sub.6 branched alkyl, C.sub.3-C.sub.8 cycloalkyl, allyl, C.sub.2-C.sub.6 straight alkenyl, branched alkenyl, C.sub.5-C.sub.8 cycloalkenyl, phenyl, C.sub.5-C.sub.8 aryl, benzyl, CH.sub.2C(OCH.sub.3).sub.2, heteroaryl, or heterocyclyl. 2. The compound of claim 1, wherein p=1 and q=1. 3. The compound of claim 1, wherein p=1 and q=2. 4. The compound of claim 1, wherein p=2 and q=2. 5. The compound of claim 1, wherein p=2 and q=3. 6. The compound of claim 1, wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each, independently, H, OH, F, Cl, Br, I, CH.sub.3, CF.sub.3, OCH.sub.3, C.sub.2-C.sub.6 alkoxy, C.sub.2-C.sub.6 straight chain alkyl, substituted C.sub.2-C.sub.6 straight chain alkyl, phenyl, C.sub.5-C.sub.8 aryl, NO.sub.2, CN, C(O)NHR.sub.14 or NHC(O)R.sub.15. 7. The compound of claim 6, wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each, independently, H, OH, F, Cl, Br, I, CH.sub.3, CF.sub.3, OCH.sub.3, or C.sub.2-C.sub.6 alkoxy. 8. The compound of claim 7, wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each, independently, H or OCH.sub.3. 9. The compound of claim 8, wherein R.sub.1, R.sub.2 and R.sub.4 are each H and R.sub.3 is OCH.sub.3. 10. The compound of claim 1, wherein X.dbd.O or S. 11. The compound of claim 1, wherein X.dbd. ##STR00361## 12. The compound of claim 1, wherein X.dbd.N-J.sub.1. 13. The compound of claim 12, wherein J.sub.1 is --(CR.sub.5R.sub.6).sub.n--(CR.sub.7R.sub.8).sub.m--Y. 14. The compound of claim 13, wherein n=0 and m=0. 15. The compound of claim 13, wherein n=1 and m=0. 16. The compound of claim 13, wherein n=1 and m=1. 17. The compound of claim 13, wherein n=1 and m=2. 18. The compound of claim 13, wherein n=5 and m=5. 19. The compound of claim 13, wherein R.sub.5 and R.sub.6 are each, independently, H or CH.sub.3. 20. The compound of claim 13, wherein R.sub.7 and R.sub.8 are each, independently, H, F, Cl, Br, I, OH, CH.sub.3, C.sub.2-C.sub.6 straight chain alkyl, CF.sub.3, C.sub.3-C.sub.6 branched alkyl, C.sub.3-C.sub.8 cycloalkyl, or C.sub.2-C.sub.6 alkoxy. 21. The compound of claim 20, wherein R.sub.7 and R.sub.8 are each, independently, H or OH. 22. The compound of claim 13, wherein Y is CH.sub.2OR.sub.16, phenyl, substituted C.sub.5-C.sub.8 aryl or benzyl. 23. The compound of claim 15, wherein R.sub.5 and R.sub.6 are each H. 24. The compound of claim 23, wherein Y is substituted or unsubstituted C.sub.5-C .sub.8 aryl. 25. The compound of claim 24, wherein the substituted C.sub.5-C.sub.8 aryl is substituted with from 1 to 5 substituents, each of which is independently CN, Cl or F. 26. The compound of claim 16, wherein R.sub.5 and R.sub.6 are each H and R.sub.7 and R.sub.8 are each, independently, H or OH. 27. The compound of claim 26, wherein Y is CH.sub.2OR.sub.16. 28. The compound of claim 27, wherein R.sub.16 is substituted or unsubstituted C.sub.5-C .sub.8 aryl. 29. The compound of claim 28, wherein the substituted C.sub.5-C.sub.8 aryl is substituted with from 1 to 5 substituents, each of which is independently C.sub.3-C.sub.6 branched alkyl, Cl, or F. 30. The compound of claim 12, wherein J.sub.1 is --S(O).sub.0--Z. 31. The compound of claim 30, wherein o=1. 32. The compound of claim 30, wherein o=2. 33. The compound of claim 30, wherein Z is CH.sub.3, CF.sub.3, C.sub.2-C.sub.6 straight chain alkyl, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl, C.sub.5-C.sub.8 aryl, or substituted C.sub.5-C.sub.8 aryl. 34. The compound of claim 12, wherein J.sub.1 is ##STR00362## 35. The compound of claim 34, wherein t=1. 36. The compound of claim 34, wherein t=2. 37. The compound of claim 35, wherein W is substituted aryl, phenyl, phenoxy, aryloxy or substituted aryloxy. 38. The compound of claim 37, wherein the aryl and aryloxy is substituted with from 1 to 5 substituents, each of which is independently CF.sub.3 or F. 39. The compound of claim 34, wherein t=2 and W is C.sub.2-C.sub.6 alkoxy. 40. The compound of claim 12, wherein R.sub.9 is H. 41. The compound of claim 12, wherein R.sub.10 and R.sub.11 are both H. 42. The compound of claim 12, wherein R.sub.12 and R.sub.13 are both H. 43. The compound of claim 12, wherein R.sub.12 is H and R.sub.13 is phenyl. 44. The compound of claim 12, wherein R.sub.16 is C.sub.3-C.sub.6 branched alkyl, C.sub.5-C.sub.8 aryl, substituted C.sub.5-C.sub.8 aryl, heteroaryl, phenyl, substituted phenyl, CH.sub.2-aryl, or benzyl. 45. The compound of claim 1, which is selected from the following compounds, or a pharmaceutically acceptable salt and/or an individual diastereomer thereof: 1'-(3-chlorobenzoyl) spiro [naphtho [1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione; 1'-(3 ,4-dichlorobenzoyl)spiro[naphtho [1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione; 4-[(5,6-dioxo-5,6-dihydro-1'H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4'-pip- eridin]-1'-yl)methyl]benzonitrile; 1'-(2-phenylethyl)spiro[naphtho[1,2-b][1,4]oxathiine -2,4'-piperidine]-5,6-dione; 1'-(4-fluorobenzyl)spiro [naphtho [1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione; 1'-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxat- hiine-2,4'-piperidine]-5,6-dione; 1'-(2-hydroxy-3-phenylpropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4'-pipe- ridine]-5,6-dione; 3-(trifluoromethyl)phenyl 5,6-dioxo-5,6-dihydro-1'H-Spiro [naphtho [1,2-b][1,4]oxathiine -2,4'-piperidine]-1'-carboxylate; 4-fluorophenyl-5,6-dioxo-5,6-dihydro-1'H-Spiro[naphtho[1,2-b][2,4]oxathii- ne-2,4'-piperidinel]-1'-carboxylate; 1'-(2-chloro-6-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4'-piper- idine]-5,6-dione; 1'-(3-chloro-4-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4'-piper- idine]-5,6-dione; 1'-(3-phenoxypropyl)spiro [naphtho [1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione; 1'-[2-(4-chlorophenoxy)ethyl]Spiro[naphtho[1,2-b][1,4]oxathiine-2,4'-pipe- ridine]-5,6-dione; 1'-[(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl]Spiro [naphtho [1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione; 1'-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho [1,2-b][1,4]oxathiine -2,4' -piperidine]-5,6-dione; 1'-[(2R)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho [1,2-b][1,4]oxathiine -2,4'-piperidine]-5,6-dione; 1'-[(2R)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxa- thiine-2,4'-piperidine]-5,6-dione; 1'-[(2S)-3-(4-chlorophenoxy)-2-hydroxypropyl]Spiro [naphtho [1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione; 1'-[(2R)-3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxa- thiine-2,4'-piperidine]-5,6-dione; 1'-[(2R)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4'- -piperidine]-5,6-dione; 1'-[(2S)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4'- -piperidine]-5,6-dione; 1'-[(2S)-2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxa- thiine-2,4'-piperidine]-5,6-dione; 1'-isopropylspiro[naphtho[1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione- ; 1'-[(2S)-3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxa- thiine-2,4'-piperidine]-5,6-dione; 1'-[(2R)-3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxat- hiine-2,4'-piperidine]-5,6-dione; and 1'-[(2R)-2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxa- thiine-2,4'-piperidine]-5,6-dione. 46. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier or excipient. 47. The pharmaceutical composition of claim 46 further comprising a second chemotherapeutic agent. 48. The pharmaceutical composition of 47, wherein said second chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatin, carboplatin, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristin, vinblastin, nocodazole, teniposide, etoposide, epothilone, navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin, idarubicin imatanib, gefitinib, erlotinib, sorafenib, sunitinib malate, trastuzumab, rituximab, cetuximab, and bevacizumab. 49. The compound of claim 1, selected from the group consisting of: ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407## ##STR00408## ##STR00409## ##STR00410## ##STR00411## ##STR00412## ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424## or a pharmaceutically acceptable salt and/or an individual diastereomer thereof. 50. A compound selected from the group consisting of: ##STR00425## ##STR00426## or a pharmaceutically acceptable salt and/or an individual diastereomer thereof.

Details for Patent 7,902,354

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2026-08-21
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2026-08-21
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2026-08-21
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2026-08-21
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2026-08-21
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2026-08-21