Claims for Patent: 8,557,806

Summary for Patent: 8,557,806

Title:	Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
Abstract:	The present invention provides methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds, as well as methods of treating, preventing or ameliorating symptoms associated with such diseases. Specific examples of autoimmune diseases that can be treated or prevented with the compounds include rheumatoid arthritis and/or its associated symptoms, systemic lups erythematosis and/or its associated symptoms and multiple sclerosis and/or its associated symptoms.
Inventor(s):	Singh; Rajinder (Belmont, CA), Argade; Ankush (Foster City, CA), Payan; Donald G. (Hillsborough, CA), Clough; Jeffrey (Redwood City, CA), Keim; Holger (Menlo Park, CA), Bhamidipati; Somasekhar (Foster City, CA), Sylvain; Catherine (San Mateo, CA), Li; Hui (Santa Clara, CA)
Assignee:	Rigel Pharmaceuticals, Inc. (South San Francisco, CA)
Application Number:	13/418,696
Patent Claims:	1. A method of treating rheumatoid arthritis and/or one or more symptoms associated therewith in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) and one or more additional compounds selected from a steroid, a membrane stabilizer, a 5LO inhibitor, a leukotriene synthesis inhibitor, a leukotriene receptor inhibitor, an inhibitor of IgE isotype switching, an inhibitor of IgE synthesis, an inhibitor of IgG isotype switching, an inhibitor of IgG synthesis, a .beta.-agonist, a tryptase inhibitor, aspirin, a COX inhibitor, methotrexate, an anti-TNF drug, rituxan, a PD4 inhibitor, a p38 inhibitor, a PDE4 inhibitor, and an antihistamine, wherein the compound of formula (I) is: ##STR00053## and salts, hydrates, solvates and N-oxides thereof, wherein: L.sup.1 and L.sup.2 are each a direct bond; R.sup.2 is selected from the group consisting of phenyl mono-substituted at the 3- or 5-position with an R.sup.8 group, phenyl di or tri-substituted with one or more of the same or different R.sup.8 group, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R.sup.8 groups; R.sup.4 is selected from the group consisting of phenyl substituted with one or more of the same or different R.sup.8 groups, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R.sup.8 groups; wherein at least one of R.sup.2 and R.sup.4 is pyrid[1,4]oxazinyl; R.sup.5 is selected from the group consisting of --CN, --NC, --NO.sub.2, fluoro, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, --C(O)R.sup.a, --C(O)OR.sup.a, --C(O)CF.sub.3 and --C(O)OCF.sub.3; R.sup.6 is hydrogen; R.sup.8 is selected from the group consisting of R.sup.e, R.sup.b, R.sup.e substituted with one or more of the same or different R.sup.a or R.sup.b, --OR.sup.a substituted with one or more of the same or different R.sup.a or R.sup.b, --B(OR.sup.a).sub.2, --B(NR.sup.cR.sup.c).sub.2, --(CH.sub.2).sub.m--R.sup.b, --(CHR.sup.a).sub.m--R.sup.b, --O--(CH.sub.2).sub.m--R.sup.b, --S--(CH.sub.2).sub.m--R.sup.b, --O--CHR.sup.aR.sup.b, --O--CR.sup.a(R.sup.b).sub.2, --O--(CHR.sup.a).sub.m--R.sup.b, --O--(CH.sub.2).sub.m--CH[(CH.sub.2).sub.mR.sup.b]R.sup.b, --S--(CHR.sup.a).sub.m--R.sup.b, --C(O)NH--(CH.sub.2).sub.m--R.sup.b, --C(O)NH--(CHR.sup.a).sub.m--R.sup.b, --O--(CH.sub.2).sub.m--C(O)NH--(CH.sub.2).sub.m--R.sup.b, --S--(CH.sub.2).sub.m--C(O)NH--(CH.sub.2).sub.m--R.sup.b, --O--(CHR.sup.a).sub.m--C(O)NH--(CHR.sup.a).sub.m--R.sup.b, --S--(CHR.sup.a).sub.m--C(O)NH--(CHR.sup.a).sub.m--R.sup.b, --NH--(CH.sub.2).sub.m--R.sup.b, --NH--(CHR.sup.a).sub.m--R.sup.b, --NH[(CH.sub.2).sub.mR.sup.b], --N[(CH.sub.2).sub.mR.sup.b].sub.2, --NH--C(O)--NH--(CH.sub.2).sub.m--R.sup.b, --NH--C(O)--(CH.sub.2).sub.m--CHR.sup.bR.sup.b and --NH--(CH.sub.2).sub.m--C(O)--NH--(CH.sub.2).sub.m--R.sup.b; each R.sup.a is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each R.sup.b is a suitable group independently selected from the group consisting of .dbd.O, --OR.sup.d, (C1-C3) haloalkyloxy, .dbd.S, --SR.sup.d, .dbd.NR.sup.d, .dbd.NOR.sup.d, --NR.sup.cR.sup.c, halogen, --CF.sub.3, --CN, --NC, --OCN, --SCN, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, --S(O)R.sup.d, --S(O).sub.2R.sup.d, --S(O).sub.2OR.sup.d, --S(O)NR.sup.cR.sup.c, --S(O).sub.2NR.sup.cR.sup.c, --OS(O)R.sup.d, --OS(O).sub.2R.sup.d, --OS(O).sub.2OR.sup.d, --OS(O).sub.2NR.sup.cR.sup.c, --C(O)R.sup.d, --C(O)OR.sup.d, --C(O)NR.sup.cR.sup.c, --C(NH)NR.sup.cR.sup.c, --C(NR.sup.a)NR.sup.cR.sup.c, --C(NOH)R.sup.a, --C(NOH)NR.sup.cR.sup.c, --OC(O)R.sup.d, --OC(O)OR.sup.d, --OC(O)NR.sup.cR.sup.c, --OC(NH)NR.sup.cR.sup.c, --OC(NR.sup.a)NR.sup.cR.sup.c, --[NHC(O)].sub.nR.sup.d, --[NR.sup.aC(O)].sub.nR.sup.d, --[NHC(O)].sub.nOR.sup.d, --[NR.sup.aC(O)].sub.nOR.sup.d, --[NHC(O)].sub.nNR.sup.cR.sup.c, --[NR.sup.aC(O)].sub.nNR.sup.cR.sup.c, --[NHC(NH)].sub.nNR.sup.cR.sup.c and --[NR.sup.aC(NR.sup.a)].sub.nNR.sup.cR.sup.c; each R.sup.c is independently a protecting group or R.sup.a, or, alternatively, two R.sup.c are taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R.sup.a or suitable R.sup.b groups; each R.sup.d is independently an R.sup.a; each R.sup.e is independently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl, and 6-16 membered heteroarylalkyl; each m is independently an integer from 1 to 3; and each n is independently an integer from 0 to 3, wherein one or both of R.sup.2 and R.sup.4, independently of one another, is an optionally substituted heteroaryl selected from the group consisting of: ##STR00054## ##STR00055## ##STR00056## wherein: p is an integer from one to three; each independently represents a single bond or a double bond; R.sup.35 is hydrogen or R.sup.8; X is selected from the group consisting of CH, N and N--O; each Y is independently selected from the group consisting of O, S and NH; each Y.sup.1 is independently selected from the group consisting of O, S, SO, SO.sub.2, SONR.sup.36, NH and NR.sup.37; each Y.sup.2 is independently selected from the group consisting of CH, CH.sub.2, O, S, N, NH and NR.sup.37; R.sup.36 is hydrogen or alkyl; R.sup.37 is selected from the group consisting of hydrogen, aryl, arylalkyl, heteroaryl, R.sup.a, R.sup.b, CR.sup.aR.sup.b--O--C(O)R.sup.8, --CR.sup.aR.sup.b--O--PO(OR.sup.8).sub.2, --CH.sub.2--O--PO(OR.sup.8).sub.2, --CH.sub.2--PO(OR.sup.8).sub.2, --C(O)--CR.sup.aR.sup.b--N(CH.sub.3).sub.2, --CR.sup.aR.sup.b--O--C(O)--CR.sup.aR.sup.b--N(CH.sub.3).sub.2, --C(O)R.sup.8, --C(O)CF.sub.3 and --C(O)--NR.sup.8--C(O)R.sup.8; R.sup.38 is selected from the group consisting of alkyl and aryl; A is selected from the group consisting of O, NH and NR.sup.38; R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R.sup.9 and R.sup.10 and/or R.sup.11 and R.sup.12 are taken together form an oxo group; each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester, and carbamate; Q is selected from the group consisting of --OH, --OR.sup.8, --NR.sup.cR.sup.c, --NHR.sup.39--C(O)R.sup.8, --NHR.sup.39--C(O)OR.sup.8, --NR.sup.39--CHR.sup.40--R.sup.b, and --NR.sup.39--(CH.sub.2).sub.m--R.sup.b; R.sup.39 and R.sup.40 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl. 2. The method of claim 1 wherein the mammal is a human. 3. The method of claim 1, wherein the one or more additional compounds comprises methotrexate, an anti-TNF drug or a combination thereof. 4. The method of claim 3, wherein the one or more additional compounds includes methotrexate. 5. The method of claim 3, wherein the one or more additional compounds includes an anti-TNF drug. 6. The method of claim 1 in which R.sup.2 is selected from the group consisting of phenyl, benzodioxanyl, benzodioxolyl, benzoxazinyl, benzoxazolyl, benzopyranyl, benzotriazolyl, 1,4-benzoxazinyl-2-one, 2H-1,4-benzoxazinyl-3(4H)-one, 2H-1,3-benzoxazinyl-2,4(3H)-dione, benzoxazolyl-2-one, dihydrocoumarinyl, 1,2-benzopyronyl, benzofuranyl, benzo[b]furanyl, indolyl, and pyrrolyl, each of which may be optionally substituted with one or more of the same or different R.sup.8 groups. 7. The method of claim 1 in which R.sup.2 and R.sup.4 are the same. 8. The method of claim 7 in which each R.sup.35 is independently selected from the group consisting of hydrogen, R.sup.d, --NR.sup.cR.sup.c, --(CH.sub.2).sub.m--NR.sup.cR.sup.c, --C(O)NR.sup.cR.sup.c, --(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --C(O)OR.sup.d, --(CH.sub.2).sub.m--C(O)OR.sup.d and --(CH.sub.2).sub.m--OR.sup.d. 9. The method of claim 8 in which each m is one. 10. The method of claim 1 in which R.sup.2 is an optionally substituted 5-15 membered heteroaryl which is attached to the remainder of the molecule via a ring carbon atom. 11. The method of claim 1 in which R.sup.4 is an optionally substituted 5-15 membered heteroaryl which is attached to the remainder of the molecule via a ring carbon atom. 12. The method of claim 1 in one of R.sup.2 or R.sup.4 is a phenyl optionally substituted with one, two or three R.sup.8 groups. 13. The method of claim 12 in which the optionally substituted phenyl is mono substituted. 14. The method of claim 13 in which the R.sup.8 substituent is at the ortho, meta or para position. 15. The method of claim 14 wherein R.sup.8 is selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, --OR.sup.d, --O--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.a, --O--(CH.sub.2).sub.m--C(O)OR.sup.a, --O--C(NH)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --NH--C(O)NR.sup.cR.sup.c, and --NH--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c. 16. The method of claim 12 in which the optionally substituted phenyl is a disubstituted phenyl. 17. The method of claim 16 in which the R.sup.8 substituents are positioned 2,3-; 2,4-; 2,5-; 2,6-; 3,4-; or 3,5-. 18. The method of claim 16 in which each R.sup.8 is independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, --OR.sup.a optionally substituted with one or more of the same or different R.sup.a or R.sup.b groups, --O--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.a, --O--(CH.sub.2).sub.m--C(O)OR.sup.a, --O--C(NH)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --NH--C(O)NR.sup.cR.sup.c, and --NH--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c. 19. The method of claim 12 in which the optionally substituted phenyl is trisubstituted. 20. The method of claim 19 in which the R.sup.8 substituents are positioned 2,3,4-; 2,3,5-; 2,3,6-; 2,4,5-; 2,4,6-; 2,5,6-; or 3,4,5-. 21. The method of claim 20 which each R.sup.8 is independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, --OR.sup.a optionally substituted with one or more of the same or different R.sup.a or R.sup.b groups, --O--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --O--C(O)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c, --O--C(O)OR.sup.a, --O--C(NH)NR.sup.cR.sup.c, --O--(CH.sub.2).sub.m--C(O)OR.sup.a, --O--(CH.sub.2).sub.m--C(NH)NR.sup.cR.sup.c, --NH--(CH.sub.2).sub.m--NR.sup.cR.sup.c, --NH--C(O)NR.sup.cR.sup.c, and --NH--(CH.sub.2).sub.m--C(O)NR.sup.cR.sup.c. 22. The method of claim 19 in which the trisubstituted phenyl has the formula: ##STR00057## wherein: R.sup.31 is methyl or (C1-C6) alkyl; R.sup.32 is hydrogen, methyl or (C1-C6) alkyl; and R.sup.33 is a halo group. 23. The method of claim 1 in which the compound of formula (I) is a compound according to structural formula (Ic): ##STR00058## or a salt, hydrate, solvate and/or N-oxide thereof, wherein: R.sup.4 is an optionally substituted pyrid[1,4]oxazinyl; and R.sup.18 is --O(CH.sub.2).sub.m--R.sup.b. 24. The method of claim 22 in which R.sup.8 is --O--CH.sub.2--C(O)--NHCH.sub.3. 25. The method of claim 3 wherein the methotrexate is administered in an amount of from about 7.5 to about 25 mg/week. 26. The method of claim 1 in which the compound of formula (I) is selected from the group consisting of: N4-[(2,2-Dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(met- hylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine; N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3-chloro-4-methoxy- phenyl)-5-fluoro-2,4-pyrimidinediamine; N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3,5-dimethoxypheny- l)-5-fluoro-2,4-pyrimidinediamine; N2-(3,4-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl- )-5-fluoro-2,4-pyrimidinediamine; N4-[(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(indazoli- n-6-yl)-2,4-pyrimidinediamine; N2-(3-tert-Butylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl- )-5-fluoro-2,4-pyrimidinediamine; N4-[(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3-hydrox- yphenyl)-2,4-pyrimidinediamine; N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3-fluoro-4-methoxy- phenyl)-5-fluoro-2,4-pyrimidinediamine; N2-(3-Chlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-- fluoro-2,4-pyrimidinediamine; N2-(3,5-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl- )-5-fluoro-2,4-pyrimidinediamine; N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(1-methyli- ndazolin-6-yl)-2,4-pyrimidinediamine; N2-(3-Chloro-4-trifluoromethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[- 1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[- 1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3-methoxy- carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine; N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[- 1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]o- xazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; N2-[3-(N-Cyclobutylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(2H-3-ox- o-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine; N2-[3-(N-Cyclopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(2H-3-o- xo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine; N2-(3,4-Dichlorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine; N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin- -6-yl)-2,4-pyrimidinediamine; N2-(3,5-Dichloro-4-methoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]ox- azin-6-yl)-2,4-pyrimidinediamine; N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl- )-2,4-pyrimidinediamine; 5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin- -6-yl)-2,4-pyrimidinediamine; N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-- 6-yl)-2,4-pyrimidinediamine; N2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl- )-2,4-pyrimidinediamine; N2-[3-(N-Cyclobutylamino)carbonylmethyleneoxyphenyl]-N4-(2,2-dimethyl-2H-- 3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; N2-(3,5-Dimethylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine; N2-(3,5-Dimethylphenyl)-N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6- -yl)-5-fluoro-2,4-pyrimidinediamine; 5-Fluoro-N2-(3-isopropylphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-- 2,4-pyrimidinediamine; N2-(3-Chloro-4-methylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-- 6-yl)-2,4-pyrimidinediamine; 5-Fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-N4-(2H-3-oxo-4H-5-pyrid[1- ,4]oxazin-6-yl)-2,4-pyrimidinediamine; 5-Fluoro-N2-(indol-6-yl)-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyr- imidinediamine; N4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(indol-- 6-yl)-2,4-pyrimidinediamine; N2-(3,5-Dichlorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine; N2-(3-Bromophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-2,4-- pyrimidinediamine; N2-(3-tert-Butylphenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine; N2-(3,4-Difluorophenyl)-5-fluoro-N4-(2H-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine; and a salt, hydrate, solvate, or an N-oxide thereof. 27. The method of claim 26, wherein the one or more additional compounds comprise methotrexate, an anti-TNF drug, or a combination thereof. 28. The method of claim 27, comprising administering the compound of formula (I) and methotrexate. 29. The method of claim 27, comprising administering the compound of formula (I) and one or more anti-TNF drugs. 30. The method of claim 6, wherein the one or more additional compounds comprise methotrexate, an anti-TNF drug, or both. 31. The method of claim 30, comprising administering the compound of formula (I) and methotrexate. 32. The method of claim 30, comprising administering the compound of formula (I) and one or more anti-TNF drugs. 33. The method of claim 12, wherein the one or more additional compounds comprise methotrexate, an anti-TNF drug, or both. 34. The method of claim 33, comprising administering the compound of formula (I) and methotrexate. 35. The method of claim 33, comprising administering the compound of formula (I) and one or more anti-TNF drugs. 36. The method of claim 18, wherein the one or more additional compounds are selected from the group consisting methotrexate and anti-TNF drugs. 37. The method of claim 36, comprising administering the compound of formula (I) and methotrexate. 38. The method of claim 36, comprising administering the compound of formula (I) and one or more anti-TNF drugs. 39. The method of claim 21, wherein the one or more additional compounds are selected from the group consisting methotrexate and anti-TNF drugs. 40. The method of claim 39, comprising administering the compound of formula (I) and methotrexate. 41. The method of claim 39, comprising administering the compound of formula (I) and one or more anti-TNF drugs.

Details for Patent 8,557,806

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2022-07-29
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2022-07-29