Claims for Patent: 8,258,308

Summary for Patent: 8,258,308

Title:	Amino nicotinic and isonicotinic acid derivatives as DHODH inhibitors
Abstract:	The present disclosure relates to compounds of formula (I): ##STR00001## or a pharmaceutically acceptable salt or N-oxide thereof. The present disclosure also relates to pharmaceutical compositions comprising the compounds of formula (I), and to their methods of use in therapy.
Inventor(s):	Castro Palomino Laria; Julio Cesar (Barcelona, ES), Erra Sola; Montserrat (Barcelona, ES), Lozoya Toribio; Maria Estrella (Barcelona, ES), Navarro Romero; Eloisa (Barcelona, ES)
Assignee:	Laboratorios Almirall, S.A. (Barcelona, ES)
Application Number:	12/520,237
Patent Claims:	1. A compound of formula (I), ##STR00072## wherein one of the G.sup.1 groups is chosen from a nitrogen atom and a CR.sup.c group and the other G.sup.1 group represents a CR.sup.c group; G.sup.2 represents a CR.sup.d group; R.sup.1 is chosen from hydrogen atoms, halogen atoms, C.sub.1-4 alkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.3-8 cycloalkyl groups which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; R.sup.2 is chosen from hydrogen atoms, halogen atoms, hydroxyl groups, C.sub.1-4 alkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, C.sub.1-4 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.3-8 cycloalkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; R.sup.a, R.sup.b and R.sup.c are each independently chosen from hydrogen atoms, halogen atoms, C.sub.1-4 alkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.1-4 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; R.sup.d is chosen from hydroxy groups, C.sub.1-3 alkoxy groups, 2,2,2-trifluoroethoxy groups and C.sub.3-4cycloalkoxy groups; one of the groups G.sup.3 and G.sup.4 is a nitrogen atom and the other is a CH group; and M is a hydrogen atom or an pharmaceutically acceptable cation; with the proviso that, when at least one of the groups R.sup.a and R.sup.b represent a hydrogen atom, then R.sup.d is chosen from C.sub.1-3 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.3-4 cycloalkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; or a pharmaceutically acceptable salt or N-oxide thereof. 2. The compound according to claim 1, wherein each of the C.sub.1-4 alkyl groups, the C.sub.3-8 cycloalkyl groups, the C.sub.1-4 alkoxy groups and the C.sub.3-8 cycloalkoxy groups is independently optionally substituted by 1, 2 or 3 halogen atoms. 3. The compound according to claim 1, wherein R.sup.1 is chosen from hydrogen atoms, bromine atoms, fluorine atoms, methyl, ethyl, cyclopropyl and cyclobutyl groups. 4. The compound according to claim 1, wherein G.sup.3 represents a nitrogen atom and G.sup.4 represents a CH group. 5. The compound according to claim 1, wherein both G.sup.1 groups represent a CR.sup.c group. 6. The compound according to claim 1, wherein each R.sup.c is independently chosen from hydrogen atoms, fluorine atoms, chlorine atoms and C.sub.1-3 alkyl groups. 7. The compound according to claim 1, wherein R.sup.d is chosen from C.sub.1-3 alkoxy groups, 2,2,2-trifluoroethoxy groups and C.sub.3-4 cycloalkoxy groups. 8. The compound according to claim 1, wherein R.sup.a is chosen from fluorine atoms, methyl groups and trifluoromethoxy groups. 9. The compound according to claim 8, wherein R.sup.b is chosen from hydrogen atoms, fluorine atoms and chlorine atoms. 10. The compound according to claim 1, wherein R.sup.2 is chosen from hydrogen atoms and halogen atoms. 11. The compound according to claim 10, wherein R.sup.2 is chosen from hydrogen atoms and fluorine atoms. 12. A compound of formula (I), ##STR00073## wherein one of the G.sup.1 groups is chosen from a nitrogen atom and a CR.sup.c group and the other G.sup.1 group represents a CR.sup.c group; G.sup.2 is chosen from a nitrogen atom and a CR.sup.d group; R.sup.1 is chosen from hydrogen atoms, halogen atoms, C.sub.1-4 alkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.3-8 cycloalkyl groups which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; R.sup.2 is chosen from hydrogen atoms, halogen atoms, hydroxyl groups, C.sub.1-4 alkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, C.sub.1-4 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.3-8 cycloalkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; R.sup.a, R.sup.b and R.sup.c are each independently chosen from hydrogen atoms, halogen atoms, C.sub.1-4 alkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.1-4 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; R.sup.d is chosen from hydrogen atoms, halogen atoms, hydroxyl groups, C.sub.1-4 alkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms, and hydroxy groups, C.sub.1-4 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.3-8 cycloalkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; G.sup.3 represents a CH group and G.sup.4 represents a nitrogen atom; and M is a hydrogen atom or an pharmaceutically acceptable cation; with the proviso that, when at least one of the groups R.sup.a and R.sup.b represent a hydrogen atom and G.sup.2 is a CR.sup.d group, then R.sup.d is chosen from C.sub.1-4 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.3-8 cycloalkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; or a pharmaceutically acceptable salt or N-oxide thereof. 13. A compound of formula (I), ##STR00074## wherein each G.sup.1 group represents a C(R.sup.c) group, R.sup.a is a fluorine atom, R.sup.b is chosen from hydrogen atoms and fluorine atoms, R.sup.1 is chosen from hydrogen atoms, bromine atoms, fluorine atoms, methyl, ethyl and cyclopropyl groups; G.sup.2 is chosen from C(OH), C(OMe) and C(OEt); R.sup.2 is chosen from hydrogen atoms, halogen atoms, hydroxyl groups, C.sub.1-4 alkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, C.sub.1-4 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.3-8 cycloalkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; R.sup.c is chosen from hydrogen atoms, halogen atoms, C.sub.1-4 alkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.1-4 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; R.sup.d is chosen from hydrogen atoms, halogen atoms, hydroxyl groups, C.sub.1-4 alkyl groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms, and hydroxy groups, C.sub.1-4 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.3-8 cycloalkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; one of the groups G.sup.3 and G.sup.4 is a nitrogen atom and the other is a CH group; and M is a hydrogen atom or an pharmaceutically acceptable cation; with the proviso that, when R.sup.b represents a hydrogen atom, then R.sup.d is chosen from C.sub.1-4 alkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups, and C.sub.3-8 cycloalkoxy groups, which may be optionally substituted by 1, 2 or 3 substituents chosen from halogen atoms and hydroxy groups; or a pharmaceutically acceptable salt or N-oxide thereof. 14. The compound according to claim 13, wherein each G.sup.1 group represents a CH group and G.sup.2 is chosen from C(OMe) and C(OEt). 15. The compound according to claim 13, wherein R.sup.c is a hydrogen atom, R.sup.d is chosen from C.sub.1-3 alkoxy groups and C.sub.3-4 cycloalkoxy groups, and R.sup.2 is a hydrogen atom. 16. The compound according to claim 13, wherein R.sup.d is chosen from a hydroxy group and C.sub.1-3 alkoxy groups. 17. The compound according to claim 15, wherein R.sup.d is a C.sub.1-3 alkoxy group. 18. The compound according to claim 15, wherein G.sup.3 represents a nitrogen atom, G.sup.4 represents a CH group, and R.sup.b is a fluorine atom. 19. The compound according to claim 15, wherein G.sup.3 represents a CH group, and G.sup.4 represents a nitrogen atom. 20. A compound chosen from: 2-(3-Fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3'-Ethoxy-3-fluorobiphenyl-4-ylamino)nicotinic acid; 2-(3'-Ethoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3'-Methoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(2,5-Difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3'-Ethoxy-2,5-difluorobiphenyl-4-ylamino) nicotinic acid; 2-(2',3-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3-Chloro-3'-ethoxybiphenyl-4-ylamino)nicotinic acid; 2-(3-Chloro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3'-Cyclobutoxy-3-fluorobiphenyl-4-ylamino)nicotinic acid; 2-(3-Fluoro-3'-(2,2,2-trifluoroethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3'-Cyclobutoxy-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3'-Ethoxy-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3,5-Difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; Lithium 3-(3'-ethoxy-3-fluorobiphenyl-4-ylamino) isonicotinate; Lithium 3-(3-fluoro-3'-methoxybiphenyl-4-ylamino)isonicotinate; Lithium 3-(3'-methoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)isonicotinate; Lithium 3-(3-fluoro-3'-(trifluoromethoxy)biphenyl-4-ylamino)isonicotinate- ; 2-(3'-Ethoxybiphenyl-4-ylamino)nicotinic acid; 2-(2',3-Difluoro-5'-isopropoxybiphenyl-4-ylamino)nicotinic acid; 2-(3-Fluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid; 2-(3,5-Difluoro-3'-hydroxybiphenyl-4-ylamino)nicotinic acid; 5-Bromo-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 5-Bromo-2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 5-Cyclopropyl-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3,5-Difluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid; 2-(3'-Ethoxy-5-fluoro-2-methylbiphenyl-4-ylamino)nicotinic acid; 2-(5-Fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid; 2-(3'-ethoxy-3,5-difluorobiphenyl-4-ylamino)-5-methylnicotinic acid; 5-cyclopropyl-2-(3'-ethoxy-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)-5-ethylnicotinic acid; 5-bromo-2-(3'-ethoxy-2,5-difluorobiphenyl-4-ylamino)nicotinic acid; 5-cyclopropyl-2-(3'-ethoxy-2,5-difluorobiphenyl-4-ylamino)nicotinic acid; 2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)-5-methylnicotinic acid; 5-cyclopropyl-2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nic- otinic acid; 2-(2',3,5-trifluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3'-cyclopropoxy-3,5-difluorobiphenyl-4-ylamino)nicotinic acid; 5-cyclopropyl-2-(2,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3'-cyclopropoxy-3,5-difluorobiphenyl-4-ylamino)-5-cyclopropylnic- otinic acid; 5-chloro-2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(2,3,5-trifluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-2-methyl-3'-(trifluoromethoxy)biphenyl-4-ylamino)nicotini- c acid; 2-(2,3,5,6-tetrafluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 3-(3'-cyclopropoxy-3-fluorobiphenyl-4-ylamino)isonicotinic acid; or a pharmaceutically acceptable salt or a N-oxide thereof. 21. A method of treating a pathological condition or disease, comprising administering to a mammal in need thereof, an effective amount of a compound according to claim 1, wherein the pathological condition or disease is chosen from rheumatoid arthritis, psoriatic arthritis, and multiple sclerosis. 22. A method of treating a pathological condition or disease, comprising administering to a mammal in need thereof an effective amount of a compound according to claim 1, wherein the pathological condition or disease is chosen from ankylosing spondylitis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis. 23. A composition comprising (i) a compound according to claim 1; and (ii) another compound chosen from: a) Anti-TNF-alpha monoclonal antibodies; b) TNF-alpha Antagonists; c) Calcineurin (PP-2B) Inhibitors / INS Expression Inhibitors; d) IL-1 Receptor Antagonists; e) Anti-CD20 monoclonal antibodies; f) p38 Inhibitors; g) NF-kappaB (NFKB) Activation Inhibitors; and h) Dihydrofolate Reductase (DHFR) Inhibitors. 24. The composition according to claim 23, wherein: a) the Anti-TNF-alpha monoclonal antibody is chosen from Infliximab, Certolizumab pegol, Golimumab, Adalimumab and AME-527; b) the TNF-alpha Antagonist is chosen from Etanercept, Lenercept, Onercept and Pegsunercept; c) the Calcineurin (PP-2B) Inhibitor / INS Expression Inhibitor is chosen from cyclosporine A, Tacrolimus and ISA-247; d) the IL-1 Receptor Antagonist is chosen from Anakinra and AMG-719; e) the Anti-CD20 monoclonal antibody is chosen from Rituximab, Ofatumumab, Ocrelizumab and TRU-015; f) the p38 Inhibitor is chosen from AMG-548, ARRY-797, Chlormethiazole edisylate, Doramapimod, PS-540446, SB-203580, SB-242235, SB-235699, SB-281832, SB -681323, SB-856553, KC-706, LEO-1606, LEO-15520, SC-80036, SD-06, RWJ-67657, RO-3201195, RO-4402257, AVE-9940, SCIO-323, SCIO-469, TA-5493, and VX-745 and VX-702; g) the NF-kappaB (NFKB) Activation Inhibitor is chosen from Sulfasalazine and Iguratimod; and the Dihydrofolate Reductase (DHFR) Inhibitor is chosen from Methrotexate, Aminopterin and CH-1504. 25. The compound according to claim 20, chosen from 2-(3'-Ethoxy-3-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid; 2-(3,5-Difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3'-cyclopropoxy-3,5-difluorobiphenyl-4-ylamino)-5-cyclopropylnicotinic acid; 2-(2,3,5-trifluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; 2-(3,5-difluoro-2-methyl-3'-(trifluoromethoxy)biphenyl-4-ylamino)nicotini- c acid; 2-(2,3,5,6-tetrafluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid; or a pharmaceutically acceptable salt or a N-oxide thereof. 26. The compound according to claim 20, wherein the compound is 2-(3,5-Difluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid or a pharmaceutically acceptable salt or a N-oxide thereof.

Details for Patent 8,258,308

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2026-12-22
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2026-12-22
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2026-12-22