Patent EA-004771-B1 (EA)
Title: Urea derivatives and use thereof as inozine-5' monophosphate-dehydrogenase derivatives
Inventor: ARMISTEAD DAVID M
IPC: C07D263/32
Filed: 1997-04-21
Abstract: 1. A compound of the general formula: wherein: E is O or S; G and G' are independently selected from R<1> or H; Ph is phenylene; D is selected from C(O), C(S) and S(O)2; B' is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, O, or S and selected from the formulae: wherein each of Ph and B' optionally comprises up to 3 substituents, wherein: the first of said substituents, if present, is selected from R<1>, R<2>, R<4> or R<5>, the second of said substituents, if present, is selected from R<1> or R<4>, and the third of said substituents, if present, is R<1>; wherein each R<1> is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R<6> or (CH2)n-Y; wherein n is 0, 1 or 2; and Y is selected from halogen, CN, NO2, CF3, OCF3, OH, SR<6>, S(O)R<6>, SO2R<6>, NH2, NHR<6>, N(R<6>)2, NR<6>R<8>, COOH, COOR<6> or OR<6>; each R<2> is independently selected from (C1-C4)-straight or branched alkyl, or (C2-C4) straight or branched alkenyl or alkynyl; and each R<2> optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from R<1>, R<4> and R<5> and the second of said substituents, if present, is R<1>; R<3> is selected from monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, O, or S, and wherein CH2 adjacent to said N, O or S maybe substituted with C(O); and each R<3> optionally comprises up to 2 substituents, wherein the first of said substituents, if present, is selected from R<1>, R<2>, R<4> or R<5>, the second of said substituents, if present, is selected from R<1> or R<4>, and the third of said substituents, if present, is R<1>; each R<4> is independently selected from OR<5>, OC(O)R<6>, OC(O)R<5>, OC(O)OR<6>, OC(O)OR<5>, OC(O)N(R<6>)2, OP(O)(OR<6>)2, SR<6>, SR<5>, S(O)R<6>, S(O)R<5>, SO2R<6>, SO2R<5>, SO2N(R<6>)2, SO2NR<5>R6, SO33R<6>, C(O)R<5>, C(O)OR<5>, C(O)R<6>, C(O)OR<6>, NC(O)C(O)R<6>, NC(O)C(O)R<5>, NC(O)C(O)OR<6>, NC(O)C(O)N(R<6>)2, C(O)N(R<6>)2, C(O)N(OR<6>)R<6>, C(O)N(OR<6>)R<5>, C(NOR<6>)R<6>, C(NOR<6>)R<5>, N(R<6>)2, NR<6>C(O)R<1>, NR<6>C(O)R<6>, NR<6>C(O)R<5>, NR<6>C(O)OR<6>, NR<6>C(O)OR<5>, NR<6>C(O)N(R<6>)2, NR<6>C(O)NR<5>R<6>, NR<6>SO2R<6>, NR<6>SO2R<5>, NR<6>SO2N(R<6>)2, NR<6>SO2NR<5>R<6>, N(OR<6>)R<6>, N(OR<6>)R<5>, P(O)(OR<6>)N(R<6>)2, and P(O)(OR<6>)2; each R<5> is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH2 adjacent to said N, O or S maybe substituted with C(O); and each R<5> optionally comprises up to 3 substituents, each of which, if present, is R<1>; each R<6> is independently selected from H, (C1-C4)-straight or branched alkyl, or (C2-C4)-straight or branched alkenyl; and each R<6> optionally substituted with R<7>; R<7> is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH.sub.2 adjacent to said N, O or S maybe substituted with C(O); and each R<7> optionally comprises up to 2 substituents independently chosen from H, (C1-C4)-straight or branched alkyl, or (C2-C4)-straight or branched alkenyl; 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2)n-Z; wherein n is 0, 1 or 2 and Z is selected from halogen, CN, NO2, CF3, OH, S(C1-C4)alkyl, SO(C1-C4)alkyl, SO2(C1-C4)alkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, N((C1-C4)alkyl)R<8>, COOH, C(O)O(C1-C4)alkyl or O(C1-C4)alkyl; and R<8> is an amino protecting group; and wherein any carbon atom in any R<2> or R<6> may be substituted with O, S, SO, SO2, NH or N(C1-C4)alkyl; wherein if Ph has no additional substituents, and all of said substituents present are on B' are R<1>, then at least one of said R<1> substituents is not chloro, bromo or iodo; and wherein B and B' are not simultaneously unsubstituted phenyl. 2. The compound according to claim 1 having the formula: wherein: K is selected from R<1> and R<4>; and J is selected fromR1, R2, and R4. 3. The compound according to claim 2, wherein D is -C(O)-. 4. The compound according to claim 2, wherein E is oxygen. 5. The compound according to claim 2, wherein J is NR<6>C(O)R<5> or NR<6>C(O)R<6>. 6. The compound according to claim 5, wherein J is NR<6>C(O)R<6>. 7. The compound according to claim 6, wherein J is N(CH3)C(O)R<6>. 8. The compound according to claim 2, wherein K is (CH2)n-Y. 9. The compound according to claim 8, wherein K is OCH3. 10. The compound according to claim 2, wherein G is hydrogen. 11. The compound according to claim 2, wherein: D is -C(O)-; E is oxygen; K is OCH3; and G is hydrogen. 12. The compound according to claim 2, wherein J is R<2>. 13. The compound according to claim 12, wherein E is oxygen. 14. The compound according to claim 12, wherein J is R<2> substituted with R<4>. 15. The compound according to claim 14, wherein R<4> is NR<6>C(O)OR<5> or NR<6>C(O)OR<6>. 16. The compound according to claim 12, wherein K is (CH2)n-Y. 17. The compound according to claim 16, wherein K is OCH3. 18. The compound according to claim 12, wherein: D is -C(O)-; E is oxygen; K is OCH3; and G is hydrogen. 19. The compound according to claim 1, wherein is selected from the group comprising compounds 2-27, 29-31, 39-51, 53-69, 71-86, 88-89, 91-102 and 104-162 as given below in tables IB and IC: Table IB 	G	K	B' 2	H	H	3-methoxyphenyl 3	H	H	3-thienyl 4	H	H	3,4-difluorophenyl 5	H	H	2,5-dimethoxyphenyl 6	H	H	3-methylthiophenyl 7	H	H	3-bromophenyl 8	H	H	3-cyanophenyl 9	H	H	3-trifluoromethyl-4-chlorophenyl 10	H	H	2-methyl-3-chlorophenyl 11	H	H	2-methoxy-5-methylphenyl 12	H	H	2-methoxyphenyl 13	H	H	3-methoxyphenyl 14	H	H	2,5-dimethoxyphenyl 15	H	H	3-nitrophenyl 16	H	H	4-nitrophenyl 17	H	H	3-methylphenyl 18	H	H	3-trifluoromethylphenyl 19	H	H	2-trifluoromethylphenyl 20	H	H	3-fluorophenyl 21	H	H	4-phenoxyphenyl 22	H	H	3-chlorophenyl 23	H	H	3-chloro-4-fluorophenyl 24	H	H	3-aminophenyl 25	H	H	3-(hydroxymethyl)phenyl 26	H	H	3-acethylenylphenyl 27	H	H	3-hydroxyphenyl 29	H	H	3-pyridinyl 30	H	H	4-pyridinyl 31	H	H	2-(5-methyl)thiazolyl 39	H	H	3,4-ethylenedioxyphenyl 40	H	H	3-methyl-4-nitrophenyl 41	H	H	3-trifluoromethyl-4-nitrophenyl 42	H	3-chloro	phenyl 43	H	3-chloro	3-methylphenyl 44	-	-	- 45	H	3-chloro	phenyl 46	H	3-fluoro	3-methylphenyl 47	H	H	3-carbomethoxymethylphenyl 48	H	H	3-carbomethoxyethylphenyl 49	H	H	3-dimethlaminophenyl 50	H	H	3-[2-(2-methyl)dioxolanyl)phenyle 51	H	H	3-aminocarbonylphenyl 53	H	H	3-furanyl 54	H	H	3-carboxymethylphenyl 55	H	3-methoxy	3-methylphenyl 56	H	3-methoxy	3-nitrophenyl 57	H	3-chloro	3-carbomethoxymethylphenyl 58	H	H	3-amino-5-methylphenyl 59	H	3-methoxy	3-aminophenyl 60	H	3-bromo	3-methylphenyl 61	H	3-chloro	3-chloro-4-(5-oxsazolyl)phenyl 62	H	3-chloro	4-(2-methypyridyl)l 63	H	3-chloro	3-carboxymethylphenyl 64	H	3-bromo	3-nitrophenyl 65	H	3-bromo	3-aminophenyl 66	H	H	3-[5-(2-methylpyrimidinyl)]phenyl 67	H	H	3-(5-oxazolyl)phenyl 68	H	3-chloro	2-thienyl 69	H	3-chloro	3-thienyl 71	H	3-chloro	3-methoxycarbamoylphenyl 72	H	3-chloro	3-acetamidophenyl 73	H	3-chloro	3-iodophenyl 74	H	3-methyl	phenyl 75	H	3-methyl	3-methylphenyl 76		3-chloro	3-methylphenyl 77		H	3-methylphenyl 78	H	3-chloro	3-nitrophenyl 79	H	3-chloro	3-aminophenyl 80	H	H	3-(cyclohexylsulfamoyl)phenylo 81	H	H	3-(methylsulfamoyl)phenyl 82	H	H	3-(phenylsulfamoyl)phenyl 83	H	3-methoxy	3-benzyloxycarbamoylphenyl 84	H	3-methoxy	3-acetamodophenyl 85	H	3-chloro	4-(2-methyl)furanyl 86	H	3-chloro	5-(2-methyl)thienyl 88	H	3-carbomethoxy	3-methylphenyl 89	H	3-carbomethoxy	3-nitrophenyl 91	H	3-chloro	4-(2-nitro)thienyl 92	H	3-chloro	4-(2-hydrpxyamino)thienyl 93	H	3-chloro	3-(N-methyl)trifluoroacetamidophenyl 94	H	3-chloro	3-(methylamino)phenyl 95	H	3-chloro	4-(2-amino)thienyl 96	H	3-methoxy	3-trifluoroacetamidophenyl 97	H	3-methoxy	3-(N-methyl)trifluoroacetamidophenyl 98	H	3-methoxy	3-(3`-picolyloxycarbamoyl)phenyl 99	H	3-methoxy	3-phenoxycarbamoyl)phenyl 100	H	3-methoxy	3-difluoroacetamidophenyl 101	H	3-acetoxymethyl	3-methylphenyl 102	H	3-hydroxymethyl	3-methylphenyl 104	H	H	3-nitro-4-fluorophenyl 105	H	3-methoxy	3-(aminomethyl)phenyl[(TFA] 106	H	3-methoxy	5-(N-acetoxy)indolinyl 107	H	3-methoxy	3-(N-methyl)acetamidophenyl 108	H	3-methoxy	3-[(2-oxo-2-3,4,5-trimethoxyphenyl)acetyl)amino]phenyl 109	H	3-amino	3-methylphenyl 110	H	3-methoxy	3-benzamidophenyl 111	H	3-methoxy	3-phenylacetamodophenyl 112	H	3-methoxy	3-phenylureidophenyl 113	H	3-methoxy	3-(t-butoxycarbamoylmethyl)phenyl 114	H	3-methoxy	3-(cyclopentylacetamido)phenyl Table IC 	L 116	NHC(O)O-t-butyl 117	NHC3C(O)O-T-butyl 118	NHC(O)O-methyl 119	NHC(O)O-phenyl 120	NHC(O)O-(S)-3-tetrahydrofuranyl 121	NHC(O)O-2-picolinyl 122	NHC(O)O-(S)-5-oxazolidinonylmethyl 123	NHC)O)O-4-carbomethoxyphenyl 124	NHC(O)O-isobutyl 125	NHC(O)O-allyl 126	NHC(O)O-5-(1,3-dioxanyl) 127	NHC(O)O-4-acetamidobenzyl 128	NHC(O)O-furfuryl 129	NHC(O)O-thiofurfuryl 130	NHC(O)O-methoxyethyl 131	NHC(O)O-4-tetrahydropyranyl 132	NHC(O)O-cyclohexyl 133	NHC(O)O-cyclopentyl 134	NHC(O)O-2-hydroxyethyl 135	NHC(O)O-cyclohesylmethyl 136	NHC(O)O-(R,S)-3-tetrahydrofuranyl 137	NHC(O)O-3-pyridyl 138	NHC(O)O-benzyl 139	NHC(O)O-3-(t-boc-amino)propyl 140	NHC(O)O-4-hydroxybutyl 141	NHC(O)O-5-hydroxypentyl 142	NHC(O)O-(R,S)-3-pyranyl 143	NHC(O)O-3-(N-t-BOC)piperidinyl 144	NHC(O)O-(R)-3-(2-oxo-4,4-dimethyl)furanyl 145	NHC(O)O-3-methylthiopropyl 146	NHC(O)O-4-[(2,2-dimethyl)-1,3-dioxanyl]methyl 147	NHC(O)O-2-di(hydroxymethyl)ethyl 148	NHC(O)O-4-(N-t-BOC)piperidinylmethyl 149	NHC(O)O-3-(N-t-BOC)piperidinylmethyl 150	NHC(O)O-(dibenzyloxymethyl)methyl 151	NHC(O)O-di(hydroxymethyl)methyl 152	NHC(O)O-2-(N-t-BOC)piperidinylmethyl 153	NHC(O)O-3-piperidinyl-TFA 154	NHC(O)O-(R,S)-(2-tetrahydropyranyl)methyl 155	NHC(O)O-4-piperidinylmethyl-TFA 156	NHC(O)O-(R,S)-3-tetrahydrofuranylmethyl 157	NHC(O)O-3-methylsulfonylpropyl 158	NHC(O)O-piperidinylmethyl-TFA 159	NHC(O)O-2-piperidinyl-TFA 1