US2004092539A1PendingUtilityA1
Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them
Priority: Jul 17, 1998Filed: Oct 21, 2003Published: May 13, 2004
Est. expiryJul 17, 2018(expired)· nominal 20-yr term from priority
C07D 239/52C07D 239/36C07D 239/47C07D 239/56A61K 31/506
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Claims
Abstract
The invention concerns novel substituted 6-benzyl-4-oxopyrimnidines of general formula (A). These compounds inhibit reverse transcriptase encoded by human immunodeficiency virus (HIV) or pharmaceutically acceptable salts thereof, and find their application in the prevention and treatment of HIV infection and the treatment of the resulting acquired immune deficiency syndrome (AIDS). Pharmaceutical compositions containing the compounds and a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HIV are also envisaged.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the formula:
wherein:
X is —O, —CH 2 , —CHK (wherein K is —H, —C 1-4 alkyl, —C 3-6 cycloalkyl), —S, —NK (wherein K is —H, —C 1-4 alkyl, —C 3-6 cycloalkyl), -aryl, -arylalkyl;
R is —H, —C 1-4 alkyl (containing one or more of heteroatoms like O, S, N), C 3-6 cycloalkyl (containing one or more of heteroatoms like O, S, N), -aryl, arylalkyl, heterocycle;
Y is —H, —C 1-4 alkyl, —C 3-6 cycloalkyl;
Z is —H, —C 1-4 alkyl, —C 3-6 cycloalkyl;
R 1 is —H, —C 1-4 alkyl, halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl), —SW (wherein W is —H, —CH 3 , -aryl);
R 2 is —H, —C 14 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl), —SW (wherein W is —H, —CH 3 , -aryl);
R 3 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , aryl), —SW (wherein W is —H, —CH 3 , -aryl);
R 4 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl), —SW (wherein W is —H, —CH 3 , -aryl);
R 5 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl), —SW (wherein W is —H, —CH 3 , -aryl), or a pharmaceutically acceptable salt or soluble derivative thereof.
2 . A compound having formula A as claimed in claim 1 wherein
X = O
Y = H
Z = H
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = O
Y = H
Z = H
R = cPen
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F.
3 . A compound having formula A as claimed in claim 1 wherein
X = S
Y = H
Z = H
R = sBu
R 1 = NO 2
R 2 = H
R 3 = H
R 4 = H
R 5 = H
X = S
Y = H
Z = H
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = H
X = S
Y = H
Z = H
R = CH 3
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = H
R = ipr
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = H
R = nBu
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = H
R = iBu
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = H
R = sBu
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = H
R = cPen
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = H
R = cEs
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = H
R = CH 3
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = H
R = iPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = H
R = nBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = H
R = iBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = H
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = H
R = cPen
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = H
R = cEs
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = CH 3
R = iPr
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = CH 3
R = cPen
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = CH 3
R = cEs
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = Et
R = iPr
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = Et
R = cPen
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = Et
R = cEs
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = H
Z = CH 3
R = iPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = CH 3
R = iBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = CH 3
R = nBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = CH 3
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = CH 3
R = cPen
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = CH 3
R = cEs
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = Et
R = iPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = Et
R = cPen
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = Et
R = cEs
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = CH 3
R = cEs
—CH═CH—CH═CH
R 3 = H
R 4 = H
R 5 = H
X = S
Y = H
Z = H
R = sBu
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = H
X = S
Y = CH 3
Z = H
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = H
X = S
Y = CH 3
Z = H
R = sBu
R 1 = Cl
R 2 = H
R 3 = H
R 4 = H
R 5 = Cl
X = S
Y = CH 3
Z = H
R = CH 3
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = H
R = iPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = H
R = nBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = H
R = iBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = H
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = H
R = cPen
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = H
R = cEs
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = CH 3
R = CH 3
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = CH 3
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = CH 3
R = cPe
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = Et
Z = H
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = iPr
Z = H
R = iPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = CH 3
R = iPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = CH 3
R = nBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = CH 3
R = iBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = CH 3
R = cEs
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = H
Z = H
R = MeSMe
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = CH 3
Z = H
R = MeSMe
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = Et
Z = H
R = MeSMe
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = S
Y = iPr
Z = H
R = MeSMe
R 1 = F
R 2 = H
R 2 = H
R 4 = H
R 5 = F.
4 . A compound having formula A as claimed in claim 1 wherein
X = NH
Y = H
Z = H
R = Et
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = H
R = nPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = H
R = iPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = H
R = cPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = H
R = nBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = H
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = H
R = MeOEt
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = H
R = cPe
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = H
R = cEs
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = CH 3
R = cPe
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = H
R = iPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = H
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = H
R = cPe
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = H
R = benz
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = CH 3
R = cPe
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = H
R = CH 3
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = H
R = CH 3
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = H
R = nPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = H
R = nBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = CH 3
R = CH 3
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = CH 3
R = nPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = CH 3
R = iPr
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = CH 3
R = nBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = CH 3
R = sBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = H
Z = CH 3
R = cEs
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = CH 3
R = CH 3
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = CH 3
R = nBu
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = NH
Y = CH 3
Z = CH 3
R = cEs
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = H
Z = H
R = (CH 3 ) 2
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = H
Z = H
R = Me-Pip
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = H
Z = H
R = Morph
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = H
Z = H
R = S-morp
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = H
Z = H
R = Piper
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = H
Z = H
R = Pyrroli
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = H
Z = H
R = Et 2
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = H
Z = H
R = (nPr) 2
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = CH 3
Z = H
R = (CH 3 ) 2
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = CH 3
Z = H
R = Me-Pip
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = CH 3
Z = H
R = Morph
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F
X = N
Y = CH 3
Z = H
R = S-morp
R 1 = F
R 2 = H
R 3 = H
R 4 = H
R 5 = F.
5 . A pharmaceutically acceptable salt or soluble derivative of a compound of claim 1 .
6 . A process for the preparation of a compound having formula A as claimed in claim 1 wherein X═O, wherein the proper methyl arylacetylalkylacetate is reacted with O-methylisourea in presence of calcium hydroxide; the so obtained 2-O-methyl(5-alkyl)-6-benzyl(substituted)uracils are reacted with the proper potassium alkoxide according to scheme A.
7 . A process for the preparation of a compound having formula A as claimed in claim 1 wherein X═S, wherein the proper ethyl arylacetylalkylacetate is reacted with thiourea in presence of sodium methoxide; the so obtained 5-alkyl-6-benzyl(substituted)-2-thiouracils are reacted with methyl iodide or with an alkyl halide in a basic medium according to scheme B.
8 . A process for the preparation of the compounds having formula A as claimed in claim 1 wherein X═NK (wherein K is —H, —C 1-4 alkyl, —C 3-6 cycloalkyl), wherein the proper S-methyl(5-alkyl)-6-benzyl(substituted)-2-thiouracil is reacted with the proper amine according to scheme C.
9 . A method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS, comprising administering to a mammal an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof.
10 . A pharmaceutical composition useful for inhibiting HIV reverse transcriptase, comprising an effective amount of a compound claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof, and a pharmaceutically acceptable carrier.
11 . A pharmaceutical composition useful for preventing or treating infection of HIV or for treating AIDS, comprising an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof, and a pharmaceutically acceptable carrier.
12 . A method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS, comprising administering to a mammal an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof in combination with another anti-HIV agent selected from the group consisting of abacavir, zidovudine, BILA 1906, BILA 2185, BM+51.0836: triazoloisoindolinone derivative, BMS 186,318: aminodiol derivative HIV-1 protease inhibitor, d4API, stavudine, efavirenz, HBY097, HEPT, KNI-272, L-697,593, L-735,524, L-697,661, L-FDDC, LFDOC, nevirapine, foscarnet, PMEA, PMPA, Ro 31-8959, RPI-3121, SC-52151, SC55389A, TIBO R82150, TIBO 82913, TSAO-m3T, U90152, UC: thiocarboxanilide derivatives, UC-781, UC-82, VB 11,328, amprenavir, XM 323, delaviridine, famciclovir, gancyclovir, penciclovir, indinavir, nelfinavir, ritonavir, saquinavir, DDI, DDC, Delaviridine, β-LddA, β-L-3′-azido-d5FC, carbovir, acyclovir, interferon, stavudine, (3′-azido-2′,3′-dideoxy-5-methyl-cytidine), 3′-azido nucleosides, β-D-dioxoiane nucleosides such as β-D-dioxolanylguanine (DXG), β-D-dioxolanyl-2,6-diaminopurine (DAPD), and β-D-dioxolanyl-6-chloropurine (ACP), D4T, FTC, 3TC, AZDU, and amprenavir.Join the waitlist — get patent alerts
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