Prodrugs of piperazine and substituted piperidine antiviral agents
This invention provides for prodrug Compounds I, pharmaceutical compositions thereof, and their use in treating HIV infection. wherein: X is C or N with the proviso that when X is N, R 1 does not exist; W is C or N with the proviso that when W is N, R 2 does not exist; V is C; E is hydrogen or a pharmaceutically acceptable salt thereof; and Y is selected from the group consisting of Also, this invention provides for intermediate Compounds II useful in making prodrug Compounds I. wherein: L and M are independently selected from the group consisting of C 1 -C 6 alkyl, phenyl, benzyl, trialkylsilyl, -2,2,2-trichloroethoxy and 2-trimethylsilylethoxy.
1. A compound of Formula I,
wherein:
X is C;
W is N with the proviso that when W is N, R 2 does not exist;
V is C;
R 1 is halogen;
R 3 is 1,2,3-triazolyl attached at position N-1;
E is hydrogen or a pharmaceutically acceptable mono or bis salt thereof;
Y is
R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each H;
R 18 is selected from the group consisting of C(O)-phenyl or quinazolinyl.
2. A compound of claim 1 wherein:
R 1 is F.
3. A compound of Formula I,
wherein:
X is C;
W is N with the proviso that when W is N, R 2 does not exist;
V is C;
R 1 is methoxy;
E is hydrogen or a pharmaceutically acceptable mono or bis salt thereof;
Y is
R 3 is triazolyl wherein said triazolyl may be independently optionally substituted with C 1-6 alkyl; and
R 18 is quinazolinyl, and R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , are each H.
4. A process for preparing Compound Iac having the structure
comprising:
(a) alkylating Compound IVa having the structure
with about 1.2 molar equivalents of di-tert-butyl chioromethyl phosphate per mole of IVa, having the structure Z
in the presence of about 2 molar equivalents of K 2 CO 3 as a base, per mole of Compound IVa, and about 5-10 ml of N-methylpyrrolidinone as a solvent per gram of IVa, at a reaction temperature of about 30° C., to form Compound R having the structure
(b) deprotecting at room temperature Compound R of both tert-butyl groups by adding to the resulting reaction mixture of step (a), about 10 ml of dichioromethane solvent per gram of IVa and about 15 molar equivalents of trifluoroacetic acid per mole of IVa; and
(c) recovering Compound Iac.
5. A process for preparing Compound Ic having the structure
comprising:
(a) alkylating Compound IVc having the structure
with about 2.5 molar equivalents of di-tert butyl chioromethyl phosphate per mole of IVc having the structure Z
in the presence of about 2.5 molar equivalents of Cs 2 CO 3 as a base per mole of IVc, about 2 molar equivalents of KI per mole of IVc, and about 5-10 ml of N-methyl-pyrrolidinone per gram of IVc, at a reaction temperature of about 25-30° C., to form a Compound IIc having the structure
(b) deprotecting at a temperature of about 40° C. Compound IIc of both tert-butyl groups in an excess of acetone and water; and
(c) recovering Compound Ic.
6. A process for preparing Compound Ibc having the structure
comprising:
(a) alkylating Compound IVb having the structure
with about 2 molar equivalents of di-tert butyl chioromethyl phosphate per mole of IVb having the structure Z
in the presence of about 2 molar equivalents of Cs 2 CO 3 as a base per mole of IVb, about 2 molar equivalents of KI per mole of IVB, and about 2.5 ml of N-methyl-pyrroiidinone per gram of IVb, at a reaction temperature of about 30° C., to form a Compound IIb having the structure
(b) deprotecting at a temperature of about 40° C. Compound IIb of both tert-butyl groups in an excess of acetone and water; and
(c) recovering Compound Ibc.
7. The compound 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine, having the following structure: