Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-02-28
2001-04-10
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C544S244000
Reexamination Certificate
active
06214811
ABSTRACT:
BACKGROUND
Antiviral agents currently in use are of limited effectiveness in treating dermal infections caused by viruses. For example, herpes simplex labialis, commonly referred to as “cold sores” do not respond to the topical treatment with acyclovir (Spruance et al.,
Am. J. Med.,
73(1A):315-319 (1982); Shaw et al. ,
Br. Med. J.
(
Clin. Res. Ed.
), 291(6487):7-9 (1985); Raborn, et al.,
Oral Surg. Oral Med. Oral Pathol.,
67(6):676-679 (1989); Spruance, et al.,
Antimicrob. Agents Chemother.,
25(5):553-555 (1984); Raborn, et al.,
J. Can. Dent. Assoc.,
55(2):135-137(1989)). Oral administration of acyclovir for the treatment of cold sores is only partially effective (Spruance et al.,
J. Infect. Diseases
161:185 (1990)).
The limited effectiveness of antiviral agents such as acyclovir applied topically to cold sores and other dermal viral infections is thought to be a consequence of the limited ability of most of these agents to penetrate the skin (Parry, et al.,
J. Invest. Dermatol.,
98(6):856-863 (1992); Spruance, et al.,
Antimicrob. Agents Chemother.,
25(1):10-15 (1984)). Topical treatments for genital herpes infections are also ineffective for the same reason. Consequently, there is a need for new antiviral agents which can penetrate the skin and which are active against viruses which cause dermal infections.
SUMMARY OF THE INVENTION
Lipophilic phosphotriester prodrugs of acyclovir, as disclosed in U.S. Ser. No. 08/635,653, filed Apr. 22, 1996, (the entire teachings of which are hereby incorporated by reference), are extremely active topically against herpes virus infection. The present invention is based on the discovery that the corresponding phosphodiester prodrugs of acyclovir, which are nonlipophilic and water soluble, are even more effective antiviral drugs than phosphotriesters and more effective than acyclovir. For example, treatment of guinea pigs with dermal herpes simplex virus-1 (HSV-1) infections with Prodrug 1 and Prodrug 2 resulted in a dramatic reduction in lesion number, in lesion area and in lesion virus titer (Examples 1 and 3) when compared to its vehicle. In contrast, comparable treatment with U.S. ZOVIRAX (acyclovir) provided results that were statistically the same as with placebo.
1) R=—CO—C(CH
3
)
3
2) R=—CO—CH
3
In one embodiment, the present invention is a prodrug of acyclovir, an analog of acyclovir, acyclovir monophosphate or an acyclovir monophosphate analog. The prodrug is represented by Structural Formula (I):
and physiologically acceptable salts thereof.
Z is oxygen or sulfur, preferably oxygen.
Y is, together with a hydroxy group, acyclovir or an analog of acyclovir.
A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphate ester, which can be converted in vivo to a hydroxy or amino group.
Another embodiment of the present invention is a method of treating a viral infection in an individual or animal. The method comprises administering to the individual or animal a therapeutically effective amount of a prodrug represented by Structural Formula (I).
Another embodiment of the present invention is a method of preparing the prodrugs of the invention and intermediate used in the synthesis of phosphate ester prodrugs, including the diester prodrugs represented by Structural Formula (I), phosphotriester prodrugs disclosed in U.S. Ser. No. 08/310,972, filed Sep. 23, 1994, and the phosphotriester prodrugs disclosed in U.S. Ser. No. 08/635,553. The intermediate is represented by Structural Formula (II):
Y′ is, together with a hydroxy group, a nucleoside analog, preferably acyclovir or an acyclovir analog.
A is a substituted benzyl group with one or more protected hydroxy or protected amine groups in the ortho or para positions, relative to the phosphate ester, which can be converted in vivo to a hydroxy or amino group.
The method for preparing the intermediate comprises reacting Y′-OH, a weak anhydrous organic acid such as tetrazole and (A—O)
2
-P (NR
21
R
22
) in an aprotic, polar organic solvent. Suitable aprotic, polar organic amide solvents include dialkyl amide solvents (e.g., dimethylformamide (DMF) or N,N-dimethylacetamide), tetraalkylurea solvents (e.g., 1,3-dimethylimidazolinone or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone); dialkyl sulfoxide solvents (e.g., dimethylsulfoxide and tetramethylene sulfoxides) and phosphoramide solvents (e.g., hexamethylphosphoramide). Preferred solvents are dialkyl amides. DMF is most preferred. R
21
and R
22
are each independently a lower alkyl, an aryl group or, taken together with the phosphoramide nitrogen, can form a five, six or seven membered nitrogen-containing heterocyclic ring (preferably a saturated heterocyclic ring). The lower alkyl, aryl or heterocyclic compound represented by R
12
and R
22
can optionally be substituted with one or more groups which do not react (or are subtantially inert) with the P—N bond or with the weak acid. Preferred examples of substituents include non-nucleophilic, non-basic inert groups such as halides, (lower alkyl)—O—, lower alkyl and aryl. Preferably, R
21
and R
22
are each a lower alkyl group such as ethyl.
The phosphodiester acyclovir prodrugs disclosed herein are more active against dermal herpes simplex virus 1 infections than acyclovir or the phosphotriester prodrugs of acyclovir disclosed in U.S. Ser. No. 08/635,553. In addition, the phosphodiester prodrugs of acyclovir disclosed herein are chemically more stable, have longer shelf lives and are generally easier to formulate than the phosphotriester prodrugs disclosed in U.S. Ser. No. 08/635,553.
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Welch, C.J., et al., “The Chemical Synthesis and Antiviral properties of an Acyclovir-Phospholipid Conjugate,” Acta Chemica Scandinavica, B39; 47-54 (1985).
Glazier Arnold
Yanachkov Ivan
Yanachkova Milka
Drug Innovation & Design, Inc.
Hamilton Brook Smith & Reynolds P.C.
Shah Mukund J.
Sripada Pavanaram K
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