CA2156120A1 - 3-substituted-2-oxindoles as inhibitors of viral replication - Google Patents

Abstract

This invention relates to the use of certain 3-substituted-2-oxindole-1-carboxamide of the formula I

and the pharmaceutically-acceptable base salts thereof wherein X is H, Cl or F; Y is H
or Cl; and R is benzyl or thienyl, each optionally substituted with Cl or F to inhibit viral replication and provide treatment or prophylaxis for mammals infected with such virus.

Description

.

Field of the Invention This invention relates to the use of certain 3-substituted-2-oxindole-1-carboxamides of the formula X~

0~C~NH

and the pharmaceutically-acceptable base salts thereof wherein X is H, Cl or F; Y is H
or Cl; and R is benzyl or thienyl, each optionally substituted with Cl or F to inhibit viral replication and provide treatment or prophylaxis for mammals infected with such virus.
Backqround of the Invention U.S. 4,569,942 discloses certain 2-oxindole-1-carboxamides of the formula o X 11_ ~0 Y O=C-NH-R2 wherein, inter alia, X is H, fluoro, chloro, bromo, (C,-C4)alkyl, (C3-C7)cycloalkyl, (C,-C4)alkoxy, (C,-C4)alkylthio, trifluoromethyl, (C,-C4)alkylsulfinyl, (C,-C4)alkylsulfonyl, 25 nitro, phenyl, (C2-C4)alkanoyl, benzoyl, thenoyl, (C,-C4)alkanamido, benzamido or N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; Y is, H, fluoro, chloro, bromo, (C,-C4)alkyl, (C3-C7)cycloalkyl, (C,-C4)alkoxy, (C,-C4)alkylthio and trifluoromethyl; R1 is (C,-C6)alkyl, (C3-C7)cycloalkyl, (C4-C7)cycloalkenyl, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted 30 phenyl)alkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy)alkyl having 1 to 3 carbons in said alkyl, naphthyl, bicyclo- [2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl or-(CH2)n-Q-R; n is zero, 1 or 2; Q is a divalent radical derived from furan, thiophene, pyrrole, pyrazole, imidazole, , thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole,1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo[b]furan and benzo[b]-thiophene; R is H or (C,-C3)alkyl; and R2 is (C1-C~)alkyl, (C3-C7)cycloalkyl, benzyl, furyl, 5 thienyl, pyridyl or ~R4 where R3 and R4 are each H, fluoro, chloro, (C1-C4)alkyl, (Cl-C4)alkoxy or 10 trifluoromethyl. That patent also discloses that said 2-oxindole-1-carboxamides are inhibitors of cyclooxygenase and lipoxygenase, possess analgesic activity in mammals and are useful in treatment of pain and alleviation of symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.
U.S. Patent 4,556,672 discloses certain 3-acyl substituted- 2-oxindole-15 1 -carboxamides of the formula o X C--R
~0 Y 0=C--N H2 wherein X, Y and R' are as described above for the compounds of U.S. Patent No.
4,569,942. The compounds of U.S. Patent No. 4,556,672 are disclosed as having the same activity as the compounds of U.S. Patent No. 4,569,942 discussed above.
U.S. Patent No. 4,861,794 discloses the use of compounds of the formula o C--R

y~0 o,~C~NH

-` 21~6120 and the pharmaceutically-acceptable base salts thereof wherein X is H, Cl or F, Y is H
or Cl and R is benzyl or thienyl to inhibit biosynthesis of interleukin-1 (IL-1 ) and to treat IL-1 mediated disorders and dysfunctions.
United States Patent No. 5,118,703 describes nonsteroidal antiinflammatory 5 agents of the formula Rl X~ OR

0=C--NH2 wherein each of X and Y is hydrogen, fluoro or chloro; R' is 2-thienyl or benzyl; and R
is alkanoyl, cycloalkylcarbonyl, phenylalkanoyl, benzoyl and certain substituted benzoyl groups, thenoyl, omega-alkoxycarbonylalkanoyl, alkoxycarbonyl, phenoxycarbonyl, 15 1-alkoxycarbonyloxy, alkylsulfonyl, methylphenylsulfonyl and dialkyl phosphonate.
United States Patent No. 5,290,802 discloses compounds of the formula X (CH2)n~~

~0 - R 1 ( I ) and the pharmaceutically-acceptable salts thereof, wherein X is H, F, Cl, Br, (CI-C6)alkyl, (C3-C8)cycloalkyl, NO2, CF3, CN, SH, S(o)mR3, 25 OR4, COR4 or CoNR4R5;
Y is H, F, Cl, Br, (C,-C6)alkyl, (C3-C8)cycloalkyl, NO2, CF3, CN, SH, S(O)qR17 OR15 or CONR'8R19;
R' is H, alkanoyl of two to ten carbon atoms, cycloalkylcarbonyl of five to seven carbon atoms, phenylalkanoyl of seven to ten carbon atoms, chlorobenzoyl, 30 methoxybenzoyl, thenoyl, omega-alkoxycarbonylalkanoyl, said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms, alkoxy carbonyl of two to ten carbon atoms, phenoxycarbonyl, 1-(acyloxy)alkyl wherein acyl has one to four carbon atoms and said alkyl has two to four carbon atoms, 1-(alkoxycarbonyloxy)alkyl wherein said alkoxy has two to five carbon atoms and said alkyl has one to four carbon atoms, alkyl of one to three carbon atoms, alkylsulfonyl of one to three carbon atoms, methylphenylsulfonyl or dialkylphosphonate whereineach of said alkyl is one to three carbon atoms;
R2 is COR6, CONR7R9, (C1-C6)alkyl, (C3-C8)cycloalkyl, phenyl or mono- or disubstituted phenyl wherein the substituent or substituents are each Cl, F, Br,(Cl-C6)alkyl, (Cl-C6)alkoxy or CF3;
Q is a B

A is H, F, Cl, Br, I, CF3, OR9, S(O)pR10, COOR'1, CONR9R11, CN, NO2, CORl, CH ORll OCORl NR9Rll N(R9)CORll SO NR9R'l ~'~3Rl2 ~R12 N_N

~LR12 1~R ~N~Z

~R Z--N 12 B is H, F, Cl, Br, I, CF3, ORl3, S(O)tRl4, CoORl5, CoNRl3R'5, CN, NO2, CoR'4, CH oRl5 OCORl4 NRl3Rls N(Rl3)CORl5 or So2NRl3Rl5;
provided that A and B cannot both be H; or A and B are taken together, bonded 25 to the same ring carbon of ol and equal oxo, or when A is not H, B is as defined above o~ (cl-c4)alkyl;
Al is F, Cl, Br, I, CF3, OR9, S(O)pRl, COORll, CONR9Rl', CN, NO2, COR10, CH2OR, OCOR, NR R, N(R )COR or SO2NR Rll;
Ql is ~ 215612~
"

Q <"3 wN~

N--U N--1~

1 0 [~

1 5 [~
Q2 is H

=~ U

A rN
N I \ N o r N / ,~ ;

25 m, n, p, q and t are each zero, one or two;
W and Z are each O, S or NR'1;
W' and w2 are each O, S or NR' provided that when one of W' or w2 is O, S
or NRl, the other is O or S;
R3, R5, R', R'4 and R'7 are each (C,-C5)alkyl or phenyl; R5, R8, R", R'5 and R'9 30 are each H, (C,-C5)alkyl or phenyl; R4, R7, R9, R'3 and Rl9 are each H or (C,-C6)alkyl;
and Rl2 is H, F, Cl, Br, CF3 or (C,-C5)alkyl.
United States Patent Nos. 4,569,942; 4,556,672; 4,861,794; and 5,290,802 are hereby incorporated by reference.

Breen, et al, J. Immunol. 144:480, 1990, teach that HIV-infected individuals have elevated plasma levels of IL-6 and increased IL-6 production from their cultured monocytes.
Littman, et al, Arch Rheum 36:5112, 1993, observed a decrease in plasma IL-6 in rheumatoid arthritis patients treated with tenidap, 5-chloro-3-(2-thenoyl)-2-oxindole-l-carboxamide.
Summary of the Invention This invention relates to medicine for treatment for a mammal with a viral infection which comprises a viral replication inhibiting amount of a compound of formula I

X

O'~C~NH

or pharmaceutically acceptable salts thereof; wherein X is H, Cl or F; Y is H or Cl; and R is benzyl or thienyl, each optionally substituted with Cl or F.
In one embodiment, this invention relates to medicine for inhibiting replication of virus in a mammal infected with such a virus which comprises a viral replication inhibiting amount of a compound of formula I.
This invention also relates to medicine for treatment for a mammal with AIDS which comprises a human immunodeficiency virus-l (HIV-l) replication inhibiting amount of a compound of ~1~6120 formula I or pharmaceutically acceptable salts thereof;
wherein X is H, Cl or F~ Y is H or Cl, and R is benzyl or thienyl, each optionally substituted with Cl or F.
In yet another embodiment, this invention relates to medicine for inhibiting replication of HIV-l in a mammal infected with HIV-l which comprises an HIV-l replication inhibiting amount of a compound of formula I.
In a still further embodiment, the invention relates to a commercial package which comprises a container containing therein the above-mentioned medicine and a written matter stating that the medicine can or should be used for the above-mentioned purpose.
Detailed Description of the Invention The compounds of this invention which are of the formula \\
C_D
y~O
o,~C~NH

and the pharmaceutically acceptable base salts thereof wherein X is H, Cl or F; Y is H or Cl; and R is benzyl or thienyl optionally substituted with Cl or F and the preparation thereof are disclosed in U. S. Patent Nos. 4,556,672 and 5,290,802.
This invention concerns new uses for such compounds which comprise methods for inhibiting the replication of viruses and 215612~

methods for treating mammals infected with such viruses including HIV-l. Compounds of the present invention do not influence the activity of the Rous sarcoma virus. ~ithout being bound to any particular mechanism of action, this suggests that the compounds of the present invention have a specific mode of action and not a general inhibitory effect on viability.
Of the methods described above, preferred therein are those where the compound employed is of the formula above wherein X is Cl, Y is H and R is thienyl, those wherein X is F, Y is Cl and R is thienyl or 4-chlorothien-2-yl; those wherein X is F, Y is Cl and R is 2-thienyl; and those wherein X is H, Y is Cl and R is benzyl. Particularly preferred are methods wherein X is Cl, Y is H and R is 2-thienyl.
As disclosed in U. S. Patent Nos. 4,556,672 and 5,290,802, the compounds of this invention hereinabove described are acidic and form base salts. All such base salts are within the scope of this invention and can be formed as-taught by those patents. Such suitable salts, within the scope of this invention, include both the organic and inorganic types and include, but are not limited to, the salts formed with ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides. Representative examples of bases which form such base salts include ammonia, primary -8a-amines, such as n-propylamine, n-butylamine, aniline, cyclo-hexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines, such as diethylamine, diethanol-amine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, triethanolamine, N,N-dimethylaniline, N-ethyl-piperidine and N-methylmorpholine, hydroxides, such as sodium hydroxide, alkoxides, such as sodium ethoxide and potassium methoxide; hydrides, such as calcium hydride and sodium hydride;
and carbonates, such as potassium carbonate and sodium carbonate.
Preferred salts are those of sodium, potassium, ammoniu~"
ethanolamine, diethanolamine and triethanolamine. Particularly preferred are the sodium salts.
Also within the scope of this invention are the solvates such as the hemihydrates and monohydrates of the compounds hereinabove described.
The medicines contain the compounds or their salts, in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition, according to standard pharmaceutical practice. Such administration can be oral or parenteral. Parenteral administration as used herein includes, but is not limited to, intravenous, intramuscular, intra-peritoneal, subcutaneous, transdermal and topical including, but not limited to oral lavage administration. However, it is generally preferred to administer such compounds and their salts orally.
In general, these compounds and their salts are most 21~6120 -8b-desirably administered in doses ranging from about 40 mg up to about 200 mg per day per patient for oral administration and from about 1 mg up to about 200 mg per day per patient for parenteral administration, although variations will still necessarily occur depending upon the weight of the subject being treated. The appropriate dose for inhibiting virus replication and alleviating the symptoms of virus infection in a mammal with the compounds and their salts of this invention will be readily determined by those skilled in the art of prescribing and/or administering such compounds.
Nevertheless, it is still to be appreciated that other variations may also occur in this respect, depending upon the species of mammal being treated and its individual response to the medicament, as well as on the particular type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful or deleterious side 2I5~12~

g effects to occur, provided that such higher dose levels are first divided into several smaller doses that are to be administered throughout the day.
For purposes of oral administration, tablets containing excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along 5 with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as, but not limited to, magnesium steardte, sodium lauryl sulfate and talc are often very useful for tableting purposes. Solid compositions of a similar type may also be 10 employed as fillers in soft elastic and hard-filled gelatin capsules; preferred materials in this connection also include, by way of example and not of limitation, lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral adl,l ,isl,~lion, the essential active ingredient may be combined with various sweetening or flavoring agents, coloring15 matter or dyes and, if so desired, emulsifying and/or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
Although the preferred mode of ad,nini~lrc-Lion of the compounds of this invention or their pharmaceutically-acceptable base salts is oral, they may be 20 administered parenterally as well.
For purposes of parenteral administration, solutions of these particular compounds in sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding water soluble base salts previously enumerated. Such aqueous solutions should be suitably buffered if 25 necessary, and the liquid diluent rendered isotonic with sufficient saline or glucose.
These particular aqueous solutions are especially suitable for intravenous, intramuscular and subcutaneous injection purposes. In this connection, the sterile aqueous media employed are readily obtained by standard techniques well known to those skilled in the art. For instance, distilled water is ordinarily used as the liquid diluent and the final 30 preparation is passed through a suitable bacterial filter such as a sintered glass filter or a diatomaceous-earth or unglazed porcelain filter. Preferred filters of this type include the Berkefeld, the Chamberland and the Asbestos Disk-Metal Seitz filter,wherein the fluid is sucked into a sterile container with the aid of a suction pump.

~1~6120 Necessary steps should be taken throughout the preparation of these injectable solutions to insure that the final products are obtained in a sterile condition. For purposes of transdermal administration, the dosage form of the particular compound may include, by way of example, solutions, lotions, ointments, creams, gels, 5 suppositories, rate-limiting sustained release formulations and devices therefor. Such dosage forms comprise the particular compound and may include ethanol, water, penetration enhancer and inert carriers such as gel-producing materials, mineral oil, emulsifying agents, benzyl alcohol and the like. Specific transdermal flux enhancing compositions are disclosed in United States Patent No. 5,196,410, which is assigned 10 to the assignee of this invention.
For purposes of topical administration, the dosage form of the particular compound may include, by way of example and not of limitation, solutions, lotions, ointments, creams and gels.
While the compounds of Formula I above are shown as ketones, it is to be 15 understood that the compounds of Formula I can assume a tautomer form of an enol.
All such tautomeric forms are within the scope of this invention. Further, the substituents on the exocyclic double bond at the 3-position of the enol form of Formula I can be syn, anti or a mixture of both. All such isomers are deemed to be depicted by Formula I and within the scope of the appendant claims.
The ability of the compounds of this invention to inhibit replication of HIV-1 and alleviate the symptoms of AIDS is demonstrated by the following Example.

Cells and virus. The CD4+ T-lymphocyte lines H9 and Jurkat and the monocyte line U937 (American Type Culture Collection (ATCC), Rockville, MD) are cultured in Roswell Park Memorial Institute Culture Medium (RPMI-1640) supplemented with 10%bovine calf serum (BCS), 100 U/ml penicillin, 100 ~g/ml streptomycin, 2 ~g/ml ciprofloxacin, 600 ~g/ml L-glutamine, and 100 ~M nonessential amino acids. HIVMN jS
produced in H9 cells. During log phase growth, cell-free supernatant is harvested, passed through a 0.22~m filter, and frozen in aliquots at -70C. HIVMN jS titered on H9 cells by endpoint dilution (see Marshall, et al., J. Virol 66:5492, 1992) with syncytium formation as the endpoint. The 50% tissue culture infectious dose (TCI Dso) is determined at 7 days post-infection.

Reaqents. Compounds of Formula I are freshly prepared for each experiment in phosphate buffered saline (PBS) and filter sterilized. Lyophilized recombinant human IL-6 (Endogen Inc., Boston, MA) is recon~liluted in PBS at a concentration of 2500 units/ml; activity is 5 x 106 units/mg.
Inhibition of HIV-1 p24 core antigen bv compounds of Formula 1. All cells are infected with HIVMN at a multiplicity of infection (MOI) of 0.10 for 1-1 .5 hours. Following infection, cells are washed 3 times with RPMI-1640, 10% BCS to remove residual virus and are incubated at 37C in 5% CO2 in the presence of various concentrations of a compound of Formula 1. At day 3 (H9), day 7 (Jurkat), or day 11 (U937), p24 antigen 10 is measured in the cell-free supernatants by p24 ELISA (DuPont NEN, Boston, MA) and cell viability is measured by trypan-blue staining.
Downregulation of HIV-1 (Long terminal repeat) LTR mediated ~ene expression.
Gene activity driven by either the HIV-1LTR or the Rous sarcoma virus (RSV) LTR is measured by transiently transfecting Jurkat cells with the appropriate vector containing 15 the LTR linked to the chloramphenicol acetyl l-cln:,~erase (CAT) reporter gene. The HIV-1 LTR CAT vector was constructed by Drs. Gary Nabel and David Baltimore and obtained from Dr. Nabel of the Howard Hughes Medical Institute, University of Michigan Medical Center. The RSV LTR vector was obtained from Dr. Debajit Biswas of the Dana-Farber Cancer Institute. Biswas, et al. J. Acquir. Immune Defic. Syndr. 6:778, 20 1993. Jurkat cells (106 cells/ml) are grown in 150 mm plates in 20 ml RPMI-1640, 10%
fetal bovine serum at 37C in 5% CO2 for 12-18 hours overnight before beginning the transfection procedure. Cells are then pelleted, resuspended in 10 ml preequilibrated transfection medium (see Somapyrac, et al., Proc. Nat. Acad. Sci USA 78:7575, 1981), and transfected with 2.5 ~Jg expression plasmid and 12.5 ~g sonicated salmon sperm 25 DNA carrier per plate via the diethyl amino ethyl (DEAE) Dextran procedure, Somapyrac, et al. Proc. Natl. Acad. Sci. USA 78:7575, 1981. After an hour at 37C, the cells are subjected to dimethyl sulfoxide shock for 5 minutes, washed, and resuspended in complete medium in new culture plates. Forty-eight hours later, 5 ml of fresh culture medium are added, and cells are grown for an additional 8 hours. Fifty-30 four hours after transfection, cells are stimulated with 20 ng/ml phorbol 1 2-myristate 13-acetate (PMA) in the presence or absence of a compound of Formula I at varying concentrations (0.3, 1.0, 3.0, 30, and 90 ~g/ml) and are allowed to grow overnight for 12-18 hours. Seventy-two hours post-transfection and 12-18 hours after drug addition, ~1~6120 cells are harvested and cytoplasmic extracts are prepared as described by Dignauc, et al., Nucleic Acids Res. 11:1475, 1983. CAT activity is measured by thin layer chromatography as described by Sodroski, et al., Science 227: 171, 1985 after standardizing the cell extracts for protein content Bradford, Amal. Biochem. 72:248, 5 1976. The thin layer chromatographs (Baker-Flex Silica Gel 1 B, J. T. Baker, Phillipsburg, NJ) are exposed to X-ray film overnight. Relative amounts of unreacted [l4C]chloramphenicol, 50-60 mCi/mM (DuPont NEN, Boston, MA) and its acetylated derivatives are quantified by densitometric scanning of the film with an LKB 2222-020 UltroScan XL Laser Densitometer (LKB Instruments, Houston, TX) and subsequent 10 integration of the surface area of the signal under the peak.
Results Compounds of Formula I decrease the replication of HIV-1 as measured by p24 core antigen in acutely infected H9, Jurkat, and U937 cells in a dose-dependent fashion. Typically 50% inhibitory concentrations (ICso) are < 1 ~g/ml for Jurkat cells, 15 and 3-5 ~g/ml for H9 and U937 cells. The 50% lethal dose (LD50), as assessed by trypan-blue staining range from 25 to 40 ~g/ml. The therapeutic index, as defined by the ratio of LD50 to IC50, is thus estimated to be from 7 (H9 and U937 cells) to >25 (Jurkat cells).

Claims (44)

1. A medicine for inhibiting replication of HIV-1 in a mammal which comprises, in admixture with a pharmaceutically acceptable carrier or diluent, an HIV-1 replication inhibiting amount of a compound of the formula or a pharmaceutically acceptable base salt thereof, wherein X
is H, Cl or F; Y is H or Cl; and R is benzyl or thienyl, each being unsubstituted or substituted with Cl or F.

2. A medicine according to claim 1, wherein X is Cl;
Y is H; and R is thienyl.

3. A medicine according to claim 2, wherein R is 2-thienyl.

4. A medicine according to claim 3, wherein the pharma-ceutically acceptable base salt is sodium.

5. A medicine according to claim 1, wherein X is F; Y
is Cl; and R is thienyl or 4-chlorothien-2-yl.

6. A medicine according to claim 5, wherein R is 4-chlorothien-2-yl.

7. A medicine according to claim 1, wherein X is H, Y
is Cl, and R is benzyl.

8. A medicine according to claim 1, which is adapted to be administered orally.

9. A medicine according to claim 1, which is adapted to be administered parenterally.

10. A medicine for treating or preventing AIDS in human which comprises, in admixture with a pharmaceutically acceptable carrier or diluent, an effective amount of a compound of the formula or a pharmaceutically acceptable base salt thereof, wherein X
is H, Cl or F; Y is H or Cl; and R is benzyl or thienyl, each being unsubstituted or substituted with Cl and F.

11. A medicine according to claim 10, wherein X is Cl Y is H; and R is thienyl.

12. A medicine according to claim 11, wherein R is 2-thienyl.

13. A medicine according to claim 12, wherein the pharma-ceutically acceptable base salt is sodium.

14. A medicine according to claim 10, wherein X is F; Y
is Cl; and R is thienyl or 4-chlorothien-2-yl.

15. A medicine according to claim 14, wherein R is 2-chlorothien-2-yl.

16. A medicine according to claim 10, wherein X is H;
Y is C1 and R is benzyl.

17. A medicine according to claim 10, which is adapted to be administered orally.

18. A medicine according to claim 10, which is adapted to be administered parenterally.

19. A medicine for inhibiting replication of virus in a mammal which comprises, in admixture with a pharmaceutically acceptable carrier or diluent, a virus replication inhibiting amount of a compound of the formula or a pharmaceutically acceptable base salt thereof, wherein X
is H, Cl or F; Y is H or Cl; and R is benzyl or thienyl, each being unsubstituted or substituted with Cl or F; with the proviso that the virus is not Rous sarcoma virus.

20. A medicine according to claim 19, wherein X is Cl;
Y is H; and R is thienyl.

21. A medicine according to claim 20, wherein R is 2-thienyl.

22. A medicine according to claim 21, wherein the pharmaceutically acceptable base salt is sodium.

23. A medicine according to claim 19, wherein X is F;
Y is Cl; and R is thienyl or 4-chlorothien-2-yl.

24. A medicine according to claim 23, wherein R is 2-chlorothien-2-yl.

25. A medicine according to claim 19, wherein X is H;
Y is Cl; and R is benzyl.

26. A medicine according to claim 19, which is adapted to be administered orally.

27. A medicine according to claim 19, which is adapted to be administered parenterally.

28. A medicine for treating or preventing a viral infection in a mammal which comprises, in admixture with a pharmaceutically acceptable carrier or diluent, an effective amount of a compound of the formula or a pharmaceutically acceptable base salt thereof, wherein X
is H, Cl or F; Y is H or Cl; and R is benzyl or thienyl, each being unsubstituted or substituted with Cl or F; with the proviso that the viral infection is not caused by Rous sarcoma virus.

29. A medicine according to claim 28, wherein X is Cl;
Y is H; and R is thienyl.

30. A medicine according to claim 29, wherein R is 2-thienyl.

31. A medicine according to claim 30, wherein the pharma-ceutically acceptable base salt is sodium.

32. A medicine according to claim 28, wherein X is F;
Y is Cl; and R is thienyl or 4-chlorothien-2-yl.

33. A medicine according to claim 32 wherein R is 2-chlorothien-2-yl.

34. A medicine according to claim 28, wherein X is H;
Y is Cl; and R is benzyl.

35. A medicine according to claim 28, which is adapted to be administered orally.

36. A medicine according to claim 28, which is adapted to be administered parenterally.

37. A medicine according to claim 1, which is adapted for oral administration and contains the compound or salt in such an amount that 40 to 200 mg of the compound or salt is administered per day per patient.

38. A commercial package which comprises (1) a container containing therein the medicine according to any one of claims 1 through 9 or claim 37 and (2) a written matter stating that the medicine can or should be used for inhibiting replication of HIV-1.

39. A medicine according to claim 10, which is adapted for oral administration and contains the compound or salt in such an amount that 40 to 200 mg of the compound or salt is administered per day per patient.

40. A commercial package which comprises (1) a container containing therein the medicine according to any one of claims 10 through 18 or claim 39 and (2) a written matter stating that the medicine can or should be used for treating or preventing AIDS.

41. A medicine according to claim 19, which is adapted for oral administration and contains the compound or salt in such an amount that 40 to 200 mg of the compound or salt is administered per day per patient.

42. A commercial package which comprises (1) a container containing therein the medicine according to any one of claims 19 through 27 or claim 41 and (2) a written matter stating that the medicine can or should be used for inhibiting replication of virus.

43. A medicine according to claim 28, which is adapted for oral administration and contains the compound or salt in such an amount that 40 to 200 mg of the compound or salt is administered per day per patient.

44. A commercial package which comprises (1) a container containing therein the medicine according to any one of claims 28 through 36 or claim 43 and (2) a written matter stating that the medicine can or should be used for treating or preventing a viral infection.