NZ229000A - 2',3'-didehydro-2',3'-dideoxynucleosides, process for their preparation and pharmaceutical compositions thereof - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £29000 229000 NO DRAWINGS Priority Date(s): . .^5 , Complete Specification Filed: Class: Q&3.Q VtD 3. Jw^j£pD. £> J>j. QIh- I A^.0S&] Publication Date: .? .? JM..

P.O. Journal. No: ... !3.^..-.

Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION PRODRUGS OF 2 ' , 3 '-DIDEOXY-2'3'-DIDEHYDRONUCLEOSIDES ' a~> oKva-"vU%)ec( «J—cj. <£^sb~v=>i WE, BRISTOL-MYERS SQUIBB COMPANY,a of 345 Park Avenue, New 1 f York, N.Y. 10154, United States of America, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: N.Z.. PATENT OFFICE -6 nov )m RECEIVED 229000 This invention relates to novel prodrugs of 2',31-didehydro-2,'31-dideoxynucleosides which are useful as antiviral agents, especially as agents effective against the human immunodeficiency viruses (HIV). This invention also relates to a pharmaceutical composition containing the above prodrugs and to the anti-HIV use of said compositions. . ' ■ .".5- '"f.-. : V -V .

Acquired immunodeficiency syndrome (AIDS) is the result of an infection by human immunodeficiency virus(es) (HIV).^" This retrovirus shows a specific tropism for the 2 helper/inducer T cells leading to their depletion. The resultant immunosuppression predisposes HIV patients to life-threatening opportunistic infections.

Although at present there is no cure for AIDS/ one nucleoside derivative, 3'-azido-3'-deoxythymidine (A2T, TM Retrovir ), has already proved to be an efficacious agent in the treatment of AIDS in clinical trials and has been licensed by the appropriate regulatory agency for use in N.Z. PATENT OFFICE -6 NOV ibau 229000 3 patients with AIDS. A number of other chemical and biological agents have been reported to have biological activity against HIV. 23'-Dideoxycytidine (ddC), 2',3'-dideoxyadenosine (ddA),^ 23'-didehydro-2',3' -dideoxycytidine (d4C),^ suramine and its analogs,^ 7 8 9 10 ribavarin, foscarnet, HPA-23, d-penicillamine, 11 12 castanospermine, fusidic acid, 3'-azido-3'- ' ' 13 14 deoxyguanosine (A2G), 3'-flupro-3'-deoxythymidine (Fddt) are all reported to be active against HIV.

A number of reports have appeared in the literature which have shown that 2',3'-didehydro-2',3'-dideoxythymidine (d4T) possesses in vitro activity against HIV in several cell lines.

J.P.H. Verheyden and J.C. Martin, U.S. Patents No. 4,612,314 and 4,609,661, disclose substituted 9-(l- or 3-monoacyloxy- or 1,3-diacyloxy-2-propoxymethyl)purines as prodrugs of the antiviral compound, DHPG.

J.C. Martin et ail., J. Pharm. Sci. 76 (2), 180-184 2 (1987), disclose mono-0-, di-0-, and N acyl derivatives of 9-((1,3-dihydro-2-propoxy)methyl]guanine (DHPG). , V. Skaric and J. Matuliz-Adamic, Helv. Chim. Acta, 63, 2179 (1980) disclose 5'-0-acetyl-2' ,3'-didehydro-2', 3'-dideoxythymidiiSe.

S. David and G. deSennyey, Carbohydrate Research, 82, 45-49 (1980), disclose 5'-0-benzoyl-2*,3'-didehydro-2',3'-dideoxyuridine.

N.Z. PATEiVT OFFICE ^_ ~B NOV I unit 229000 R. Mengel and J. M. Seifert, Tetrahedron Lett., No. 48, 4203-4206 (1977), disclose a dipivaloyladenosine compound.

J. Lim et al., Antimicrobial Agents and Chemotherapy, July 1987, 998-1001 disclose methoxyacetate and ethoxypropionate esters of cyclaradine as prodrugs.

P.F. Torrence et al. , Abstracts of the 2nd International Conference on Antiviral Research, Williamsburg, VA., 10-14 April 1988, page 118, disclose heteroarylcarbonyloxy esters, namely the 1,4-dihydro-l-methyl-3-pyridinylcarbonyloxy ester, as a prodrug of AZT.

T.J. Bardos et al., U.S. Patent 4,468,384 disclose the use of prodrugs of 4-deoxopyrimidines as antiviral agents.

In one aspect, this, invention provides.a 51-O-acyl-23'-didehydro-2',3'-dideoxynucleoside of the formula wherein B and R are a base and an acyl group, respectively, as defined below. The invention also provides a'pharmaceutical composition containing compound of the"formula (I).

N.Z. PATENT OFFICE -6 nov j3su 229000 In the canpound of formula (I), R is selected frcm H-and a physiologically hydrolyzable ester group consisting of alkanoyl, cycloalkanoyl, cycloalkylalkanoyl, alkenoyl, cycloalkylalkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl groups wherein the alkanoyl, cycloalkanoyl, cycloalkylalkanoyl, alkenoyl, and cycloalkylalkenoyl each have up to 20 carbon atoms and 1 or 2 optional substituents selected from halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano, and the aroyl, aralkanoyl, and aralkenoyl, each have up to 20 carbon atoms including from 6 to 10 carbon atoms in the aryl portion each aryl portion having optional substituents selected from 1 to 3 alkyl groups, hydroxy, alkoxy, halo, amino, alkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano; and 229000 B is a nitrogen heterocycle attached through a ring nitrogen atom thereof and selected from 9-purinyl of Formula II and 1-pyrimidinyl of Formula III R1 R.5 (in <ni> wherein 1 2 R and R are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, amino, alkylamino, dialkylamino, alkoxy., and cyano and each of . said alkyl and alkoxy groups has from 1 to 3 carbon atoms, 3 R is hydroxy, amino, or sulfhydryl, R^ is hydrogen, hydroxy, sulfhydryl, or amino, and R6 is hydrogen, c1-3 alkyl, C2_3alkenyl, C2-3 haloalkenyl having 1 to 5 halogen atoms, alkynyl/ alkoxy, cyano, fluorine, chlorine, bromin£, or iodine provided that when B is thymine R is other than acetyl, and when B is uridine R is other than benzoyl, / and when R is H, then B is a pyrimidine of Formula III wherein R^ is hydrogen or sulfhydryl. twoffice -6 nov 1991/ 229000 The pharmaceutical composition comprises an antiviral effective amount of the compound having Formula I and a pharmaceutically acceptable carrier.

In yet another aspect, this invention is a method for reducing the infectivity of the human immunodeficiency virus by contacting in vitro the virus with an antiviral effective amount of the compound having Formula I.

As is described above, in one aspect this invention concerns prodrug esters which:are 5'-0-acyl-2',3'-didehydro- 2 ' , 3 '-dideoxynticleosides wherein the base component B is derived from a member selected from the group of bases consisting of unsubstituted and substituted purine, aza-purine, deaza-purine, pyrimidine, aza-pyrimidine, deaza-pyrimidine, and triazole ring bases. Preferably, the base is selected from purine and pyrimidine bases. More preferably, the base is a pyrimidine base. Most preferably, the base is a pyrimidine base selected from thymine, cytosine, and uracil.

In another preferred embodiment, this invention concerns prodrugs which are 2',3'-didehydro-2',3'- dideoxynucleoside derivatives wherein, according to Formula 1/ R is H and Bis selected from 2-hydroxy-4-thiopyrimidines 3 5 (Formula III below, R =OH, R =SH), 2-hydroxypyrimidines 3 5 (Formula III below, R =OH, R =H). The remaining ring atoms may be unsubstituted or substituted as described for pyrimidine bases having Formula III below.

These bases are produced as described in Torrence et a^. and Bardos et al_. , respectively, mentioned above. - 7 HJL PATENT OFFICE -6 nov 19b0 RECEIVED 229000 Suitable unsubstituted and substituted purine bases from which the component B may be derived include those purine bases represented Formula II R1 ,xx> (Il> 1 2 wherein R and R may be the same or different and are selected from-hydrogen, hydroxy, halo (F, CI, Br), amino, monoalkylamino, dialkylamino, alkoxy and cyano groups wherein the alkyl moiety is selected from C^-C^ alkyl groups.

Suitable unsubstituted and substituted 1-pyrimidyl bases comprising component B include those represented by Formula III »5 (111) 3 wherein R is selected from hydroxy, amino and sulfhydryl groups; R is selected from hydrogen, hydroxy and sulfhydryl, and amino groups; and R^ is selected from hydrogen, C^C^ alkyl, C2~C3 alkenyl, C2~C3 haloalkenyl having from 1 to 5 halo groups as defined herein, C2~C3 alkynyl, alkoxy wherein the alkyl moiety has 1-3 carbon atoms, cyano and halo (F, CI, Br and I). 22 9 0 When derived from purine bases, representative of B are the following: 6-aminopurin-9-yl (aden-9-yl) 2-aminopurin-9-yl 2,6-diaminopurin-9-yl 2-amino-6-hydroxypurin-9-yl (guanin-9-yl) 6-hydroxypurin-9-yl (hypoxanthine) In addition to the above, the B component may be 2-halopurin-9-yl, 6-halopurin-9-yl, or 2,6-dihalopurin-9-yl.

When derived from pyrimidine bases, representative of B are the following: 2,4-dihydroxyprimidin-l-yl (uridyl) 5-methyl-2,4-dihydroxypyrimidin-l-yl (thymidyl) 5-ethyl-2,4-aminopyrimidin-l-yl , 2-hydroxy-4-aminopyrimidin-l-yl (cytidyl) 5-vinyl-2,4-dihydroxypyrimidin-1-yl 5-halovinyl-2,4-dihydroxypyrimidin-1-yl 5-halomethyl-2,4-dihydroxypyrimidin-l-yl 5-haloethyl-2,4-dihydroxypyrimidin-l-yl The above-mentioned 5-methyl and 5-ethyl substituents are representative of 5-alkyl substituents and the 5-vinyl substituent is representative of 5-alkenyl substituents. Examples of halo-groups of the 5-halovinyl (or 5-haloalkenyl) group include 1 to 4 F, CI, and Br groups.

As is described above, in the case when R is other than H, then R is a member selected from the group of physiologically hydrolyzable ester groups consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl and aryloxycarbonyl groups wherein the alkyl moiety consists of unsubstituted and substituted, straight-chain and branched-chain and cyclic alkyl groups having 1-20 carbon atoms, unsubstituted and substituted, straight-chain and branched-chain and cyclic alkenyl groups having 1-20 carbon atoms, unsubstituted and substituted phenyl, and phenalkyl groups wherein the alkyl moiety contains 1-3 carbon atoms and the phenyl moiety is unsubstituted or substituted, 229000 provided that when B is thymidyl then R is not acetyl and when B is uridyl then R is not benzoyl.

By the expression a*-kyln an<* n<~l~C20 ^^oxy" wherein the alkyl moiety is more particularly unsubstituted alkyl, is meant straight-chain or branched-chain or cyclic alkyl (monovalent hydrocarbon) groups having a total of 1-20 carbon atoms. Examples of suitable straight-chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, n-octyl, dodecyl, palmityl and the like groups. Examples of suitable branched-chain alkyl groups include isopropyl, sec-butyl, t-butyl, 2-methylbutyl, 2-pentyl, 3-pentyl and the like groups. Examples of suitable cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. The alkyl groups may be substituted, generally with 1 or 2 substituents, wherein the substituents are independently selected from halo, hydroxy, alkoxy, amino, mono- and dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano groups. By the expression "phenalkyl" is meant benzyl, phenethyl (phenylethyl) and phenylpropyl groups wherein the phenyl moiety may be substituted. When substituted, the phenyl group or the phenyl moiety of the phenalkyl group may contain, independently, from 1 to 3 alkyl, hydroxy, alkoxy, halo, amino, mono- and dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano groups.

By the expression "alkenyl" is meant unsubstitpted or substituted, straight-chain or branched-chain or cyclic monovalent hydrocarbon substituents having 2 to 20 carbon atoms and having one double bond. Examples of suitable "alkenyl" groups include vinyl (ethenyl), 1-propenyl, i-butenyl, pentenyl, hexenyl, n-decenyl and c-pentenyl and the like.

N.Z. PATENT OFFICE -6 NOV ibbU RECEIV~T 22 9 0 By the expression "heteroaryl" is meant aryl groups containing a heteroatom such as, for example in a preferred embodiment, 1,4-dihydro-l-methyl-3-pyridimyl which is mentioned above. See Torrence et al., supra.

As used herein, the expression "halo" is meant in the conventional sense to include F, CI, Br, and I.

In more preferred embodiments, R is selected from the group consisting of CH3C(0) (acetyl) C6H5C(0) (benzoyl) (CH3)3CC(0) (pivaloyl) CH^OCI^CfO) (methoxyacetyl) C?H15C(0) (heptoyl) C^H3^C(0) (palmitoyl) CH30C(0) (methoxycarbonyl) CgH^OC(O) (n-octyloxycarbonyl) c-CgH^OC(O) (cyclohexyloxycarbonyl) (CH3)3C0C(0) (t-butoxycarbonyl) /-=\ O ^ N-c ~ (imidazolylcarbonyl) ,C(0) (1,4-didhydro-l-methyl-3- pyridinylcarbonyl) Stated another way and to summarize, the present invention provides compounds of Formula I wherein a compound having Formula I wherein R is selected from H and a physiologically hydrolyzable ester group consisting of alkanoyl, cycloalkanoyl, cycloalkylalkanoyl, alkenoyl, cycloalkylalkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl, alkoxycarbonyl, aryloxycarbonyl, or 22 94 heteroaryloxycarbonyl groups wherein the alkanoyl, cycloalkanoyl, cycloalkylalkanoyl, alkenoyl, and cycloalkylalkenoyl each have up to 20 carbon atoms and 1 or 2 optional substituents selected from halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano, and the aroyl, aralkanoyl, and aralkenoyl, each have up to 20 carbon atoms including from 6 to 10 carbon atoms in the aryl portion each aryl portion having optional substituents selected from 1 to 3 alkyl groups, hydroxy, alkoxy, halo, amino, alkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano; B is a nitrogen heterocycle attached through a ring nitrogen atom thereof and selected from 9-purinyl of Formula II and 1-pyrimidinyl of Formula III. 1 2 In Formulas II and III above, R and R are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, amino, alkylamino, dialkylamino, alkoxy, and cyano and each of said alkyl and alkoxy groups has from 1 to 3 carbon atoms, 3 R is hydroxy, amino, or sulfhydryl, R5 is hydrogen, hydroxy, sulfhydryl, or amino, and R^ is hydrogen, alkyl, C2_3alkenyl, C2-3 haloalkenyl having 1 to 5 halogen atoms, C2-3 alkynyl, C^_3 alkoxy, cyano, fluorine, chlorine, bromine, or iodine provided that when B is thymine R is other than acetyl, and when B is uridine R is other than benzoyl, and when R is H, then B is a pyrimidine of Formula III wherein R^ is hydrogen or sulfhydryl.

As is mentioned above, the compound according to this invention may be provided as a pharmaceutical composition 22 9 0 containing an antiviral effective amount, more particularly an anti-HIV effective amount, of the compound according to this invention having Formula I and a pharmaceutically acceptable carrier.

The pharmaceutical carrier may be solid or liquid to provide solid or liquid compositions. Solid form compositions suitable for oral administration include powders, tablets, capsules, caplets, dispersible granules, and cachets. Suitable solid carriers include at least one carrier substance which may function only as a carrier or may in addition serve a further function such as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, encapsulating agent and the like. Inert solid carriers include, to name but a few, magnesium carbonate and stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, and the like. The compounds according to the invention may be provided as sterile soluble compounds or compositions, including solutions and suspensions and emulsions thereof, which can be dissolved in sterile water or other liquid medium for oral administration or for parenteral administration. Examples of liquid carriers suitable for oral administration include water, alcohol, polypropylene glycol, polyethylene glycol and mixtures of two or more of the above. Examples of liquid carriers suitable for parenteral use include water-for-injection, physiological saline, and other suitable sterile injection media.

Suitable buffers for use with the liquid carrier to provide, generally, a suitable buffered isotonic solution include trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine, and L(+)-arginine to name but a few representative buffering agents.

For aerosol administration, the carrier may be a combination of a suitable surfactant and propellant as the 22 9 0 0 vehicle for the finely divided solid form or solution form of the active ingredient having Formula I.

An art-recognized compendium of pharmaceutical compositions including methods of preparation and ingredients is Remington's Pharmaceutical Sciences by E. W. Martin (Mark Pubb. Co., 15 Ed., 1975).

The pharmaceutical composition will contain an amount of active component, that is, compound of Formula I or mixture thereof with other anti-viral or anti-HIV active ingredient, which may be varied or adjusted widely depending upon the particular application, the form, the potency of the particular compound used, and the desired concentration of compound in the composition. Generally, the amount of active component in the pharmaceutical composition will range between about 0.5-90% by weight based on total weight of composition.

As mentioned above, this invention is also a method for eliminating or reducing the infectivity of the human immunodeficiency viruses by contacting therewith an anti-HIV effective amount of the compound of Formula I, generally provided as a pharamceutical composition described above.

In therapeutic use for treating a mammalian host, for example a human patient or an experimental animal host, affected by the human immunodeficiency viruses (HIV), the compounds of this invention will be administered in an amount effective to eliminate or reduce the infectivity of HIV that is, an anti-HIV effective amount of dosage. Generally, the anti-HIV effective amount will be in the range of about 1.0 to about 200 mg/kg of total body weight/day, more preferably about 1.0 to 30.0 mg/kg total body weight/day, most preferably about 5.0 to 20.0 mg/kg total body weight/day. It is to be understood that the actual preferred dosage of compound will vary widely depending upon the requirements of the animal being treated, 22 9 0 0 the particular animal host and situs and disease being treated, the composition being used, and the route of administration. Many factors will be taken into account as is known by one skilled in the art to which this invention pertains including, for example, age, body weight and sex of the animal host; diet; time of administration; rate of excretion; condition of the host; severity of the disease; and the like. Administration may be carried out simultaneously or periodically within the maximum tolerated dose. Optimal administration (or application) rates for a given set of conditions may be readily ascertained by those skilled in the art using conventional dosage determination tests.

The compounds of Formula I may be prepared from the corresponding 5'-hydroxy-2',3'-didehydro-2',3'-dideoxy-nucleosides (Formula I wherein R = H) by reacting the 5'-hydroxy group with the desired acyl anhydride or acyl chloride according to methods well known for protecting hydroxy groups. Several suitable methods are described above in the section "Description of the Background and Related References." The following examples illustrate but a few representative embodiments of the compounds having Formula I according to this invention and the preparation of the same and are set forth to teach those skilled in the pertinent art how to practice this invention and are not to be construed as limiting in scope. All parts and percentages are by weight and temperatures are in degrees Celsius unless otherwise specified. The structural formulas are set forth in TABLE 1.

The physiologically hydrolyzable esters according to this invention function as "pro-drugs" by being hydrolyzed in the body of the mammalian host, e.g., an experimental 229000 animal and a human patient, to yield the corresponding 2',3'-didehydro-2',3'-dideoxynucleoside per se. Early data reported in the pertinent literature tends to show that the 2',3'-didehydro-2',3'-dideoxynucleosides derived from purine bases are less active or potent than those derived from pyrimidine bases. See DeClercq et al., J. Med. Chem., 30, 1270 (1987). Thus, the pro-drugs of the latter are more preferred than those of the former. In addition to providing the corresponding 2',3'-didehydro-2',3'-dideoxynucleoside under physiological hydrolysis conditions, the compound according to this invention having Formula I may afford other advantages such as advantages in formulation ' and prolonged and sustained action of active ingredient, stability in formulation and upon storage, and the like.

The most preferred embodiments of the present invention are the follow esters of thymidine: acetyl, benzoyl, methoxyacetyl, pivaloyl, methoxycarbonyl, imidazolylcarbonyl, cyclohexyloxycarbonyl, and n-octyloxycarbonyl.

DESCRIPTION OF SPECIFIC EMBODIMENTS Abbreviations: d4T imidazoyl d4T 2',3'-didehydro-2',3'-dideoxythymidine 5'-(1-imidazolylcarbonyl)-2',3'--didehydro-2',3'-dideoxythymidine 229000 Example 1: '-O-Acetyl-2', 3'-didehydro-2', 3'-dideoxythymidine (v.Skaric et al., loc. cit.) To a stirred solution of 10.0 g (44.6 mmol) of d4T in 100 mL of pyridine was added 4.10 mL (58.0 mmol) of acetyl chloride. The mixture was stirred at 50°C for 1 h, cooled and diluted with 1 L of toluene. The solvents were removed in vacuo. The yield of product, recrystallized from ethanol was 9.3 g. 1H NMR (360 MHz) 9.01 (1H, s, NH), 7.23 (1H, s, C6H), 6.99 (1H, d, J=1.1 Hz, Cl'H), 6.24 (1H, d, J=5.8 Hz, C2'H), 5.88 (1H, d, J=5.5 Hz, C3'H), 5.02 (1H, s, C4'H), 4.3 (2H, m, C5'H2), 2.07 (3H, s, CH3 acetate), 1.90 (3H, s, C5CH3). MS m/z (relative intensity) 533 (M+, 3), 347 (40), 287 (50), 155 (40), 127 (100), 81 (80). IR (KBr) cm"1 3010, 1740, 1700, 1470, 1260, 1230. Anal, calculated c12Hi4N2°5 C 54.12 H 5.30 N 10.52; found C 53.97 H 5.36 N 10.45.

Example 2: '-0-Benzoyl-2',3'-didehydro-2',3'-dideoxythymidine.

To a solution of 10.0 g (44.6 mmol) of d4T in 290 mL of pyridine was added 8.2 mL (71.4 mmol) of benzoyl chloride. The mixture was heated at 50°C for 6 h, cooled, and half of the volatiles were removed in vacuo. The residue was poured in 800 mL of ice water and the resulting precipitate was collected, washed with ice water and air dried. The solid was recrystallized from ethanol to give 12.87 g of title product. XH NMR (300 MHz, DMS0) 11.35 (1H, s, NH), 7.91 (2H, d, J=7.8 Hz, Ph), 7.65 (1H, t, J=7.2 Hz, Ph), 7.51 (2H, d, J=7.8 Hz, Ph), 7.09 (1H, s, C6H), 6.78 (1H, s, Cl'H), 6.50 (1H, d, J=6.1 Hz, C2'H), 6.02 (1H, d, J=6.1 Hz, C3'H), 5.08 (1H, s, C4'H), 4.48 (2H, m, C5'CH2), 1.33 (3H, s, CSCH^). MS m/z relative intensity) -329 (M+H, 12), 155 22 9 0 0 (45), 127 (100), 81 (85). IR (KBr) cm"1 3100-3000, 1710, 1460, 1280. Anal, calculated C17H16N205 C 62.20 H 4.92 N 8.54; found 62.25 H 4.91 N 8.28.

Example 3: '-O-Methoxyacetyl-2',3'-didehydro-2',3'-dideoxythymidine.

To a solution of 4.50 g (20.1 mmol) of d4T in 50 mL of pyridine was added 2.45 mL (26.8 mmol) of methoxyacetyl chloride. The reaction was stirred at 22°C for 24 h, diluted with 200 mL of toluene and stripped to dryness in vacuo. The residue was recrystallized from ethanol. NMR analysis of the product indicated presence of pyridine hydrochloride. The solid was suspended in 100 mL of water, collected by filtration, and washed with absolute ethanol to give 2.50 g of methoxyacetate. 1NMR (300 MHz, CDCl^) 9.27 (1H, s, NH), 7.14 (1H, d, J=1.3 Hz, C6H), 6.96 (1H, s,. Cl'H), 6.23 (1H, d, J=6.0 Hz, C2'H), 5.88 (1H, d, J=6.1 Hz, C3'H), 5.01 (1H, s, C4*H), 4.3 (2H, m, C5'H), 4.02 (2H, m, 0CH2), 3.39 (3H, s, 0CH3), 1.88 (3H, s, C5CH3). MS m/z (relative intensity) 297 (M+H, 40), 251 (20), 207 (40), 155 (50), 127 (100), 81 (100). IR (KBr) cm"1 3200-3000, 1760, 1700, 1480, 1260. Anal, calculated C13H16N206 C 52.70 H 5.44 N 9.46; found C 52.59 H 5.40 N 9.11.

Example 4: '-0-Pivaloyl-2', 3'-didehydro-2',3'-dideoxythymidine.

To a solution of 1.84 g (8.21 mmol) of d4T in 20 mL of pyridine was added 1.31 mL (10.67 mmol) of pivaloyl chloride. The mixture was heated at 65°C for 3h, cooled and diluted with 100 mL of toluene. The solvents were removed 22 9 0 0 0 in vacuo and the residue was recrystallized from isopropyl alcohol to give 0.72 g of pivaloate. NMR (300 MHz, DMSO) 11.40 (1H, s, NH), 7.19 (1H, s, C6H), 6.75 (1H, s, Cl'H), 6.37 (1H, d, J=6.0 Hz, C2'H), 6.00 (1H, d, J=6.0 Hz C3'H), 4.91 (1H, s, C4'H), 4.16 (2H, m, C5'H2), 1.74 (3H, s, C5CH3), 1.10 (9H, s, t-butyl). MS m/z (relative intensity) 309 (M+H, 30), 207 (70), 155 (60), 127 (100), 81 (80). IR (KBr) cm"1 3100-3000, 1735, 1700, 1470, 1135. Anal, calculated c15H2C)N205.0.04H20 C 58.31 H 6.63 N 9.07; found C 57.91 H 6.72 N 9.08.

Example 5: '-0-Methoxycarbonyl-2',3'-didehydro-2', 3'-dideoxythymidine.

A suspension of 1.21 g (3.80 mmol) of imidazoyl d4T in 30 mL of methanol was heated to reflux for 15 minutes. Upon initially reaching reflux temperature, the reaction became homogeneous.. The fiaek was cooled to room temperature (22°C), then placed in an ice bath at 0°C for 30 minutes. The resulting precipitate was collected and washed with cold methanol. The filtrate was cooled at 0°C for 16 h and the resulting solid was collected and washed with cold methanol. The solids were combined to give 0.85 g of methoxycarbonyl d4T. 1H NMR (300 MHz, CDC13) 8.55 (1H, s, NH), 7.35 (1H, s, C6H), 7.03 (1H, m, Cl'H), 6.27 (1H, m, C2'H), 5.85 (1H, d, J=6.0 Hz, C3'H), 4.99 (1H, m, C4'H), 4.36 (2H, m, C5'H2), 3.77 (3H, s, 0CH3), 1.87 (3H, s, C5CH3). MS m/z (relative intensity) 283 (M+H, 20), 207 (40), 155 (50), 127 (100), 81 (100). IR (KBr) cm"1 2975, 1750, 1700, 1280, 1260. Anal, calculated C12H14N206 C 51.06 H 5.00 N 9.93; found C 50.90 H 4.89 N 9.87. 129 0 0 0 Example 6: '-0-Cyclohexyloxycarbonyl-2',3'-didehydro-2' , 3'-dideoxythymidine .

A suspension of 1.00 g (3.14 mmol) of imidazoyl d4T in 20 mL of cyclohexanol was heated at 100°C for 18 h, after which time the reaction was homogeneous. The reaction was cooled and the solvents were removed in vacuo at 50°C (0.1 mm). The residue was purified on a 50 mm flash chromatography column, eluting with 2% Me0H-CH2Cl2 (1000 mL), 5% MeOH- CH2C12, (500 mL), then 10% Me0H-CH2Cl2 (500 mL). The fractions containing the desired product were combined and the solvent was removed to give an oil which still contained cyclohexanol by NMR. The oil was suspended in 30 mL of water and the solvents were removed by freeze-drying (0.005 mm) for 16 h to give 0.51 g of cyclohexyloxycarbonate. NMR (200 MHz, CDCl^) 8.20 (1H, s, NH), 7.45 (1H, s, C6H) , 7.08 (1H, m, Cl'H), 6.30 (1H, m, C2'H), 5.85 (1H, m, C3'H), 4.05 (1H, m, C4fH), 4.6 (1H, m, CHO), 4.4 (2H, m, C5'CH2), 2.1-1.0 (13H, m, C5CH3 + cyclohexyl CH2). MS m/z (relative intensity) 351 (M+H, 55), 207 (50), 155 (40), 127 (50), 81 (100). IR (KBr) cm"1 2975, 1750, 1700, 1280, 1260. Anal, calculated C1?H22N206 C 58.27 H 6.33 N 8.00; found C 58.23 H 6.05 N 7.90.

Example 7: '-0-(1-Imidazoylcarbonyl)-2',3'-didehydro-2',3'-dideoxythymidine To a solution of 4.50 g (0.0201 mol) of d4T in 50 mL of DMF was added 5.67 g (0.035 mol) of carbonyldiimidazole. The reaction was stirred at 22°C for 45 minutes, during which time a thick white precipitate formed. The solid was collected and washed with 5 mL of DMF. The filtrate was 22 9 0 0 0 cooled to 0°C for 16 h, and the resulting solid collected and washed with cold DMF. The combined solid was dried in a vacuum dessicator for 16 h at 0.1 mm to give 5.50 g of imidazoate which contains about 5% imidazole (determined by NMR analysis). NMR (300 MHz, DMSO) 8.22 (1H, s, imid.

H), 7.55 (1H, s, imid. H), 7.11 (1H, s, imid. H), 7.11 (1H, s, C6H), 6.77 (1H, d, J=1.9 Hz, Cl'H), 6.49 (1H, d, J=6.0 Hz C2'H), 6.04 (1H, d, J=5.9 Hz, C3'H), 5.02 (1H, s, C4'H), 4.5 (2H, m, C5'CH2), 1.53 (3H, s, C5CH3).

MS m/z (relative intensity) 319 (M+H, 100), 207 (10), 149 (20), 127 (20), 81 (25). IR (KBr) cm'1 3085, 1760, 1700, 1690, 1670, 1415, 1260.

Example 8 '-0-Benzoyl-2'# 3'-dihydro-2',3'-dideoxy-4-thio-thymidine A suspension of 5-0-benzoyl-2',3'-didehydro-23'-dideoxythymidine (12.6 g, 38.45 mmoles) and 2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane-2,4-di sulfide (Lawesson's reagent) 10.87 g, 26.9 mmoles) in chloroform (270 mL) was heated to reflux for 4 h. The homogeneous reaction mixture was concentrated and purified by flash column chromatography using methylene chloride/ethyl acetate (9:1) as eluent. The product was collected as a solid (10.56 g, 80%). Mp 171-173°C. 1H NMR (300 MHz, dg-DMSO) 12.76 (s, 1H, NH), 7.90 (d, 2H, .ortho Ph), 7.64 (t, 1H, para Ph), 7.50 (t, 2H, meta Ph), 7.22 (s, 1H, H6), 6.74 (d, 1H, HI1), 6.52 (d, 1H, H3'), 6.04 (d, 1H, H2'), 5.12 (s, 1H, H4'), 4.45 (m, 2H, H51 ) and 1.53 (s, 3H, CH3).

Anal. Calc. for C17H16N204S: C, 59.29; H, 4.69; N 8.14. Found: C, 59.15; H, 4.64; N. 8.10. 22 9 0 0 0 Example 9 2' , 3 '-Didehydro-2',3'-dideoxy-4-thio-thymidine A solution of 5'-0-benzoyl-2',3'-didehydro-23'-dideoxy -4-thio-thymidine (3.09 g, 9 mmole) in anhydrous methanol (145 mL) was warmed and sodium methoxide (0.54 g, 10 mmole) was added. The solution was heated to reflux for 30 min. The pH of the solution was monitered and kept at pH 8. The reaction mixture was allowed to cool and then concentrated. The product was purified by flash column chromatography, using methylene chloride/methanol (4:1) as eluent. The product was collected as a solid (2.1 g, 99%). Mp 127-129°C. 1H NMR (300 Mhz, dg-DMSO) 12.7 (s, 1H, NH), 7.8 (s, 1H, H6), 6.76 (m, 1H, HI')/ 6.38 (m, 1H, H3' ), 5.90 (m, 1H, H2 ' ), 5.03 (t, 1H, OH), 4.77 (s, 1H, H4'), 3.58 (m, 2H, H5') and 1.88 (s, 3H, CH3).

Anal. Calc. for C10H12N203S: C, 47.83; h, 5.03; N, 11.16; Found: C, 48.16; H, 5.33; N, 11.08.

Example 10 '0-Benzoyl-2',3'-didehydro-2',3'-dideoxyuridine 2',3'-Didehydro-2'3,'-dideoxyuridine (10 g, 47.6 mmol) in pyridine (250 mL) was treated with benzoyl chloride (68.1 mmol, 9.5 g, 7.9 ml) at 50-55°C, and the reaction stirred for 5 h. The pyridine was then removed by azeotropic distillation with toluene. The residue was dissolved in water and extracted out with ethyl acetate. This solution was then concentrated down to give the product (14.7 g, 95%). The compound was used in the following reaction without further purification. ^H NMR (300 MHz, d^-DMSO) 7.5-8.0 (m, 5H, aromatic), 7.35 (d, 1H, J=7.5 HZ, H-6), 6.8 (s, 1H, H-1'), 6.5 (d, 1H, H-3'), 6.05 d, 1H, H-2'), 5.15 (d, 1H, J - 7.5Hz, H-5), 5.1 (m, 1H, H-4'), and 4.5 (m, 2H, H-5' ) . 22 9 0 0 0 Example 11 '-O-Benzoyl-2',3'-didehydro-2', 3'-dideoxy-4-thio-uridine 5'-O-Benzoyl-23'-didehydro-23'-dideoxyuridine (15 g, 47.78 mmol) in chloroform (250 mL) was treated with Lawesson's reagent (23.89 mmol, 9.67g). The reaction mixture became homogenous after 10 minutes at reflux and was then heated at reflux for 6.5 h. The mixture was then concentrated using a stream of dry N2. The residue was purified by flash column chromatography using methylene chloride/ethyl acetate (9:1) as eluent. The desired product was isolated as a bright yellow solid (9.8 g, 60%); mp 128-129°C; ^ NMR (300 MHz, dg-DMSO) 7.90 (d, 2H, HI, H6 aromatic), 7.67 (T, 1H, H4 aromatic), 7.53 (t, 2H, H3, H5 aromatic), 7.27 (d, 1H, J=7.5 Hz, H6), 6.77 (s, 1H, HI'), 6.55 (d, 1H, H3'), 6.05 (d, 1H, H2'), 5.85 (d, 1H, J -7.5Hz, H5), 5.15 (s, 1H, H4'), 4.46 (m, 2H, H5'); 13C NMR (75 MHz, dg-DMSO) 190.49 (C4), 165.55 (C=0), 148.03 (C2), 133.68, 129.40, 129.26, 128.95 (aromatic), 135.66 (C6), 134.08 (C3'), 126.50 (C2'), 112.72 (C5), 90.20 (CI'), 84.56 (C4'), 65.26 (C5'); IR (KBr) cm-1 3350-3150, 3150-2800, 1725, 1615, 1470; MS m/z (relative intensity) 331 (M+H, 2.5), 283 (3.25), 129 (100), 81 (42).

Anal. Calc. ci6Hl4N2°4Sl C 58-i"7 H 4-27 N 8*48 Found: C 57.44; H 4.03; N 8.38; K.F. = 2.18% Example 12 '-O-Benzoyl-2',3'-didehydro-21,3'-dideoxycytidine 5'-O-Benzoyl-2',3'-didehydro-2',3'-dideoxy-4-thio-uridine (1 g, 2.9 mmole) was treated with methanolic ammonia (20 mL) in a metal bomb at 100°C for 1 h. The reaction mixture was concentrated and the residue purified by flash column 22 9 0 0 chromatography eluting with 10% MeOH/Cf^C^- NMR (300 MHz, dg-DMSO) 7.93 (d, 2H, ortho Ph), 7.68 (t, 1H, para Ph), 7.54 (t, 2H, meta Ph), 7.34 (d, 1H, H6), 7.18 (d, 1H, NH), 6.89 (s, 1H, HI'), 6.44 (d, 1H, H3'), 6.00 (d, 1H, H2'), 5.42 (d, 1H, H5), 5.09 (br s, 1H, H4'), 4.47 (m, 2H, H5'); 13C NMR (75.5 MHz, dg-DMSO) 165.66, 154.35, 140.79, 133.58, 132.73, 129.39, 129.18,. 128.83, 127.79, 94.34, 90.01, 83.73, 65.48.

Anal. Calc for C16H15N304.0.5H20: C, 59.61; H, 4.69; N, 13.03.

Found: C, 59.68; H, 5.10; N, 12.49.

Example 13 '-(3-Pyridinylcarbonyl)-2',3'-didehydro-2',3'-dideoxythymidine Under an atmosphere of nitrogen, to a stirred solution of 0.92 g (4.10 mmol) of d4T in 15 mL of dry pyridine was added 0.95 g (5.34 mmol) of nicotinyl chloride hydrochloride. The reaction was placed in an oil bath and heated at 70 °C for 3 h. The reaction was cooled and the solvents were removed under a gentle stream of nitrogen at 22 °C for 16 h. The crude residue was purified on a 50 mm flash column, eluting with 5%Me0H/CH2Cl2• The appropriate fractions were combined and evaporated to constant weight to give 1.07 g (79%) of 5*-(3-Pyridinylcarbonyl)-2',3'-didehydro-2 3 ' -dideoxythymidine . Mp. 179-181 °C. *H NMR (CDC13; 300 MHz) 9.20 (1H,d,J=2.2.H2''), 8.80 (lH,dd,J=6.9,1.7,H6''), 8.52 (1H,br s,NH), 8.25 (lH,m,H4'')# 7.39 (1H,m,H5''), 7.02 (lH,s,H6), 6.97 (lH,m,Hl'), 6.37 (lH,m,H3'), 5.93 (lH,m,H2'), 5.15 (lH,m,H4'), 4.57 (2H,d, J=3.7,H5'), 1.58 (3H,d,J=2.3,CH3). 22 9 0 0 0 '-(l-Methyl-3-pyridiniumcarbonyl)-2 ',3 '-didehydro-2',3' -dideoxythymidine To a suspension of 5'-(3-Pyridinylcarbonyl)-23'-dide-hydro-23'-dideoxythymidine (0.85 g, 2.6 mmol) in 30 mL of acetone was added 1.5 mL (24 mmol) of methyl iodide. The mixture was refluxed for 24 h, cooled, and the solvents were removed under a gentle stream of nitrogen to afford 1.16 g of a bright yellow solid of 5'-(l-methyl-3-pyridinium-carbonyl)-2',3'-didehydro-2',3'-dideoxythymidine. NMR (DMSO; 300 MHz) 9.51 (lH,s,H2"), 9.15 (1H, d, J=6. 0, H6 " ), 8.92 (lH,d,J=8.1,H4" ), 8.22 (1H,dd,J=7.8,6.2, H5 " ), 7.21 (1H,s,H6), 6.80 (1H,t,J=1.9,HI'), 6.51 (1H,d,J=6.1,H3'), 6.05 (1H,d,J=6.0,H2'), 5.10 (lH,br s,H4'), 4.55 (2H,m,H5'), 4.39 (3H,s,Nl"CH3), 3.28 (1H, s, exchangable, NH), 1.58 (3H,s,C5CH3) . '-(1,4-Dihydro-l-methyl-3-pyridinylcarbonyl)-2',3'-didehydro-2 ',3'-dideoxythymidine In a 250 mL round bottomed flask flushed with nitrogen and externally cooled in an ice bath was added solid 5'-(l-Methyl-3-pyridiniumcarbonyl)- 2',3'-didehydro-2',3'--dideoxythymidine (1.03 g, 2.19 mmol), sodium hydrosulfite (1.90 g, 10.9 mmol), and sodium bicarbonate (0.92 g, 10.9 mmol). To this stirred mixture was added 100 mL of 4 °C water which had been deaerated by bubbling nitrogen through the solution for 15 min. The ice bath was removed from the flask and the reaction was stirred for 20 min. The resulting solid was collected, washed with cold, deaerated water, and dried with suction for 5 min. The slightly yellow, wet solid was dried under vacuum for 12 h to give 0.53 g of 5'-(1,4-Dihydro-l-methyl-3-pyridinylcarbonyl)-2',3' -didehydro-2',3'-dideoxythymidine. Mp. 145-147°C. ^H NMR 22 9 0 0 0 (DMSOdg; 300MHz) 7.12 (lH,s,H6), 7.00 (1H,s,H1'), 6.75 (1H,m,H2''), 6.38 (lH,d,J=5.9,H3'), 5.94 (1H,d,J=6.0,H2'), 5.79 (1H,d,J=8.2,H6''), 4.92 (lH,br s,H4'), 4.69 (1H,dt,J=8.1,3.2,H5''), 4.18 (2H,m,H5'), 2.89 (5H,s, H4"+N1"CH3), 1.72 (3H, s,C5CH3) . 22 9 0 0 0 Antiviral Assays The anti-HIV/LAV activity of several compounds 4 representative of this invention and of d4T for comparison was measured in cultures of CEM-F cells. The results are set forth in the table below. The CEM cells were infected with approximately 30 tcid^q (50% tissue culture infectious dose) of HIV (LAV strain). The cells were then incubated for 45 min 37°C. The test compounds, in culture medium, were added at various concentrations to the infected cells and then incubated for a further 8 days. After 8 days the antiviral activity was evaluated in the culture media supernatant for p-24 gag protein by an enzyme capture assay (ELISA). The antiviral activity was expressed as the dose which inhibits 50% of the virus expression (id^q in yM) as detected by the assay described.

Antiviral Activity Example *P5Q (yM) 1 3.2 3 0.4 4 4.8 3.2 6 0.6 8 0.5 11 0.5 12 0.1 d4T 0.2 22 9 References (a) Barre-Sinoussi, F; Chermann, J.C.; Rey, R.; Nugeyre, M.T.; Chamaret, S.; Gruest, C.; Dauguet, C.; Axler-Blin, C.; Rouzioux, C.; Rozenbaum, W. ; Montagnier, L. Science (Washington, D.C. ) 1983, 220, 868-871. (b) Broder, S.; Gallo, R.C. N. Engl. J. Med. 1984, 311, 1292-1297. (c) Broder, S; Gallo, R.C. Annu Rev. Immunol. 1985, 3^ 321-336.

Popovic, M.; Sarngadharan, M. G.; Read E.; Gallo, R. C Science (Washington D. C.V 1984, 224, 497-500. (b) Gallo, R. C.; Sarngadharan, M. G.; Popovic, M.; Shaw, G. M.; Hahn, B.; Wong-Stahl, F.; Robert-Guroff, M.; Salahaddian, Z., Markham, P.D. Prog. Allergy 1986, 37, 1-45.

Fischl, M. A.; Richman, D. D.; Grieco, M. H.; Gottlieb M. S.; Volberding, P. A.; Laskin, 0. L.; Leedom, J. M. Groopman, J. E.; Mildvan, D.; Schooley, R. T.; Jackson G.G.; Durack, D. T.; King, D. New Engl. J. Med., 1987, 317, 185.

Mitsuya, H.; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 1911-1915. (a) Lin, T. S.; Shinazi, R.; Chen, M. S.; Kinney-Thomas, E.; Prusoff, W. H. Biochem. Pharmacol. 1987, 36, 311. (b) Balzarini, J.; Pauwels, R.; Herdewijn, P.; De Clercq, E.; Cooney, D. A.; Kang, G-J.; Dalai, M.; Johns, D.G.; Broder, S. Biochem. Biophys. Res. Comm. 1986, 140, 735.

Cheson, B. D.; Levine, A. D.; Mildvan, D,; Kaplan, L. D.; Wolfe, P.; Rios, A.; Groopman, J.; Gill, P.; Volbdering, P. A.; Poiesz, B. J.; Gottlieb, M. S.; Holden, H.; Volsky, D. J.; Silver, S. S.; Hawkins, M. J. J. Amer. Med. Assoc. 1987, 258, 1347. 22 9 0 0 0 7. (a) Balzarini, J.; Mitsuya, H.; De Clercq, E.; Broder, S. Int. J. Med., 1986, 32, 451. (b) McCormick, J.B.; Getchell, J.B.; Mitchell, S. W.; Hicks, D. R. Lancet 1984, ii, 1367. 8. (a) Sarin, P. S.; Taguchi, Y.; Sun, D.; Thornton, A. ; Gallo, R.C.; Oberg, B. Biochem. Pharmacol. 1985, 34, 4075. (b) Sandstrom, E. G.; Kaplan, J. C.; Byington, R. E.; Hirsch, M. s. Lancet 1985, 480. 9. Lane, H.C.; Fauci, A. S. Ann. Intern. Med. 1985, 103, 714.

. Chandra, P.; Sarin, P.S. Arznrim-Forsch/Drug Res. 1986, 36, 184. 11. Tyms, A.S.; Berrie, E.M.; Ryder, T. A.; Nash, R. J.; , Hegarty, M. P.; Taylor, D. L.; Mobberley, M. A.; Davis, J. M.; Bell, E. A.; Jeffries, D. A.; Taylor-Robinson, D. ; Fellows, L. E. Lancet 1987, _ii_, 1025. 12. Faber, V.; Newell, A.; Dalgleish, A. G.; Malkovsky, M. Lancet 1987, ii, 827. 13. (a) Hartmann, H. ; Hunsmann, G.. ; Eckstein, F. Lancet 1987, i., 40. (b) Baba, M. ; Pauwels, R. ; Balzarini, J.; Herdewiijn, P.; De Clercq, E. Biochem. Biophys. Res. Comm. 1987, 145. 1080. 14. (a) Herdewijn, P.; Balzarini, J.; De Clercq, E.; Paules, R.; Baba, M.; Broder, S.; Vanderhaeghe, H. J. Med. Chem. 1987, 30, 1270. (b) Mattes, E.; Lehmann, C.; Scholz, D.; von Janta-Lipinski M.; Gaertner, K.; Rosenthal, H. A.; Langen, P. Biochem. Biophys. Res. Comm. 1987, 148, 78. (c) Polski, B.; Gold, J. M. W.; Hardy, W.D.; Baron, P.A.; Zuckermann, E.E.; Chou, T-C.; Levine, S.M.; Flomenberg, N.; Wang, L.; Watanabe, K.

A.; Fox, J. J.; Armstrong, D. 27th ICAAC 1987, Abstract 368, pl61. . (a) Lin, T. S.; Chen, M. S.; Gao, Y-S.; Ghazzouli, I.; Prusoff, W. H. J. Med. Chem. 1987, 30, 440. (b) Lin, T. S.; Shinazi, R. F.; Prusoff, W. H. Biochem. 229000 Pharmacol. 1987, 17., 2713. (c) Baba, M. ; Pauwels, R.; De Clercq, E.; Desmyter, J.; Vandeputte, M. Biochem. Biophys. Res. Comm. 1987, 142, 128. (d) Balzarini, J.; Kang, G-J.; Dalai, M.; Herdewjin, P.; De Clercq, E.; Broder, S.; Johns, D. G. Mol. Pharmacol. 1987, 32, 162. (e) Hamamoto, Y.; Nakashima, H.; Matsui, T.; Matsuda, A.; Ueda, T.; Yamamoto, N. Amtimicrob. Agents Chemother. 1987, 31., 907. 16. Horwitz, J.; Chua, J. in "Synthetic Procedures in Nucleic Acid Chemistry" (Vol. 1), Zorbach, W. W.; Tipson R. S. (eds); Interscience, New York, p. 344. 17. Horwitz, J.; Chua, J.; Da Rooge, M. A.; Noel, M.; Klundt, I. L. J. Org. Chem. 1966, 3_1, 205. (followed by page 30a)

Claims (1)

1. TfiBLE 1 229000 7 8 10 11 IS 13 exfirtple rl r* r* 1 chj oh ch3 8 cahs oh chj 3 ch5o oh chj A <chj>jc oh ch, 5 chjochi oh ch, 6 O oh chj \=J c€h6 c4h8 c4h8 c4h5 or N 6h$ oh sh oh sk nhe oh chj chj h h h chj 30a N.Z, PATENT OFFICE -6 nov iyyu RECEIV-l (followed by page 31) 22 9®©0 WHAT ifyWE CLAIM fS:- What ia claimed: 1. A compound having Formula I b ro ( i ) wherein R is selected from H and a physiologically hydrolyzable ester group consisting of alkanoyl, cycloalkanoyl, cycloalkylalkanoyl, alkenoyl, cycloalkylalkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl groups wherein the alkanoyl, cycloalkanoyl, cycloalkylalkanoyl, alkenoyl, and cycloalkylalkenoyl each have up to 20 carbon atoms and 1 or 2 optional substituents selected from halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano, and the aroyl, aralkanoyl, and aralkenoyl, each have up to 20 carbon atoms including from 6 to 10 carbon atoms in the aryl portion each aryl portion having optional substituents selected from 1 to 3 alkyl groups, hydroxy, alkoxy, halo, amino, alkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano; 22 9 0 00 B is a nitrogen heterocycle attached through a ring nitrogen atom thereof and selected from 9-purinyl of Formula II and 1-pyrimidinyl of Formula III R 1 <H) (III) wherein 1 2 R and R are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, amino, alkylamino, dialkylamino, alkoxy, and cyano and each of said alkyl and alkoxy groups has from 1 to 3 carbon atoms, 3 R is hydroxy, amino, or sulfhydryl, R^ is hydrogen, hydroxy, sulfhydryl, or amino, and R^ is hydrogen, alkyl, C^^alkenyl, C2_3 haloalkenyl having 1 to 5 halogen atoms, C2_^ alkynyl, alkoxy, cyano, fluorine, chlorine, bromine, or iodine provided that when B is thymine R is other than acetyl, and when B is uridine R is other than benzoyl, and when R is H, then B is a pyrimidine of Formula III wherein R^ is hydrogen or sulfhydryl. - 32 - 229000 A compound of Claim 1 wherein R is hydrogen. A compound of Claim 1 wherein R is other than hydrogen. A compound of Claim 3 wherein B is the purinyl group of Formula II. A compound of Claim 3 wherein B is the pyrimidinyl group of Formula III. A compound according to Claim 3 wherein R is selected from the group consisting of CH3C(0) (acetyl), CgHgC(O) (benzoyl), (CH3)3CC(0) (pivaloyl), CH30CH2C(0) (methoxyacetyl), C?H15C(0) (heptyl), C15H31C(0) (palmityl), CH30C(0) (methoxycarbonyl), C8Hi70C(0) (n-octyloxycarbonyl), c-CgH^OC(O) (cyclohexyloxycarbonyl) , (CH3)3C0C(0) (t-butoxycarbonyl), Im-C(O) (imidazolylcarbonyl), and (1,4-dihydro-l-methyl-3- pyridinylcarbonyl 220000 7. a compound according to Claim 5 wherein B is selected from the group consisting 5-methyl-2,4-dihydroxypyrimidine (thymine), 2-hydroxy-4-aminopyrimidine (cytosine), and 2,4-dihydroxypyrimidine (uracil). 8. a compound according to Claim 7 wherein B is 5-methyl-2,4-dihydroxypyrimidine. a compound according to Claim 7 wherein R is selected from the group consisting of CH3C(0) (acetyl), C6H5C(°) (benzoyl), (CH3)3CC(0) (pivaloyl)/ CH30CH2C(0) (methoxyacetyl), CH30C(0) (methoxycarbonyl), C8Hi70C(°) (n-octyloxycarbonyl), C-C6H110C(0) (cyclohexyloxycarbonyl), Im-C(O) (imidazolylcarbonyl)• arid L 10. A compound as claimed in claim 1 and specifically v identified in this specification with reference to any one of examples 2 to 9 and 11 to 13. 11. A process for producing a compound as claimed in claim 1, substantially as described in this specification with reference to any one of examples 2 to 9 and 11 to 13. - 34 - 229000 12„ a process for producing * compound of Formula I wherein R la a physiologically hydrolyzable aitar group, and B is a purine or pyrimidine base excepting thymine when R la acetyl, and.uridine when R ia benzoyl which comprises reacting the compound corresponding to Formula I wherein R ie H with the appropriate acyl anhydride or acyl halide required to provide the R group under reaction conditions known to be suitable for introducing • r hydroxy-protecting groups. The process of Claim 12 wherein acetyl chloride la said acyl halide. 14.- The process of Claim 12 wherein benzoyl chloride is » said acyl halide. 15.. The process of Claim 12 wherein said acyl anhydride is di(l-lmldasolyl)carbonyl and the compound produced has Formula I wherein R la 1-imidarolylcarbonyl. (I) 35 -6 NOV 1930 229000 16. The process of claim 15 further comprising the additional step of reacting the compound produced therein with an alkanol or cycloalkanol thereby producing a compound of Formula I wherein R is an alkoxycarbonate or cycloalkoxycarbonate group. 17. The process of Claim 16 wherein methanol is said alkanol. 18. The process of Claim 16 wherein cyclohexanol is said cycloalkanol. 19. A process for preparing a compound of the formula 3 6 in which R and R are as defined in claim 1, which comprises reacting the ester of Formula I as defined in claim 12 wherein B is a pyrimidine base of the formula oh L in which R3 and R6 are as defined in claim 1 with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphot2ne-2,4-disulfide (Lawesson's reagent), and thereafter hydrolyzing said hydrolyzable ester group. - 36 - 229000 20. A compound of the formula I whenever prepared by a process according to any one of claims 11 to 19. 21. A pharmaceutical composition comprising an antiviral effective amount of a compound of any one of claims 1 to 10 and 20 and a pharmaceutically effective carrier therefor. 22. A pharmaceutical composition according to claim 21 wherein the compound has the formula and wherein.R is selected from CH3~, CH-^OCH^-, 23. A method for reducing the infectivity of the human immunodeficiency virus by contacting in vitro said virus with an antiviral effective amount of a compound according to any one of claims 1 to 10 and 20. 0 I