USE OF 2-BETA-D-RIBOFURANOSYLTHIAZOLE-4-CARBOXAMIDES FOR THE MANUFACTURE OF MEDICAMENTS INHIBITING MALIGNANT TUMORS

Abstract: The compound 2-β-D-ribofuranosylthiazole-4-­ carboxamide has been found to be effective in the treatment of malignant tumors in warm blooded animals, as have esters of this compound, for instance 2-(2,3,5-tri-O-acetyl-β-­ D-ribofuranosyl)-thiazole-4-carboxamide and 2-(5-O-­ phosphoryl-β-D-ribofuranosyl)-thiazole-4-carboxamide. Dis­ closed also are pharmaceutical compositions containing 2-β-D-ribofuranosylthiazole-4-carboxamide or a related com­ pound as the active ingredient; as well as processes for producing the novel compounds and compositions.

Description: 2-ss-D-RIBOFURANOSYLTHIAZOLE-4-CARBOXAMIDE AND RELATED COMPOUNDS AS AGENTS FOR INHIBITING MALIGNANT TUMORS, PHARMACEUTICAL COMPOSITIONS CONTAINING SUCH COMPOUNDS, AND PROCESSES FOR PRODUCING SUCH COMPOUNDS AND COMPOSITIONS This invention relates to the compound 2-ss-D-ribofuranosylthiazole-4-carboxamide and related compounds (such as esters) as agents for inhibiting malignant tumors, pharmaceutical compositions containing such compounds, and processes for producing such compounds and compositions. Complete control of malignant tumors in man and other warm blooded animals still remains an unrealized goal. Within the last few decades, understanding of malignancy has made significant progress; however, conquest of the malignant disease state has not been realized. Conventional therapy of both humans and other valuable animal species inflicted with malignant tumors presently includes surgical excision of the tumor, local radiation therapy of the afflicted patient, and chemotheraphy by administration of Åa chemotherapeutic agent to the patent. The death of a significant number of patients inflicted with malignant tumors is attributable not to the primary tumor but instead to metastasis.of the primary tumor to secondary sites in the host. If a primary tumor is detected early, it can normally be eliminated by surgery, radiation or chemotheraphy or combinations of these. The metastatic colonies of these primary tumors, however, are considerably harder to detect and eliminate, and the unsuccessful management of them remains a serious medical problem. Tumors are normally classified either as benign or malignant. The malignant tumor is distinguished from the benign by its ability to invade both surrounding tissue and to colonize distant sites via metastisis. Certain organs are more prone to metastisis than others, and included in this group are the lung, the brain, the liver, the ovaries and the adrenal glands. It has further been suggested that both surgery and radiation of a primary tumor in certain instances actually promotes metastasis. In view of the inability of current cancer therapy to control successfully the malignant tumor and its metastisis, it is evident that there exists a need for additional chemotherapeutic agents. In a paper entitled Synthesis and Antivial Activity of Certain Thiazole C-Nucleosides, j. Med.Chem. 1977, Volume 20, No. 2,256, Professor R.K. Robins et al disclosed the synthesis of, and certain preliminary in vitro antiviral activity of, the compounds 2-ss-D-ribofuranosylthiazole-4-carboxamide (sometimes hereinafter referred to as the "parent compound") and 2-(2,3,5-tri-O-acetyl-ss-D-ribofuranosyl) thiazole-4-carboxamide. These two compounds were used in an in vitro test system utilizing three viruses, namely type 1 herpes simplex virus, type 3 parainfluenza virus and type 3 rhinovirus. The in vitro activity of the compound 2-ss-D-ribofuranosylthiazole-4-carboxamide against these three viruses was only moderate. With the compound 2-(2,3,5-tri-O-acetyl-ss-D-ribofuranosyl) thiazole-4-carboxamide, only moderate activity was seen with type 1 herpes simplex virus whereas with the type 3 parainfluenza virus and the type 13 rhinovirus the activity was negative. While, as indicated, certain marginal in vitro antiviral activity was observed, then, quite to the contrary, in vivo antiviral testing for both 2-B-D-ribofuranosylthiazole- 4-carboxamide and 2-(2,3,5-tri-O-acetyl-ss-D- ribofuranosyl)thiazole, as judged by the number of test animal deaths, was negative. In the in vivo tests, the number of deaths for the test animals for both the 2-ss-D-ribofuranosylthiazole-4-carboxamide and 2-(2,3,5-tri-O-acetyl-ss-D-ribofuranosyl)thiazole- 4-carboxamide equalled or exceeded the number of deaths of the placebo control animals indicating that both of the compounds 2-B-D-ribofuranosylthiazole4-carboxamide and 2-(2,3,5-O-acetyl-ss-D-ribofuranosyl) thiazole-4-carboxamide demonstrated no useful in vivo antiviral activity. With regard to the above noted in vitro antiviral testing for both 2-B-D-ribofuranosylthiazole-4carboxamide and 2-(2,3,5-tri-O-acetyl-ss-D-ribofuranosyl) thiazole-4-carboxamide, these compounds were tested against viruses for which the known antiviral compound Ribavarin (registered Trade Mark) is known to have positive antiviral activity. In view of the preliminary marginal in vitro activity of 2-ss-D-ribofuranosylthiazole- 4-carboxamide against these test viruses, it was expected that the spectrum of activity of 2-B-D-ribofuran- osylthiazole-4-carboxamide would be similar to the spectrum of activity of the compound Ribavarin. Ribavarin is known to be an active in vitro antiviral agent and in vivo anti viral agent and is further known to exhibit no significant antitumor activity. Additionally, certain derivatives of Ribavarin, such as its 5'monophosphate, are also known to be inactive as antitumor compounds. It was reasonable to expect, in comparing the preliminary in vitro antiviral activity of 2-ss-D-ribofuranosylthiazole-4-carboxamide with that of Ribavarin, that 2-B-D-ribofuranosylthiazole- 4-carboxamide would exhibit positive in vivo antiviral activity and negative antitumor activity similar to Ribavarin. Totally contrary to expectations, the compound 2-ss-D-ribofuranosylthiazole-4-carboxamide possessed no useful in vivo antiviral activity and, quite unexpectedly, has demonstrated positive antitumor activity. Thus, a basis of the present invention is the discovery that the compound 2-B-D-ribofuranosylthiazole- 4-carboxamide and its esters, including 2-(2,3,5- tri O-acetyl-ss-D-ribofuranosyl)thiazole-4-carboxamide and 2-(5-O-phosphoryl-ss-D-ribofuranosyl)thiazole- 4-carboxamide, exhibit anti tumor activities of such significance as to be useful as anti tumor agents in vivo. According to one aspect of the present invention there is provided as an agent for use in inhibiting a malignant tumor in a warm blooded animal, a compound having the following general formula: EMI4.1 wherein each of R1 and R2, which are the same or different, is a hydrogen atom or a C1 18 acyl radical, and R is a hydrogen atom, a C1 18 acyl radical or EMI4.2 or a physiologically acceptable salt thereof. According to a preferred aspect of the present invention there is provided as an agent for use in inhibiting a malignant tumor in a warm blooded animal, a compound having the following general formula: EMI5.1 where each of R1 and R2, which are the same or different, is a hydrogen atom or a C1 8 acyl radical, and R3 is a hydrogen atom, a C1 8 acyl radical or EMI5.2 or a physiologically acceptable salt thereof. Another aspect of the present invention provides novel compounds having the following general formula: EMI5.3 where each of RÚ and Rê, which are the same or different, Is a hydrogen atom or C1-18 acyl radical, and R is a hydrogen atom, a C1-18 acyl radical or EMI5.4 with the proviso that not all of R1, R2 and R3 are simultaneously all hydrogen atoms or all acetyl radicals; or a physiologically acceptable salt thereof. -6 Preferably, when any of R1, R2 and R3 is an acyl radical, that radical is a C1 8 acyl radical. Conveniently at least one of the radicals R1, R2 and R3 is a benzoate ester radical. The present invention also provides 2-(5-O phosphoryl-ss-D-ribofuranosyl)thiazole-4-carboxamide or a physiologically acceptable salt thereof. A further aspect of the present invention provides an antitumor composition suitable for use in the treatment of a malignant tumor in vivo containing in addition to a physiologically acceptable carrier and as an active ingredient an effective amount of a compound selected from 2-B-D-ribofuranosylthiazole- 4-carboxamide, ester derivatives of 2-B-D-ribofuran- osylthiazole-4-carboxamide, and physiologically acceptable salts thereof. The active compound in the composition may be 2-ss-D-ribofuranosylthiazole-4-carboxamide; or an acyl derivative thereof, for instance where the acyl ester is an acetate ester or benzoate ester; or a phosphoryl ester thereof. The present invention also provides a process for producing a compound having the following general formula: - EMI6.1 wherein R3 is a C1-18 acyl radical or EMI6.2 which process comprises reacting the compound 2-ss-D-ribofuranosylthiazole-4-carboxamide in the presence of a base with a compound selected from an acyl anhydride and an acyl chloride. Conveniently the acyl anhydride is a carboxylic acid anhydride or phosphate acid anhydride and the acyl chloride is a carboxylic acid chloride or phosphoric acid chloride. The present invention further provides a process for producing 2-(5-O-phosphoryl-B-Dribofuranosyl)-thiazole-4-carboxamide, which process comprises reacting the compound 2-B-D-ribofuranosylthiazole- 4-carboxamide in the presence of a base with phosphoryl chloride in a polar solvent; and treating the reaction mixture with water and isolating the desired product. Conveniently the desired product is isolated by desalting the reaction mixture with activated charcoal and eluting the product out of the charcoal. The present invention additionally provides a process for producing an antitumor composition, which comprises incorporating the active ingredient (as indicated above) in a physiologically acceptable carrier. The compound 2-B-D-ribofuranosylthiazole-4- carboxamide has been shown to exhibit significant antitumor activity in vivo. The present invention relates to the use of this compound and certain related derivatives in treating malignant tumors in warm blooded animals. The anti tumor properties of 2-ss-D-ribofuranosylthiazole-4-carboxamide and its related esters may be utilized by administering to a warm blooded animal an effective amount of a pharmaceutical composition containing as the active compound at least 0.1 percent by weight, based on the total weight of the composition, of a compound of the following general formula: EMI8.1 wherein R1 R2 and R3 are as defined above, or a physiologically acceptable salt thereof. In a preferred group of active compounds R1 and R2 are H or C1 18 acyl and R3 is H, C1 18 acyl or EMI8.2 or a physiologically acceptable salt thereof. Specifically noted for R1, R2 and R3 as preferred acyl groups are acetyl, propionyl, butyl, isobutyl and benzoyl. Specifically noted as acceptable salts are the alkali metals and ammonium or substituted ammonium salts such as sodium, potassium and ammonium salts. Preferably, when R1 and R2 are H, R3 is H, C1-18 acyl or EMI8.3 and, when R1 and R2 are C1-18 acyl, R3is C1-18 acyl. For use in the pharmaceutical composition of the present invention, a pharamceutical carrier would be utilized such that, preferedly, the pharamceutical carrier would be chosen to allow administration of a suitable concentration of the active compounds of the present invention as solutions or suspensions by injection into an afflicted warm blooded animal. Depending on the host harbouring the malignant tumor, the type of tumor, and the tumor site, administration by injection would be intraveneously, intramuscularly, intracerebrally, subcutaneously, or intraperitoneally. Alternatively, the composition of the present invention might suitably be formulated in appropriate pharmaceutical carriers allowing for administration by other routes such as oral administration, ophthalmic administration, topical administration or administration by suppository. The parent compound of the present invention, the compound 2-ss-D-ribofuranosylthiazole-4-carboxamide (which is also referred as Compound 1, as it is the product of Example 1), is preferredly prepared as described in the following Example 1. An alternative synthesis of this compound appears in J. Org. Chem. Vol. 41, No. 26, 1976, 4074, herein incorporated by reference. Certain esters of 2-B-D-ribofuranosylthiazole-4- carboxamide, Compound 1, such as 2-(2,3,5-tri-O-acetyl ss-D-ribofuranosyl)thiazole-4-carboxamide, Compound 2 or 2-(5-O-phosphoryl-3-D-ribofuranosyl)-thiazole-4carboxamide, Compound 3, are prepared as described in Examples 2 and 3 respectively, Additionally, other esters, such as the monoester 2-(5-O-acetyl-B-D- ribofuranosyl)thiazole-4-carboxamide, Compound 4, can be prepared as in the synthesis described in Example 4. For other preferred carboxylic esters of the present invention, substitution of acetic anhydride with a suitable anhydride such as propionic anhydride, butyric anhydride or benzoic anhydride is made. Alternatively, the. appropriate acid chloride could be substituted for the acid anhydride. The esters of Compound 1 can assist in delivery of the compound in an afflicted host. Such esters of the compound can be formed by reacting one or more of the hydroxyl groups of the sugar moiety of Compound 1 with suitable reversible blocking groups which could be cleaved in vivo from the parent Compound 1 by certain in situ chemical or enzymatic reactions. For reaction with the hydroxyl groups, esters such as, but not necessarily limited to, acyl and phosphoryl esters can be considered. The acyl groups can be those of acids selected from straight chain, branch chain, substituted, unsaturated, saturated or aromatic acids such as, but not necessarily limited to, acetic, trifluoroacetic, propionic, n-butyric, isobutyric, valeric, caproic, pelargonic, enanthic, capyrlic, lactic, acrylic, propargylic, palmitic, benzoic, phthalic, salicylic, cinnamic and naphthoic acids. If a phosphoryl group is chosen, the phosphoryl ester could be as a free acid or as a salt form. Acceptable salts of the phosphate moiety of the phosphoryl ester can be selected from, but not necessarily limited to, the group of. alkali metal and alkaline earth metal salts, e.g. sodium, potassium, calcium, magnesium, lithium, ammonium and substituted ammonium, trialkylammonium, dialkylammonium, alkylammonium, e.g. triethylammonium, trimethylammonium, diethylammonium, octylammonium, cetyltrimethylammonium and octylpyridium. As preferred agents in the form of esters of the present invention, Compounds 2, 3 and 4 are mentioned. In addition to these, other tri-O-acyl esters such as the 2',3', 5'-tri-O-benzoyl may be mentioned. Additionally, other mono-esters such as the 5'-O-benzoyl can be considered. Generally, for carboxylic esters the preferred esters would include C1 18 acyls, a more preferred group being C1 .8 acyls. Preferredly, when phosphoryl esters are utilized, the phosphate groups would be formed as a salt, preferredly as a sodium salt or other alkali metal salt or ammonium. Ester forms of Compound 1, as is shown in the examples herein, are useful in delivering the compound to the affected site in an affected host. As is shown in the examples, the-tri-acetyl ester, Compound 2, is indicated as being an effective antitumor agent when injected intraperitoneally into an affected host. The described tri-acetyl compound and any other acyl ester of Compound 1 would be expected to be hydrolyzed to Compound 1 in certain biological fluids such as the acid environment of the stomach or an environment which includes an appropriate enzyme capable of in vivo enzymatic cleavage of the ester to Compound 1. Without wishing to be bound by theory, if the phosphoryl ester of Compound 1, such as the 51-phosphate, were used, other enzymes present in vivo might also be expected appropriately to cleave enzymatically the phosphate to yield an in situ delivery of Compound 1. Compound 3, the phosphoryl ester of Compound 1, as is shown in the examples, is indicated as being an effective antitumor agent when injected in a effected host. At this time it is not known whether its activity is expressed as the 5'-phosphate or whether it is enzymatically cleaved to Compound 1. Further, it is possible that Compound 1 might be promoted in situ by other enzymatic reactions to Compound 3. In any event, both Compound 1 and Compound 3 are indicated as being effective in vivo antitumor agents as is indicated by the examples. In performing the present invention, Compound 1, or a selected ester form thereof, is appropriately mixed with a suitable pharmaceutical carrier which may be as simple as sterilized water or could be a complex carrier having appropriate agents suitably to mimic certain biological environments, i.e. a pH, and salt adjusted solution suitable for intraveneous, intramuscular or other injections. In selecting a suitable pharmaceutical carrier, consideration should be made to the type of tumor, the site of the tumor and the health and age of the host. Additionally, if an ester form of Compound 1 is used, consideration of the chemical reactivity of the ester should also take place. Thus, carboxylic acyl ester would preferredly be suspended or solubilized in an appropriate non-acidic medium. A phosphoryl ester might be appropriately used in the presence of a suitable buffer or as a salt as discussed above. Preferredly, Compound 1 or any of the other agents or compounds of the present invention, is mixed with an appropriate pharmaceutical carrier such that Compound 1 or a derivative thereof would be suitably soluble in the carrier. Alternatively, however, suspensions, emulsions and other formulations of the compounds of the present invention could be used where indicated. The pharmaceutical carrier, in addition to having a solubilizing or suspending agent therein, might also include suitable dilutants, buffers, surface active agents and other similar agents as are typically used in pharmaceutical carriers. The total composition of the pharmaceutical carrier would, however, be chosen to be compatible with the site of delivery, the concentration of the active ingredient and other parameters as are standard in pharmaceutical industry. Compound 1, or the other agents or compounds of the invention, would be suitably mixed with the pharmaceutical'carrier such that it would be present in a concentration of at least 0.1 percent by weight of the total composition. Preferredly, it would be present in the pharmaceutical carrier at a concentration of from 10% to 90% by weight of the total composition. Effective amounts of Compound 1 , or the other compounds of the present invention, typically range from about 2.5 milligrams per kilogram (mg/Kg) of the total body weight of the treated warm blooded animal to about 200 mg/Kg, per day. Preferredly, the range is from 12.5 mg/Kg to 100 mg/Kg, per day. An even more preferred range would be from 15 mg/Kg to 50 mg/Kg, per day. As with other factors noted above, the amount of compound utilized in treating an afflicted animal would take into account parameters such as the type of tumor, the tumor site, the form of administering the compound and the physical size and condition of the host. In any event, the actual amount should be sufficient to provide a chemotherapeutically effective amount of the agent to the host in a convenient volume, which will be readily within the ability of those skilled in the art to determine given the disclosure herein. In at least one study, Compound 1 of the invention has been injected at dosages up to 2000 mg/Kg into tumor-bearing animals and no deaths of the animals were attributed to the toxicity of Compound 1 on the toxicity day of the test. In a host which has been diagnosed as being terminally ill with a malignant tumor excessive amounts beyond any toxicity range might be indicated if there is any probability of cure of the terminally ill host as is commonly practised in current cancer chemotherapy. As in the examples used.for illustrative purposes below, a tumor bearing host was treated once daily with the indicated test compound. Depending upon the clinical situation, the daily dose of Compound 1 or any of the other compounds of the present invention, might be similarly given; however, the daily dose could also be broken up into sub-unit doses which, in their totality, equal the daily dose. Thus, for example, at a 50 mg/Kg dose level the patient might be appropriately treated four times a day with doses of 12.5 mg/Kg. A composition used for inhibiting malignant tumors in warm blooded animals might be suitably prepared by adding compound 1 or any of the other compounds of the invention, to a pharmacologically eompntible solvent followed by sterilization and packuging in nppro priatc sealnble vials at a known concentration Appropriate doses of the compound are then witl)drawn from the vial and administered by injection to the host. EXAMPLE 1 2-ss-D-Ribofuranosy) thiazole-4-Carboxamide, COMPOUND 1 Ethyl 2-(2,3,5-tri-o-benzoyl-@ D-ribofuranosyl) thiazole-4-carboxamide was utilized as prepared in Srivastova et. al, J. Med. Chem, 1977. Volume 20, No. 2, 256. herein incorporated by reference. A concentrated solution of ethyl 2-(2,3.5-tri-O-benzyl-ss-D-ribofuranosyl) thiazole-4-carboxamide (5.0 g, 8.31 mmol) in methanol (15 ml) was stirred with methanolic ammonia (saturated at 0 C, 100 ml) in a prcssure bottle at rcom temperature for 2 days. The solvent was evaporated and the residue was chromatographed through a column (2.5 x 35 cm) of silica gel (100 g) packed in ethyl acetate. Elution of the column with a solvent system (ethyl acetatc-1-propanolwater, 4:1:2; v/v; top layer) removed the fast-moving methyl benzoate and benzamide. The slower moving, major, UV and sugarpositive fractions were collected and the solvent was evaporated n vacuo. Tic residue (syrup), thus obtained, was readily crystallized from ethanol-ethyl acetate to provide 1.6 g (74 %) of pure product, compound 1 : mp 144-145 C; [&alpha;] 25 p-14.3 (c 1, DMF) ; UV@ amx pIll 237 nm ( 8640); UV max plIII 238 nm ( 8100); 1HNMR(Me2SO- @@@ 7.5 - 7.8 [S(or).Z,CONH2]1 hnmr (Me2SO-d6-D2O).f4.99' (d, 1, J - 5 Mz, H1'). 8.25 (s, 1, H5). Anal. (CgH12N205S) C, H, N, S. EXAMPLE 2 2-(2,3,5-Tri-O-Acciyl-ss-D-Ribofuranosyl) thinzolc-4-Carboxamide, COMPOUND 2 Acetic anhydride (2.0 ml) was added to an icc-cold solution of compound 1 (1.04 g, 4 mmol) in nnllydrous pyridine (16 nil) and the reaction solution was stirred nt room temperature for 17 h. The solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with water and dried (MgSO4). The ethyl acetate portion was cvaporatcd in vacuo and the residue thus obtained was crystalized from water to provide 1.4 g (90%) of compound 2 as white needles; mp 1030 C; 1H NMR (CDCl3) 2.1 (3 s, 9,tri-O-acetyl), 6.2 and 7.15 [pair of s(br), 2, CONH2l, 8.2 (s, 1, H5). Anol. (C15H18N2O8S) C,H,N,S. EXAMPLE 3 2-(6-O-Phosphoryl-ssD-Ribofuranosyl thinzole-4 Carboxamide (2-ss-D-Ribofuranosylthinzolo-4-Carboxamide 5'-Phospheic), COMPOUND 3 Water (151 mg, 8.4 mmol) was added carefully to a solution (maintained at 0 C with stirring) of freshly distillcd phosphoryl chloride (2.0 g, 13.2 mmol). pyeidine (1.21 g, 14.4 mmol) and ucolonitrile (2.3 g, 50.7 mmol). 2-ss-@-R@ofuranosylthiazole-4- carboxamide, compound 1, (dried over P205 and powdered, 800 mg, 3.0 mmol) was added to the solution and the reaction mixture was stirred continuously for 4 hrs at OOC. The reaction mixture was poured into ice water (ca. 50 ml) and the pH was adjusted to 2.0 with 2N sodium hydroxidc. The solution was applied to a column of activated charcoal (20 g), and the celumn was washed thoroughly with water until the eluate was salt-free. The column was cluted with a solution ethanol-water-concentraled ammonium hydroxide (10:10:1) and the fractions (25 ml each) were collected. The fructions containing ptire (tlc, silica gel. acctonitrile-0.1 N ammo niuln chloride (7:3)) nuelcotide, compound 3, were collected and evaporated to dryncss under vacuum. The anhydrotis residue was dissolved in water and pissed through n column of dowex 50 W-X@ (20-50 mesh, H+ form, 15 ml). The column was washed with water and the fractìbn containing the nuclcotide was collected. The solution was concentrated to a smnll volume (5 ml) and passed tlurouglt A column of Dowex 50W-X8 (20-50 mesh, Na+ form. 15 ml). The column was wasllcd with water. The nuclcotide containing fraction was lyophilized. The residuc was triturated with ethanol. collected by filtration and dried (P205), to provide 560 mg (47%) of compound 3 as monosodium dihydrate in the crystalline form. Anal. each. for C9H12N2O8PSNa.2H2O : C, 27.13; H. 4.04; N, 7.04; P, 7.78; S, 8.05. Found: C, 27.42; H, 3.87; N, 7.07 ; P. 8.03; S, 8.41. EXAMPLE 4 2-(5-O-Acetyl-ss-D-Ribofuranosyl) thiazole-4-carboxamide COMPOUND 4 A solution of 2-(2,3-O-isopropylidene- /; -D-ribofuranosyl) thie- zole-4-carboxamide (1.5 g, 5 mmol) (prepared as per Fucrtes, et al, J. Org. Chem., Volume 41, NO. 26, 3976, 4074) in anhydrous pyridine (20 ml) was chilled in an ice-water bath and acetic anhydride (2.5 ml) was slowiy added with stirring. The rcaction solution was sllowed to warm to room temperature and stirring was continued for 15 h. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with water. The ethyl acetate portion was evaporated in vacuo and the residue was dissolved in 80 % acetic acid (25 ml). The solution was heated on a steam bath for 30 mins. and the solvent evaporated in vacuo. The residue was dissolved in ethyl acetate, washed once with water and dried over Mg SO4. The ethyl acetate portion was evaporated and the crude product was passed through a column of silica gel (100 g, packed in chloroform) and eluted with 20 (V/V) ethyl acetate in chloroform. The nucleoside bearing fractions were pooled and evaporated to yield 1.05 g (70 %) of compound 4. (C111{14N2065). As illustrative examples of the use of compound 1 and other illustrative compounds of the invention, examples 5 through 12, below, are given. In these cxam2]es, the efficacy of the compounds is demonstrated using the standard tests against certain mnlignant tumors. The tests utilized in these illustrative exatnples were conducted by the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute. The tests were supervised by this agency utilizing their standard protocols and procedures. All tests conformed to these protocols and all tests were evalated under the criteria defined by these protocols. The following representative examples illustrate confirmed activity of the illustrative compounds of the invention against screening tumor systems of the National Cancer Institute. I:or purposes of the following examples, the abbreviation IP stands for intraperitoneal and IV stands for intravenous. The mean and mcdian survival times ore calculated in instruction 14 (revised 6/78) of the Screening Data Summary, Developmental Therapeutics Program, Division of Cancer Trcatment, National Cancer Institute. The contents of this Screening Data Summary including appropriate revisions are herein incorpornted by reference. In the illustrated examples below, the vehicle used as carrier for the drug was injected (minus any drug therein) into the control animals at the same level of use of the vehicle in the drug treated animals in order to eliminate any vehicle effect of the tests. EXAMPLE 5 As an indicator of reproducible activity, compound 1 of the invention was screened against L--1210 lymphoid leukemia in vivo using CD2F1 male mice as the testing species. The parameter of effiency chosen was based upon the medinn survival time of animals treated with the drug vs. appropriate control group animals. Both drug treated animals and control group animals were inoculated IP with 105 secd cells of L-1210 lymphoid leukemia in Ascitic fluid. One day after tumor inoculation, the drug group of animals was placed on a regimen of treatment of compound 1 at the dose levels ns noted below, table 1. The drug treated group of animals was inoculated once daily for five days at the doses noted by IP injection of the test compound appropriately diluted with water. Day six was chosen as an indication of drug toxicity. In this example, all drug treated animals survived through day six. Death of drug treated animals after day six was, therefore, attributed to tumor deaths and not drug toxicity. The median death day, of the control group was day 8.5. As noted in table 1 below, the medinn death day of the drug treated group was longer at all levels of drug tested and was significantly longer at greater than 50 mg/Kg (amount of drug/weight of test animal). The results shown in table 1 below indicate that in this multiple dose assay, the drug showed positive activity. A percent of drug treated animals/control animals greater than 125% is taken as positive drug activity. TABLE 1 Percent Drug Dose Treated Group Control Group Treated Animals/ mg/Kg Survival Time Survival Time Control Animals 200 14.3 8.5 168 % 100 12.7 149% 50 11.0 129)ó 25 10.2 120% 12.5 9.5 111% EXAMPLE 6 Compound 2, 2-(2,3,5-tri-O-acctyl-ss-D-ribofuranosyl) thiazole-4 carboxamide was screened in a manner similar to that shown in Example 5, however, tl)e tumor system used ns the test tumor was P388 lymphocytic leukemia. 106 seed cells were used to initiate the tumor in, both the control group and the drug treated group of 'animals The same strain of mice was used except female mice were substituted for males. Tcst results were based on mean survival time and are expressed as T/C percentages (treated animals/control animals) RS per Example 5. In the drug treated animals, treatment was initiated one day after tumor inoculation and the drug was given at the dose levels noted below in table 2. Drug treatment was for nine days and drug toxicity, as in Example 5, was mcasured on day six. At the 100 mg/Kg level, one animal did not survive the toxicity cut-off date. Average day of death for the control group was 10.2 days whereas at the lowest level of drug treatment the treated animals survived for more than 15 days. As with Example 5, 125% increase in longevity of treated animals over control animals was taken as indicative of positive drug response. TABLE 2 Percent Drug Dose Treated Group Control Group Treated Animals/ mg/Kg Survival Time Survival Time Control Animals 200 18.3 10.2 179% 100 18.0 176% 50 15.3 150% Compound 1 is also indicated as being active against P388 lymphocytic leukemia as per Examp]cs Ga, b, and c, and 2-(2,3,5-tri- O-acctyl-ss-D-ribofuranosyl) thiazole-4-carboxamide, compound 2, is indicated also as being active against P388 lymphocytic leukemia ns per Example 7. In both of these examples, the compound successfully passed the DN 2 (Decision Network) critcria of the National Cnnccr institute Testing. For examples 7 nnd-8, CD2F1 female mice were used and challenged with P388 lymphocytic Icy cumin tun0ors. The mcdinn survival time of the drug treated animals was compared to appropriate control animals and based on this critcria both of the compounds tested were considered as active antituinor agents. The test period was for thirty days in both Examples 7 and 8. For Examples 7 and 8, as well as Examples 9 and 10 below, any animal of the drug treated group which survived beyond the end of the testing period was then evaluated and placed in one of three groups. The first group was designated as cured, meaning the animal was successfully cured of the tumor. The second group designation was no-takes, meaning survival of the animal was considered to-be due to failure of tumor implant. The remaining group was designated as tumor survivors meaning the animals lived beyond the test cut-off date but could not be classified as either cured or no-takes. For both Examples 7 and 8, thirty animals were used as the control group and six animals each were used at each dose level indicated in tables 3 and 4 below in the drug treated groups. In both Exnmples 7 and 8, for both the conirol group and the drag trealcd groups, tumors were induced by 1P inoculation of tumor seed cells on day zero followed by initiation of drug treatment on day one. For both Examples 7a and 8, saline with tween/80 was used as the drug vehicle. For Examples 7b and 7c, water was used as the drug vehicle. In both the control group and the drug treated group in Examples 7 and 8, the test animals were inoculated on day zero IP with 106 seed cells of P388 lymphocytic leukemia. In both Examples 7 and 8, treatment of the drug group was started on day one and the drug was given IP once daily for nine dnys. Day six was utilized ns the cut-off date for death altributable to toxicity of the drug. In only one instance, in Example 7b, was animal mortality attributed to drug toxicity. Efficacy of treatment wns detcrmined by coniparing median survival time of the drug treated animals compared to nledian survival time of the control animals, and is expressed ss percentage increase of treated animals/control animals (T/C) as per Example 5. EXAMPLE 7a In this example drug treated animals were injected lP with the dose level noted in Table 3 below. Six animals were treated at each dose level. No control animals survived beyond day 18 with a median death date of day 12.6. The mcdinn death day of the drug treated animals is as shown in Table 3a below. At the 50 mg/Kg level, one drug treated animal survived and was judged as a no-take. EXAMPLE 7b This example was performed as per Example 7a at dose levels as nosed in Table 3b below. A survivor at both the 700 and 800 mg/hg level was judged as cured. No controls survived beyond day 12 and the mean death day of the control group was day 11. EXAMPLE 7c This example was run as per Example 7a above at dose levals noted in Table 3c below. All controls were dead by day 14 with a mean death date of day 11.9. At the 500 mg/Kg level, one animal was judged as a cure. EXAMPLE 8 Compound 2, 2-(2,3,5-tri-O-acctyl-ss-D-ribofuranosyl) thiazole-4carboxamide was tested as per Exaiaple 7a above at dose levels noted in Table 4 below. No controls survived beyond day 18 with an average death date of day 12.6. At the 50 mg/Kg level, one surviving animal was judged ns a no-take. Both compounds 1 and 2 are indicated as being active anti tumor agents in the multiple dose studies noted in Examples 7 and 8. TABLE 3a Percent Drug Dose Treated Group Control Group Trcated Animals/ Mg/KG Survival Time Survival Time Control Animals 400 20.3 12.6 161% 200 19.0 150 % 100 18.3 1 50 15.3 12196 25 14.3 11396 12.5 13.9 110% TABLE 3b Percent Drug Dose Treated Group Control Group Treated Animals mg/kg Survival Time Survival Time Control Animals 800 $27.0 11.0 700 27.0 245% 600 25.8 234% 500 21.8 190% 400 24.7 224% 300 21.8 198% TABLE 3e Pc reent Drug Dose Treated Group Control Group Treated Animals/ Survival Time Survival Tune Control Animals 800 11.8 11.9 99% 700 10. 86% 600 28.3 237% 500 25.0 210% 500 24.0 201% 300 23.0 1 9396 TABLE 4 Percent Drtig Dose Treated Group Control Group Treated Animals/ mg/Kg Survival Time Survival Time Control Animals 400 20.3 12.6 161% 200 19.0 150% 100 18.3 145% 50 15.3 121% 25 14.3 113% 12.5 13.7 110% Compound 1 is indicated as being active against L-1210 lymphoid leukemia as per Example 9, and successfully passed the DN 2 criteria of the National Cancer institute testing. For Example 9a and 9b, CD2F1 male mice were used and challenged with L-1210 lymphoid leukemia. The mcan survival time of the test animals was compared to appropriate control auimals and based on this critcria, compound 1 was considered as an nctive antituinor agent. The test period was for thirty days. Test results are expressed aS T/C as per Example 5. In Example 9a, 24 control animals were used and six test animals at each drug dose level ns is indicated below in table qa, li) Example 9b. forty control animals were used and ten test animals each at dn)g dose levels ns shown in table 9b below. l'or both the control group and the drug tesl group, tumors were induccd by IP inoculation of tumor seed cells on day zero followed by initiation of drug treatment on day one. For Example 9a, water was used as the drug vehicle and for Example 9b saline was used as the drug vehicle. In both the control groups and the drug treated groups in Examples 9a and 9b, the test animals were inoculated on day zero IP with 106 seed cells of L-1210 lymphoid leukemia. For Example 9u, drug treatment was started on day one and compound 1 given once daily for nine days. Day five was utilized ns the cutoff date for death attributable to toxicity of tile drug. In only one instance in Example 9b wes mortality attributed to drug toxicity. Efficacy of treatment was determined by comparing mcan survival time of drug treated animals with mcan survival time of the control animals and is expressed as percentage increase of treated animals/conirol animals (T/C) as per Example 5. EXAMPLE 9a In this example, the drug treated animals were injected IP with dose ieveis noted In table 5a bolow Six amimals were trcated at each dose level. No control animals survived beyond day ten with a mean death date of day 9 7. The mean death day of the drug treated animals is as shown in table Sa below. EXAMPLE 9b In this example, drug treated animals were injected IP with the dose level noted in table Sb below. Tcn animals were treated at each dose level. No control animals survived beyond day ten with a mean death date of day 9.0. The -mcnn death day of the treated animals is as shown in table Sb below. TABLE Sa Percent Drug Dose Treated Group Control Group Trcated Aninsals/ mg/kg Survival Time Survival Time Control Animats van 18.7 9.7 192 % 200 15.3 157% 100 14.0 144% 50 13.2 136% 25 12.8 131% TABLE Sb Percent Drug Dose Treated Group Control Group Treated Animals/ mg/Kg Survival Time Survival Time Control Animals 800 15.4 9.0 171% 600 20.7 230% 400 20.2 224% 200 16.4 182% 100 16.5 183% Compound 1 is indicated as being active against Lewis lung carcinoma as per example 10 and successfully passed the ON 2 criteria of the National Cancer institute Testing. For Example 10, B6D2F1 male mice were used and challenged with Lcwis lung careinema. The median survival time of the test animals was compared to appropriate control animals and based on this criteria compound 1 was considered as nn effective anti tumor agent. In Example 10, forty control animals were used and ten test aniinnls each at dose levels indented below in Table 6. For both the control group and the drug treated group. tumors were induccd by IV injection on day zero followed by initiating of drug treatment on day onc. For Example 10 water was used as the drug vchicle. In both tic control group arid the drug treated gronp in Example 10, the animals were inoculated on day zero with n homogenate of 106 socd cells of Lewis lung carcinoma. For Example 10, drug treatment was started on day one nnd compound 1 1 given once doily for nine drips. Day five was utilized as tlie cut-off daic for dcaths attributable to toxicity of tic drug. There was no mortality attributable to drug toxicity in this example. Efficacy of treatment was determined by comparing median survival time of drug treated animals with median survival time of the control animals and is expressed as percentage increase of treated animals/control animals (T/C) as per Example 5. T)ie test period was for sixty days and at the end of the sixty day period all animals surviving in the test groups were evaluated as either cured, no-takes, or tumor survivors ns per Example 5 above. EXAMPLE 10 In this example, the drug treated animals were injected IP with the dose level noted in table 6 below. Tcn animals were treated at each dose level. No control animals survived beyond day 23 with a median death date of day 38.4. At the test levels of 400, 200 and 25 mg/Kg all test animals survived the sixty day test period. Bocause of this fact, the T/C ratio noted ia table 6 bolow is a constant figure based on assigning survival day rote of sixty to the treated animals and a mcdisn death date of 18.4 days to the control animals. In Example 10 at both the 200 and 400 mg/Kg level, all ten surviving test animals were judged as cured. At the 100 mg/Rg level, there were eight cures and one tumor survivor with one death noted on day 46. At the 50 mg/Kg level, there were nine cures and one death on day 47. Compound 1 is indicated ns being an active antituinor agent in the multiple dose studies noted in Example 10. Table 6 Percent Percent Drug Dose Treated Group Control Group Treated Animals/ mg/Kg Survival Time Survival Time Control Animals 400 60 18.4 326 % 200 60 100 60 326% 50 60 326% 25 60 326% As is shown in Example 10 above, compound 1 shows outstanding activity against Lewis lung carcinoma. Lewis lung careilloma is an excellent example of a metestatic tumor system. The tests and control animals of Example 10 were inoculated r" with a homogenate of the tumor. Dramatic expression of this tumor is then seen in the lungs. As was noted previously, the ability to metastasize is a property that uniquely characterizes a malignant tumor from a benign tumor. In Example 10, not only was the median survival time of drug treated animals dramatically extended but, at the cessation of the test poriod, excopi id one dose lovei, at lenat 90 cores were noted and at two of those levels 100% cures were present. EXAMPLE 11 Compound 3, 2-(5-O-phosphoryl-ss-D-ribofuranosyl) tl@azole-4-car boxamide is indicated as being active against L-1210 Lymphoid lcukemin as per example lla and 11b. These exomples were performed essontially as per example 9 above excopt as noted. The compound test dosage levels are as noted in tables 7a und 7b below for Example lia and llb respcctively. In these examples, tllirty-six costtol animals were used and six test animals each at the dong dose levels as is shown in tables 7a and 7b. Saline was uscd as the drug vchiclc. No drug toxicity was noted in the test animals for cither examples 11a or 11b. No control animals survived beyond day 10 in exnmple 1 la with a mean dcatll date of dny 8.3 and beyond day eleven in oxample 11b with a mean dcoth date of day 10.1. For both the control groups and the drug test groups, tumors were induced by IP inoculation of tumor secd cells on day zero followed by initiation of drug treatment on day one wherein compound 3 was given once daily for 5 days. Tcst results arc expressed as T/C as per example 5. Table 7a Percent Drug Dose Treated Group Control Group Treated Animals mg/Kg Survival Time Survival Time Control Animals 800 16.3 8.3 196 % 400 15.2 183% 20û ' 21.5 259% 100 15.5 186% 50 11.3 136% Table 7b Percent Drug Dose Treated Group Coatrol Group Treated Animals mg/Kg Survival Time Survival Time Coatrol Animals 600 16.2 10.1 160% 400 15.7 155% 200 14.7 145% 100 12.3 1211; 50 13.0 128% EXAMPLE 12 For Example 12, compound 1 as given IP to R group of AKD2F1 micc which were infücted by intoreranial inocalation witl Lewis lung seed cells to establish brain tumors. The results in Table 8 below indicate that the 1P inoculation of the afflicted animals with compound 1 resulted in reduction of the brain tumors indicating successful crossing of the blood brain barricr by compound 1 following the IP injection into ttle afflicted animals. For this test, 32 control animals were used and no control animels survived beyond day eleven with a mcan death date of day 9.6 for the controls. Eight test animals were used for each drug dose level with the' exception of the 30G mg/Kg level as is SilOWil in table 8 below. Water was used as the drug vehicle. For both the control group and tlie test group, tumors were induced on day zero with initiation of drug treatment on day one where compound I was given oace deily for nine days. Test results are expressed as T/C as per example 5. Table 8 Percent Drug Dose Treated Group Control Group Treated Animals mg/Kg Survival Time Survival Time Control Animals 800 21.3 9.6 231% 700 20.3 211% 600 20.3 211% 300 20.5 213% 150 20.5 197% 75 19.0 185% 37.5 16.0 166% 25.0 16.6 172% In a significant number of disease states of the brain of both pathogenie and host dysfunction origins, treatment is inhibited by the lark of drug transfer aeross the blood brain barier. In Certain instances wherein appropriate treatment of a disense stale is known, complications can arise in trending these diseases when they are locaied intercranially bccause of the lack of transier across the blood brain barrier of effective concentrations of approptiate chemothersputie agents. The indication, as secn in table 8, that compound 1 successfully orosses the blood brain barrier is thus very promising for the treatment of brain tumors. The following representative examples, 13 througll 17, are given for the formulations of the active compound of the invention in illustrative pharmaceutical compositions utilizing illustrative carriers. In these examples, example 13 illustrates the use of the compounds of the invention in injcctables suitable for intrivenous or other types of injection into the host animal. Example 14 is directed to nn oral syrup preparation, Examples 15 to an ornl cnpsule prcparation and Example 16 to oral tablets. Example 17 is dirccted lo use of the compounds of the invention in suitable suppositories. For example 13 through 17 the ingredients are listed followed by the methods of preparing the composition. EXAMPLE 13 INJECTABLES Example 13a Compound 1 Compound 1 250 mg 1000 mg Water for injection USP q.s. Compound 1 is dissolved in the water and passed through a 0.22y1 filter. The filtered solution is added to ampoules or vials, sealed and sterilized. Example.3b Compound 3 Compound 3 ns a Sodium Salt 250 mg 1000 mg Water for lnjection USP q.s. Prcpared as per Example 3a. above. EXAMPLE 14 SYRUP Example 14n Compound 1 250 mg Active ingredient/5 ml syrup Compound 1 50 g Purifi@d Water USP 200 ml Cherry Syrup q.s. or 1000 ml Compound 1 is dissolved in the water and to this solution the syrup is added with mild stirring. Example 14b Compound 3 250 mg Active Ingredient/5 mls syrup Compound 3 cs a Sodium Salt 50.0 g Purified Water USP q.s. or 200 ml Cherry Syrup q.s. ad 1000 ml Prepared as per Example 14a above. EXAMPLE 1 CAPSULES Example 15a Compound 1 100 mg, 250 mg or 500 mg Compound 1 500 g Lactose USP, Anhydrous q.s. or 200 g Sterotex Powder HM 5 g Combine compound 1 and the Lactose in a twin-shell blender equipped with an intensifi@r bar. Tumble bl@nd for two minutes, followed by blending for one minute with the intensifier bar and then tumble blend again for one minute. A portion of the blend is then mixed with the Sterotex Powder, pissed through a &num; &num;30 screen and added back to the remainder of the blend. The mixed ingredients are then blended for one minute, blended with the intensifier bar for thirty seconds and tumble blended for an additional minute. Appro priate sizcd capsules are filled with 141 mg, 352.5 mg or 795 mg of the blend. respectively, for the 100 mg, 250 mg and 500 mg containing capsules. Example 15b Example 15 I) Compound 2 100 more, 250 me or 500 mg Compound 2 500 g Lactose USP, Anllydrous q.s. or 200 g Sterotex Powder lIM 5 g Mix and fill ss per Example 15a. Example 15c Compound 4 100 mg, 250 mg or 500 mg Compound 4 500 g Lactose USP, Anhydrous q.s. or 200 g Sterotex Powder HM 5 g Mix and fill as per Example 16a EXAMPLE 16 TABLETS Example 16a Compound 1 100 mg, 200 mg or 500 mg Compound 1 500 g Corn Starch NF 200.0 g Cellullosc, Microcrystalline 46.0 ; Sterotex Powder HM 4.0 g Purified Water q.s. or 300.0 ml Combine the corn starch, the cellulose and Compound 1 together in a planetary mixer and mix for two minutes. Add the water to this combination and mix for one minute. The resulting mix is sprcad on trays and dried in a hot air oven at 50 C until a moisture level of 1 to 2 percent is obtaiiied. The dried mix is their milled with J Pilzmill through a &num;RH2B sercen at medium specd. The Sierotex Powder is addcd to a portion of the mix and passed through a &num; 30 screen, and added back to tile milled mixture and the total blended for five minutes by drum rolling. Compressed tablets of 150 mg, 375 mg and 750 mg respectively, of the total mix are formed with appropriate sized punchcs for the 100 mg, 250 mg or 500 mg containing tablets. EXAMPLE 17 SUPPOSITORIES Example 17a Compound 1 250 mg, 500 mg or 1000 mg per 3 g Compound 1 250 mg 500 mg 1000 mg Polycthylone Glycol 1925 mg 1750 mg 1400 mg 3540 Polyethylene Glycol 825 mg 750 mg 600 mg 8000 Melt the Polyethylene Glycol 1540 and the Polyethylene Glycol 8000 together at 600 C and dissolve Compound 1 into the melt. Mold this total nt 250 C ill to appropriate suppositorics. Example 17b Compound 2 250, 500, 1000 mg per 3 g Compound 2 250 mg 500 mg 1000 mg Polyethylene Glycol 1925 mg 1750 mg 1400 mg 1540 Polyethylene Glycol 825 mg 750 mg 600 mg 8000 Prepare as per Example 17a Above.

Claims: CLAIMS (for all designated States except Austria): 1. As an agent for use in inhibiting a malignant tumor in a warm blooded animal, a compound having the following general formula: EMI34.1 wherein each of R and R", which are the same or different, is a hydrogen atom or a C1 18 acyl radical, and R is a hydrogen atom, a C1 18 acyl radical or EMI34.2 or a physiologically acceptable salt thereof. 2. As an agent for use in inhibiting a malignant tumor in a warm blooded animal, a compound having the following general formula: EMI34.3 where each of R1 and R2, which are the same or different, is a hydrogen atom or a C18 acyl radical, and R is a hydrogen atom, a C1-8 acyl radical or EMI35.1 or a physiologically acceptable salt thereof. 3. A compound having the following general formula: - EMI35.2 where each of R1 and R2, which are the same or different, is a hydrogen atom or C1-18 acyl radical, and R is a hydrogen atom, a C1-18 acyl radical or EMI35.3 with the proviso that not all of R1, R2 and R3 are simultaneously all hydrogen atoms or all acetyl radicals; or a physiologically acceptable salt thereof. 4. A compound according to Claim 3, wherein, when any of R1, R2 and R3 is an acyl radical, that radical is a C1-8 acyl radical, 5. A compound according to Claim 3, which is 2-(5-O-phosphoryl-ss-D-ribofuranosyl) thiazole-4carboxamide or a physiologically acceptable salt thereof. 6. A compound according to Claim 3, wherein at least one of the radicals R1, R2 and R3 is a benzoate ester radical. 7. An antitumor composition suitable for use in the treatment of a malignant tumor in vivo containing in addition to a physiologically acceptable carrier and as an active ingredient an effective amount of a compound selected from 2-ss-D-ribofuranosyl- thiazole-4-carboxamide, ester derivatives of 2-ss-D-ribofuranosylthiazole-4-carboxamide, and physiologically acceptable salts thereof. 8. A composition according to Claim 7, wherein the active compound is 2-B-D-ribofuranosylthiazole- 4-carboxamide. 9. A composition according to Claim 7, wherein the active compound is an acyl ester derivative of 2-ss-D-ribofuranosylthiazole-4-carboxamide. 10. A composition according to Claim 9, wherein the acyl ester is an acetate ester. 11. A composition according to Claim 9, wherein the acyl ester is a benzoate ester. 12. A composition according to Claim 7, wherein the active compound is a phosphoryl ester of 2-B-D- ribofuranosylthiazole-4-carboxamide. 13. A composition according to any one of Claims 7 to 12, wherein the active compound is present in the composition in an amount of from 10% to 90% by weight of the total composition. 14. A process for producing a compound having the following general formula EMI36.1 wherein R is a C1 18 acyl radical or EMI37.1 which process comprises reacting the compound 2-ss-D-ribofuranosylthi-azole-4-carboxamide in the presence of a base with a compound selected from an acyl anhydride and an acyl chloride. 15. A process according to Claim 14, wherein the acyl anhydride is a carboxylic acid anhydride or phosphotic acid anhydride and the acyl chloride is a carboxylic acid chloride or phosphoric acid chloride. 16. A process for producing 2-(5-O-phosphor.yl- 6-D-ribofuranosyl)thiazole-4-carboxamide, which process comprises reacting the compound 2-ss-D-ribofuranosylthiazole-4-carboxamide in the presence of a base with phosphoryl chloride in a polar solvent; and treating the reaction mixture with water and isolating the desired product. 17. A process according to Claim 16, wherein the desired product is isolated by desalting the reaction mixture with activated charcoal and eluting the product out of the charcoal. 18. A process for producing an antitumor composition according to Claim 7, which comprises incorporating the active ingredient in a physiologically acceptable carrier. CLAIMS (for Austria alone): 1. A process for producing an antitumor composition suitable for use in the treatment of a malignant tumor in vivo, which process comprises incorporating into a physiologically acceptable carrier an active compound selected from 2-B-D-ribofuranosylthiazole-4- carboxamide, ester derivatives of 2-B-D-ribofuranosyl- thiazole-4-carboxamide, and physiologically acceptable salts thereof. 2. A process according to Claim 1, wherein the active compound is 2-B-D-ribofuranosylthiazole-4- carboxamide. 3. A process according to Claim 1, wherein the active compound is an acyl ester derivative of 2-ss-D-ribofuranosylthiazole-4-carboxamide. 4. A process according to Claim 3, wherein the acyl ester is an acetate ester. 5. A process according to Claim 3, wherein the acyl ester is a benzoate ester. 6. A process according to Claim 1, wherein the active compound is a phosphoryl ester of 2-ss-D-ribofuranosylthiazole-4-carboxamide. 7. A process according to any preceding claim, which comprises incorporating the active compound in the carrier in an amount of from 10% to 90% by weight of the total composition. 8. A process according to Claim 1, wherein the active compound has the following general formula: EMI38.1 wherein each of R and R2 which are the same or different, is a hydrogen atom or a C1-18 acyl radical, and R3 is a hydrogen atom, a C1-18 acyl radical or EMI39.1 or a physiologically acceptable salt thereof. 9. A process according to Claim 1, wherein the active compound has the following general formula: EMI39.2 where each of R1 and R2, which are the same or different, is a hydrogen atom or a C1-8 acyl radical, and R is a hydrogen atom, a C1-8 acyl radical or EMI39.3 or a physiologically acceptable salt thereof. 10. A process' for producing a compound having the following general formula: EMI39.4 where each of R1 and R2, which are the same or different, is a hydrogen atom or C1 18 acyl radical, 3 and R is a hydrogen atom, a Cl¯l8 acyl radical or EMI40.1 with the proviso that not all of R1, R2 and R3 are simultaneously all hydrogen atoms or all acetyl radicals; or a physiologically acceptable salt thereof: which process comprises converting a compound of similar formula, but in which all of R1, R2 and R3 are simultaneously hydrogen atoms or simultaneously acetyl radicals, to the desired compound having the desired radicals, by acylation or phosphorylation. 11. A process according to Claim 10, wherein, when any if R1, R2 and R3 is an acyl radical, that radical is a C18 acyl radical. 12. A process according to Claim 10, wherein the desired product is 2-(5-O-phosphoryl-S-D- ribofuranosyl)thiazole-4-carboxamide or a physiologically acceptable salt thereof. 13. A process according to Claim 10, wherein at least one of the radicaliR1, R2 and R3 is a benzoate ester radical. 14. A process for producing a compound having the following general formula: EMI40.2 wherein R3 is a C1-18 acyl radical or EMI41.1 which process comprises reacting the compound 2-B-D-ribofuranosylthiazole-4-carboxamid in the presence of a base with a compound selected from an acyl anhydride and an acyl chloride. 15. A process according to Claim 14, wherein the acyl anhydride is a carboxylic acid anhydride or phosphoric acid anhydride and the acyl chloride is a carboxylic acid chloride or phosphoric acid chloride. 16. A process for producing 2-(5-O-phosphoryl ss-D-ribofuranosyl) thiazole-4-carboxamide, which process comprises reacting the compound 2-ss-D-ribofuranosylthiazole-4-carboxamide in the presence of a base with phosphoryl chloride in a polar solvent; and treating the reaction mixture with water and isolating the desired product. 17. A process according to Claim 16, wherein the desired product is isolated by desalting the reaction mixture with activated charcoal and eluting the product out of the charcoal.

Inventors: ROBINS, ROLAND KENITH
Applicants: VIRATEK, INC.
Application year: 1981
Main classification: C07D409
IPC codes: C07D417