MXPA03009148A - Process for the preparation of (+-)- r-7- benzyloxymethyl- cyclopenta- cis- [4, 5][1, 3]- oxazolo[3, 2-a] pyrimidinone compounds as versatile precursors of carbocyclic nucleosides. - Google Patents

Abstract

The present invention describes a novel method for the synthesis of carbocyclic nucleosides by means of the direct coupling of a nitrogenous base to carbocyclic rings through the reaction of iodinefunctionalization of olefins.

Description

Obtaining (±) -r-7-benzyloxymethyl-cyclopenta-cis- [4,5] [1,3] -oxazolo [3,2-a] pyrimidlnones compounds as versatile precursors of carbocyclic nucleosides.

Field of Invention The present invention relates to the field of the synthesis of chemical compounds, specifically to the synthesis of carbocyclic nucleosides.

BACKGROUND OF THE INVENTION The synthesis of biologically active molecules is one of the most important areas of research in chemistry, since in addition to providing new synthesis techniques, it can contribute to the development of new drugs. Currently the design of molecules with biological activity at the level of nucleic acids is very efficient for the synthesis of compounds useful in the treatment of various diseases. Within this field, the nucleoside, oligo and polynucleotide analogs have turned out to be potent antiviral and antitumor agents1. However, to discuss the synthesis and mechanisms of action of this type of compounds it is necessary to examine the structure of nucleic acids as well as their functions. Nucleic acids are composed of long chains of molecules called nucleotides, which, in turn, are composed of a nitrogenous base, a sugar molecule and a phosphate group. The nitrogenous bases are called purines and pyrimidines. The former include adenine and guanine and the latter, cytosine, thymine and uracil. There are two different nucleic acids, one contains the sugar deoxyribose or deoxyribonucleic acid (DNA) and the other contains ribose or ribonucleic acid (RNA), both acids contain cytosine and the same purine bases, however, thymine appears only in the DNA, while uracil does so only in RNA (figure 1). The three-dimensional structure of nucleic acids is explained according to the model proposed by Watson and Crick2, "who based on various studies including X-ray diffraction, suggested that the DNA molecule is composed of two nucleotide chains arranged in a double These chains are held together by hydrogen bonds formed between the nitrogenous bases which are directed towards the center of the helix, as shown in Figure 2. The arrangement of the bases is not random, a purine base in a chain , always paired with a pyrimidine of the other, that is, adenine binds specifically with thymine forming two hydrogen bonds and guanine with cytosine forming three sugar units, are located outside the double helix, along with the phosphate groups that carry negative charges along the chains.When the DNA is in solution in vitro, these charges are neutralized with the nion to metal ions such as Na +, while in the natural state in vivo, some positively charged proteins are used for neutralization213. For the case of RNA, the three-dimensional structure can be the double helix similar to DNA, although the main structure is formed of a single chain. With the model of Watson and Crick not only the three-dimensional structure is explained, but also the process of transporting genetic information in the spheres. Because the two polynucleotide chains are linked by hydrogen bonds, they can be separated without breaking covalent bonds. The specificity of base pairing suggests that each separate chain can act as a template for the synthesis of a new complementary chain, such that the latter can be assembled perfectly in the original chain. The sequence of the new chain is determined by the template chain, for example, an adenine of the original chain places a thymine in the new chain due to its selective pairing, this phenomenon is also known as molecular recognition. Therefore, in DNA synthesis or replication the two polynucleotide chains are separated and each is used as a template for the synthesis of their complement (figure 3), this ensures the conservation of genetic information in cells215. DNA replication is carried out by specific enzymes called DNA polymerases, which recognize the template chains and catalyze the addition of nucleosides present in the cell to the new chain that is being synthesized. It is precisely in the replication process, when most nucleoside analogues, due to their structural resemblance to their natural counterparts, can act as potent inhibitors of viral DNA replication, DNA of tumor cells and the action of enzymes DNA polymerases (figure 3). For example, nucleoside analogues:? -β-D-arabinofuranosilcitosina (ara-C) (1) and 5-fluoro-2'-deoxiuhdina (2) show anticancer activities3, 2'-fluoro-5-iodo-1-p-D-arabinofuranosilcitosina (FMAU) (3) and 2'-fluoro-5-iodo-1-pD-arabinofuranosyluracil (FIAU) (4), exhibit activity against herpes simplex virus (HSV) 4 and currently some nucleoside analogues such as 3 '-zido-3'-deoxythymidine (AZT) (5) and 2', 3'-dideoxycytidine (ddC) (6) are important drugs in the treatment against human immunodeficiency virus (HIV) 5. The structures of these nucleosides are shown in Figure 4. However, this type of nucleosides presents two problems, the first of which is that they are sensitive substrates for glycosylases, which causes their degradation before completing their therapeutic function, and the second , is their inability to differentiate between normal cells and cells infected by viruses or carcinogens. In order to avoid these enzymatic degradations and to improve the selectivity, nucleoside analogs have been synthesized with another type of modifications in their structure, either in the sugar or in the nitrogenous base. Of great interest are the modified nucleoside analogs in the furan ring where the oxygen atom has been replaced by a methylene group, generically termed carbocyclic nucleosides. These compounds have received a lot of attention in the last two decades because they exhibit interesting biological activities and good resistance to glycosylases6. Among the most important carbonucleosides with biological activity are aristeromycin (7) 7 and neplanocin (8) 8, which are naturally occurring and have a broad antibacterial spectrum.; the carbocyclic analog BVDU (9) 9, which is currently used in the treatment of HSV and WZ infections (Zoster varicella virus) and finally the carbohydrides carbovir (10) 10 and abacavir (11) 11 are potent inhibitors of HIV (figure 5). Prior to the present invention, the synthesis of carbocyclic nucleosides was done in two different ways: a) By direct coupling of the heterocyclic base to the functionalized carbocyclic ring, and b) By the linear construction of the heterocyclic base from an amino substituent in the carbocyclic ring. The first strategy has been the main objective of extensive synthesis works which have been summarized in several reviews12,13,14, while the second one can be carried out more easily through linear methods very well known in the literature15. In order to give a general idea about the carbonucleoside synthesis techniques known to date, an example of each of the main strategies of direct coupling between the nitrogenous base and the carbocycle is described, as well as an example of linear constructions of purine and pyrimidine bases. 1. Direct coupling of the heterocyclic base and the carbocyclic ring. The direct coupling can be carried out by four main known methods: 1. 1) Displacement catalyzed by palladium of an ester or allyl epoxide. This is one of the most used methods in the synthesis of carbonucleosides, in which an ester or allyl epoxide is treated with Pd (0) to generate an intermediate complex of allyl palladium, which reacts with an anion of a purine or a pyrimidine. In this coupling, both regioisomers of the oster (12) or (13) form the same allyl palladium complex (14), where the Pd is found on the anti face to the R group. The complex undergoes the nucleophilic attack by the nitrogenous base in the carbon with less estoric impediment and in an anti-way to the Pd atom, which causes the formation of the carbonucleoside (16) with retention of the configuration (figure 6) 13 The first example of direct substitution of a heterocyclic base in a carbocyclic ring, catalysed by Palladium, was reported by Trost in a racemic synthesis of aristeromycin16 (Figure 7). The synthesis starts with the reaction between the cyclopentadiene monoepoxide (16) and adenine in the presence of the palladium (0) catalyst generated in situ. The alkylated product 1, 4-c / s (17) is obtained from the reaction in a yield of 67%. The next stage of the synthesis involves the substitution of the allyl alcohol (17) by the nitrosulfonylmethane group which generates the nitrosulfone (19) with retention of the configuration. The subsequent reactions of c / s-hydroxylation of the double bond with KMn04 followed by the protection of the c-diol and the conversion of the nitrosulfone to the carboxylic acid using O3 in sodium methoxide solution produce the oster (21) in 75%. Finally, the reduction with DIBAL-H of the oster (21) produces the carbonucleoside aristeromycin (22) in a yield of 66%. 1. 2) Direct coupling by Mitsunobu reaction. Another method used for the connection of the carbocyclic ring and the heterocyclic base is the Mitsunobu reaction. The activation of a hydroxyl group by the complex formed between an azodicarboxylate and triphenylphosphine allows the direct substitution of an alcohol, with inversion of the configuration. A recent example of Mitsunobu coupling for carbocyclic nucleoside synthesis (26) was described by Lundt17 and is shown in figure 8. The reaction of allyl alcohol (23) with 6-chloropurine as a nucleophile, in the presence of DEAD and PPh3 generates the nucleoside analogue (24) as the main N-alkylated product. The reduction of lactone using calcium borohydride and treatment with NH3 generates in modest yield the carbocyclic nucleoside (26). 1 .3) Nucleophilic displacement of a halide ion or an activated alcohol. The direct displacement SN2 of halogens, mesylates, tosylates or triflates has also been used in the coupling of the carbocyclic ring and the nitrogenous base. This method is illustrated in the synthesis of Neplanocin, recently described by Hegedus18. The synthesis involves the use of butenolide (27) as raw material, so that the c / 's-dihydroxylation of this with KMnC and the protection of the diol generate the corresponding acetonide, which in turn suffers an opening of the lactone and a disclosure of the corresponding Wadsworth-Emmons type alcohol to produce the α, β-unsaturated ketone (30). With the reduction of the carbonyl and protection of the corresponding alcohol, the latter compound generates the mesylate (31) which is the appropriate substrate for the nucleophilic displacement by adenine and which in the presence of K2CO3 gives the corresponding substitution product. The elimination of the two protective groups with BCI3 completes the synthesis of the carbonucleoside Neplanocin (32) by 41% (Figure 9). 1 .4) Opening of an epoxide. The opening of an epoxide by purines and pyrimidines in the presence of bases such as NaH and K2CO3 is well known, however in most cases the. yields are low20. This method leads to the formation of a hydroxyl group in position a with respect to the nitrogenous base, unfortunately, the lack of regioselectivity in the opening and the dependence of it on electronic and electronic effects usually leads to obtain a mixture of isomers. Differently, the reaction of an epoxide using nitrogenous bases such as thymine and Lewis acids as catalysts has been described in acceptable yields. Such is the case of the reaction between the epoxide (33) and (bistrimethylsilyl) thymine (34) in the presence of BF3 to give the carbonucleoside (35) in a 71% yield (Figure 10) 21. 2. Linear construction of the heterocyclic base from an amino substituent The nitrogenous base of the carbocyclic nucleosides can be introduced through a linear strategy in which an amino group present in the carbocycle is used to construct the heterocycle. When said strategy is used, the amino group is converted to the N-9 of the purine or the N-1 of the pyrimidine, as the case may be. 2. 1) Synthesis of purines. The construction of adenine and its derivatives is generally carried out by the reaction of a substituted cycloalkylamine with substituted 4,6-dichloropyrimidines to generate the cycloalkylaminopyrimidines. These compounds in turn are condensed with triethyl or trimethyl orthoformate generating the required purine. Márquez et al22 used this method in the synthesis of conformationally anchored carbonucleosides as shown in Figure 1 1. The cycloalkylamine (36) reacts with 5-formamido-4,6-dichloropihmidine in the presence of Et ^ N to produce the formyl derivative (37) in 78%. The closure of the imidazole ring of (37) is carried out by reaction with diethyl orthoformate and HCl and generates the corresponding 6-CI-purine (38). The displacement of the chloride ion by NH3 produces the adenine (39) in good yields, which after the deprotection of the hydroxyl groups under the conditions shown in Figure 11 generates the carbonucleosides (40). 2. 2) Synthesis of pyrimidines. The pyrimidines can be prepared generally by acidic delation of acryloylureas, which can be formed from the reaction between substituted cycloalkylamines and acryloyl isocyanates.

This method has been used effectively by Evans and colleagues in the synthesis of carbonucleosides23. As seen in Figure 12, 5-ethyl-uracil was prepared linearly in the carbocycle from an acidic delation of acryloylurea (43), which in turn comes from the reaction of 3-ethoxy- / V-carboethoxy-2-ethylacrylamide (42) and cycloalkylamine (41). Thus, due to the pharmaceutical importance of the carbonucleosides, it is interesting to research new and efficient total synthesis of these, as well as the search for new derivatives with powerful antiviral activities. Even before the present invention there were no simplified methods for obtaining carbonucleosides. Likewise, the invention proposes new routes of synthesis for obtaining in a simple and inexpensive way and obtaining new carbonucleosides, compounds that have a marked antiviral or anticancer activity and low toxicity.

Brief description of the drawings. Figure 1. Components of DNA and RNA. Figure 2. Three-dimensional structure of DNA. Figure 3. Replication of DNA (left)? inhibition by structural analogs of nucleosides (right). Figure 4. Nucleoside analogues with important biological activity. Figure 5. Carbonucleosides with important biological activity. Figure 6. Synthesis of carbonucleosides according to Crimmins. Figure 7. Direct substitution of a heterocyclic base in a carbocyclic ring catalyzed by Palladium according to Trost. Figure 8. Mitsunobu reaction. Figure 9. Synthesis of Neplanocin. Figure 10. Reaction of an epoxide according to Maag. Figure 11. Synthesis of carbonucleosides conformationally anchored according to Márquez. Figure 12. Synthesis of pyrimidines according to Evans. Figure 13. Reaction of iodofunctionalization of olefins. Figure 14. Technique of Kim and Misco.

Figure 15. Synthetic method of the invention for obtaining carbocyclic nucleosides. Figure 16. Synthesis of 3-cyclopenten-1-yl-methanol. Figure 17. Synthesis of cyclopenta-oxazolo tricyclic compounds of the invention. Figure 18. Chemical shifts of 1 H NMR for compounds (55), (56) and (57). The spectra were obtained in a mixture of CDC + MeOD and the chemical shifts are given in ppm. Figure 19. Chemical shifts of 3 C NMR for compounds (55), (56) and (57). The spectra were obtained in a mixture of CDCI3 + MeOD and the chemical shifts are given in ppm. Figure 20. Molecular perspective of the compound (56), the numbering corresponds to that used in the CIF file. Figure 21. Synthesis I of analogs known as intermediates in the synthesis of carbonucleosides. Figure 22. Synthesis II of analogs known as intermediates in the synthesis of carbonucleosides. Figure 23. Elimination reaction (a), basic hydrolysis (b) and catalytic hydrogenation (c) of the compounds of the present invention. Figure 24. Known synthesis of carbonucleosides. Figure 25. Summary of the carbonucleoside synthesis method of the present invention. Figure 26. 1 H spectrum (300 MHz) of compound (55) in CDCl 3. Figure 27. 1 H spectrum (300 MHz) of compound (56) in CDCl 3. Figure 28. 1 H spectrum (300 MHz) of compound (57) in MeOD. Figure 29. 1 H NMR spectrum (300 MHz) of compound (71) in CDCl 3. Figure 30. 1 H NMR spectrum (300 MHz) of compound (73) in CDCl 3.

Objectives of the invention. Therefore, it is one of the objects of the present invention to provide simplified and efficient methods for obtaining carbonucleosides.

Another object of the invention is to provide new methods of synthesis of carbonucleosides by direct coupling of the nitrogenous base to carbocyclic rings through the iodic functionalization reaction of olefins. Another object of the invention is to provide new methods of synthesis of carbonucleosides using derivatives of 3-cyclopenten-1-yl methanol and pyrimidine bases. Another objective of the invention is to provide new methods of synthesis of carbonucleosides that allow to obtain new carbonucleosides and those already described as biologically active carbonucleosides. It is another objective of the invention to provide new compounds that serve as starting material for the preparation of new carbonucleosides and those already described as biologically active carbonucleosides. Another objective of the invention is to provide new carbonucleosides with biological activity. Another object of the invention is to provide pharmaceutical compositions containing the novel carbonucleosides obtained herein.

Detailed description of the invention. The synthesis methods of the present invention are based on the coupling of the nitrogenous base and the five-membered ring in the synthesis of carbonucleosides by the io-functionalization reaction of olefins; this method has a great versatility in the introduction of different functional groups starting from a double bond24. The common technique for iodofunctionalization involves the use of iodine or / V-iodo-succinimide in the presence of a double bond and a subsequent addition of a nucleophile (Figure 13). Very few examples of synthesis of natural nucleosides using the iodofunctionalization of olefins as a key step in the coupling between nitrogenous bases and sugar are described in the literature. Such is the case of the technique reported by Kim and Misco25, which consists of the coupling between silylated thymine and the fricagic glycine (45) for the synthesis of nucleoside type (48) (figure 1). For the present invention and in general, the synthetic route for obtaining carbonucleosides starts with the compound type I, derived from the protection of 3-cyclopenten-1-yl methanol, figure 15. Subsequently by elimination and / or substitution reactions. of the iodine and the corresponding deprotection are obtained carbocyclic nucleosides, type IV and VI. The first step of the carbonucleoside synthesis methods of the present invention consists in the protection of the hydroxyl group of the 3-cyclopenten-1-yl methanol compound by an etherification reaction. Said protection is preferably carried out in the presence of benzyl bromide and sodium hydride. Subsequently the ether obtained from formula I, where R is benzyl or an alkyl group of 1 to 3 carbons, it is reacted with a silylated pyrimidine by a coupling reaction through the iodofunctionalization of olefins in the presence of molecular iodine, obtaining compounds of formula? G where Ri is -C2H5, -C3H7, -CHMe2, H or methyl, R2 is -SCeH5 or H and X is O or NH. For the purposes of the present invention, the pyrimidines used may be pyrimidines-5-substituted, pyrimidines-6-substituted, and / or pyrimidines-5,6-substituted. In one of the embodiments of the invention, the pyrimidines used are of the formula In one of the synthesis methods of the invention, the compounds of formula? G are subjected to elimination reactions in the presence of a base selected from potassium t-butoxide (? -BuOK) and 1,8-Diazabicyclo [5.4.0] ] undecane (DBU), obtaining compounds of formula IV In another of the methods of synthesis of the invention, the compounds of formula? G undergo basic hydrolysis, where said hydrolysis is preferably carried out in the presence of NaOH in ethanol, obtaining the compounds of formula V, Subsequently, the compounds of formula V are subjected to a catalytic hydrogenation, preferably in the presence of Pd / C and acetic acid, obtaining the following carbonucleosides of formula VI which are known in the literature.

On the other hand, the compounds of formula III and IV serve as inhibitors of DNA replication and possess antitumor activity! and antiviral, so they can be used in treatments against diseases that have this characteristic. Also, with the mentioned compounds, pharmaceutical compositions with therapeutic activity can be generated in the presence of pharmaceutically acceptable vehicles.

As a way to illustrate the present invention, the following examples are presented, without limiting the scope thereof.

Example 1. Preparation of 3-cyclopenten-1-yl methanol. To obtain 3-cyclopenten-1-yl methanol, the synthesis was carried out in three steps according to the methodology already described26 and shown in figure 16. The cycloalkylation reaction of dimethyl malonate with c / s-1, 4-Dichloro-2-butene was carried out in the presence of LiH in a mixture tetrahydrofuran (THF) -1,3-dimethyl-3,4,5,6-tetrahydro-2- (IH) -pyrimidinone (DMPU) ( 9: 1) as solvent. From this reaction, 3-cyclopentene-1,1-dicarboxylic acid (49) was obtained in 90% yield as white crystals. This last compound was decarboxylated at 120 ° C for 6 h, obtaining a yellow oil with an irritating odor and corresponding to 3-cyclopentene-1-carboxylic acid (60). This monoacid was purified by two different methods, the first, by distillation as indicated by the technique described and the second one by column chromatography using silica gel as the stationary phase and a mixture of hexane / EtOAc (9: 1) as the mobile phase. The compounds (49) and (50) have been described26 and their spectroscopic data correspond to those published in the literature. Subsequently, the reduction reaction of (50) was carried out with LiAIH4 in THF at 0 ° C, thus obtaining 3-cyclopenten-1-yl methanol (51), in a 98% yield. This alcohol is characterized in the literature and its spectroscopic data did not show significant differences with those described.

Example 2. Protection of the hydroxyl group of 3-cyclopenten-1-yl methanol. Once the alcohol was obtained (61), the second step in the synthesis route (figure 15) consisted in the protection of the hydroxyl group, for which an etherification reaction was carried out using benzyl bromide in the presence of NaH in anhydrous THF, forming the benzyl ether (54), in a performance similar to that reported.

Example 3. Coupling of benzyl ether with silylated base. Subsequently, the ether (54) was subjected to a coupling reaction with silylated thymine in the presence of molecular iodine, obtaining a white solid at 30% conversion at 12 h of reaction. After purification by recrystallization (CH2Cl2 / hexane, 1: 9) the product was characterized by R N of 1 H and 13C. In the analysis of the 1H spectrum (figure 26) a simple signal was observed in 7.06 ppm corresponding to the CH of thymine and a simple signal in 1.90 ppm corresponding to the group CHa of the same, obtaining as a product of the reaction the compound 7 -benzyloxymethyl-3-methyl-5aH-cyclopenta-c / s- [4,5] [1, 3] oxazolo [3,2-a] pyrimidin-2-one (55) (Figure 17). The yield of this reaction was optimized up to 72% when the reaction time was increased to 72 h. Iodofunctionalization reaction was also carried out using the pyrimidine bases uracil and cytosine, in both cases the formation of the corresponding cyclopenta-oxazolo tricyclic compounds (56) and (57) was observed (Figure 17).

Example 4. NMR spectrometry of the obtained compounds. Figures 18 and 19 show some of the important displacements of 1 H and 13 C for the three new compounds (55), (66) and (57), in order to make a comparison between them. The 1 H NMR spectra for the three compounds are shown in Figures 26, 27 and 28. As can be seen, the displacements of the H-6, H-7 and H-8 hydrogens and their corresponding ring carbons Cyclopentane does not show significant differences between the three compounds. In a different manner, the hydrogens H-5a, H-8a and H-4 of the cytosine-derivative compound (67) are displaced at high frequencies with respect to the displacements of the same hydrogens of the compounds (65) and (56) derivatives of thymine and uracil, in the order of 0.3 ppm. While the corresponding carbons follow the same trend but displacement, but the displacement is in the order of 3 ppm.

Example 5. X-ray diffraction analysis of the obtained compounds. For compound 56, crystals suitable for X-ray diffraction analysis were obtained. Figure 20 shows the ORTEP diagram, where the syn orientation of uracil with respect to the benzyloxymethyl group, which is characteristic of the groups, can be observed. bound to the C-1 'and C-4' carbons in the natural nucleosides; In addition, the stereochemistry assigned to these compounds is confirmed. The conformation of the cyclopentane ring in the solid state is about with atoms C-1 1, C-10, C-9 and C-13 in the plane and the C-12 atom raised by 12 degrees outside it. The C-C bond distances for cyclopentane range from 1.47-1.52 A which are slightly less than 1.54 A which is the average value of the C-C bond distance in cyclopentanes. In the oxazole ring, the bond distance C-N is 1.41 A, which is a value very close to the average for C-N bonds. (1.47 A) Differently, the bond distance C-0 in the same ring is slightly less than the average for C-0 bonds (1.A). The pyrimidine base and the oxazole ring are flat and coplanar with each other. The arrangement of the cyclopentane ring with respect to the oxazole ring is perpendicular and the valence angles that define such a position are N1-C9-C13 and O8-C10-C11 and have a value of 1 1.73 ° and 110.33 ° respectively.

Example 6. Synthesis of carbon ucleosides using compounds 55 and 56 as intermediates in the presence of t-BuOK and DBU. Compounds 55 and 56 were subjected to elimination reactions with the γ-BuOK and DBU bases. In the case of the reaction in the presence of potassium io-butoxide in different solvents (THF,--BuOH and DMF) and at different temperatures (20 ° C and 50 ° C), the compound containing the olefin was obtained in good yields. replaced (figure 23). Finally, when DBU was used, the results were the same as in the case of potassium t-butoxide. By means of this strategy, compounds 71 and 72 were formed. In the 1 H NMR spectrum for compounds 71 (FIG. 29) and 72, the 5.80 and 6.10 ppm signals respectively corresponding to the carbocylic proton in the carbocycle stand out. The presence of the double bond formed by the signals at 140.0 and 127.8 ppm for compound 71 and at 141.4 and 127.8 ppm for compound 72 is manifested in the 13 C NMR spectrum.

Example 7. Synthesis of carbonucleosides using compounds 55 and 56 as intermediates by basic hydrolysis. Compounds 55 and 56 were subjected to basic hydrolysis in the presence of NaOH in ethanol at room temperature obtaining the 2'-hydroxy-3'-deoxypyrimidine-carbonucleosides 73 and 74 in good yields (figure 23). In the 1H NMR spectrum of these compounds it is important to highlight the signal in 9.64 (73) (figure 30) or 9.41 (74) ppm assigned to the proton of the NH group of free thymine and the signals in 4.72 (73), 4.78 (74) and 4.25 (73), 4.22 (74) ppm corresponding to protons H-1 'and H-2' respectively. In addition, the presence of the hydroxyl group is confirmed by the appearance of broad bands at 3420 and 3444 cm "1 in the IR spectrum.

Example 8. Obtaining carbonucleosides. Subsequently, the alcohols 73 and 74 were subjected to a catalytic hydrogenation in the presence of Pd / C and acetic acid, whereby the carbonucleosides 75 and 76 were obtained (figure 23), which are known in the literature29,30. Making a comparison between the syntheses described for the carbonucleosides 75 and 76 (Figure 24) and the proposed synthesis of the present invention (Figure 25), it is observed that the latter presents multiple advantages since the number of steps is significantly smaller, the reactants Employees are easy to acquire and the returns are better than with the methods reported in the literature. Likewise, the benzyl ether 54 used as a raw material in the synthesis process, is easily formed in the laboratory. Unlike the known syntheses and shown in Figures 21 and 22, the synthesis of the present invention has the advantage of obtaining the cyclopenta-oxazole system in a single step and in good yields. The present invention can also be applied in the use of uracil and cytosine as pyrimidine bases. In addition, the cyclopenta-oxazole compounds 55, 56 and 57 are fully characterized and, like other known analogs, are versatile intermediates in the synthesis of carbonucleosides. On the other hand, two analogs of 55 were previously reported in the literature as intermediates for the synthesis of carbonucleosides27,28. The structures and method of obtaining these compounds are shown in figures 21 and 22. As can be seen, the synthesis of compounds 61 and 65 has only been explored using thymine as a base and in both the formation of the cyclopenta-oxazole system needs At least two previous reactions. This method is very limited in comparison with the synthesis methods of the present invention, since pyrimidine bases can generally be used in the latter, obtaining a greater variety of carbonucleosides in suitable yields. Likewise the spectroscopic data of compound 61 are known, while for 65 they are not described; besides that there is no report in which the study of the X-ray diffraction of this class of compounds is carried out. This situation is completely different from that presented for the compounds obtained by the synthesis methods of the present invention.

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Claims (1)

1. Claims 1. A carbocyclic nucleoside of formula characterized in that R is benzyl or an alkyl group of 1 to 3 carbons, Ri is -C2H5, -C3H7I -CHMe2, H or methyl and R2 is -SCeH5 or H. 2. The carbocyclic nucleoside of claim 1 characterized in that R is benzyl , R1 is -C2H5l -C3H7l -CHMe2, H or methyl and R2 is -SCeH5 or H. 3. The carbocyclic nucleoside of claim 1 characterized in that R is Me, R1 is -C2H5l -C3H7l -CHMe2, H or methyl and R2 is -SCeH5 or H. 4. The carbocyclic nucleoside of claim 1 characterized in that R is ethyl, R1 is -C2H5, -C3H7, -CHMe2, H or methyl and R2 is -SCeH5 or H. 5. The carbocyclic nucleoside of the claim 1 characterized in that R is propyl, R1 is -C2H5l -C3H7l -CHMe2, H or methyl and R2 is -SCeH5 or H. 6. The carbocyclic nucleoside of claim 2 characterized in that R is benzyl, RI is methyl and R2 is H 7. The carbocyclic nucleoside of claim 2 characterized in that R is benzyl, 8. A pharmaceutical composition characterized by comprising a therapeutically effective amount of the compound of claim 1 to 7 in a pharmaceutically acceptable carrier. 9. The use of the compound of claim 1 to 7 as an antiviral and antitumor agent. 10. The use of the compound of claim 1 to 7 for the treatment of viral diseases. 11. A carbocyclic nucleoside of the formula characterized in that R is benzyl or an alkyl group of 1 to 3 carbons, Ri is -C2H5, -C3H7, -CHMe2, H or methyl and R2 is -SC6H5 or H. 12. The carbocyclic nucleoside of claim 11 characterized in that R is benzyl, R1 is -C2H5l-C3H7l-CHMe2l H or methyl and R2 is -SCeH5 or H. 13. The carbocyclic nucleoside of claim 11 characterized in that R is Me, R1 is -C2H5, -C3H7l -CHMe2, H or methyl and R2 is -SC6H5 or H. 14. The carbocyclic nucleoside of claim 11 characterized in that R is ethyl, R1 is -C2H5, -C3H7, -CHMe2, H or methyl and R2 is -SCeH5 or H 5. The carbocyclic nucleoside of claim characterized in that R is propyl, R1 is -C2H5l-C3H7, -CHMe2IH or methyl and R2 is -SC6H5 or H. 16. The carbocyclic nucleoside of claim 12 characterized in that R is benzyl, R1 is methyl and R2 is H. 17. The carbocyclic nucleoside of claim 12 characterized in that R is benzyl or, 18. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of the compound of claim 11 to 17 in a pharmaceutically acceptable carrier. 19. The use of the compound of claim 11 to 17 as an antiviral and antitumor agent. 20. The use of the compound of claim 11 to 17 for the treatment of viral diseases. 21. A compound of formula characterized in that R is benzyl or an alkyl group of 1 to 3 carbons, Ri is -C2Hs, -C3H7l -CHMe2, H or methyl, R2 is -SCeHs or H and X is O or NH. 22. The compound of claim 21 characterized in that R is benzyl, Ri is -C2H5, -C3H7 | -CHMe2, H or methyl, R2 is -SCeH5 or H and X is O or NH. 23. The compound of claim 21 characterized in that R is Me, R1 is -C2H5, -C3H7, -CHMe2, H or methyl, R2 is -SCeHs or H and X is O or NH. 24. The compound of claim 21 characterized in that R is ethyl, R1 is -C2H5, -C3H7I -CHMe2, H or methyl, R2 is -SCeH5 or H and X is O or NH. 25. The compound of claim 21 characterized in that R as propyl, R1 is -C2H5, -C3H7, -CHMe2, H or methyl, R2 is -SC6H5 or H and X is O or NH. 26. The compound of claim 22 characterized in that R is benzyl, R1 is methyl, R2 is H and X is O. 27. The compound of claim 22 characterized in that R is benzyl, R1 is H, R2 is H and X is O. 28. The compound of claim 22 characterized in that R is benzyl, R1 is H, R2 is H and X is NH. 29. The use of the compound of claim 21 to 28 for the synthesis of carbocyclic nucleosides. 30. The use of claim 29, wherein the synthesis of carbocyclic nucleosides is performed by the iodofunctionalization reaction of olefins. 31. A method of obtaining carbocyclic nucleosides characterized in that it comprises: a) the coupling of a pyrimidine through its nitrogenous base and the five-membered ring of the compound with protected hydroxyl group of formula I R where R is benzyl or an alkyl group of 1 to 3 carbons, by a iodofunctionalization of defines, b) removal and / or substitution of iodine, and c) deprotection of the protected hydroxyl group. The method of claim 31, characterized in that it comprises the following steps: a) Protect the hydroxyl group of the compound 3-cyclopenten-1-yl methanol by etherification reaction, obtaining the compound of formula I where R is benzyl or an alkyl group of 1 to 3 carbons, Reacting the compound of formula I with a silylated pyrimidine by a coupling reaction through iodination of defines in the presence of molecular iodine, obtaining the compound of the claim 21. c) Reacting the compound of claim 21 with a base selected from the group consisting of potassium f-butoxide and 1,8-Diazabicyclo [5.4.0] undecane by an elimination reaction, obtaining the carbonucleosides of claim 1. 33. The method of claim 32, characterized in that the etherification reaction of part a) is carried out in the presence of benzyl bromide and sodium hydride. 34. The method of claim 32 characterized in that the pyrimidine is selected from the group consisting of 5-substituted pyrimidines, 6-substituted pyrimidines, and / or 5,6-substituted pyrimidines. 35. The method of claim 34 characterized in that the pyrimidine is thymine, cytosine or uracil. 36. The method of claim 32 to 35, characterized in that the elimination reaction of part c) is carried out in the presence of potassium f-butoxide. 37. The method of claim 32 to 36, characterized in that the elimination reaction of part c) is carried out in the presence of 1,8-Diazabicyclo [5.4.0] undecane. 38. The method of claim 32 to 37 characterized in that R is benzyl, is H, R2 is H or methyl and X is O. 39. The method of claim 31, characterized in that it comprises the following steps: a) Protect the hydroxyl group of the 3-cyclopenten-1-yl methanol compound by an etherification reaction, obtaining the compound of formula I where R is benzyl or an alkyl group of 1 to 3 carbons, b) Reacting the compound of formula I with a silylated pyrimidine by means of a coupling reaction via iodofunctionalization of olefins in the presence of molecular iodine, obtaining the compound of the claim 21. c) Submitting to a basic hydrolysis the compound of claim 21, obtaining the carbocyclic nucleoside of claim 11. d) Submitting the compound of claim 11 to a catalytic hydrogenation, obtaining the carbocyclic nucleoside of formula 40. The method of claim 39, characterized in that the etherification reaction of part a) is carried out in the presence of benzyl bromide and sodium hydride. 41. The method of claim 39 characterized in that the pyrimidine is selected from the group consisting of 5-substituted pyrimidines, 6-substituted pyrimidines, and / or 5-substituted 5-pyrimidines. 42. The method of claim 41, characterized in that the pyrimidine is thymine, cytosine or uracil. 43. The method of claim 39 to 42, characterized in that the basic hydrolysis of part c) is carried out in the presence of NaOH in ethanol. 44. The method of claim 39 to 43, characterized in that the catalytic hydrogenation of part d) is carried out in the presence of Pd / C and acetic acid. 45. The method of claim 39 to 44 characterized in that R is benzyl, Ri is H, R2 is H or methyl and X is O.