Esters of nucleosides, the pharmaceutical composition

 

(57) Abstract:

The invention relates to new compounds of formula I Nu-O-Fa, where O is oxygen, Nu is a nucleoside or nucleoside analogue, including such nitrogen base, as adenine, Esenin, cytosine, uracil, thymine; Fa - acyl monounsaturated C18YPD C20-9-fatty acids, which fatty acid etherification hydroxyl group in 5-position of the sugar portion of the nucleoside or nucleoside analog, or a hydroxyl group, an acyclic chain of an analogue of the nucleoside. Pharmaceutical composition containing as active ingredient the compound I, has an antiviral effect. 2 S. and 19 C.p. f-crystals, 14 ill.

The invention relates to new compounds of General formula I:

Nu-O-Fa,

where O denotes oxygen;

Nu is a nucleoside or nucleoside analogue;

Fa is an acyl group monounsaturated Cl18or C20fatty acid.

The invention also relates to antiviral pharmaceutical or veterinary compositions containing the compound of General formula I, one or in combination with a pharmaceutically acceptable carrier.

The present invention also relates to a method for lecinena formula I.

It is known that a large number of serious diseases, such as AIDS, hepatitis b, herpes and gynecologic cancer, as well as according to the latest data human warts are caused by viral infections.

Viruses are small infectious agents that are incapable of independent replication and, therefore, depend for replication of the host cell. The genetic material of the virus is either RNA or DNA.

When the infecting organism is a virus that attacks a specific host cell. Once attached, the virus penetrates through the cytoplasmic membrane and the viral genome is released from the viral particles. The viral genome is usually transported into the cell nucleus, where new replicated viral genomes. New viral block is synthesized in the cytoplasm and new particles are formed or near to cytoplasmic or nuclear membrane.

Some viruses have genomic material (DNA virus) or not (reverse transcription of RNA retrovirus) is included in the genome of the host cell.

Extracellular viruses neutralized by circulating antibodies and cellular immune apparatus can attack and remove infected cell. The virus is awns cells.

Immune attack on your organs contributes to the disease mechanism, usually caused by a virus called immunopathology.

The mechanisms that lie at the basis of some of the more important viral diseases are different.

When HIV-infected T-helper cells of patients are affected and destroyed. This leads to a state of immunodeficita that makes the patient very susceptible to infections, which are usually suppressed by the immune system without any dangerous consequences for the patient.

Hepatitis b virus infects the liver cells and the patient may be very ill, when the immune system tries to rid the body of these infected cells. If the infection is not suppressed by the immune system in the early stages, the result is chronic hepatitis. Therefore, the patient will be infected for life. In some patients chronic hepatitis will develop cirrhosis or liver cancer.

For infections of simple herpes virus initially penetrates into the epidermal cells. Herpes simplex virus reaches the nervous center, where he is calm before the outbreak after a certain time interval. Although b every time when it comes to flash.

The human papilloma virus, particularly in the urinary tract of women, the viral genome is localized in the nuclei of epithelial cells, but not integrated into the chromosome of the cells. This is a stable condition and in some strains, promoting tumor, integration finally occurs, leading to the development of the disease. In this case, the viral genome has a critical initiating step in the process that leads to cancer.

If the immune system copes with the release of the body from the virus at an early stage, this leads to long-term immunity. On the other hand, if the virus is too aggressive and suppresses the immune system, immunity is not achieved and the result is a constant state of infection.

Due to different mechanisms, the treatment strategy should be different for these States.

The ultimate goal in the treatment of HIV/AIDS is the liberation of the patient from infectious virus. It seems unlikely at present. However, much can be achieved by improving the General condition of the patient. The reduction in viral load will increase the duration of the asymptomatic period and reduce infectivity, which is the e agents have toxic side effects, which makes it impossible fairly intensive treatment.

It is believed that there are between 250 and 300 million carriers of hepatitis b worldwide. It is known that many of them developing hepatoma or liver failure due to infection. Encouraging results in the treatment media of this state have been obtained in recent years in the induction of immune responses by interferon. Therapy, reducing viral load is important in this mode, since effective treatment of acute hepatitis b will reduce the number located in the state media. Recently identified hepatitis C virus causes a very large number of cases of hepatitis, of which a large number of patients become carriers. Preliminary studies indicate that the medium state can be interrupted therapeutic modes, such modes for hepatitis C.

Herpes simplex 1 and 2 often infect people, causing carrier status with returns of local infection. Common infections including encephalitis is a rare but catostrophically for the patient. There are large individual variations in the frequency of localized infections, For those patients who underwent who is social. None of the developed up to the present therapeutic regimens will not cure latent infection of cells of the Central nervous system. Thus, therapeutic objective is to minimize the clinical manifestations of returns as the symptoms and duration.

The prevalence of viral infections genital warts has increased dramatically in the 1980-ies. It is now established that some genotypes are carcinogenic, i.e., they initiate changes in the cell, which, after a latent period turn into cancer. The human papilloma virus genital tract gives a long lasting resistant infections. Factors that cause malignant transformation of the damage is not fully known, but I believe that the important role played by the immune system. It is believed that damage to the body, progressing over months and years, are those which transform into cancer. Genital papilloma called condylomas, currently treated by physical means, such as surgical removal, necrotising funds, liquid nitrogen, etc., Genital warts first become tumors with altered enzyme set, acting together with other moments and nucleoside metabolism analogousness warts.

Preventive vaccination was very successful for acute infections such as polio, measles, epidemic paretic and so on, but vaccination was not effective for many other serious viral infections,

Even though in recent decades, considerable efforts have been made to obtain effective antiviral drugs currently cannot be offered satisfactory medical treatment for most viral diseases. Efforts were especially significant because of the emergence of HIV and related viral infections that spread in the world at an alarming rate, in addition, the effects obtained with such agents as azidothymidine (AZT) and acyclovir (ACV) in AIDS and herpes can only be described as partially successful. These most promising antiviral agents, therefore, are derivatives of nucleosides of natural origin that have been modified or at the base or sugar fragment. However, they do not have the desired therapeutic potential because they cause serious side effects in some patients or have a weak or have no action on the other. In addition, treatment of these is diversified infections, such as AIDS, receive such treatment. Patients suffering from less serious, but also very painful viral infections are often left without any treatment, allowing infection to develop in their own way.

The patient without treatment carries a very high infectious burden and represents a danger to the lives of those around him. If he gets an antiviral agent, the goal is the reduction of infectious load to force the immune system to suppress the infection. Another aim is to reduce contagion rates and, consequently, the number of new patients and carriers.

Thus the need for the compounds possessing better therapeutic index is obvious.

The need is especially great for chronic or recurrent infections with dangerous acute phase or when long term illness affects the health or well-being, such as AIDS, hepatitis b and C infection group herpes and human viral infections. Similarly, there is also the need for antiviral agents useful for treating animals suffering from viral diseases.

To improve the impact has already been developed derivatives of esters of fatty acids nucleosides or nucleoside analogues, to improve the lipophilicity and to achieve the best passage through the membrane.

Known esters of arabino-furanosyl-thymine (T Ara) with saturated acids having 1-17 carbon atoms. (EP N 56265).

Also known lipid derivative, United, especially through the phosphate group to the 5'-position pentose group of the nucleoside (PCT N 90/00555). The purpose of this derivatization is more lipophilic nucleosides, so they can be incorporated into liposomes, which preferably penetrate macrophages and monocytes, cells which were found to contain the HIV virus. It is established that the result is the effect of the target.

From EP 393 920 famous unsaturated, preferably polyunsaturated16and higher fatty acid esters or amides of nucleosides or nucleoside analogues. Established that the fatty acid portion of these molecules preferably presents polyunsaturated fatty acids such as linolenic or linoleic acid.

To improve the effect of the proposed complex fatty acid esters of antiviral nucleosides or nucleoside analogues, according to the invention, where the fatty acid is monounsaturated WITH18or

It is known that as nucleosides and nucleoside analogues in themselves, and some unsaturated fatty acids by themselves exhibit antiviral effects, the magnitude of the effects achieved with the compounds of the present invention, indicates that there is not total, but rather a synergistic activity, which is specific for compounds of formula 1.

The mechanism of these effects is currently not known, but they are an order of magnitude better than the next related compounds known in the prior art. They may occur only due to membrane effect or the effect of the target.

The effects are achieved with the compounds according to the invention in systems where no effects cannot be achieved with the parent nucleoside compound.

Compounds of the present invention described General formula I

Nu - O - Fa,

where O is oxygen;

Nu is a nucleoside or nucleoside analogue;

Fa is an acyl group of monounsaturated C18or C20fatty acid.

Nyguyen, United with ribosomal unit. The nucleoside analogues or base or ribosomal unit modified. For example, ribosomal unit may be replaced by another sugar fragment or acyclic chain.

Fatty acid etherification hydroxyl group in 5-position of the sugar portion of the nucleoside or a hydroxyl group, an acyclic group nucleoside analogue.

Nucleosides or nucleoside analogues, which can be selected as Nu in the compounds of formula I, preferably may be represented by formula II

S - B

where S is a monosaccharide or a derivative selected among 1--D-arabinofuranose or 2,3-di-deoxy-3-azido-1-a-D-ribofuranose, or selected in a group of 2-acetoxymethyl, 4-hydroxy-3-/oximeter/-butyl, 2-hydroxy-1-/oximeter/-ethoxymethyl or 2,3-dioxirane;

B is a nitrogen base selected from adenine, guanine, cytosine, uracil, Tamina or derived Tim General formula:

< / BR>
where X is deuterium or fluorine.

Examples of these nucleosides or nucleoside analogues are:

< / BR>
< / BR>
< / BR>
< / BR>
or nucleoside analog, where R is an acyclic group

Examples of the group R in the mode of double bonds in fatty acids. In this application used the system, where the position of the double bonds in unsaturated fatty acids is considered to be the limit noted, for Example, Aksenova acid (C20:1 -9 has 20 carbon atoms in the chain and the double bond is between carbon atoms 9 and 10, counting from the end of the chain.

The selected group of fatty acids that can react with nucleoside or nucleoside analogues with the formation of the esters according to the present invention with pronounced activity was found to consist only of C18and C20monounsaturated fatty acids. In addition, even though the observed effect is somewhat different for acids with the same chain length, when the double bond is CIS-or TRANS-configuration, both show strong activity. Also important is the position of the double bond, since it appeared that the esters of C18or C20fatty acids having unsaturation in the -9 position will have unexpectedly high activity.

C18or C20-9 fatty acids, which being associated with the nukes, give unexpectedly high effect, are as follows: oleic acid (C18: 1, -9, CIS), saginova acid (C18
Ara A-oleic acid,

Ara A-saginova acid,

Ara A-Aksenova acid, Cys,

Ara A-Aksenova acid, trance,

Ara T-oleic acid,

Ara T-saginova acid,

Ara T-Aksenova acid, Cys,

Ara T-Aksenova acid, trance,

ACS - oleic acid,

ACS - saginova acid,

ACS - Aksenova acid, Cys,

ACS - Aksenova acid, trance,

AZT - oleic acid,

AZT - saginova acid,

AZT - Aksenova acid, Cys,

AZT - Aksenova acid, TRANS.

Their formulas are shown in Fig.4.

Compounds according to the present invention have antiviral action, and, therefore, the present invention includes a pharmaceutical or veterinary composition comprising at least one compound of formula 1, one or in combination with a pharmaceutically acceptable carrier or excipients.

In addition, some nucleosides or nucleoside analogues with monounsaturated fatty acids are especially suitable for the treatment of certain viral infections. Thus, it is clear that AZT derivatives of fatty acids are especially useful for treatment of AIDS.

Fatty acid production the La treatment of human viral infections.

Obtaining the necessary immune response to suppress viral infection, such as hepatitis, in some cases, it may be caused by interferon.

Depending on what kind of viral infection being treated and at what stage the infection, or whether the patient is human or an animal, can be used both systemic and local administration.

For the local introduction of the compounds may be formulated as is known in the prior art, for application to the skin or mucous in any suitable form.

The local introduction of the compounds of formula I may be formulated as ointments, creams, gel, tincture, spray, lotion, etc., containing the compounds of formula I in a mixture with an inert, solid or liquid carrier which is common in preparations for local application. Particularly suitable use of the formulation, which protects the active ingredient oxidation or decomposition.

Pharmaceutical formulations containing the compounds of formula I, can also be introduced systemically, or interline, or parenterale.

When enteral introduction of the compounds of formula I can be formulated the surface, suspensions or solutions.

When parenteralna the introduction are suitable formulations of the compounds of formula I in the form of solutions for injection or infusion, suspensions, or emulsions.

The preparations can contain inert or pharmacodynamically supplements. Tablets or pellets, for example, can contain a series of binding agents, fillers, substance carrier or diluents. Liquid formulations can be, for example, in the form of a sterile solution. Capsules may contain a filler or thickener in addition to the active ingredient. In addition, can also be improving the taste additives and substances commonly used as preservatives, stabilizers, moisture-retentive and emulsifying agents, salts for modifying the osmotic pressure, buffets and other additives.

Dose, which is administered preparations according to the present invention may vary in accordance with the method of administration, and by using, as well as the requirements of the patient. The daily dose for systemic therapy for adult average patient will be about 0.1-100 mg/kg body weight/day, preferably 1-20 mg/kg/day. For local application suitable misreport the compounds of formula I may contain an antioxidant, for example, tocopherol, N-methylcobalamin, bottled oxyanion, ascorbic acid or bottled oxytrol.

Further, the invention relates also to a method of treatment of viral infections, which is the introduction of at least one of the compounds of formula I to a human or animal in need of such treatment.

In addition, the invention also includes a method of treating a patient in need of such treatment, a combination of the compounds of formula I and interferon.

Biological effects

Description of drawings

In Fig. 1A presents the inhibitory activity of the esters of fatty acids and management information system; the compounds according to the present invention compared to the known compound (ACS linoleate, see EP-A-393920 and C22 monounsaturated -9 complex ether (ACS Erakat).

In Fig. 1B presents a comparison of the two compounds according to the present invention with the parent nucleoside in two different concentrations.

In Fig. 2 shows the inhibitory effect achieved with esters yeah; the connection according to the present invention compared to the known compound - rich complex ether Ara T Ara T palmitate, see EP-56265), two protec is a comparison of the dose-survival for young mice, infected with HSV 2, after the introduction of ACS and ACS elaidate.

In Fig.4 shows the complete structure of the most preferred compounds according to the present invention.

A. in vitro Experiments

Method plaques: tissue Culture virus

Viral drug HSV 2 (3rd passage clinical isolate) were diluted to 3103pfu /cell and then inoculant to the cells and incubated for 1 h in tissue culture right cells. During this time the virus is activated in cells.

Then these cells are cultured for 24 hours with anti-viral agent. Then they can be frozen, which leads to rupture of the cells and the appearance of free virus in the melting process.

Prepare a dilution of 1/100 or 1/10000 and added to fresh tissue culture. Incubation for 1 hour leads to the inclusion of the virus into cells.

Add carboxymethylcellulose (CMC), to prevent migration of the virus between cells through the environment. The spread of the virus upon contact with cells is more effective, causing the formation of plaques.

One plaque will be one infectious virus. Therefore, the counting of plaques give an updated count of the number of infectious viruses.

1.1. Acicl The R N 393920), and compared ester of monounsaturated fatty acids with longer chain is added to the tissue culture dissolved in dimethylsulfoxide (DMSO) at a concentration of 0.94 Ámol/A. This concentration is less than the effective inhibitory concentration of acyclovir in the used strain of Herpes simplex 2. The results are shown in Fig.1A. As can be seen in Fig.1A, nucleoside esters of fatty acids according to the invention even at this concentration have an inhibitory effect on the virus with values better than the parent compound acyclovir. In addition, Fig. 1A shows an increased inhibitory effect when compared with the compounds in accordance with the prior art provided by ACS-linoleate (C18:3 -3) and also when compared with nucleoside complex ester of monounsaturated fatty acids with longer chain, ACS erucatum (C22:1 -9), having unsaturation in the same position in the chain. Inhibitory effect achieved with three compounds of the present invention, is close to 100%.

The effect of increasing concentrations shown in Fig.1B. In this test strain HSV 2, are relatively resistant ACS, compound: ACS, ACS-oleate and CV-lidat, add the gain increases greatly at higher concentrations while the parent nucleoside, ACV, remains at the same level.

1.2. AraT esters

Conduct relevant expericence with Ara T Ara T-oleate, one complex ester of saturated fatty acid, representing the prior art, Ara T-palmitate (C16:0), and Ara T-undecene (C11:11, -I), a complex ester of monounsaturated fatty acids with shorter chain. Antiviral agents are added at a concentration of 3.9 Ámol/L. the Results are presented in Fig.2.

As noted previously for ACV-esters, Ara T ester according to the invention, Ara T oleate, has significantly improved inhibitory activity. In this test, the inhibition reaches 100%.

B. results Achieved in vivo reduction of mortality.

The virus Herpes simplex 2

The in vivo experiments performed using female mice 3-4 weeks of age N MRI. This strain is sensitive to the virus human herpes at the age of approximately 6 weeks, after that they become relatively stable. Using mice below this critical age, with mass 13-17,

Herpes 2 is the third passage of the isolate and its inoculant in the left lobe of the ear by Stanko neurotrophic and 95% of the animals developed fatal encephalitis, usually 7-9 days. Therefore, HSV 2 is particularly suitable as a system for evaluating therapeutic effectiveness by counting the number of cases of encephalitis.

The introduction of the tested compounds is carried out at very low concentration, in order to better observe the difference in action. Animals receive approximately 12 mg/kg body weight/day from drinking water. Compounds added to drinking water in the form of micelles with deoxycholate. The final concentration is 0.22 mmole /liter

As a control group and groups treated with compound composed of 10 animals each group. Test compounds were ACV-elitet and ACV in comparison with the control. Treatment was started on day 3 after inoculation. During this time the infection was well obosnovalas in the Central nervous system. Mortality of animals put on the schedule and the results are shown in Fig.3.

This test system is a very tough conditions.

As can be seen from Fig.3, all animals of the control group died from the infection, the Parent nucleoside acyclovir has no therapeutic effect at this concentration, when the processing starts after the well-developed infection at day 3 after and then the ez 21 days the animals of this group were examined by Theresianum, they had no signs of encephalitis.

Compounds of General formula 1 in total p can be obtained in accordance with the following reaction equation:

< / BR>
where Nu, O and Fa have the previously indicated meanings and X can be Cl, Br, O-CO-R', where R' is Fa, CH3CH2CH3or CF3.

Thus the reaction proceeds by acylation of the nucleoside or its equivalent. Its carried out using a suitable reactive derivatives of fatty acids, preferably of golodnikov and antihydrogen acids. When using galoyanized, such as the acid chloride of the acid, add a tertiary amine catalyst such as triethylamine, N,N-dimethylaniline, pyridine or N, N-dimethylaminopyridine, in the reaction mixture to bind the released kaleidotrope acid. The reaction is preferably carried out in an inert solvent, such as N,N-dimethylformamide, or a halogenated hydrocarbon, such as dichloromethane. If desired, any of the above tertiary amine catalysts may be used as solvent, while closely that there is a suitable excess. The reaction temperature varies between 0oC and 40oC, preferably, 5oC - 25o

The method is illustrated by the following examples.

Example 1

5'-0-Hexadecanoyl-1---arabinofuranosyladenine

To a solution of 0.5 g (1,94 10-3mole) of I--D-arabinofuranosyladenine (ARA-T) in 20 ml of anhydrous pyridine was added 3 ml of the original solution of 0.58 g (2,13 10-3mole) of palmitoylated 5.5 ml of dichloromethane. The reaction mixture is stirred under nitrogen at room temperature for 12 hours, when thin-layer chromatography shows a partial conversion. Add the rest of the solution palmitoylated and the resulting mixture is stirred for 24 hours. The reaction mixture is evaporated to dryness and the residue partitioned between 50 ml of chloroform and 50 ml of water. Centrifugation of the resulting emulsion gives a semi-solid product, which is recrystallized from ethanol/heptane 1:1, obtain 0.7 g (72%) of the price), to 7.32 (1H, s, H-6), equal to 6.05 (1H, d, H-1'), THE 5.65 (1H, d, HE-2' ), TO 5.58 (1H, d, HE-3'), 4,50 (1H, m, H-5'1), is 4.15 (1H, m, H-5'2), was 4.02 (1H, m, H-2'), TO 3.92 (1H, m, H-3'), 3,88 (1H, m, H-4'), 2,31 (2H, t, CH2-Soo), a 1.75 (3H, s, CH3-5), of 1.55 (2H, m, CH2-C-COO), 1,20 (24N, m, CH2) to 0.85 (3H, t, CH3- CH2)

13C-YOKES (DMSO-d6), 75 MHz/ :172,81 (soo), 163,78 (CO-4), 150,37 (CO-2), 137,88 (C-6), 107,21 (C-5), 85-29 (C-1'), 81,74 (C-4'), 76,06 (C-3'), 74,65 (C-2'), 63,23 (-5'), 33,41, 31,26, 28,97 28,82, 28,66, 28,33, 24,44, 22,05 (CH2), 13,89 (CH3CH2), 12,15 (CH3- 5).

Example 2

5'-0-/CIS-9-Hexadecanoic/-1--D-arabinofuranosyladenine

To a solution of 4.0 g (15,72 10-3mole) of CIS-9-hexadecenoic acid in 40 ml of anhydrous benzene was added 1.5 ml (17,72 10-3mole) of oxalicacid and stirred the mixture in nitrogen at 35oC for 3 hours. Remove the solvent and excess reagent in a high vacuum and the residue is diluted with 10 ml of dichlormethane to get the original solution of CIS-9-hexadecanolide. To a solution of 1.0 g (a 3.87 10-3mole) ARA-T in 20 ml of anhydrous pyridine and 10 ml of N, N-dimethylformamide was added 2 ml of the original solution and the reaction mixture is stirred under nitrogen at room temperature. Add an additional 4 ml of the original solution in portions of 1 ml with an interval of approximately 8 hours. After su is chloroform. Centrifugation of the resulting emulsion gives a semi-solid mass which is recrystallized from ethanol/heptane 1: 1, gain of 1.15 g (60%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz) : at 11.25 (1H, s, N - H), 7,32 (1H, s, H-6), equal to 6.05 (1H, d, H-1'), THE 5.65 (1H, d, HE-2' ), OF 5.55 (1H, d, HE-3'), WITH 5.3 (2H, m, -CH= CH), of 4.45 (1H, m, H-5'1), is 4.15 (1H, m, H-5'2), 3,98 (1H, m, H-2'), OF 3.95 (1H, m, H-3'), 3,90 (1H, m, H-4'), TO 2.35 (2H, t, CH2-Soo), to 1.98 (4H, m, = CH-CH2-), a 1.75 (3H, t, CH3-5), of 1.52 (2H, m, CH2With soo), 1, 20 (N, m, CH2) to 0.85 (3H, t, CH3- CH2)

13C-NMR (DMSO-d6, 75 MHz) 172,31 (soo), 163,31 (CO-4), 149,90 (CO-2), 137,89 (C-6), 129,13 and 129,03 (SNON-), 106,74 (C-5), 84,83 (C-1'), 81,26 (C-4'), 75,59 (C-3'), 74,16 (C-2'), 62,76 (-5'), 32,98, 30,62, 28,57, 28,50, 28,02, 27,91, 27,84, 27,76, 26,07, 26,03, 23,95, 21,56 (CH2), 13,39 (CH3-CH2), 11,68 (CH3-5).

Example 3

5'-0-/CIS-6-Octadecenoic/-1--D-arabinofuranosyladenine

To a solution of 1.0 g (a 3.87 10-3mole) ARA-T in 20 ml of anhydrous pyridine and 10 ml of N,N-dimethylformamide was added 2 ml of the original solution of 2.1 g (6,98 10-3mole) of octadecenoamide in 6 ml dichloromethane and stirred the reaction mixture in nitrogen at room temperature. The remaining mother liquor is added in portions of 2 ml at intervals of approx izbavlyayut 65 ml of chloroform and 65 ml of water. The resulting emulsion was centrifuged and the organic phase is treated with brine, concentrated and the residue recrystallized, obtain 1.1 g (55%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz) : to 11.28 (1H, s, N - H), 7,35 (1H, s, H-6), equal to 6.05 (1H, d, H-1'), THE 5.65 (1H, d, HE-2' ), OF 5.55 (1H, d, HE-3'), 5,28 AN, m, -CH= CH), of 4.45 (1H, m, H-5'1), is 4.15 (1H, m, H-5'2), 3,98 (1H, m, H-2'), OF 3.95 (1H, m, H-3'), 3,90 (1H, m, H-4'), TO 2.35 (2H, t, CH2-MEO) of 1.97 (4H, m, = CH-CH2-), a 1.75 (3H, t, CH3-5), of 1.52 (2H, m, CH2With soo), 1, 25 (20N, m, CH2) to 0.85 (3H, t, CH3- CH2)

13C-NMR (DMSO-d6, 75 MHz) : 172,73 (soo), 163,81 (CO-4), 150,40 (CO-2), 137,88 (C-6), 129,88 and 129,10 (CH=CH), 107,24 (C-5), 85,34 (C-1'), 81,76 (C-4'), 76,10 (C-3'), 74,66 (C-2'), 63,28 (-5'), 33,29, 31,28, 28,99, 28,84, 28,69, 28,57, 28,43, 26,54, 26,29, 24,07, 22,07 (CH2), 13,89 (CH3-CH2), 12,16 (CH3-5).

Example 4

5'-0-/CIS-9-Octadecenoyl/-1--D-arabinofuranosyladenine

To a solution of 1.0 g (a 3.87 10-3mole) ARA-T in 20 ml of anhydrous pyridine and 10 ml of N,N-dimethylformamide was added 2 ml of the original solution of 2.1 g (6,98 10-3mole) of CIS-9-octadecenoamide in 6 ml dichloromethane and stirred under nitrogen at room temperature. The remaining mother liquor is added in portions of 2 ml at intervals of about 12 hours. Chloroform and 65 ml of water. The resulting emulsion was centrifuged and the organic phase is treated with brine, concentrated and the residue is recrystallized receive 1.2 g (60%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6/ : to 11.28 (1H, s, N - H), 7,35 (1H, s, H-6), equal to 6.05 (1H, d, H-1'), THE 5.65 (1H, d, HE-1'), THE 5.65 (1H, d, HE-2'), OF 5.55 (1H, d, HE-3'), 5,28 (2 H, m, CH=CH), of 4.45 (1H, m, H-5'1), is 4.15 (1H, m, H-5'2), 3,98 (1H, m, H-2'), OF 3.95 (1H, m, H-3'), OF 3.95 (1H, m, H-3'), 3,90 (1H, m, H-4'), TO 2.35 (2H, t, CH2-MEO) of 1.97 (4H, m, CH2CH=), a 1.75 (3H, t, CH3-5), of 1.52 (2H, m, CH2With soo), 1,25 (20N, m, CH2), 0,35 (3H, t, CH3- CH2).

13C-NMR (DMSO-d6, 75 MHz) : 172,75 (soo), 163,80 (CO-4), 150,39 (CO-2), 137,88 (C-6), 129,58 and 129,49 (CH=CH), 107,21 (C-5), 85,36 (C-3'), 81,79 (C-4'), 76,11(C-1'), 74,67 (C-2') 63,26 (-5'), 33,42, 31,27, 29,08, 29,02, 28,84, 28,68, 28,55, 26,43, 28,37, 26,54, 24,44, 22,07 (CH2), 13,86 (CH3-CH2), 12,15 (CH3-5).

Example 5

5'-0-/TRANS-9-Octadecenoic/-1--D-arabinofuranosyladenine

To a solution of 1.0 g (a 3.87 10-3mole) ARA-T in 20 ml of anhydrous pyridine and 10 ml of N,N-dimethylformamide was added 2 ml of the original solution of 2.1 g (6,98 10-3mole) of TRANS-9-octadecenoamide in 6 ml dichloromethane and stirred the reaction mixture in nitrogen at room temperature. The remaining source solution adds sang in a high vacuum and the residue was diluted with 65 ml of chloroform and 65 ml of water. The usual treatment and recrystallization yield of 1.30 g (65%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 11,35 (1H, s, N - H), 7,35 (1H, s, H-6), equal to 6.05 (1H, d, H-1'), THE 5.65 (1H, d, HE-2' ), OF 5.55 (1H, d, HE-3'), WAS 5.35 (2 H, m, CH= CH), of 4.45 (1H, m, H-5'), IS 4.15 (1H, m, H-5'2), 4,0 (1H, m, H-2'), OF 3.95 (1H, m, H-3'), 3,90 (1H, m, H-4'), TO 2.35 (2H, t, CH2-MEO) of 1.93 (4H, m, CH2-CH=), a 1.75 (3H, s, CH3-5) and 1.51 (2H, m, CH2With soo), 1, 25 (20N, m, CH2) to 0.85 (3H, t, CH3- CH2).

13C-NMR (DMSO-d6, 75 MHz) : 172,77 (soo), 163,80 (CO-4), 150,45 (CO-2), 137,98 (C-6), of 130.03 and 129,97 (CH=CH), 107,24 (C-5), 85,44 (C-1'), 81,89 (C-4'), 76,17(C-3'), 74,69 (C-2') 63,34 (-5'), 33,48, 31,99, 31,35, 29,6, 29,00 28,91, 28,78, 28,61, 28,56, 28,44, 28,40, 24,50 and 22,15 (CH2), 13,90 (CH3-CH2), 12,20 (CH3-5).

Example 6

5'-0-/CIS-11-Octadecenoic/-1--D-arabinofuranosyladenine

To a solution of 1.0 g (a 3.87 10-3mole) ARA-T in 20 ml of anhydrous pyridine and 10 ml of N,N-dimethylformamide was added 2 ml of the original solution of CIS-11-octadecenoate (2.1 g, 6,98 10-3mol) in 6 ml dichloromethane and the reaction mixture is stirred under nitrogen at room temperature. The reaction is completed in the usual manner and the crude product is purified by chromatography on silica gel, using as eluent 5% methanol in chloroform. Homogeneous RAR (DMSO-d6, 300 MHz/ : 11,25 (1H, s, N - H), 7,35 (1H, s, H-6), equal to 6.05 (1H, d, H-1'), THE 5.65 (1H, d, HE-2' ), OF 5.55 (1H, d, HE-3'), 5,32 (2H, m, -CH=CH), of 4.45 (1H, m, H-5'1), is 4.15 (1H, m, H-5'2), 3,98 (1H, m, H=2'), 3,90 (1H, m, H-3'), 3,88 (1H, m, H-4'), OF 2.33 (2H, t, CH2-Soo), of 1.95 (4H, m, CH2-CH=), a 1.75 (3H, s, CH3-5), of 1.52 (2H, m, CH2With soo), 1, 25 (20N, m, CH2), of 0.95 (3H, t, CH3- CH2).

13C-NMR (DMSO-d6, 75 MHz) : 172,78 (soo), 163,78 (CO-4), 150,38 (CO-2), 137,87 (C-6), 129,56 (SN-SN), 107,21 (C-5), 85,31 (C-1'), 81,73 (C-4'), 76,07(C-3'), 74,65 (C-2') 63,24 (-5'), 33,41, 31,10, 29,05, 28,81, 28,74, 28,64, 28,50, 28,34, 28,24, 26,56, 26,52, 24,43, 22,04 (CH2), 13,85 (CH3-CH2), 12,15 (CH3-5).

Example 7

5'-0-/TRANS-11-Octadecenoic/-1--D-arabinofuranosyladenine

To a solution of 1.0 g (a 3.87 10-3mole) ARA-T in 20 ml of anhydrous pyridine and 10 ml of N,N-dimethylformamide was added 2 ml of the original solution of 2.1 g (6,98 10-3mole) of TRANS-11-octadecenoamide in 6 ml dichloromethane and stirred the reaction mixture in nitrogen at room temperature. The reaction is completed in the usual manner and the crude product is recrystallized get 1.3 g (65%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 11,25 (1H, s, N - H), 7,35 (1H, s, H-6), equal to 6.05 (1H, d, H-1'), THE 5.65 (1H, d, HE-2' ), OF 5.55 (1H, d, HE-3'), WAS 5.35 (2 H, m, HC= CH), of 4.45 (1H, m, H-5'1CH3-5), of 1.52 (2H, m, CH2With soo), 1, 25 (20N, m, CH2) to 0.85 (3H, t, CH3- CH2).

13C-NMR (DMSO-d6, 75 MHz) 172,75 (soo), 163,79 (CO-4), 150,38 (CO-2), 137,90 (C-6), 129,98 (CH=CH), 107,19(C-5), 85,34 (C-1'), 81,77 (C-4'), 76,11 (C-3'), 74,65 (C-2') 63,26 (-5'), 33,42, 31,91, 31,10, 28,95, 28,83, 28,76, 28,65, 28,40, 28,37, 28,12, 24,44 and 22,04 (CH2), 13,83 (CH3-CH2), 12,13 (CH3-5).

Example 8

5'-0-/CIS-11-Eicosenoic/-1--D-arabinofuranosyladenine

To a solution of 1.0 g (a 3.87 10-3mole) ARA-T in 20 ml of anhydrous pyridine and 10 ml of N,N-dimethylformamide was added 2 ml of the original solution of 2.1 g (6,38 10-3mole) of CIS-11-eicosanoid in 6 ml dichloromethane and stirred the mixture with nitrogen at room temperature. The reaction is completed in the usual manner and the crude product is purified on a column of silica gel using 10% methanol in chloroform as additionally separated by. The homogeneous fractions are evaporated earn 1.25 g (58%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 11,25 (1H, s, N - H), 7,35 (1H, s, H-6), equal to 6.05 (1H, d, H-1'), THE 5.65 (1H, d, HE-2' ), OF 5.55 (1H, d, HE-3'), WAS 5.35 (2H, m, CH= CH), of 4.45 (1H, m, H-5'1), is 4.15 (1H, m, H-5'2), 3,98 (1H, m, H-2'), 3,90 (1H, m, H-3'), 3,88 (1H, m, H-4'), OF 2.33 (2H, t, CH2-Soo), of 1.95 (4H, m, CH2-CH= ), a 1.75 (3H, s, CH3-5), of 1.52 T (2H, m, CH2With soo), 1, 25 (24N, m, 9,89 (CO-2), 137,38 (C-6), 129,05 (CH= CH), 106,71 (C-5), 84,85 (C-1'), TO 81.28 (C-4'), 75,60 C-3'), 74,16 (C-2') 62,76 (-5'), 32,92, 30,78, 28,58, 28,34, 28,19, 28,08, 27,88, 26,04, 23,95, 21,58 (CH2), MADE 13.36 (CH3-CH2), 11,65 (CH3-5).

Example 9

5'-0-/CIS-13-Docosenoic/-1--D-arabinofuranosyladenine

To a solution of 1.0 g (a 3.87 10-3mole) ARA-T in 10 ml of anhydrous pyridine and 10 ml of N,N-dimethylformamide was added 2 ml of the original solution of 2.15 g (6,02 10-3mole) of CIS-13-docosenoic in 6 ml dichloromethane and the reaction mixture is stirred under nitrogen at room temperature. The complete reaction and purify the product on a column of silica gel (10% Meon/HCl3gain of 1.15 g (51%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 11,25 (1H, s, N - H), 7,35 (1H, s, H-6), equal to 6.05 (1H, d, H-1'), THE 5.65 (1H, d, HE-2' ), OF 5.55 (1H, d, HE-3'), 5,32 (2 H, m, CH=CH), of 4.45 (1H, m, H-5'1), is 4.15 (1H, m, H-5'2), 3,98 (1H, m, H-2'), 3,90 (1H, m, H-3'), 3,88 (1H, m, H-4'), OF 2.33 (2H, t, CH2-Soo), of 1.95 (4H, m, CH2-CH=), a 1.75 (3H, s, CH3-5), of 1.52 (2H, m, CH2With soo), 1, 25 (28N, m, CH2), of 0.95 (3H, t, CH3- CH2).

13C-NMR (DMSO-d6, 75 MHz) : 172,63 (soo), 163,48 (CO-4), 150,43 (CO-2), 137,88 (C-6), 129,44 (CH= CH), 107,21 (C-5), 85,51 (C-1'), 81,92 (C-4'), 76,20(C-3'), 74,69 (C-2'), 63,36 (-5'), 33,47, 31,40, 29,20, 29,15, 29,03, 28,83, 28,73, 28,55, 26,63, 24,50, 22,16 (CH2), 13,79 (NIN

To a solution of 1.0 g (4,43 10-3mole) of 9-/2-acetoxymethyl/guanine (acyclovir, ACV) in 20 ml of anhydrous pyridine and 10 ml of N,N-dimethylformamide was added 2 ml of the original solution 4,29 g (15,72 10-3mole) of CIS-9-hexadecanolide in 10 ml of dichloromethane and the reaction mixture is stirred under nitrogen at room temperature. Add an additional 4 ml of the original solution in portions of 2 ml with an interval of about 10 hours. After 60 hours total reaction time, the solvent is removed under high vacuum and the residue was diluted with 65 ml chloroform and 65 ml of water. Zentrifugenbau and recrystallization (ethanol) is obtained semi-solid mass give 1.35 g (66%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 10,65 (1H, s, NH), OF 7.82 (1H, s, CH-8), of 6.50 (2H, s, NN2), to 5.35 (2H, s, CH2-1'), 5,2-5,4 (2H, m, CH=CH), 4,07 (2H, t, CH2-4'), the 3.65 (2H, t, CH2-3'), of 2.21 (2H, t, CH2-Soo), to 1.98 (4H, m, CH2-CH=), to 1.48 (2H, m, CH2With soo), 1,25 (N, m, CH2) to 0.85 (3H, t, CH3-CH2).

13C-NMR (DMSO-d6, 75 MHz) : 172,72 (soo), 156,79 (CO-6), 153,91 (C-2), 151,41 (C-4), 137,62 (CH-8), 129,56 (CH=CH), 116,43 (C-5), 71,81 (CH2-1'), 66,55 (CH2-3'), 62,53 (CH2-4'), 33,28, 31,14, 29,08, 28,54, 28,47, 28,40, 28,29, 26,59, 24,35, 22,07 (CH2), 13,86 (CH3CH3
mole) of ACV in 20 ml of anhydrous pyridine and 10 ml of N, N-dimethylformamide was added 2 ml of the original solution of 2.1 g (6,98 10-3mole) of CIS-6-octadecenoamide in 6 ml dichloromethane and stirred the reaction mixture in nitrogen at room temperature. The reaction is completed in the usual way and precrystallization product, obtain 1.6 g (80%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 10,65 (1H, s, NH), OF 7.82 (1H, s, CH-8), of 6.52 (2H, s, NH2), a 5.25 to 5.4 (4H, m, CH2-1' and CH=CH), 4,07 (2H, t, CH2-4'), the 3.65 (2H, t, CH2-3' in), 2.25 (2H, t, CH2-Soo), of 1.95 (4H, m, CH2-CH=), to 1.48 (2H, m, CH2With soo), 1,20 (20N, m, CH2) to 0.85 (3H, t, CH3-CH2).

13C-NMR (DMSO-d6, 75 MHz) : 172,66 (soo), 156,72 (CO-6), 153,87 (C-2), 151,37 (C-4), 137,58 (CH-8), 129,85 and 129,17 (CH=CH), 116,42 (C-5), 71,81 (CH2-1'), 66,52 (CH2-3'), TOTALS 62.52 (CH2-4'), 33,28, 31,25, 29,06, 28,97, 28,85, 28,66, 28,57, 28,43, 26,56, 26,26 23,96, 22,05 (CH2), 13,88 (CH3-CH2).

Example 12

9-/2'-/CIS-9-Octadecanoyloxy/ethoxymethyl/-guanine

To a solution of 2.0 g (8,89 10-3) ACV in 40 ml of anhydrous pyridine and 20 ml of N, N-dimethylformamide was added 4 ml of the original solution of 4.25 g (14,12 103mole) of CIS-9-octadecenoamide in 8 ml dichloromethane and stirred the reaction is 4 ml every 8 hours. After a total reaction time of 40 hours to remove the solvents under high vacuum. The residue is suspended in 50 ml of water and 100 ml of chloroform. Centrifugation of the emulsion gives a semi-solid mass which is recrystallized from ethanol, to obtain 3.7 g (85%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 10,65 (1H, s, NH), OF 7.82 (1H, s, CH-8), of 6.52 (2H, s, NH2), a 5.25 to 5.4 (4H, m, CH2-1' and CH=CH), 4,07 (2H, t, CH2-4'), the 3.65 (2H, t, CH2-3' in), 2.25 (2H, t, CH2With MEO) to 1.98 (4H, m, CH2-CH=), to 1.48 (2H, m, CH2With soo), 1,20 (20, m, CH2) to 0.85 (3H, t, CH3-CH2).

13C-NMR (DMSO-d6, 75 MHz) / : 172,72 (soo), 156,70 (CO-6), 153,85 (C-2), 151,37 (C-4), 137,58 (CH-8), 129,58 (CH=CH), 116,46 (C-5), 71,76 (CH2-1'), 66,51 (CH2-3'), 62,50 (CH2-4'), 33,25, 31,23, 29,03, 28,78, 28,63, 28,54, 28,48, 28,42, 28,35, 26,54, 24,32, 22,03 (CH2), 13,87 (CH3CH2).

Example 13

9-/2'-/TRANS-9-Octadecanoyloxy/ethoxymethyl/-guanine

To a solution of 2.0 g (8,89 10-3mole) of ACV in 40 ml of anhydrous pyridine and 20 ml of N, N-dimethylformamide was added 4 ml of the original solution of 4.25 g (14,12 10-3mole) of TRANS-9-octadecenoamide in 8 ml of dichloromethane and the reaction mixture was stirred at room temperature in nitrogen. The remaining chlorine solution is tons solvent in a high vacuum. The residue is suspended in 50 ml of water and 100 ml of chloroform and centrifuged emulsion receive semi-solid mass which is recrystallized from ethanol, to obtain 3.75 g (86%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 10,65 (1H, s, NH), OF 7.82 (1H, s, CH-8), of 6.75 (2H, s, NH2), a 5.25 to 5.4 (4H, m, CH2-1' and CH=CH), 4,07 (2H, t, CH2-4'), the 3.65 (2H, t, CH2-3'), of 2.21 (2H, t, CH2-Soo), to 1.98 (4H, m, CH2-C=), to 1.45 (2H, m, CH2With soo), 1,25 (20N, m, CH2) to 0.85 (3H, t, CH3-CH2).

13C-NMR (DMSO-d6, 75 MHz) : 172,77 (soo), 156,72 (CO-6), 154,17 (C-2), 151,36 (C-4), 137,52 (CH-8), of 130.03 (CH=CH), 116,44 (C-5), 71,77 (CH2-1'), 66,54 (CH2-3'), 62,55 (CH2-4'), 33,28, 31,93, 31,26, 28,98, 28,95, 28,82, 28,69, 28,49, 28,38, 28,33, 24,35 and 22,08 (CH2), 13,91 (CH3- CH2).

Example 14

9-/2'-/CIS-11-Octadecanoyloxy/ethoxymethyl/-guanine

To a solution of 1.0 g (4,43 10-3mole) of ACV in 20 ml of anhydrous pyridine and 10 ml of N, N-dimethylformamide was added 2 ml of the original solution of 2.1 g (6,98 10-3mole) of CIS-11-octadecenoate in 6 ml dichloromethane and stirred the reaction mixture in nitrogen at room temperature. The reaction is completed in the usual way and the product precrystallization, obtain 1.8 g (90%) of target compound in wines2), a 5.25 to 5.4 (4H, m, CH2-1' and CH=CH), 4,07 (2H, t, CH2-4'), the 3.65 (2H, t, CH2-3' in), 2.25 (2H, t, CH2-Soo), of 1.95 (4H, m, CH2-CH=), to 1.48 (2H, m, CH2With soo), 1,20 (20N, m, CH2) to 0.85 (3H, t, CH3-CH2).

13C-NMR (DMSO-d6, 75 MHz) : 172,74 (soo), 156,62 (CO-6), 153,91 (C-2), 151,34 (C-4), 137,58 (CH-8), 129,58 (CH=CH), 116,22 (C-5), 71,82 (CH2-1'), 66,55 (CH2-3'), 62,50 (CH2-4'), 33,26, 31,09, 29,06, 28,81, 28,79, 28,62, 28,54, 28,36, 28,23, 26,55, 24,33, 22,04 (CH2), 13,87 (CH3CH2).

Example 15

9-/2'-/TRANS-11"-Octadecanoyloxy/ethoxymethyl/-guanine

To a solution of 1.0 g (4,43 10-3mole) of ACV in 20 ml of anhydrous pyridine and 10 ml of N, N-dimethylformamide was added 2 ml of the original solution of TRANS-11-octadecenoamide (2.1 g, 6,98 10-3mol) in 6 ml dichloromethane and the reaction mixture is stirred under nitrogen at room temperature. The reaction is completed in the usual way and the crude product is recrystallized, and receive 1,7 (78%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : or 10.60 (1H, s, NH), 7,81 (1H, s, CH-8), 6,60 (2H, s, NH2), a 5.25 to 5.4 (4H, m, CH2-1' and SN=SN), of 4.05 (2H, t, CH2-4'), the 3.65 (2H, t, CH2-3'), 2,22 (2H, t, CH2-Soo), of 1.95 (4H, m, CH2-C=), to 1.45 (2H, m, CH2With soo), 1,20 (20N, m, CH2) to 0.85 (3H, t, CH<30,03 (CH=CH), 116,48 (C-5), 71,79 (CH2-1'), 66,54 (CH2-3'), TOTALS 62.52 (CH2-4'), 33,29, 31,92, 31,09, 28,95, 28,79, 28,63, 28,38, 28,12, 28,35 and 22,05 (CH2), 13,86 (CH3-CH2).

Example 16

9-/2'-/CIS-11-Eicosenoic/ethoxymethyl/-guanine

To a solution of 1.0 g (4,43 10-3mole) of ACV in 20 ml of anhydrous pyridine and 10 ml of N, N-dimethylformamide was added 2 ml of the original solution of 1.59 g (a 4.83 10-3mole) of CIS-11-eicosanoid in 4 ml dichloromethane and stirred the reaction mixture in nitrogen at room temperature. The remaining solution chloranhydride acid are added in portions of 1 ml every 8 hours. After a total reaction time of 60 hours to remove the solvents under high vacuum. The residue is treated with chloroform and water, and finally purified on a column of silica gel (10% Meon) (SNS), get 0,92 g (40%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 10,65 (1H, s, NH), 7,81 (1H, s, CH-8), of 6.50 (2H, s, NH2), a 5.25 to 5.4 (4H, m, CH2-1' and CH=CH), 4,08 (2H, t, CH2-4'), the 3.65 (2H, t, CH2-3'), of 2.21 (2H, t, CH2-Soo), and 2.0 (4H, m, CH2-C=), to 1.45 (2H, m, CH2With soo), 1,25 (24N, m, CH2) to 0.85 (3H, t, CH3-CH2).

13C-NMR (DMSO-d6, 75 MHz) : 172,73 (soo), 156,70 (CO-6), 153,90 (C-2), 151,37 (C-4), 137,59 (CH-8), 129,58 (CH=SUB>), 13,88 (CH3CH2).

Example 17

9-/2'-/CIS-13-Docosenoic/ethoxymethyl/-guanine

To a solution of 1 g (4,43 10-3mole) of ACV in 20 ml of anhydrous pyridine and 10 ml of N, N-dimethylformamide was added 2 ml of the original solution of CIS-13-docosenoic (2.10 g, 5,8810-3mol) in 6 ml dichloromethane and stirred the reaction mixture in nitrogen at room temperature. The reaction is complete and the product is recrystallized (ethanol), obtain 1.24 g (52%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 10,65 (1H, s, NH), 7,80 (1H, s, CH-8), of 6.50 (2H, s, NH2), 5,2-5,4 (4H, m, CH2-1', CH=CH), 4,10 (2H, t, CH2-4'), the 3.65 (2H, t, CH2-3'), 2,22 (2H, t, CH2-Soo), was 2.05 (4H, t, CH2-C=), to 1.45 (2H, m, CH2With soo), 1,25 (28N, m, CH2) to 0.85 (3H, t, CH3-CH2).

13C-NMR (DMSO-d6, 75 MHz) 172,74 (soo), 156,70 (CO-6), 153,87 (C-2), 151,38 (-4), 33,28, 31,25, 29,06, 28,98, 28,85, 28,66, 28,56, 28,39, 26,53, 24,35, 22,06 (CH2), 13,89 (CH3-CH2).

Example 18

5-O-/CIS-9-Octadecenoyl/-3'-deoxy-3'-azido-thymidine

To a solution of 1.0 g of 3'-deoxy-3'-azidothymidine (AZT) (3,75 10-3mole) in 20 ml of anhydrous pyridine was added 2 ml of the original solution of CIS-9-octadecenoamide (70%, 1.7 g, 3.9 to 10-3mol) in 6 ml of d is added in portions of 2 ml at intervals of approximately 8 hours. After a total reaction time of 60 hours, the solvent is distilled off in high vacuum and the residue is diluted with 100 ml of chloroform and 50 ml of water. The organic phase is treated with brine, dried over magnesium sulfate and concentrated, to obtain a viscous oil. The product was then purified by chromatography on a column elwira 3% methanol in chloroform. The homogeneous fractions are evaporated gain of 1.65 g (82%) of target compound in the form of a colorless viscous oil.

1H-NMR (DMSO-d6, 300 MHz/ : 11,25 (1H, s, NH), WAS 7.45 (1H, s, H-6), 6,12 (1H, t, H-1'), A 5.25 TO 5.4 (2H, m, CH=CH), of 4.45 (1H, m, H-3'), OF 3.95 (1H, m, H-4'), 2,25-OF 2.45 (2H, m, CH2-2'), to 2.35 (2H, t, CH2-MEO) of 1.97 (4H, m, CH2-CH= ), or 1.77 (3H, s, CH3-5), of 1.53 (2H, m, CH2With soo), 1,25 (20N, m, CH2) to 0.85 (3H, t, CH3-CH2).

13C-NMR (DMSO-d6, 75 MHz) : 172,51 (soo), 163,58 (CO-4), 150,32 (CO-2), 135,91 (CH-6), 129,55 and 129,49 (CH=CH), 109,81 (C-5), 83,61 (CH-1'), 80,61 (CH-3'), 63,11 (CH2-5'), 60,17 (CH-4') 35,67 (CH2-2'), 33,30, 31,29, 29,10, 29,06, 28,85, 28,70, 28,61, 28,54, 28,43, 26,56, 24,30, 22,09 (CH2), 13,85 (CH3-CH2),12,04 (CH3-5).

Example 19

5-O-/CIS-9-Octadecenoyl/-9-- D-arabinofuranosyl-adenine

To a solution of 1.0 g (3,74 10-3mole) of 9-D-arabinofuranosyl-adenine (ARA-A) in 10 ml of anhydrous pyridine and 20 ml of N,N-dimethylformamide was added 2 ml of amerivault nitrogen at room temperature. The remaining mother liquor is added in portions of 2 ml at intervals of approximately 8 hours. After a total reaction time of 50 hours, the solvent is distilled off in high vacuum and dissolve the residue in 10% methanol in chloroform and filtered through a column of silica gel. Fractions concentrated product was then purified on a column of silica gel, to obtain 0.6 g (30%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : 8,18 (1H, s, AGN), to 8.12 (1H, s, AGN), 7,25 (2H, s, NH-2), 6,30 (1H, d, H-1'), 5,78 (1H, d, HE-2'), OF 5.68 (1H, d, HE-3'), 5,2-5,4 (2H, m, CH=CH), to 4.38 (1H, m, H-5'1), 4,25 (1H, m, H-5'2), is 4.15 (2H, m, H-2', H-3'), OF 3.95 (1H, m, H-4'), IS 2.30 (2H, t, CH2-Soo), of 1.95 (4H, m, CH2With=), 1,50 (2H, m, CH2With soo), 1,25 (20N, m, CH2) to 0.85 ( 3H, t, CH3-CH2)

13C-NMR (DMSO-d6, 75 MHz) 172,73 (soo), 155,43 (C-6), 151,85 (C-2), 149,28 (C-4), 140,60 (C-8), 129,66 and 129,54 (CH=CH), 118,22 (C-5), 83,82 (C-1'), 81,23 (C-4'), 75,88 (C-2'), 75,11 (C-3'), 63,88 (-5'), 33,37, 31,29, 29,09, 29,05, 28,85, 28,70, 28,59, 28,48, 28,42, 26,56, 24,41, 22,08 (CH2), 13,87 (CH3-CH2).

Example 20

5'-O-/TRANS-9-Octadecenoic/-1--D-arabinofuranosyl-/N-6-methyl/-adanin

To a solution of 1.0 g (3,55 10-3mole) of 9-D-arabinofuranosyl-N-6-methyl-adenine in 10 ml of anhydrous pyridine and 15 ml of N,N-dimethylformamide was added 2 ml shotnames nitrogen at room temperature. The remaining mother liquor was added with 20 ml at intervals of approximately 8 hours. After a total reaction time of 60 hours, the solvent is distilled off in high vacuum and the residue solvent in 5% methanol and chloroform and re-chromatographic on a column of silica gel, to obtain 0.7 g (36%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz/ : of 8.25 (1H, s, AGN), 8,10 (1H, s, AGN), of 7.75 (1H, s, NH), OF 6.29 (1H, d, H-1'), 5,78 (1H, d, HE-2'), 5,70 (1H, d, HE-3'), 5.25 to 5.35 (2H, m, CH= CH), and 4.40 (1H, m, H-5'1), 4,27 (1H, m, H-5'2), is 4.15 (2H, m, H-2', H-3'), OF 3.95 (1H, m, H-4'), 2,95 (3H, Shir, N-CH3), is 2.30 (2H, t, CH2-Soo), 1,90 (4H, m, CH2-C=), 1,50 ( 2H, m, CH2With soo), 1,25(20N, m, CH2) to 0.85 (3H, t, CH3-CH2)

13C-NMR (DMSO-d6, 75 MHz) : 172,75 (soo), 154,89 (C-6), 152,43 (C-2), 149,33 (C-4), 140,02 (C-8), 129,99 (CH=CH), 118,20 (C-5), 83,61 (s-1), 81,06 (C-4'), 75,77 (C-2'), 75,06 (C-3'), 63,76 (-5'), 33,36, 31,90, 31,25, 28,97, 28,90, 28,81, 28,68, 28,47, 28,36, 28,30 (CH2), 27,20 (N-CH2), 24,41 22,07 (CH2), 13,89 (CH3-CH2).

Example 21

9-/4'/TRANS-9"Octadecanoyloxy/-3'-oxometalates/-guanine

To a solution of 1.0 g (3,98 10-3mole) of 9-/4-hydroxy-3-oxometalates/guanine (penciclovir) in 10 ml of anhydrous pyridine and 40 ml of N,N-dimethylformamide was added 2 ml of the original races of the nitrogen at room temperature. The remaining mother liquor is added in portions of 2 ml at intervals of approximately 8 hours. After a total reaction time of 65 hours and distilled off the solvent under high vacuum and the residue is dissolved in 15% methanol in chloroform and elute through a column of silica gel. Homogeneous fractions are recrystallized from ethanol, to obtain 0.45 g (22%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz) : 10,50 (1H, s, NH), the 7.65 (1H, s, CH-8), to 6.43 (2H, s, NH2), 5,33 (2H, m, CH=CH), to 4.62 (1H, t, OH), of 4.00 (4H, m, CH2-H) and RCOOCH2), to 3.38 (2H, m, CH2-OH in), 2.25 (2H, t, CH2-COO), 1,90 (4H, m, CH2-C= ), 1,60-1,80 (CH and CH2-CH2N) to 1.45 (2H, m, CH2-C-COO), 1,20 (20H, m, CH2) to 0.85 (3H, t, CH3).

13C-NMR (DMSO-d6, 75 MHz) : 172,90 (soo), 156,75 (C-6), 153,40 (C-2), 151,07 (C-4), 137,22 (C-8), 130,02 (CH=CH), 116,57 (C-5), 63,80 (RCOOCH2), OF 60.50 (CH2OH), 40,67 (CH2N), TO 37.54 (CH), 33,44, 31,88, 31,88, 31,22, 28,95, 28,90, 28,77, 28,64, 28,43, 28,27, 24,38, 22,04 (CH2), 13,90 (CH3).

Example 22

9-/2'-(TRANS-9-octadecanoyloxy)-1'-oxymethyluracili/-guanine

To a solution of 9-{ [2-hydroxy-1-(oxymethyl)ethoxy]methyl}guanine (Ganciclovir) (0,655 g, 2,56 10-3mole) in 10 ml of anhydrous pyridine and 40 ml of N,N-dimethylformamide was added 2 ml of the original solution of TRANS-9-octadecenoate the original solution are added in portions of 2 ml with an interval of about 10 hours. The residue is suspended in 100 ml of water and 100 ml dichloromethane and centrifuged emulsion receive semi-solid mass which is recrystallized from ethanol, to obtain 0.9 g (60%) of target compound in the form of a white solid product.

1H-NMR (DMSO-d6, 300 MHz) : or 10.60 (1H, s, NH), 7,81 (1H, s, CH-8), to 6.58 (2H, c, NH2), the 5.45 (2H, s, OCH2N) to 5.35 (2H, m, CH=CH), is 4.85 (1H, t, OH), 4,08 (1H, m), 3,90 (1H, m) and 3.75 (1H, m) (RCOOCH2and CH-O), to 3.35 (2H, m, CH2-OH), 2,08 (2H, t, CH2-COO), of 1.93 (4H, m, CH2-C=), 1,10-1,45 (22H, m, CH2) to 0.85 (3H, t, CH2CH2).

13With ASR (DMSO-d6, 75 MHz) : 172,64 (soo), 156,85 (C-6), 153,84 (C-2), 151,34 (C-4), 137,62 (C-8), 130,02 (CH=CH), 116,48 (C-5), a 76.88 (CH-O), 71,29 (OCH2N), 63,13 (RCOOCH2), 60,39 (CH2OH), 33,19, 31,97, 31,29, 29,02, 28,85, 28,72, 28,53, 28,41, 27,07, 27,02, 24,32, 22,10 (CH2), 13,90 (CH3).

EXAMPLES OF PREPARATION OF THE DRUG

Example D

Medication in the form of a cream for topical use containing as an active ingredient saidat ACV receive the following composition:

Component, wt.%:

ACV elaidate (active ingredient) - 5,00

Emulsifying wax - 10,0

White soft paraffin - 5,0

Mineral oil - 15,00

Liquid silicone 200 - 1,00

Polysorbate 60 - 1,00

Propylparaben - 0,20

Glycerol - 4,00

Methylparaben of homogeneous cream.

Phase And includes emulsifying wax, white soft paraffin, mineral oil, liquid silicone 200 (increases skin sensitivity and the ability to spread propylparaben and the ACV elaidate.

The second phase, phase, includes glycerol (co-solvent to improve mitigation), methylparaben and water.

Two phases independently from each other are mixed at 70oC up until all the ingredients will not be either together.

Then phase b is added to phase a at 70oC and continue mixing for 5 minutes the resulting mixture is then removed from the heating source and vigorously Parasiva, combine until then, until a homogeneous cream when the temperature drops to 30 - 35oC.

Example F

This example illustrates the preparation of a liposomal preparation containing saidat ddC for oral administration. Get the original solution of lecithin (100 mg) dissolved in a mixture of chloroform/methanol (1 : 1 vol./about. 2 ml), and phosphatidylglycerol (10 mg) dissolved in the same solvent mixture (1.0 ml).

A 25 ml flask with a round bottom mixing 0.2 ml of lecithin and 0.1 ml of phosphatidylglycerol. The active ingredient, saidat ddC (5 mg) dissolved in a mixture S="ptx2">

The solvent is removed using a rotary evaporator apparatus, leaving a thin "vitreous" film. It is dried in high vacuum for 1 h In a flask, add phosphate buffer (1.5 ml) and vigorously shaken.

Get a milky white suspension which is stable to dialysis against phosphate buffer.

The particles have a size in the range of 4-15 MM (average 10M), measured over the sieve Malvina.

After maturation (for 5 days at 5oC) the suspension remains stable. There is some delamination, no precipitation (solid) emulsion.

Example E

In this example, the prepared capsules filled with a dry mixture containing saidat GCV as the active ingredient.

Preparation for filling capsules with the following:

Component weight (g)

The GCV saidat - 6,600

Lactose - 4,950

Corn starch - 1,518

Colloidal silica is of 0.066

Magnesium stearate - 0,006

Each of the above ingredients are carefully weighed and then transferred into a polypropylene vessel and mixed together. The resulting mixture is then passed through ito. Mix with assorted trays then mixed and passed through the same sieve a second time. The mixture is awn 60 rpm for 1 h

The obtained product is then filled in manually tverdoplamennoe capsules having a size of 1, so that each capsule contained 200 mg of the drug.

(1) On graphs esters according to the present invention are esters of elaidic and Aksenovo acids. Characteristics of the esters used for the purposes of comparison, the following:

(a) esters Petroselinum and vaccinology acids are other monounsaturated fatty acids18, i.e., acids with unsaturated bond, not in the same position as omega-9;

(b) ether palettename acid is derived from a monounsaturated fatty acid WITH16and so is a close analogue of fatty acids used according to the present invention;

(c) the stearates are fully saturated fatty acid WITH18i.e. another close analogue of the fatty acids used according to the present invention; and

(d) esters of linolenic and linoleic acids are polyunsaturated fatty acids that are used in existing patents.

(2) Fig. 5, 6, 8, 9, 13 and 14 show the measured values 1C-50 for a large number of different tested compounds acting on the strains wirrabara required, to reduce the formation of stains growth of the virus by 50% and therefore the lower the value 1C, the more active is an antiviral drug.

(3) From Fig. 5, 6, 8, 9, 13 and 14 can be seen that the compounds presented in this invention, namely the elaidic ester and Aksenovo acids (elaidate and agosenate) show consistently high antiviral activity. Some other esters which have been tested, sometimes show more activity than the compounds of the present invention, but only derived elaidic and Aksenovo acids according to the present invention act against all the different strains of viruses that have been tested.

(4) In Fig. 7 shows a selectivity index of various derivatives of GCV. Index selectivity is defined under the graph and, as you can understand, the higher this value is, the better.

(5) In Fig. 10 and 11 an important point that should be noted is that there is a great difference between GCV and its ester with elaidic acid according to the present invention at low concentrations of the drug, which is usually assigned to a person. For example, in Fig. 10 when the largest concentration of 5 mm and six is the GCV survived only two of the mouse.

Similar results are shown in Fig. 11.

(6) in Fig. 12 shows that Elaida GCV according to this invention prevents the development of encephalitis, while at the same time GCV has no effect.

(7) In Fig. 14 important are the results obtained with the strain of human immunodeficiency virus (HIV-1) US as it polyresistant clinical strain of HIV. As you may know, AZT is a drug commonly used to treat HIV infections, and Fig. 10 shows that Elaida AZT according to this invention has a high activity exceeds the activity of conventional medicines.

In General, graphics included here provide additional convincing evidence that the improvements that can be obtained using the present invention does not depend on the structure of the nucleoside or nucleoside analog, is attached to the remainder of the fatty acids.

Applied graphics also give experimental data related to AZT and GCV.

Esters PCV and AraA show similar properties compared with PCV and AraA.

1. Esters of nucleosides of General formula I

Nu - O - Fa,

where O is oxygen;

Nu is a nucleoside or nucleoside analogue, on the>8
or C20-9 fatty acids, which fatty acid etherification hydroxyl group in 5-position of the sugar portion of the nucleoside or nucleoside analog, or a hydroxyl group, an acyclic chain of an analogue of the nucleoside, except 5'-O-oleyl-Ara-cytidine and 2,2'-anhydrous-5'-O-oleyl-Ara-cytidine.

2. Connection on p. 1, wherein Nu is a residue of the formula S - B, where S is a monosaccharide residue, selected from 1-D-arabinofuranose or 2,3-dideoxy-3-azido-1--D-ribofuranose or 2-hydroxy-ethoxymethyl, 4-hydroxy-3-(oxymethyl)butyl, 2-hydroxy-1-(oxymethyl)-ethoxymethyl, 2,3-dioxypurine, and B is a nitrogen base selected from adenine, guanine, cytosine, uracil, thymine.

3. Connection on p. 2, wherein Nu is arabinofuranosyladenine (T Ara), arabinofuranosyladenine (Ara), acyclovir (ACV), azidothymidine (AZT), pornoargentino General formula

< / BR>
where R1- NH2, NHCH3or analog of a nucleoside of the General formula

< / BR>
where R is an acyclic group.

4. Connection on p. 3, characterized in that R is [2-hydroxy-1-(oxymethyl)ethoxy]the stands.

5. Connection PP.1 to 4, characterized in that the Fa is elaidic acid.

6. Connection on p. 1, characterized in that that Nu is aciclovir and Fa is elaidic acid.

8. Connection on p. 1, wherein Nu is aciclovir and Fa is CIS - or TRANS-Aksenovo acid.

9. Connection on p. 1, wherein Nu is the AraT and Fa is elaidic acid.

10. Connection on p. 1, wherein Nu is the AraT and Fa is oleic acid.

11. Connection on p. 1, wherein Nu is the AraT and Fa is CIS - or TRANS-Aksenovo acid.

12. Connection on p. 1, wherein Nu is the AraT and Fa is CIS - or TRANS-Aksenovo acid.

13. Connection on p. 1, wherein Nu is the AraT and Fa is oleic acid.

14. Connection on p. 1, wherein Nu is the AraT and Fa is elaidic acid.

15. Connection on p. 1, wherein Nu is ganciclovir and Fa is elaidic acid.

16. Connection on p. 1, wherein Nu is AZT and Fa is elaidic acid.

17. Connection on p. 1, wherein Nu is AZT and Fa is oleic acid.

18. Connection on p. 1, wherein Nu is the antiviral action, including an active ingredient and a pharmaceutically acceptable carrier or excipient, characterized in that the active ingredient used esters of nucleosides of formula 1 under item 1 in an effective amount.

20. The composition according to p. 19, possessing antiviral activity against HIV, characterized in that as a complex ester of the nucleoside use a nuke on one of the PP.16 - 18.

21. The composition according to p. 19, which has antiviral effect against the virus HSV 1 or 2, characterized in that as the active ingredient it contains the connection PP.6 - 8.

22. Compounds of General formula I under item 1, which has antiviral activity.

 

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The invention relates to mono-, di - or tri-esters of 2-amino-6-(C1-C5-alkoxy)-9-(-D-arabinofuranosyl)-N-purine General formula (I)

< / BR>
where arabinofuranosyl residue substituted for 2'-, 3'- or 5'-positions, and esters formed by carboxylic acids, in which decarbonising part selected from n-propyl, tert-butyl, n-butyl, methoxymethyl, benzyl, phenoxymethyl, phenyl, methanesulfonyl and succinyl

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< / BR>
where R is C1-C4-alkyl, does not necessarily substituted by one or more groups, or R is:

< / BR>
a benzyl, robotjam, 2-deoxyribosyl or (CH2)n-OR1where n is 1 or 2, and R1is CH2CH2OH or< / BR>
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a benzyl, ribosom, 2-deoxyribosyl or (CH2)n-OR SIG1where n is 1 or 2, and R1is CH2CH2HE or CHor their salts

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< / BR>
where R is benzene, p-toluensulfonyl or linear aliphatic acyl radical containing 2-6 carbon atoms; R1H or benzoyl or linear aliphatic acyl containing 2 to 6 carbon atoms; R and R1same or different when R1has a value other than hydrogen; n is 1-5; And is the equivalent of the acid with PKandless than 2.5

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d-arabinofuranosyl)-n-purine, method for their preparation and use and pharmaceutical composition" target="_blank">

The invention relates to mono-, di - or tri-esters of 2-amino-6-(C1-C5-alkoxy)-9-(-D-arabinofuranosyl)-N-purine General formula (I)

< / BR>
where arabinofuranosyl residue substituted for 2'-, 3'- or 5'-positions, and esters formed by carboxylic acids, in which decarbonising part selected from n-propyl, tert-butyl, n-butyl, methoxymethyl, benzyl, phenoxymethyl, phenyl, methanesulfonyl and succinyl
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The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula I:

< / BR>
where R is C1-C4-alkyl, does not necessarily substituted by one or more groups, or R is:

< / BR>
a benzyl, robotjam, 2-deoxyribosyl or (CH2)n-OR1where n is 1 or 2, and R1is CH2CH2OH or< / BR>
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