Covalent conjugates of lipids with phosphonocarboxylates acid, their preparation and use as antiviral drugs

 

(57) Abstract:

The invention relates to a phospholipid derivative phosphonocarboxylate acids of formula I (see formula), in which1denotes the group -(CH2)eSUS in which -(CH2)edenotes a linear or branched, saturated alkylenes chain, where e is 4-16; R2denotes a linear saturated alkyl chain with 1-20 carbon atoms; R3denotes H or a linear alkyl chain with 1-6 carbon atoms; X denotes sulfur, Y represents oxygen, SUS denotes cyclic alkyl residue with 5-7 C-atoms or phenyl, one - or multi-substituted C1-C10-alkyl, C1-C10-alkoxy or halogen, m is 0.1 to 3, provided that R1can be equal to R2if R2at the same time denotes R1and their physiologically acceptable salts. It also describes the medicinal product containing the specified connection as active substances for the treatment of viral, including retroviral diseases. 2 S. and 9 C. p. F.-ly, 4 PL.

The invention relates to a new lipid derived phosphonocarboxylate acids and their esters of the General formula

< / BR>
in Coto branched saturated alkylenes chain.

e is an integer from 4 to 16, with one of the carbon atoms, starting from position 3, may be replaced by heteroatoms (oxygen, nitrogen, or sulfur),

R2denotes hydrogen, a linear or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms,

R3denotes H, a linear or branched alkyl chain with 1-6 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, neopentyl, Texel or phenyl, choline, ethanolamine, carnitine, C5-C7-cycloalkyl, benzyl or one of the following groups

< / BR>
< / BR>
< / BR>
and R4represents C1-C6-alkyl, benzyl or phenyl and R5and R6denote C1-C6-alkyl and n is 1, 2 or 3,

X denotes a valence bond, oxygen, sulfur, oxycarbonyl, carbonyloxy, carbonamide, amidocarbonyl, sulfinyl or sulfonyloxy group

Y denotes a valence bond, oxygen, sulfur, oxycarbonyl, carbonyloxy, carbonamide, amidocarbonyl, sulfinyl or sulfonyloxy group

Cycl denotes cyclic alkyl residue with 5-7 C atoms or phenyl, and the carbon atom in the ring may be replaced by nitrogen, and saturated or SUB>1-C10-allylmercaptan or halogen,

m denotes 0, 1, 2 or 3,

provided that R1can be equal to R2if R2at the same time takes a value of R1, i.e., R1and R2can be interchanged in their values,

to their tautomers and their physiologically acceptable salts with inorganic and organic bases, and also to the way they are received and containing these compounds medicines.

As compounds of General formula I contain asymmetric carbon atoms, all optically active forms and racemic mixtures of these compounds are the subject of the present invention.

Therapy of malignant neoplasms (carcinoma, sarcomas, hematological neoplasia), inflammatory diseases or autoimmune diseases, and diseases caused by viruses or retroviruses, such as, for example, AIDS, ARC (related SPED the complex), infection cytomegaly and herpes or hepatitis, along with the lack of effectiveness of therapeutic active substances, often associated with their highly undesirable side effects. This effect is due to the low selectivity in vivo, respectively limitation is the cue properties of pharmacologically active substances, show them in vitro, often cannot be transferred to conditions in vivo.

So many years of trying by modifying the chemical structure of pharmacologically active substances to create new materials with improved therapeutic spectrum of action. In addition, often get new dosage forms of pharmaceuticals for the purpose them to transport the active substance is in the right place, where they must exercise their therapeutic effect. In particular, it is necessary to prevent unwanted interaction with healthy cells. In the case of tumor cells with the appropriate surface antigens were obtained, for example, antibodies that recognize these special surface antigens and thereby sighting associated with a cancer cell. Antibodies modified with suitable toxins so that after binding to a cancer cell, the toxin is released, and the cancer cell dies. Another possibility of improving therapeutic range is that by a slight modification of pharmacologically active substances, for example, by obtaining salt accession acid or. harm. Sci. 79, 531 (1990)] the physical properties of the active substance change so that was improved solubility or tolerability of the active substance. These slightly chemically modified compounds are frequently referred to as "prodrugs", as they are in contact with body fluids or in the liver (first pass metabolism) almost directly can be converted into a therapeutically active agents. Such "prodrugs" of the compounds of General formula I also include the present invention.

To improve catabolic stability carry out chemical binding of nucleosides, for example, ara-C and ara-A, with phospholipids. The corresponding derivatives are less toxic and more stable in vivo in comparison with non-modified nucleosides. However, it did not exert any influence on the absorption and permeability of cells [J. Med. Chem. 32, 367 (1989), Cancer Res. 37, 1640 (1977) and 41, 2707 (1981)] . Other phospholipid derivatives of nucleosides is described, for example, in the following sources:

In J. Biol. Chem. 265, 6112 (1990) described the preparation and use of liposuction as antiviral drugs. However, in this case was researched and manufactured vospalitelnye remains of their structure esters of fatty acids.

In J. Med. Chem, 33, 1380 (1990) described nucleoside conjugates of tiefenriede with cytidinediphosphocholine, which have antitumor activity and can find application in Oncology.

In Chem. Pharm. Bull. 36, 209 (1988) described 5'-(3-SN-phosphatidyl)-nucleosides with protivoanemicheskoe activity, as well as their enzymatic synthesis from the corresponding nucleosides and phosphocholine in the presence of phospholipase D transferase activity.

Enzymatic synthesis of liposuction also described, in particular, in Tetrahedron Lett; 28, 199 (1987) Chem. Pharm. Bull, 36, 5020 (1988).

In WO 94/13324 described orally applied active substance with 1-O-alkyl-, 1-O-acyl-, 1-S-acyl - and 1-S-alkyl-sn-glycero-3-phosphate as a carrier lipid.

In the application EP 418814, as well as in J. Med. Chem. 34, 1912 (1991) described isoprenylcysteine as inhibitors stvalentines.

In Biochem. Biophys. Res. Commun. 171, 458 (1990) described the lipid conjugate antiretroviral foscarnet with palmitostearate, and in J. Med . Chem. 20, 660 (1977) shows atni-HIV activity (hexyloxy)-hydroxyphenylarsonic acid.

In principle, significant assistance was provided by the finding efficient ways to transport therapeutic concentrations of drugs of the lymph system, considered the main reservoir of viral replication.

Postemergence acid (PFA = phosphonoformic acid) and phosphonooxy acid (PAA = phosphonoacenic acid) show high antiviral activity against herpes simplex virus (HSV) 1 and 2, influenza, hepatitis b virus (HBV), varicella zoster virus (VZV), Epstein-Barr (EVB), and retroviral infections.

Postemergence and phosphonooxy acids and their derivatives are in some cases an effective alternative to, respectively, the addition of nucleosides, as they inhibit a wide range of DNA - and RNA-polymerases, as well as RT retroviruses with sufficient selectivity.

Themselves postemergence and phosphonooxy acid due to their similarity with the pyrophosphate show toxicity due to accumulation in the bones.

Compounds according to the present invention have valuable pharmacological properties. In particular, they are suitable for therapy and prophylaxis of infections caused by DNA viruses, such as herpes simplex virus, the virus cytomegaly, papova viruses, varicella zoster virus, hepatitis virus, or Epstein-Barr, or RNA viruses, such as viruses, Toga, or, in particular, retro the human immunodeficiency virus HIV-1 and 2.

Particularly suitable compounds of the formula I for the treatment of clinical manifestations of retroviral HIV infection in humans, such as prolonged generalized lymphadenopathy (PGL), advanced stage AIDS related complex (ARC) and the full clinical picture of AIDS and associated viral infections cytomegaly (CMV) and herpes simplex (HSV).

In J. Infect. Dis. 172, 225 (1995) described the anti-virus/anti-retroviral effect of foscarnet (trinacria salt phosphonopropionic acid/phosphonomycin acid) anti-HIV patients with CMV-retinitis.

Antiviral effects in a mouse cytomegaly virus (CMV) is described in Antiviral Res. 26, 1 (1995).

Further, in JAMA 273, 1457 (1995) described the treatment of CMV-retinitis using phosphonopropionic acid.

The conjugates of postemergence and phosphonooxy acid with 2', 3'-dideoxy-3'-thiacytidine inhibiting HIV-1 replication, as described in J. Med. Chem. 37, 2216 (1994), and in J. Pharm. Sci. 83, 1269 (1994) described a complex aryloxyalkyl esters foscarnet.

Of particular interest are the application of the U.S. 5194654, respectively PCT application WO 94/13682. They describe lipid derivatives phosphonocarboxylate acids and their application in the liposomes with the formation of particularly stable lipni 1-O-alkyl-sn-glycero-3-phosphonocrotonate acid, which are particularly well integrated into the double lipid layer of the liposome. The stated alkyl residues can contain from 2 to 24 carbon atoms, but they are not substituted.

In the example described and confirmed by the data about antivirus action only connection 1-O-octanediol-sn-glycero-3-phosphonoformate (batil-phosphonoformate). In the research, and when receiving the connection was unstable. In contrast to the mentioned patent applications this compound was used as a pure substance in solution/suspension, and not in the liposomes.

Proposed according to the present invention compounds of General formula I in the same conditions for sustainable and have both in vitro and in vivo model in mice) are obvious advantages.

Esters lipidosterolic acids in vitro have the same efficiency as the corresponding free carboxylic acid. In vivo they are, however, show clear advantages, particularly in oral introduction. Esters of carboxylic acids of formula I are subject to less degradation in the acidic environment by decarboxylation and, therefore, provide associated with this is the best bioavailability. In accordance with the agrees permeability through the membrane, for example, when overcoming the blood-brain barrier and the passage through the cell membrane into the target cell. As an ester of carboxylic acid in vivo must be cleaved by esterases, the half-life in serum is lengthened.

The compounds claimed in this application, is an interesting addition to the publications WO 94/13682 and US 5194654, however, they are not described in these applications.

The compounds of formula I are new. Along with higher resistance (in substance and in solution) of the claimed compounds they are still the best action in comparison with known lipid derivatives.

Unexpectedly, it was found that pharmaceutically active substances of the formula I possess in comparison with the pharmacologically active unbound, respectively unmodified substances broader therapeutic spectrum. In addition, they improve their time in the body, bioavailability and is often known as a critical factor permeability through the membrane (e.g., blood-brain barrier, the cell membrane, and so on ). The compounds of formula I are thus as a carrier system for pharmacologist who owned the escrow system drugs the system of targeting drugs and drug delivery. They cause pharmacologically active substance after oral administration released inside the cell, and this release, preferably, does not occur in all cells, organs or tissues of the body, but only sighting in these cells, which contain a specific enzyme. However, it is particularly striking that the cleavage takes place not during the transport of the substrate in body fluids such as blood, serum or lymph fluid, or in the liver, but only on or in the respective target cells. This prevents unwanted selection phosphonocarboxylates acid kidney or cleavage of the conjugate in the liver, allowing a much larger part of the active substance is transported on or in appropriate target cells. Such cells, as already mentioned above, are, in particular, physiologically or pathophysiologically activated cells, which can be used as a target for delivery of pharmacologically active substances, for example, peripheral blood leukocytes, lymphocytes, macrophages and other cell populations immunology of the lymphatic system. If this is Ah, platelets, monocytes, and so on ), which play a pathophysiological or symptomatic role in specific pathological process. In addition, we have in mind also the cells infected with viruses, bacteria, fungi, or other microorganisms.

Unexpectedly, it was also found that therapeutic range of pharmacologically active phosphonocarboxylates acid and its esters is significantly improved, if the substance is associated with a very special lepidobalanus molecule-carrier. Thus obtained conjugate serves as a new active substance to obtain the dosage forms of the pharmaceutical preparation. The General result of this binding is enhanced activity of pharmaceutically active phosphonocarboxylates acid in vivo, because the resulting system of escrow, shipping and transport of the drugs causes localization of pharmacologically active substances in the target cells and thus improves the efficacy and tolerability of pharmacologically active substances. This means that, on the one hand, prescribed dosage pharmacologically active phosphonocarboxylates acid can be reduced, and on the other hand, when the same effective as dostate released from the conjugate by enzymatic hydrolysis of the conjugate.

The conjugates of formula I have obvious advantages in comparison with unconjugated pharmaceutically active phosphonocarboxylates acid, respectively, with its esters. Specific covalently associated with the pharmaceutically active substance carrier improves the bioavailability of poorly rezorbiruetsa pharmaceutically active substances, tolerance to potentially toxic active molecules, time quickly removed or metabolisable medicines and penetration through the membrane compounds with poor membrane permeability (for example, through the blood-brain threshold, cells, and so on ).

Enzymatic cleavage of the lipid component in vivo occurs, as a rule, not in the serum, but only inside cells. In addition, the component carrier improves its lecithinase structure, which is essential for the discussed effect, penetration through the membrane pharmaceutically active substances and contributes to the effect of the Deposit. In addition, gastrointestinal tolerability lipid conjugates many times better in comparison with pure pharmaceutically active phosphonocarboxylates acid. And when resorption lipid conjugate is better penetrates through the membrane Er, through the blood-brain barrier.

Further, due to better binding of the conjugate to plasma and tissue proteins improves the distribution in vivo. In the normal biotransformation conjugate initially oxidized from tiefer in sulfoxide, which, however, due to the equal action sulfoxide in comparison with tieferen is not a disadvantage. Slow release of pharmaceutically active phosphonocarboxylates acid of the conjugate provides a low, but constant for a long period of time the active substance, and thereby improves its action and/or eliminates toxic side effects. Released pharmaceutically active substance in the form of monophosphate due to its high hydrophilic properties no longer leaves the cell.

The half-lives of pharmaceutically active substances in the organism as a whole and in cell bodies due to conjugation significantly increase because of longer residence time of the conjugate in the body. Because there is no splitting activity in serum and in various organs, it is almost not observed or observed only a very slight toxicity to bone m the various target organs, tissues or cells.

The compounds of formula I can be used as active substances to obtain drugs used to treat those diseases which are required or useful high levels of pharmaceutically active substances in cells, organs or tissues. Essential to this system, referred to as the escrow system, delivery and targeting of drugs, is that interesting in the sense of planned therapy cells have an enzyme cleavage, so that at the first stage, the active substance is bound and then transported across the cell membrane into the cell and cleavage of the active substance in a physiologically active phosphonocarboxylate acid occurs essentially simultaneously with the transport through the cell membrane or later partly inside the cell. Intracellular cleavage occurs, in particular, in cases where the enzyme cleavage also localized within the cell.

Suitable target cells are, in particular, the immunological cells of the lymphatic system (e.g., peripheral blood leukocytes, monocytes, macrophages, lymphocytes) or infected cells.

It has been unexpectedly takii virus-specific DNA, accordingly RNA transcription. These substances can have, through the inhibition of the reverse transcriptase enzyme, the effect on the multiplication of retroviruses (see Proc. Natl. Acad. Sci. USA 83, 1911, 1986 or Nature 325, 773, 1987). Special therapeutic interest inhibitory effect on HIV-the virus that causes the disease is human immunodeficiency (AIDS). For the treatment of AIDS currently admitted 3'-azido-3'-deoxythymidine (DE-A-3608606). However, toxic side effects of 3'-azido-3'-deoxythymidine on the bone marrow in approximately 50% of patients require a blood transfusion. Compounds of General formula I do not have these disadvantages. Their antiviral activity is not associated with cytotoxicity in pharmacologically relevant doses.

Compounds according to the present invention and their pharmaceutical preparations can also be used in combination with other drugs for treatment and prophylaxis of the abovementioned diseases. Examples of these other drugs include tools that can be used for the treatment and prevention of HIV infections or diseases that accompany this disease, such as 3'-azido-3'-deoxythymidine, 2', 3'-dideoxynucleoside, such as 2', 3'-dideoxycytidine, 2', 3'-dimethoxyethane protease, such as, for example, invirase, interferons, such as interferon, cytokines and interleukins (e.g. interleukin 16), chemokines, such as, for example, MIP1 , MIP1 , CC1, inhibitors of the renal secretions, such as, for example, probenecid, an inhibitor of the transport of nucleosides, such as, for example, dipyridamole, as well as immunomodulators such as interleukin II or stimulating factors, such as, for example, factors, colony stimulating granulocyte-macrophage (GM-CSF), factors stimulating colony of granulocytes (G-CSF, metropoitan), thrombopoietin and thrombopoietin-like factors. Compounds according to the present invention and the other drug can be used each separately, possibly at the same time, respectively, in a single dosage form or in two different dosage forms, or at different times, so that the synergy effect.

As possible salts of compounds of General formula I can be treated primarily salts of alkali and alkaline earth metals and ammonium carboxyl and phosphonate group. As the alkali metal salts are preferred salts are lithium, sodium and potassium. As salts of the alkaline earth metal is omahuta salt, containing ammonium ion, which can be substituted by up to four alkyl residues with 1 to 4 carbon atoms and/or Uralkalij residues, preferably, benzyl residues. The substituents can be identical or different.

In formula I, the residue R1preferably refers to a linear, saturated alkylenes chain, where "e" denotes 5-12 carbon atoms. Cycl, preferably, is a tsiklogeksilnogo or cyclopentadienyl residue, respectively phenyl, which is optionally substituted C1-C4-alkyl or halogen. X and Y independently of one another preferably represent sulfur, sulfinil, sulfonyl, oxygen or a valence bond. Particularly preferably, when X is sulfur, and Y is oxygen. Balance -(CH2)e-Cycl, preferably, is in position 3 C3-the basics, "e", especially preferably equal to 6-10, (CH2)e-Cycl, particularly preferably denotes phenylhexa or cyclohexyl-hexyl. Preferred alkyl residues for R2are linear or branched, saturated or unsaturated alkyl chain with 8 to 12 carbon atoms. Especially preferred alkyl residues detailname paired phosphonocarboxylate acids in the proposed conjugates of General formula I are:

- postemergence acid,

- phosphonooxy acid,

- phosphonopropionic acid.

Compounds of General formula I can be obtained by the fact that

1. the compound of General formula II

< / BR>
in which R1, R2and n have the above meanings, is subjected to the interaction with the compound of General formula III,

< / BR>
in which m and R3have the above significance and R3preferably represents C1-C6is an alkyl residue, in the presence of, if necessary substituted acid chloride arylsulfonic acid in an organic basis, respectively, in the presence of a base in an inert organic solvent, and then an ester of carboxylic acid is transferred by alkaline saponification in a derived formula I, respectively in its physiologically acceptable salt,

or

2. get a mixed anhydride of the compound of formula III and the acid chloride alkyl - or arylsulfonic acid and injected it into reaction with the alcohol of formula II in the presence of a base in an inert organic solvent, respectively, directly at the base, and then, if necessary, subjected to an ester of carboxylic acid to alkaline saponification,

m of formula II in the presence of a base and, if necessary, substituted acid chloride arylsulfonic acid and, if desired, transferred to a physiologically acceptable salt or ester,

or

4. a mixed anhydride of the compound of formula III, in which3denotes hydrogen, and the acid chloride alkyl - or arylsulfonic acid is injected into reaction with the alcohol of formula II in the presence of a base, respectively, in an inert organic solvent, conjugate and translate, if necessary, in a physiologically acceptable salt,

or

5. dichlorohydrin phosphonic acids of General formula IV

< / BR>
which can be obtained according Bangle al. (Synthetic Commun. 17, 1071 (1987)), on the basis of the complex bis-trimethylsilyl ether phosphonic acid by subsequent interaction with oxalylamino, is subjected to interaction with alcohol of General formula II in the presence of a base in a molar ratio of 1: 1,

or

6. the compound of formula III is transferred using oxalicacid, as described in Tetrahedron Letters 33, 7473 (1992), in the appropriate dichlorohydrin phosphonic acid of the formula IV, which is then subjected to interaction with alcohol of formula II in the presence of a base in a molar ratio of 1: 1. Received as romanovas acid by alkaline saponification in a derived formula I, accordingly, in its physiologically acceptable salt.

Obtaining compounds of General formula II are described in the examples in EP 0545966.

Containing the compounds of formula I of the medicinal product for the treatment of, for example, viral infections may be applied in liquid or solid form interline or parenteral. An acceptable common forms of application, for example, tablets, capsules, pills, syrups, solutions or suspensions. As injection medium preferably use water containing conventional in injection solutions of additives, such as stabilizers, agents dilution buffer and mix. Such additives are, for instance, tartrate and citrate buffer, ethanol, complexing agents such as ethylenediaminetetraacetic acid and its non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide to regulate viscosity.

Liquid carriers for injection solutions must be sterile, and preferably, they poured into the ampoules. Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, more high molecular weight fatty acids such as stearic acid, gelatin, such as glycols, etc. Preparations suitable for oral administration, optionally, may contain flavorings and sweeteners.

The dosage may depend on various factors such as method of application, type of disease, age and individual condition of the patient. Compounds according to the invention is usually used in an amount of from 0.1 to 100 mg, preferably from 0.2 to 80 mg per day and kg body weight. The daily dose is preferably divided 2-5 techniques, and at each visit take 1-2 tablets with a content of active substance of from 0.5 to 500 mg Tablet can also be retardirani, so the number of doses per day is reduced to 1-3. The content of the active substance in retardirovannah tablets can range from 2 to 1000 mg. of Active substance may be administered by continuous infusion, and, as a rule, sufficient quantity of from 5 to 5000 mg per day.

In addition to the compounds mentioned in the examples and the resulting combination of all mentioned in the claims of the values of the substituents in the scope of the present invention can be considered, the following compounds of formula I:

1. ((3-(4-Chlorophenyl)Gex is iblogextensibility)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid.

3. [3-(Phenyl)oxy meximerica)-2-decyloxy] propoxy)- hydroxyasparagine acid.

4. [3-(Phenyl)getelementat)-2-decyloxy] propoxy)- hydroxyasparagine acid.

5. Pentalogy ether ((3-(6-cyclohexylcarbamate)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid.

6. [3-(m-Ethylphenyl)decelerate-2-decyloxy] propoxy)- hydroxyasparagine acid.

7. [3-(p-tert-Butylphenyl)artillerie-2-decyloxy] propoxy - hydroxyasparagine acid.

8. [3-(Cyclohexyl)getelementat-2-decyloxy] propoxy - hydroxyasparagine acid.

9. [3-(Cyclopentyl)noninterrupt-2-decyloxy] propoxy - hydroxyasparagine acid.

10. [3-(Cycloheptyl)artillerie-2-decyloxy] propoxy - hydroxyasparagine acid.

11. [3-(Cyclohexyl)oxy Intermarket-2-decyloxy] propoxy - hydroxyasparagine acid.

12. [3-(Cyclohexyl)mercapto-Intermarket-2-decyloxy] propoxy - hydroxyasparagine acid.

13. [3-(Phenyl)undecylenate-2-decyloxy] propoxy - hydroxyasparagine acid.

14. [3-Dodecylmercaptan-2-(phenyl)Huck is ripto] propoxy - hydroxyasparagine acid.

16. [3-(p-Chlorophenyl)meximerica-2-decyloxy] propoxy - hydroxyphenylacetate acid.

17. [3-(p-tert-Butylphenyl)oxy acceleroto-2-decyloxy] propoxy - hydroxyphenylacetate acid.

18. Benzyl ether of ((3-(6-cyclohexylcarbamate)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid.

19. [3-(Phenyl)getelementat-2-decyloxy] propoxy - hydroxyphenylacetate acid.

20. [3-(p-Chlorophenyl)hydroxy-Intermarket-2-decyloxy] propoxy - hydroxyphenylacetate acid.

21. [3-(m-Ethylphenyl)decelerate-2-decyloxy] propoxy)- hydroxyphenylacetate acid.

22. [3-(p-tert-Butylphenyl)-artillerie-2-decyloxy] propoxy - hydroxyphenylacetate acid.

23. [3-(Cyclohexyl)getelementat-2-decyloxy] propoxy - hydroxyphenylacetate acid.

24. [3-(Cyclopentyl)noninterrupt-2-decyloxy] propoxy - hydroxyphenylacetate acid.

25. [3-(Cycloheptyl)artillerie-2-decyloxy] propoxy - hydroxyphenylacetate acid.

26. [3-(Cyclohexyl)oxy Intermarket-2-decyloxy] propoxy - hydroxyphenylacetate acid.

27. [3-(Cyclohexyl)mercapto-Intermarket is propoxy - hydroxyphenylacetate acid.

29. [3-Dodecylmercaptan-2-(phenyl)meximerica] propoxy - hydroxyphenylacetate acid.

30. [3 Decyloxy-2-(cyclohexyl)meximerica] propoxy - hydroxyphenylacetate acid.

31. [3-(p-Chlorophenyl)meximerica-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

32. [3-(p-tert-Butylphenyl)oxy acceleroto-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

33. [3-(Phenyl)oxy meximerica-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

34. [3-(Phenyl)getelementat-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

35. [3-(p-Chlorophenyl)hydroxy-Intermarket-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

36. [3-(m-Ethylphenyl)decelerate-2-decyloxy] propoxy)- hydroxyphenylpropionic acid.

37. [3-(p-tert-Butylphenyl)artillerie-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

38. [3-(Cyclohexyl)getelementat-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

39. [3-(Cyclopentyl)noninterrupt-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

40. [3-(Cycloheptyl)artillerie-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

42. [3-(Cyclohexyl)mercapto-Intermarket-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

43. [3-(Phenyl)undecylenate-2-decyloxy] propoxy - hydroxyphenylpropionic acid.

44. [3-Dodecylmercaptan-2-(phenyl)meximerica] propoxy - fosforilirovanija acid.

45. [3 Decyloxy-2-(cyclohexyl)meximerica] propoxy - hydroxyphenylpropionic acid.

46. Butyl ether ((3-(6-cyclohexylcarbamate)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid.

47. Ethyl ester of ((3-(6-familycentered)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid.

48. Propyl ether ((3-(6-familycentered)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid.

49. tert-Butyl ether ((3-(6-familycentered)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid.

50. (2-Dimethylamino)ethyl ester of ((3-(6-familycentered)-2-decyloxy)- propoxy)- hydroxyphenylpyruvic acid.

Example 1

R, S-((3-(6-familycentered) -2-decyloxy)-propoxy)- hydroxyasparagine acid, Dontsova salt 1 (Ph6S10OP-PFA)

6-Phenyl-1-hexanethiol 13

In the atmosphere azo is, alvarenga in 40 ml of ethanol, to the solution of 7,10 g (93,3 mole) of thiourea in 30 ml of ethanol. After incubation for 7 h at the temperature of reflux distilled cooled to room temperature, mixed with 33 ml of concentrated ammonia and heated for 4 h under reflux. Then acidified with 15 ml of concentrated HCl to pH 1. Extracted three times each time with 200 ml of ether, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and remove the solvent in vacuo. The residue is dissolved in dichloromethane, the solid is sucked off, optionally washed with dichloromethane and the filtrate concentrated in vacuo. Get 9.80 g (82%) of 13 as a colorless oil.

R, S-2-Decyloxy-3- (6-familycentered)-1-propylbenzoate 14

In the atmosphere of nitrogen load 9.60 g (49,4 mmole) 13 and 6.80 g (49,4 mmole) of potassium carbonate in 100 ml of methyl ethyl ketone, stirred for 15 min and then mix from 19.7 g (49,4 mmole) of 3-bromo-2-decyloxy-1-propyl-benzoate 12 (EP 0545966) and a crystal of potassium iodide. After adding 5 ml of dimethylformamide is stirred for 48 h at room temperature. The potassium carbonate is sucked off, the residue is washed with heptane and the filtrate concentrated in vacuo. The residue is dissolved in water, extracted with heptane and promis%) 14, which is used without further purification for the synthesis of 15.

R, S-2-Decyloxy-3- (6-familycentered)-1 - propanol 15

Under nitrogen atmosphere a mixture of 25.5 g (49,7 mmole) 14, 30 ml of ethanol and 12 ml (60,0 mmole) 5 N. NaOH is stirred for a total of 48 h at room temperature. Concentrated in vacuo, dissolved in water, extracted with dichloromethane, washed with 1 N. NaOH, water, dried over magnesium sulfate and remove the solvent in vacuo. Gain of 18.9 g (93%) of product, raw. Cleaning produced by flash chromatography on silica gel (mobile phase: heptane/ether acetic acid 7: 1), and allocate 12.8 g (63%) of 15 as a colorless oil.

Methyl ester dichlorophenylamino acid 16

In nitrogen atmosphere of 28.2 g (99,2 mmole) of a compound methyl ester di-(trimethylsilyloxy)-hydroxyphenylpyruvic acid (Synthetic Commun. 17, 1071 (1987), Tetrahedron Lett. 33, 7473) is dissolved in 150 ml of dichloromethane and 5 drops of dimethylformamide and added dropwise at 0oC within 30 min of 37.8 g (0,297 mmole) of oxalicacid. After 2 h stirring at room temperature the solvent is removed in vacuo and distilled in high vacuum. Get 12,1 g (69%) 16, TKip= 42-45oC/0,19 mbar.

Methyl ester of R, S-((3-fere nitrogen 1.50 g (8,48 mmole) of a compound of methyl ether of dichlorophenylamino acid 16 was dissolved in 15 ml dichloromethane and cooled to 5oC. for 15 minutes is added dropwise a mixture of 3.50 g (8,48 mmole) of R, S-2-decyloxy-3-(6-familycentered)-1-propanol 15 and 900 mg (8,48 mmole) of triethylamine, dissolved in 20 ml of dichloromethane, and the temperature rises to 10oC. After 30 min stirring at 10oC is stirred for further 3 h at room temperature and then poured into a solution of 7.85 ml of 1 N. NaOH and 200 ml of ice water. Twice extracted, each time with 100 ml dichloromethane, washed the combined organic phases with water and dried over magnesium sulfate. After removal of solvent in vacuo obtain 4.3 g (95%) of oil, which is purified by flash chromatography on silica gel. After elution of unspent 15 (1.35 g, mobile environment: the ester of acetic acid), and manifestations of dichloromethane/methanol 10: 1 gain in total 2,52 g (56%) 17 (example 21) in the form of a colorless oil.

In nitrogen atmosphere mix a mixture of 2.50 g (4,71 mmole) 17, 20 ml ethanol and 20 ml of tetrahydrofuran with 4.7 ml (14,1 mmole) 3 N. NaOH. Stirred for 2 h at room temperature, removing the solvent on a rotary evaporator, the residue is dissolved in 250 ml of water and extracted twice each time with 50 ml tert-butyl methyl ether. Bring the pH of the aqueous phase to a value of 8.5 is

Example 2

The disodium salt of R, S-((3-(12-fielddeclaration)-2-decyloxy)- propoxy)-hydroxyphenylpyruvic acid 2 (Ph12S10OP-PFA)

12-Phenyl-1-dodecanthiol

18 at the time of receipt 13 (example 1), 15.0 g (46,1 mmole) 1-bromo-12-phenyl-dodecane is subjected to interaction with 5.3 g (69.2 mmole) of thiourea. Obtain 11.1 g (87%) 18.

R, S-2-Decyloxy-3-(12-finaldecision)-propyl-benzoate 19

Of 10.8 g (38,8 mmole) and 15.3 g (38,8 mmole) 12 gain of 20.0 g (92%) 19.

R, S-2-Decyloxy-3-(12-finaldecision)-propanol 20

Hydrolysis and 4.40 g (7,37 mmole) 19 with 3.0 ml (15 mmole) 5 N. NaOH get is 3.08 g (85%) of 20 as a colorless oil.

Analogously to example 1 from 1,90 g (9,95 mmole) 16 and of 4.90 g (9,95 mmole) of R, S-2-decyloxy-3- (12-fielddeclaration)-1 - propanol 20 get 3,39 g (52%) of a compound methyl ester of R, S-((3-(12-fielddeclaration)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid (example 12.22) as a colourless oil. After saponification with sodium hydroxide solution (as in example 1) get 2,90 g (94%) 2 with TPL224oC.

Example 3

The disodium salt of R, S-((3-(10-fenilcetonuria)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid 3 (Ph10S10OP-PFA)

Analogously to example 1 from 1.10 g (6,29 mmole) 16 and of 2.92 g (6,29 mmole) of R, S-2-decyloxy-3- (aloxi)-propoxy)- hydroxyphenylpyruvic acid (example 12.23) in the form of a colourless resin. After saponification with sodium hydroxide solution (as in example 1) obtain 0.71 g (79%) 3 with TPL219-220oC.

Example 4

The disodium salt of R, S-((3-(5-(4-chlorophenyl)- pantellerite)-2-decyloxy) -propoxy)- hydroxyphenylpyruvic acid 4 (CIPh5S10OP-PFA).

Analogously to example 1 from 1.10 g (6,29 mmole) 16 and 2.70 g (6,20 mmole) of R, S-2-decyloxy-3- (5-(4-chlorophenyl)-pantellerite)- 1-propanol get 3,30 g (97%) of a compound methyl ester of R, S-((3-(5-(4-chlorophenyl)-pantellerite)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid (example 12.24) as a colourless oil. After saponification 2,80 g of the ester with sodium hydroxide solution (as in example 1) get 2,90 g (96%) 4 with TPL170-172oC.

Example 5

The disodium salt of R, S-((3-(10-(4-tert-butylphenoxy)-decelerate)-2-decyloxy)-propoxy)- hydroxyasparagine acid 5 (tBuPhO10S10OP-PFA).

Analogously to example 1 from 1.10 g (6,20 mmole) 16 and 3,34 g (6,20 mmole) of R, S-2-decyloxy-3- (5-(4-tert-butylphenoxy)-decelerate)-1 - propanol obtain 1.92 g (58%) of a compound methyl ester of R, S-((3-(5-(4-tert-butylphenoxy) -decelerate)-2-decyloxy) -propoxy)- hydroxyphenylpyruvic acid (example 12.25) as a colourless oil. After saponification with sodium hydroxide solution (similar to primacy)-propoxy)- hydroxyphenylpyruvic acid 6 (CH5S10OP-PFA)

Analogously to example 1 from 1.10 g (6,20 mmole) 16 and 2.48 g (6,20 mmole) of R, S-2-decyloxy-3-(5-cyclohexylaniline)-1-propanol get 2,60 g (81%) of a compound methyl ester of R, S-((3-(5-cyclohexylaniline)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid (example 12.26) in the form of a colorless oil. After saponification with sodium hydroxide solution (as in example 1) to obtain 1.50 g (92%) 6 TPL217-219oC.

Example 7

The disodium salt of R, S-((3-(6-cyclohexylcarbamate)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid 7 (CH6S10OP-PFA)

Analogously to example 1 from 1.30 grams (7,30 mmole) 16 and 3.00 g (7,30 mmole) of R, S-2-decyloxy-3- (6-cyclohexylcarbamate)-1 - propanol get 2,80 g (72%) of a compound methyl ester of R, S-((3-(6-cyclohexylcarbamate)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid (example 12.27) as a colourless oil. After saponification 2,02 g of this ester with sodium hydroxide solution (as in example 1) receive a 2.00 g (93%) 7 with TPL199-202oC.

Example 8

The disodium salt of R, S-((3- (12-cyclohexyldimethylamine)-2-decyloxy) -propoxy)- hydroxyphenylpyruvic acid 8 (CH12S10OP-PFA)

Analogously to example 1 from 0.55 g (3,10 mmole) 16 and 1.50 g (3,10 mmole) of R, S-2-decyloxy-3-(12-cyclohexanol is siloxy)-propoxy)- hydroxyphenylpyruvic acid (example 12.28) as a colourless oil. After saponification of 1.50 g of this ester with sodium hydroxide solution (as in example 1) to obtain 1.10 g (71%) 8 TPL105-107oC.

Example 9

The disodium salt of R, S-((3-(8-cyclohexylcarbamate)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid 9 (CH8S10OP-PFA)

Analogously to example 1 from 1.10 g (6,29 mmole) 16 and 2.75 g (6,29 mmole) of R, S-2-decyloxy-3-(8-cyclohexylcarbamate)-1-propanol get 2,40 g (68%) of a compound methyl ester of R, S-((3-(8-cyclohexylcarbamate)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid (example 12.29) as a colourless oil. After saponification of 1.37 g of this ester with sodium hydroxide solution (as in example 1) obtain 0.95 g (68%) 9, the decomposition at > 250oC.

Example 10

The disodium salt of R, S-((3-(10-cyclohexylcarbamate)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid 10 (CH10S10OP-PFA)

Analogously to example 1 from 1.10 g (6,29 mmole) 16 and 2,96 g (6,29 mmole) of R, S-2-decyloxy-3-(10-cyclohexylcarbamate)-1-propanol get to 1.15 g (37%) of a compound methyl ester of R, S-((3-(10-cyclohexylcarbamate)-2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid (example 12.30) as a colourless oil. After saponification with sodium hydroxide solution (as in example 1) to obtain 1.06 g (89%) bezruki) -propoxy)- hydroxyphenylpyruvic acid 11 (CIPhO5S10OP-PFA)

Analogously to example 1 from 1.10 g (6,29 mmole) 16 and 2,80 g (6,29 mmole) of R, S-2 - decyloxy-3-(5-(4-chlorphenoxy)-pantellerite)-1-propanol obtain 1.27 g (36%) of a compound methyl ester of R, S-((3-(5-(4-chlorphenoxy) -pantellerite)-2-decyloxy)- propoxy)- hydroxyphenylpyruvic acid (example 12.31) as a colourless oil. After saponification with sodium hydroxide solution (as in example 1) gain of 1.34 g (99%) 11 with the consistency 7, TPL175-177oC.

Example 12

Analogously to examples 1-11 receive contained in table 1, examples on the application 21-51 (see the end of the description).

Selected NMR data and the values of Rfexamples 1-11 and 12.21-12.51

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These values of Rfwere obtained on the finished silikagelevye plates 60F254DC Merck, Darmstadt (material N 5715) when the coating weight of 10 ág/ál with a fluid medium 36 (isopropanol/butyl acetate/water/ammonia 50: 30: 15: 5, about. /about. ). Detection was carried out using a spray reagent HCl, Perlina acid. These13C-offsets refer to the carbonyl carbon atom (doublet, J = 250 Hz).

Example 13

Test Filipino-foscarnet conjugates in a murine model of cytomegaly virus (MCMV) in vivo

Tested various Filipino-foscarnet the control animals, who were given placebo, survival after infection with a virus MCMV on day + 9 after infection (table 2).

Animals were infected (except control I and II), introducing each animal at 2105plaque-forming units (PFU) intraperitoneally on day 0. All animals (except control (I) day - 1 suppressed the immune response with 100 mg/kg cyclophosphamide (oral). All experimental animals were daily injected intraperitoneally a single dose of 30 mgkg-1day-1starting from day 0 (+1 h after infection) and ending at +8. From each group were taken for 10 animals. The number of surviving animals was determined on day +9.

As follows from the table. 2, in the control group III (group 3), which gave a PBS placebo (= hospitallevel buffer solution), survived until day +9 only 1 animal out of 10. In this test demonstrated the effectiveness of all tested compounds. With regard to survival time, for the tested substances was obtained characteristic correlation between structure and effect, and the most active compounds were TBUPHO10S10OP-PFA, CLPH5S10OP-PFA and PH6S10OP-PFA.

Determination of antiviral activity of conjugates derived foscarnet

1. Materials and methods

1.1 Analysis of syncytial viral nl the CI was used to assess compounds for activity against infection of HIV-1, as described Kucera 1990, AIDS Research &Human Retroviruses 6, 491-501. The monolayer CEM-SS (T-lymphocytes) was prepared by dispensing cells in the amount of 50,000 in 50 μl of RPMI-1640 medium in the absence of serum in each well treated with poly-L-lysine 96-well microtiter tablet. The monolayer of cells formed after 30 minutes incubation at 37oC was insulinomas 30-60 units of HIV-1, contributing to the formation of plaques in the medium RPMI-1640, promoting growth. After 120 minutes of adsorption of the virus, the infected monolayer cells were covered with 100 µl of medium growth with the addition of serial dilutions of the tested compounds. The highest concentration of the tested compounds was twice or more lower than the IC50for toxicity to the cells. The control consisted of a serial dilution of AZT. All plaques were incubated at 37oC in a humid atmosphere containing 5% CO2and 95% air. After three days of incubation were added to the second layer from the top in the amount of 100 µl of medium growth dilution test or control compounds, and incubated at 37oC for 5 days. Plaques were counted using a lens with a 10x zoom and a weak microscope. The value of the IC50for antiviral activity against virus HIV-1 raspisannoj Chou with TCS. and Piantadosi with TCS. in J. Med. Chem. , 1991, 34, 1408-1414.

The hepatitis B virus (HBV)

Compounds were tested for activity against virus HBV, using the cell line of hepatoblastoma person that is infected with HBV (HepG2 2.2.15), as described Korba and Gerin 1992, Antiviral Research, 55-70.

Cells in the number of 5104in the phase of logarithmic growth were placed in 96-well microtiter tablet using DMEM, 10% fetal bovine serum, L-glutamine, penicillin and streptomycin (growth medium). After 2 hours incubation at 37oC upper layer of the medium was removed and placed in fresh growth medium containing serial concentrations of the tested compounds. Each concentration of the tested compounds was determined in three holes. The top layer of the medium was transferred daily, excluding weekends, in fresh medium containing the same concentration of the test compound in a total of 10 days. After 10 days the top layer of medium containing particles of HBV, were analyzed for the formation of "e" antigen of hepatitis B virus, using commercially available EIA (INCSTAR Corp. Stilwater, MN). Monolayers of cells were investigated in the IC50using the test of neutrality to the red paint.

2. Results

Antiviral activity against the government. These data demonstrate a direct link structure of the compound and its activity.

Example 14

Calcium salt of methyl ester of R, S- ((3-(8-cyclohexyl-artillerie) -2-decyloxy)-propoxy)- hydroxyphenylpyruvic acid

The free acid was obtained according to example 12.29 and dissolved in methanol. By adding an aqueous solution of calcium acetate precipitated calcium salt and an hour at room temperature were stirring.

The solid was aspirated, washed with methanol and acetone and dried in an oven under vacuum at a temperature of 40oC.

Yield: 89%, So pl. 198-199oC, Rf= 0,63 (Polygram SIL G/UV254, Macharey & Nagel, 805021, 0.2 mm; eluent chloroform/methanol/conc. ammonia at a ratio of 70/30/4).

1. Phospholipid derivatives phosphonocarboxylate acids of General formula 1

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in which R1denotes the group -(CH2)eCycl, in which - (CH2)edenotes a linear or branched saturated alkylenes chain, where e is an integer from 4 to 16, with one of the carbon atoms, starting from position 3, may be replaced by oxygen atom;

R2denotes a linear saturated alkyl C Y denotes oxygen;

X is sulfur;

l denotes cyclic alkyl residue with 5-7 C-atoms or phenyl, and saturated or aromatic ring can be single - or multi-substituted C1-C10-akilam,1-C10-alkoxy or halogen;

m denotes 0, 1 to 3, provided that R1can be equal to R2if R2at the same time denotes R1,

their physiologically acceptable salts with inorganic and organic bases.

2. Connection on p. 1, in which R2denotes a linear saturated alkyl chain with 8 to 12 carbon atoms.

3. Join one of the p. 1 or 2, in which R3is not hydrogen.

4. Join one of the PP. 1-3, in which m denotes 0, 1 or 2.

5. Join one of the PP. 1-4, in which R3denotes methyl, ethyl, propyl, butyl, tert-butyl.

6. Join one of the PP. 1-5, in which e denotes 6-10.

7. Join one of the PP. 1-6, in which l denotes cyclohexyl, cyclopentyl or phenyl, if appropriate, substituted by halogen or C1-C4-alkyl.

8. Join one of the PP. 1-7, in which R2indicates nonyl, decyl, undecyl exelexis, if necessary, substituted tert-bootrom or chlorine.

10. Join one of the PP. 1-9, suitable for the treatment of viral, including retroviral diseases.

11. Medicine containing the active substance together with conventional pharmaceutical excipients and carriers, characterized in that the active substance it contains at least one compound of formula 1 according to one of paragraphs. 1-9 for the treatment of viral, including retroviral diseases.

 

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< / BR>
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