Nucleoside analogues with carboxamidine-modified monocyclic base

FIELD: medicine.

SUBSTANCE: method involves treating hepatitis C virus infection or hepatitis B virus infection by introducing carboxamidine of formula 1 or its pharmaceutically permissible salt at a dose of 0.1-40.0 mg/kg of body mass. Α-interferon is also introduced. Compound of formula 1 is in D-configuration.

EFFECT: enhanced effectiveness of treatment.

7 cl, 5 dwg

 

In this application claimed the priority of 15 February 2000, according to provisional application U.S. No. 60/182676 and from 16 June 2000 in accordance with the application U.S. serial No. 09/595365, each of which is incorporated herein by reference in full.

The scope of the invention

The present invention relates to the field of nucleoside analogues.

Prior art

Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nucleoside analog which has demonstrated efficacy in treating a viral disease as monotherapy (respiratory syncytial virus, Hall, S.; McBride, J..; Walsh, E.E.; Bell, D..; Gala, .L; Hildreth, S.; Ten Eyck, L.G.; W.J. Hall. Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection. N. Engl. J. Med. 1983, 308, 1443-1447)and in combination therapy with interferon-alpha (hepatitis C, Reichard, O.; Norkrans, G.; Fryden, A.; Braconier, J.-H.; Sonnerborg, A.; Weiland, 0. Randomized, double blind, placebo controlled trial of interferon alpha-2B with and without ribavirin for chronic hepatitis C. Lancet 1998, 351, 83-87). In a recently described studies have shown that the effectiveness of ribavirin in vivo may be the result of direct inhibition of viral replication, but also its ability to enhance mediated T cell immunity (Hultgren, S.; Milich, D.R.; Weiland, O.; Sallberg, M. The antiviral compound ribavirin modulates the T helper Typel/Type 2 subset balance in hepatitis In and With virus-specific immune responses. J. Gen. Virol. 1998, 79, 2381-2391; Ning, Q.; Brown, D.; Parodo, .; Cattral, M.; Fung, L.; Gorczynski, R.; Cole, E.; Fung, L; Ding, J. W.; Liu, M. F.; Rotstein, 0.; Phillips, M. J.; Levy, G. Ribavirin inhibits viral-induced macrophage production of tumor necrosis factor, interleukin-1, procoagulant activity fgl2 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response. J. Immunol. 1998, 160, 3487-3493; Martin, M. J.; Navas, S.; Quiroga, J. A.; Pardo, M.; Carreno, V. Effects of the ribavirin-interferon alpha combination on cultured peripheral blood mononuclear cells from chronic hepatitis To patients. Cytokine 1998, 79, 2381-2391). This immunomodulatory effect of ribavirin can be demonstrated in vitro by measuring the levels of type 1 cytokines produced by activated T cells from both humans and mice (Tarn, R. S.; Pai, C.; Bard, J.; Lim, S.; Averett, D. R.; Phan, U. T.; Milovanovic, T. Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile. J. Hepatol. 1999, 30, 376-382), as well as with other dimensions. Induction of changes in cytokine type 1 ribavirin is functionally important in vivo in murine systems (Tarn, R. S.; Lim, S.; Bard, J.; Pai, C. Contact hypersensitivity responses following ribavirin treatment in vivo are influenced by the Type 1 cytokine polarization, regulation of IL-10 expression and costimulatory signaling. J. Immunol. 1999, 163, 3709-3717).

The immune system of mammals contain two major classes of lymphocytes: b lymphocytes (cells that originate from bone marrow; and T lymphocytes (T cells), which originate from the thymus. In cells is largely responsible for humoral immunity (production of antibodies), whereas T cells are largely responsible for cell-mediated immunity is.

It is believed that T cells are subdivided into two subclasses, helper T cells and cytotoxic T cells. Helper T cells activate other lymphocytes, including b cells and cytotoxic T cells and macrophages through the release of soluble protein mediators, called cytokines, which are involved in cell-mediated immunity. Lymphokines, as that term is used here, are a subset of cytokines.

It is considered that helper T cells are subdivided into two subclasses, the cells of type 1 and type 2. Cell type 1 produce interleukin 2 (IL-2), tumor necrosis factor (TNFα) and interferon gamma (IFNγ) and are primarily responsible for cell-mediated immunity such as delayed-type hypersensitivity and antiviral immunity. In contrast, cells of type 2 produce interleukins IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13 and primarily involved in the promotion of humoral immune responses such as those observed in response to allergens, such as switching isotype antibodies lgE and lgG4 (Mosmann, 1989, Annu Rev Immunol 7:145-173).

Assume that the terms "replies" type 1 and type 2, as they are used here, include the full range of effects resulting from the induction of lymphocyte type 1 and type 2 respectively. Among other things such re what you include changing production of relevant cytokines through transcription, translation, secretion, and possibly other mechanisms, increased proliferation of the respective cells, and other effects associated with increased production of cytokines, including the effects of mobility.

The previous application (09/462714, 09/291097, 09/291093, 09/471513, 60/164365, 60/164366, 60/172097, 60/175111), each of which is incorporated herein by reference, relate to aspects of the recent discoveries of authors of inventions, including the influence of various nucleosides (defined here as including derivatives and analogs of natural nucleosides) on the selective modulation lymphocytic responses relative to each other. Among other things, the inventors have shown that the answer either type 1 or type 2 can be selectively supression, while the other one is either raised or remains relatively unaffected, and the answers either type 1 or type 2 can be selectively induce, while the other one is either supression, or remains relatively unaffected. The inventors have also discovered the surprising fact that some nukes, effective in the selective modulation of responses of type 1 and 2 relative to each other, tend to have a bimodal effect. Among others, some of nucleosides, which are prone to total suppression or induction of both activities of type 1 and type 2 includes the flax higher dose prone to selective modulation of type 1 and 2 relative to each other in lower doses.

It is shown that Viramidine™ (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride, viramidine) has activity in ten different viruses, which is comparable with ribavirin (J.. Witkowski, R.. Robins, G.P. Khare, R.W. Sidwell, J. Med. Chem., 16, 935-937, 1973; R.W. Sidwell, J. H. Huffman, D.L. Barnard, D.Y. Pifat, Antiviral Research, 10, 193-208, 1988; B. Gabrielsen, M.J. Phelan, L. Barthel-Rosa, C. See, J.W. Huggins, D.F. Kefauver, T.P. Monath, M.A. Ussery, G.N. Chmurny, E.M. Schubert, K. Upadhya, C. Kwong, D.A. Carter, J.A. Secrist III, J.J. Kirsi, W.M. Shannon, R.W. Sidwell, G.D. Kini, R.K. Robins, J. Med. Chem., 35, 3231-3238, 1992). In addition, Viramidine™ like the ribavirin is an inhibitor of IMP dehydrogenase (insimenator-dehydrogenase) (R.C. Willis, R.K. Robins, J.E. Seegmiller, Molecular Pharmacology, 18, 287-295, 1980). In addition, preliminary Toxicological studies suggest that Viramidine™ is less toxic than ribavirin (D.Y. Pifat, R.W. Sidwell, P.G. Canonico, Antiviral Research, 9, 136, 1988). Also recent research in the laboratory of the inventors (R. Tarn, K. Ramasamy Thursday, ICN Pharmaceuticals, Inc., unpublished results, 1999) revealed that Viramidine™ and ribavirin are similar immunomodulatory properties. These results together with low bioavailability and toxicity inherent in the ribavirin, has convinced the authors of the invention not only to develop Viramidine™ for other viral diseases, but will also get the other derivatives Viramidine™ including the synthesis of prodrugs of Viramidine™and perform their screening as potential antiviral agents.

The influence of other compounds representing nucleoside analogs, selective modulation lymphocytic responses relative to each other not previously studied or not documented. The inventors have discovered that a bimodal effect or selective modulation of responses of type 1 and 2 relative to each other have also been observed after administration of other compounds representing nucleoside analogues, such as proletarienne forms of these compounds.

There are many barriers to be overcome in the development of biologically active compounds to clinically useful agents. Many potent biologically active compounds will never become clinically useful agents because of their undesirable biopharmaceutical properties, which include poor bioavailability due to low penetrating ability through biological barriers such as the blood-brain barrier (BBB) and the intestinal barrier. Although the bioavailability of drugs is affected by many factors, unwanted physical-chemical properties (e.g. charge, lipophilicity potential hydrogen bonds formation, size) many of karstenii funds probably are one of the most common factors that prevent the penetration of drugs through biological barriers. Therefore, optimization of the physico-chemical properties (charge, lipophilicity, potential hydrogen bonds formation, size) of the medicinal product, is perhaps most likely common strategy for promoting the transport of drugs through the membrane barriers.

One possible optimization strategies physico-chemical properties of drugs is the strategy of prodrugs (H. Bundgaard, Design of Prodrugs, Elsevier, Amsterdam, 1985; N. Bodor, L. Prokai, W. M. Wu, H. Farag, S. Jonalagadda, M. Kawamura, J. Simpkins, Science, 257. 1698-1700, 1992; N.E. Taylor, C.V. Sloan, J. Pharm. Sci., 87, 5-20, 1998). The term "prodrug" is used to describe the agent who must undergo chemical or enzymatic conversion to an active source or drugs after the introduction, so that the metabolic product or the original remedy could be desired pharmaceutical response. By obtaining temporary and biologically reversible derivatives of some polar functional groups in small organic molecules undesirable physical and chemical characteristics (for example, the charge potential of the hydrogen bonds formation) these groups are "masked" without irreversible is th change the pharmacological properties of these molecules. This strategy very successfully applied in cases when obtaining procarcinogen derived involved the conversion of a carboxyl or hydroxyl functional groups in the ester that is easily hydrolyzed in vivo to either chemical or enzymatic means. As a promising General concept of prodrugs of the inventors expect that the introduction of other groups in the original remedy would increase its bioavailability, absorption and antiviral effects.

Although there is not yet specific mechanisms, the inventors have discovered that a huge potential benefits can be obtained by selective modulation of responses of type 1 and 2 relative to each other. The inventors have concluded, for example, that specific modulation of type 1 relative to type 2 may be useful in the treatment of a wide variety of conditions and diseases ranging from infections, infestations, tumors and hypersensitivity to autoimmune diseases.

These findings are especially important because modern treatment strategies for many of the above diseases have limited effectiveness, significant side effects, or both shortcomings. The treatment of autoimmune diseases, for example, often limiting what about the palliative measures, removing toxic antibodies (as in severe pseudoparallelism infants) and the introduction of harmful drugs, including corticosteroids, chloroxine derivatives and antimetabolites or anticancer drugs, and drugs such as cyclosporine, which focused on cells of the immune system.

Summary of the invention

The present invention relates to compounds representing new nucleoside analogs, and related compounds, such as prodrugs to their therapeutic application and synthesis.

In one aspect of the invention proposed connections, which represents a nucleoside analogs of formula 1:

In another aspect of the invention proposed pharmaceutical composition comprising a therapeutically effective amount of carboxamidine formula 1 or its pharmaceutically acceptable complex ester or salt, in a mixture with at least one pharmaceutically acceptable carrier.

In another aspect of the invention proposed pharmaceutical composition comprising Palekastro form of carboxamidine formula 1 or its pharmaceutically acceptable complex ester or salt, in a mixture with at least one pharmaceutically acceptable carrier.

The next speaker is the object of the invention is the compound according to the formula 1 is used in the treatment of any condition, when there is a positive response to the introduction of this connection, and in accordance with any drug and Protocol, in which there was a positive response. Among other things, believe that the compounds of formula 1 can be used to treat infection, invasion, cancer, tumors or other neoplasm, giant cell arteritis diagnostics or autoimmune diseases.

A brief description of graphic materials

Figure 1 is an exemplary synthetic scheme for the synthesis of compounds according to formula 1.

Figure 2 is a graphical depiction of the impact of the compounds and other compounds on the synthesis of type 1 cytokines in SEB-activated T cells.

Figure 3 is a graphical depiction of the effect of 0.625-10 μm concentrations of the compounds being considered for the synthesis of type 1 cytokines in SEB-activated T cells.

Figure 4 is a graphical depiction of the impact of the compounds on AU responses in BALB/c mice.

Figure 5 is a graphical representation of the peak response and the maximum range of the considered compounds and other compounds in relation to the synthesis of type 1 cytokines in SEB-activated T cells.

Detailed description of the invention

Where the following terms are used in this description, their use is, as defined below.

The terms "nucleoside" and "connection, which represents a nucleoside analog"are used interchangeably and refer to a compound consisting of any pentose or modified pentose group attached to a specific position of the heterocycle, aromatic heterocycle, or to the natural position of the purine (9-position) or pyrimidine (1-position), or to an equivalent position with equivalent.

The term "nucleotide" refers to a phosphate complex ether, formed by the 5'-position of the nucleoside.

The term "heterocycle" refers to a monovalent saturated or unsaturated carbocyclic to a radical, having at least one heteroatom, such as N, O or S, within the ring, each available position of which may be independently substituted, for example, hydroxy, oxo, amino, imino, lower alkyl, bromo, chloro and/or cyano. In this class alternates included purines, pyrimidines.

The term "purine" refers to nitrogen the bicyclic heterocycles.

The term "pyrimidine" refers to monocyclic nitrogen to heterocycles.

The term "D-nucleoside" refers to a nucleoside compounds that have D-robozou sugar group (e.g., adenosine).

The term "L-nucleoside" refers to a nucleoside compounds that have L-R is basnou sugar group.

The terms "L-configuration" and "D-configuration" is used throughout the present invention to describe chemical configuration ribofuranosyl group of compounds, which is stitched with pyrrolo-pyrimidine plot of the molecule.

The term "C-nucleosides" are used throughout the description to characterize the type of bond that is formed between ribose sugar group and a heterocyclic base. In the C-nucleosides this relationship starts from the position C-1 ribose sugar group and attaches the carbon atom of the heterocyclic base. The bond that is formed in the C-nucleosides, belongs to the type of carbon-carbon bonds.

The term "N-nucleosides" are used throughout the description to describe the type of bond that is formed between ribose sugar group and a heterocyclic base. In N-nucleosides this relationship starts from the position C-1 ribose sugar group and attaches the nitrogen atom of the heterocyclic base. The relationship that is formed on the N-nucleosides, belongs to the type of the carbon-nitrogen.

The term "protective group" refers to a chemical group, which is added to an atom of oxygen or nitrogen to prevent further interaction during the process of obtaining derivatives other groups in the molecule, in which locales the van this oxygen atom or nitrogen. A wide variety of protective groups for oxygen and nitrogen is known to experts in the field of organic synthesis.

The term "lower alkyl" refers to stands, ethyl, n-propylene, isopropyl, n-butile, mpem-butile, isobutyl or n-hexyl. Further examples of this term is cyclic, branched or normal chain of carbon atoms in the amount of from one to six.

The term "aryl" refers to monovalent unsaturated aromatic carbocyclic to a radical, having a single ring (e.g. phenyl) or two condensed rings (e.g. naphthyl), which can be substituted by hydroxyl, lower alkyl, chloro and/or cyano.

The term "heterocycle" refers to a monovalent saturated or unsaturated carbocyclic to a radical, having at least one heteroatom, such as N, O, S, Se or P, within the ring, each available position of which may be unsubstituted or independently substituted, for example hydroxy, oxo, amino, imino, lower alkyl, bromo, chloro and/or cyano.

The term "monocyclic" refers to a monovalent saturated carbocyclic to a radical, having at least one heteroatom such as O, N, S, Se or P, within the ring, each available position of which may be independently substituted sugar is Oh group or any other groups, like bromo, chloro and/or cyano, so this is a monocyclic ring system ultimately is aromatized [e.g thymidine].

The term "immunomodulator" and "modulator" are used here interchangeably, and they refer to natural or synthetic products, is able to modify the normal or aberrant immune system through stimulation or suppression.

The term "effective amount" refers to the amount of the compounds of formula (1), which can restore immune function to normal levels or improve immune function above normal levels in order to eliminate the infection.

The compounds of formula 1 can have multiple asymmetric centers. Accordingly you can get them in either optically active form or as racemic mixtures. In the scope of the invention as described and claimed, included individual optical isomers and their nerezisca mixtures and racemic forms of the compounds of formula 1.

The termα" and "β" indicates the specific stereochemical configuration of the substituent at an asymmetric carbon atom in the chemical structure, as shown.

The term "enantiomers" refers to a pair of stereoisomers that are non-overlapping mirror reflection of each other. The mixture pairs Anant is the Windows in the ratio of 1:1 represents a "racemic" mixture.

The term "isomers" refers to different compounds that have the same formula. "Stereoisomers are isomers that differ only by the orientation of the atoms in space.

"Pharmaceutically acceptable salt" may be any salts derived from inorganic and organic acids or bases.

Connection

Compounds representing the nucleoside analogues of the present invention, generally described by formula 1:

where chemical configuration of this connection can be an L-configuration or D-configuration. An exemplary synthesis of the considered compounds (here: Viramidine™) may follow the methodology as described below and shown in figure 1.

3-Cyano-1 -(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazole (7): a Mixture of 3-cyano-1,2,4-triazole (18,8 g, 200 mmol) (6), 1,2,3,5-Tetra-O-acetyl-β-D-ribofuranose (63,66 g, 200 mmol) and bis(para-nitrophenyl)phosphate (1 g) was placed in a RB flask (500 ml). The flask was placed in a preheated oil bath at 165-175°in a vacuum generated by a water aspirator, with stirring for 25 minutes. Displaced acetic acid was collected in a cooled in an ice trap that was placed between the aspirator and the RB flask. The flask was removed from the oil bath and allowed it to cool. When the temperature value of the flask reached about 60-70° With introduced EtOAc (300 ml) and saturated NaHCO3(150 ml) and was extracted in EtOAc. The aqueous layer was again extracted with EtOAc (200 ml). The combined EtOAc extract was washed with saturated NaHCO3(300 ml), water (200 ml) and brine (150 ml). The organic extract was dried over anhydrous Na2SO4, was filtered, and the filtrate evaporated to dryness. The residue was dissolved in ether (100 ml), which, after cooling to 0°C for 12 h gave colorless crystals. This solid substance was filtered off, washed with a minimal amount of cold EtOH (20 ml) and dried under high vacuum over solid NaOH. Output: of 56.4 g (80%). So pl. 96-97°C.1H NMR (CDCl3): δ 2.11 (s, 3H, PINES3), 2.13 (s, 3H, PINES3), 2.14 (s, 3H, PINES3), 4.22 (dd, 1H), 4.46 (m, 2H), 5.52 (t, 1H, J=6.0 Hz), 5.70 (m, 1H), 6.01 (d, 1H, CrH J=3.6 Hz) and 8.39 (s, 1H, C5H). Analytically calculated for C14H16N4O7(352,30): C, 47,73; N, 4,58; N, 15,90. Found: C, 47,70; N, 4,63; N, 16,01.

1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamidine (Viramidine™) hydrochloride (8): a Mixture of (7) (14,08 g, 40.0 mmol), NH4Cl (2.14 g, 40.0 mmol) and anhydrous ammonia (150 ml) was heated in a steel tank at 85°C for 18 hours This steel container was cooled, opened and the contents evaporated to dryness. The residue was led from MeCN-EtOH to obtain 10.6 g (95%) 8. So pl. 177-179°C.1H NMR (DMSO-d6): δ 3.44-4.2 (m, 3H), 4.40 (m, 2H), 5.04 (t, 1H), 5.29 (m, 1H), 5.74 (m, 1H), 5.87 (d, 1H, C1'H), 8.96 (bs, 3H) and 9.17 (s, 1H, C5H). Analytically calculated for C8H14ClN5O4(279,68): C, 34,35; N, Of 5.05; N, 25,04; Cl, 12,69. Found: C, 34,39; N, 5,10; N, 25,14; Cl, 12,71.

Alternative synthesis can be performed from commercially available Ribavirin™ as follows:

2',3',5'-Tri-O-acetyl-1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (9). A suspension of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Ribavirin™) (28.4 g, 116,4 mmol) of (5) in acetic anhydride (200 ml) and pyridine (50 ml) was stirred at room temperature overnight. The resulting clear solution was concentrated in vacuum to obtain a transparent foam (43,1 g, quantitatively). This foam was homogeneous according to TLC results, and it was used directly for the next stage without purification. A small amount was purified flash chromatography to obtain the analytical sample.1H NMR (300 MHz, DMSO-d6): δ 2.01, 2.08, 2.09 (3s, 9H, PINES3), 4.10 (m, 1H), 3.52 (m, 2H), 5.58 (t, 1H), 5.66 (m, 1H), 6.33 (d, 1H, J=3.0 Hz, C1H), 7.73, 7.92 (2s, 2H, CONH2), 8.86 (s, 1H, C5H-triazole). Analytically (C10H18N4O8): C, H, N.

3-Cyano-2',3',5'-tri-O-acetyl-1-β-D-ribofuranosyl-1,2,4-triazole (10). To a solution of 9 (43,1 g, 116,4 mmol) in chloroform (500 ml) was added triethylamine (244 ml), and the mixture was cooled to 0°in ice salt bath. Was added drop the phosphorus oxychloride (30,7 ml, 330 mmol) under stirring, the solution was allowed to warm to room temperature. After stirring the mixture at room temperature for 1 h, TLC (hexane/acetone 3:1) showed complete disappearance of starting material. This brown reaction mixture was concentrated to dryness in vacuo and the residue was dissolved in chloroform (500 ml). This organic solution was washed with saturated aqueous sodium bicarbonate (3×200 ml), dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was subjected to chromatography on silica gel (flash chromatography) with 20%acetone in hexane to obtain 33,14 g (81% of ribavirin) net 10 in the form of amorphous solids. This solid substance was identical in all respects to an authentic sample: so pl. 101-103°C; IR (potassium bromide) ν 2250 (CN), 1750 (C=0), cm-1.1H NMR (300 MHz, CDCl3): δ 2.04, 2.06, 2.07 (3s, 9H, acetylethyl), 4.15 (dd, 1H), 4.40 (m, 1H), 5.47 (t, 1H), 5.63 (dd, 1H), 5.95 (d, 1H, J=3.2 Hz, C1H), 8.34 (s, 1H, C5H triazole).

1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (8). To a suspension of 10 (4.0 g, to 11.4 mmol) in methanol (100 ml) was added a molar methanol solution of sodium methoxide (12 ml), and the mixture was stirred at room temperature overnight. This solution was acidified to pH 4 washed with methanol resin Dowex H+, the resin was filtered, and the filtrate concentration is Aravali to dryness in vacuum. The residue was dissolved in minimum amount of methanol (15 ml) and transferred into a pressure vessel. Was added ammonium chloride (0,61 g of 11.4 mmol) and a solution of methanol saturated at 0°With dry gaseous ammonia (75 ml), the vessel was sealed, and the solution was stirred at room temperature overnight. This solution was concentrated to dryness in vacuo and the resulting residue was led from acetonitrile/ethanol to obtain 8 in the form of a crystalline solid (2,95 g, 93%). This sample was identical in all respects to an authentic sample.

In certain pharmaceutical dosage forms, it is preferable proletarienne form compounds, especially including acylated (acetylated or other) derivatives, pyridine esters and various salt forms of these compounds, and this form you can enter by way of treatment of the patient. Ordinary skilled in the art will understand, easier to modify these connections to proletarienne forms to facilitate the delivery of active compounds to the target site within the body of the host or patient. Ordinary skilled in the art also will understand the advantage of favorable pharmacokinetic parameters proletarienne forms, where they WLL is we, upon delivery of these compounds to the target site within the body of the host or patient to maximize the intended effect of this connection.

Consider the example of education proletarienne forms of the compounds disclosed here, is the following. One of the simplest prodrugs Viramidine™ tri-O-acetyl derivative Viramidine™. It's three-O-acetyl derivative gain, as shown in figure 1:

Scheme 1

5'-Ratioline derived Viramidine™ is another simple proletarienne form and receive it as follows:

Scheme 2

Other 5'-derivatives Viramidine™ include derivatives is shown in scheme 3:

Scheme 3

Most of these compounds can be obtained as described (C. Sergheraert, C. Pierlot, A. Tartar, Y. Henin, M. Lemaitre, J. Med. Chem., 36, 826-830, 1993).

Synthesis proletarienne form Viramidine™ on the basis of coumarin can be done as follows:

Scheme 4

Esters of amino acids are considered the best proletarienne forms in connection with the possible involvement of stereoselective vector. Amino acid derivatives Viramidine™ can be synthesized as shown below:

Scheme 5

For specific drug delivery to the liver and biliary system an attractive candidate is endogenous transport of bile acids. Synthesis of conjugates of Viramidine™ with bile acids can be implemented as shown below:

Scheme 6

Another class of prodrugs or proletarienne forms are nucleotide derivatives. Getting protected 5'-monophosphate derivatives shown below. By protecting the negative charges of the phosphates neutral deputies will form a more lipophilic derivative, which is expected, will be transformed back to the corresponding monophosphate immediately when injected into the cell.

Scheme 7

R1represents an alkyl group, such as CH3C(O)S-CH2CH2-; (CH3)2SNA(O)S-CH2CH2-; (CH3)3SS(O)S-CH2CH2-; (CH3)3SS(O)och2-; C6H5C(O)S-CH2CH2or HOCH2CH2SS-CH2CH2-.

Phosphoramidate amino acids represent another class of prodrugs, which can be synthesized as described below:

R=any, with the exception of hydrogen

Scheme 8

Other derivatives of monopo Fatih prodrugs listed below:

R = alkyl, lipids, vitamins, bile acids, derivatives of cholesterol

Scheme 8A

Prodrugs of Viramidine™ on the basis of musk can be obtained according to the following scheme:

Scheme 9

Prodrugs of nucleoside 5'-di - or triphosphates will be more interesting, because they will be around more metabolic steps.

The following compounds are potential nucleotide lipophilic prodrugs and get them as shown below:

Scheme 10

Scheme 11

These compounds constitute another class of potential phosphonate prodrugs of Viramidine™.

Scheme 12

Other possible prodrugs include the possible combinations of the groups shown in the patent applications PCT WO 98/39342, WO 98/39343, WO 98/39344 and WO 99/45016.

Prodrugs of Viramidine™ you can get not only by modification of the sugar section of the original molecule, but also by obtaining derivatives amedieval functional groups. The following compounds represent several classes of prodrugs that can be obtained by modification amedieval group, as described below:

Scheme 13

Scheme 14

Scheme 15

Scheme 16

R=CH3-

R = phenyl

R=R1-S-S-Ph - and

R1= alkyl, lipids, vitamins, bile acids, derivatives of cholesterol

Application

Suppose that the compounds according to the formula 1 will be used for the treatment of a wide variety of conditions, and in fact any condition that gives a positive response to the introduction of one or more than one of the compounds. Among other things, specifically, suppose that the compounds according to the invention can be used to treat infection, invasion, cancer, or tumors or autoimmune diseases. Further suppose that the compounds according to the invention can be used for targeted treatment of conditions or diseases in a specific organ such as the liver or heart.

Consider the infection to be treated by the compounds of the present invention, include respiratory syncytial virus (RSV), hepatitis b virus (HBV), hepatitis C virus (HCV), herpes simplex virus type 1 and type 2, genital herpes, herpes of the cornea, encephalitis herpes, herpes zoster, human immunodeficiency virus (HIV), influenza virus a, virus hantann (hemorrhagic fever), human papilloma virus (HPV), measles and fungus.

Russ is Trivimi invasion, subject to treatment by the compounds of the present invention, include protozoal infestations, as well as worm and other parasitic infestations.

Consider cancers and tumors to be treated include those caused by a virus, and the effect may be involved in the inhibition of the transformation of virus-infected cells in neoplastic condition, inhibiting the spread of viruses from the transformed cells to other normal cells and/or stop the growth of virus transformed cells.

Consider autoimmune and other diseases to be treated include arthritis, psoriasis, intestinal disease, juvenile diabetes, lupus, multiple sclerosis, gout and gouty arthritis, rheumatoid arthritis, graft rejection, giant cell arteritis diagnostics, allergies and asthma.

In addition, further use of the compounds according to the present invention include use as intermediates in chemical synthesis of other nucleoside or nucleotide analogs, which, in turn, are useful as therapeutic agents or for other purposes.

In another aspect, a method of treatment of a mammal includes the introduction of therapeutically and/or prophylactically effective alicescuriosities.com drug containing the compound of the present invention. This aspect effect may relate to the modulation of some part of the immune system of a mammal, particularly to the modulation profiles of lymphokines type 1 and type 2 relative to each other. When the modulation lymphokines type 1 and type 2, in particular believe that this modulation may include or suppression of lymphokines as type 1 and type 2, and more preferably the stimulation of lymphokines type 1, or a relative increase of response type 1 compared with type answer 2.

In particular, suppose that Viramidine™ (1,39 µg/ml) increased the expression and synthesis of type 1 cytokines (preferably activated) T-lymphocytes, and the results of various experiments are presented in figure 2-5. Figure 2 presents the effect of 5 μm of viramidine (compounds according to formula 1), ribavirin and levovirin on the synthesis of type 1 cytokines in SEB-activated T cells of the patients (n=5 donors), where viramidine shows a clear increase response type 1 compared with control triazole. Figure 3 is a graphical representation of the effect of viramidine dose-response in the range of 0.625-10 μm in relation to the synthesis of type 1 cytokines in SEB-activated (SEB, staphylococcal enterotoxin B) T cells (data represent 4 individual donors). The effect in vivo, prolapsus is the action scene in the increased response of type 1 in the analysis of contact hypersensitivity (SHS) of viramidine clearly demonstrated in figure 4, as figure 5 shows a comparison between viramidine and levovirin/ribavirin against nucleoside concentration peak response and the maximum range of responses (on the y-axis shows the number of respondents in a particular experiment).

Getting drug T cells and activation in vitro

Mononuclear cells from peripheral blood were isolated from healthy donors or patients with rheumatoid arthritis using centrifugation in a density gradient with subsequent T-cell enrichment using Lymphokwik (One Lambda, Canoga Park CA). Contaminating monocytes were removed by adherence to plastic. Purified T cells were a >99% CD2+, <1% HLA-DR+ and <5% CD25+, and supported them in medium RPMI-AP5 (medium RPMI-1640 containing 20 mm HEPES buffer, pH 7.4, 5% autologous plasma, 1% L-glutamine, 1% penicillin/streptomycin and 0.05% 2-mercaptoethanol).

To determine the levels of cytokine protein T cells (1×106cells in a volume of 1 ml) was activated by adding 10 ng of PMA (phorbol-12-myristate-13-acetate) plus 0.5 μg of ionomycin (both reagents from Calbiochem, La Jolla, CA) and incubated in 24-hole tablets in the presence of from 0 to 20 μm nucleoside over a period of time up to 48 h at 37°C and 5% CO2in the humidified incubator. After activating supernatant analyzed for the production of cytokines cellular origin. To study the s proliferation and viability of the above Protocol was modified for 96-well format tablet, using 0,2×106cells in a volume of 0.2 ml and the activation of 2 ng of PMA and 0.1 μg of ionomycin. In separate experiments 5×106T cells in 2 ml of activated 20 ng of PMA plus 1 μg of ionomycin. Alternative cells can be activated in vitro with SEB, following published methods. Here, the total RNA was isolated from T cells after 6-24 h of incubation and analyzed using RT-PCR to determine mRNA levels of various cytokines and inflammatory mediators. In some experiments, T cells were additionally purified (using reagents enrichment of cells from Stem Cell Technologies, Vancouver, BC) to obtain pure populations of subgroups of T cells CD4+ (<1% CD8+ when you use reagent for isolation of T cells human CD4+ RosetteSep) and CD8+ (<1% CD4+ when you use reagent for isolation of T cells human CD4+ RosetteSep), then 1×106cells / ml activated PMA and ionomycin, as in the experiments with total T cells.

Analysis of extracellular cytokines

The levels of cytokines man was determined in cell supernatants after appropriate dilution using ELISA kits (ELISA analysis), specific for IL-2, IFNγ, TNFα, IL-4 and IL-5 (Biosource International, Camarillo, CA). The levels of cytokines mice were determined using ELISA kits specific for murine IFNγ and IL-4 (R and D Systems, Minneapolis, MN). All the ELISA results were expressed in PG/ml Some data are presented as the percentage of activated control, calculated as the ratio of the level of cytokines by activated T cells in the presence of the test nucleoside to the level of cytokines raw activated T cells × 100%. The null effect of the test nucleosides in relation to the levels of cytokines will give a percentage of the value of the activated control, equal to 100%. Alternative data were presented as percentage changes from the activated control ([test(PG/ml) - activated controls PG/ml)/activated control PG/ml]×100%). The null effect of the test nucleosides in relation to the levels of cytokines will be 0%.

Contact hypersensitivity (AU)

Reactivity to the contact allergen, DNFB (dinitrophenol), were determined in BALB/c mice as described previously (Ishii, N., K. Takahashi, N. Nakajima, S. Tanaka, P. W. Askenase, 1994. DNFB contact sensitivity (CS) in BALB/c mice. J. Invest. Dermatol. 102: 321). Briefly, mice were subjected to sensitization by applying 20 μl of 0.3% DNFB in acetone: olive oil 4:1, clean-shaven abdomen intact mice. For optimal manifestations AU mice was performed stimulation on both sides of each ear 20 μl of 0.12%DNFB through 5 days after sensitization. Desensibilisation mice also conducted stimulation and used them as controls in each experiment. After 24 h p is bodily measure the thickness of the ear, and the answer to DNFB was estimated by subtracting the values after stimulation of the values before stimulation. Where indicated, enter a 7-β-D-ribofuranosyl-4-oxopyrrolo[2,3-d]pyrimidine-5-carboxamidine dose of 6.2 µg in 50 µl SFR (phosphate buffered saline) solution (0.3 mg/kg) or 12.4 µg in 100 µl SFR (0.6 mg/kg) by intraperitoneal injection at the time of stimulation with DNFB. These doses are 7-β-D-ribofuranosyl-4-oxopyrrolo[2,3-d]pyrimidine-5-carboxamidine gave the maximum effect in prior research optimization. After the final measurement of ear thickness of mice were killed by cervical dislocation and removed axillary/lateral axillary lymph nodes. After extraction of total cellular RNA from the selected cells of the lymph nodes was performed RT-PCR and southern blot analyses for monitoring levels of IFNγ, IL-2 and IL-10 mRNA in the mouse.

Additional experiments

In General I believe that the shift of the immune response in the direction of the response type 1 is favorable. Therefore, I believe that connection, which is the object of the invention may be particularly useful in the treatment of viral diseases (preferably viral infections, in which the response type 1 is reduced or suppression). To confirm the effectiveness of modulating the immune response, conducted various experiments, and the following performance is to place a rough summary of some experiments, conducted the connection:

In vitro - viramidine inhibited viral infection In Punta LLC-MK2 (the kidney cells of rhesus monkeys) with EC50equal to 8 mg/ml (strain Adames) and 12 mg/ml (strain Balliet), - CC50320 mg/ml (normalized by the virus 1,0-1,2).

In vivo introduction of viramidine subcutaneously or orally has resulted in 100%survival (10 C57BL/6 mice per group) after subcutaneous injection PTV (Adames strain).

Within 24 h after infection PTV in vivo minimally effective subcutaneous dose was 32 mg/kg of ribavirin and viramidine she was 96 mg/kg, given subcutaneously twice daily for 5 days. Within 24 h after infection PTV in vivo minimum effective oral dose was 20 mg/kg of ribavirin and 40 mg/kg for viramidine given subcutaneously twice daily for 5 days.

In General, the most preferred applications according to the present invention are those in which the active compounds are relatively less cytotoxic against cells of the host, not targeted, and relatively more active against the target. In this regard, it may be preferred that the L-nucleosides may have increased stability compared to the D-nucleosides that can lead to a better pharmacokinetics. This result can be achieved, is as L-nucleosides may not be recognized by enzymes and therefore, they may have longer half-lives.

Suppose that the compounds of the present invention will be entered in vivo, in vitro or ex vivo in any suitable pharmaceutical drug and in accordance with any suitable Protocol. Thus, the administration can be oral, parenteral (including subcutaneous injections, intravenous, intramuscular, introduction by intrasternal injection or infusion techniques), by inhalation spray solution, or rectally, by local and so forth, and in the preparations of standard forms containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and solvents.

For example, suppose that the compounds according to the present invention can be included in the drugs in a mixture with a pharmaceutically acceptable carrier. For example, the compounds of the present invention can be administered orally in the form of pharmacologically acceptable salts. Since the compounds of the present invention are generally soluble in water, they can be administered intravenously in a physiological salt solution that is buffered to a pH of about 7.2 to 7.5). For this purpose you can use conventional buffers such as phosphate, bicarbonate or citrate. Of course, ordinary specialist in the art can modi is the substance of the drugs within the guidelines of this specification, to ensure that a variety of drugs for a specific route of administration, without making the compositions of the present invention is unstable or not compromising their therapeutic activity. In particular, the modification of these compounds, for example, in order to make them more soluble in water or other media, in particular, can easily be implemented with minor modifications (salt, esterification, and so forth), which are within the competence of the ordinary person skilled in the art. Also within the competence of the ordinary practitioner in the art are modifications of route of administration and dosage of a particular compound to control the pharmacokinetics of these compounds to achieve the most effective results for patients.

In addition, the compounds according to the present invention can be entered separately or in combination with other agents for treatment of the above infections or conditions. When combination therapies according to the present invention is administered at least one compound according to the present invention, or its functional derivative and at least one other pharmaceutically active ingredient. This active ingredient (ingredients) and pharmaceutically active agents can enter individual p is or together, and separate introduction can be performed simultaneously or separately in any order. The amount of the active ingredient (ingredients) and pharmaceutically active agent (agents) and relative clocks of administration should be chosen in such a way as to achieve the desired combined therapeutic effect. Preferably combinational therapy involves the introduction of one of the compounds of the present invention or a physiologically functional derivative and one of the agents mentioned here below.

Examples of other drugs or active ingredients, alleged as effective when combined with a modulator according to the formula 1, are antiviral agents such as interferon, including, but not limited to, interferon α and γ, ribavirin, acyclovir, and AZT™; antifungal agents, such as tolnaftate, Fungizone (Fungizone™), lotrimin (Lotrimin™), mycelex (Mycelex™), nystatin and amphotericin; antiparasitic agents such as mintezol (Mintezol™), necklace (Niclocide™), vermox (Vermox™) and flagyl (Flagyl™), gastrointestinal agents, such as immodium (Immodium™), lomotil (Lomotil™) and FISIM (Phazyme™); antineoplastic agents, such as interferon α and γ, adriamycin (Adriamycin™), cytoxan (Cytoxan™), imuran (Imuran™), methotrexate, mithracin (Mithracin™ ), tianfuan (Thiazofurin™), Taxol (Taxol™); dermatological agents, such as acrobat (Aclovate™), cyclocort (Cyclocort™), denorex (Denorex™), Florin (Floron™), oxsoralen (Oxsoralen™), coal tar and salicylic acid; caused drugs, such as ergotamine compounds; steroids and immunosuppressants not listed above, including cyclosporine, diproson (Diprosone™), hydrocortisone; floron (Floron™), lidex (Lidex™), topicort and Alison; and metabolic agents, such as insulin, and other drugs that are not exactly fall into the above categories, including cytokines, such as IL2, IL, IL, IL, IL and IL. Particularly preferred primary drugs are AZT, 3TC, 8-substituted guanosine analogs, 2,3-dideoxynucleoside, interleukin II, interferons, such as IαB-interferons, tucaresol (tucaresol), levamisole, isoprinosine and cyclodecane.

Examples of such additional therapeutic agents include agents that are effective to modulate the immune system or associated conditions, such as AZT, FTC, 8-substituted guanosine analogs, 2',3'-dideoxynucleoside, interleukin II, interferons, such as α-interferon, tucaresol, levamisole, isoprinosine and cyclodecane. Some compounds according to the present izobreteniya to be effective to enhance the biological activity of some agents according to the present invention by reducing metabolism or inactivation of other compounds, and as such, they are added together for this intended effect.

In relation to dosage of ordinary skilled in the art will understand that therapeutically effective amount will vary depending on the infection or condition that should be treated, the severity of this condition, the mode of treatment that should be applied pharmacokinetics of the agent used, as well as the patient (animal or human), which are treated. I believe that various alternative dosing are also suitable, including doses between 0.5 mg/kg and 0.1 mg/kg or less, but also dosage between 0.5 mg/kg and 1.0 mg/kg or more. Further suppose that, although certain medical conditions treatment success can be achieved at relatively low concentrations of the considered compounds in plasma, in other viral infections may be needed relatively high dosage. However, I believe that the appropriate mode should be developed through the introduction of a small amount, and then increase this number up until the side effects will not be overly harmful, or until the intended effect is not achieved.

Introduction active compounds can vary in the range from continuous injection (intravenous drip) to several oral put in place the events in the day (for example, four times per day) and may include, among other routes of administration oral, local, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include the agent, increasing penetration), transbukkalno introduction and introduction of suppositories.

For the manufacture of pharmaceutical compositions according to the present invention a therapeutically effective amount of one or more than one of the compounds according to the present invention preferably thoroughly mixed with a pharmaceutically acceptable carrier according to conventional techniques of the pharmaceutical compounding to obtain the dose. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral, or parenteral. In the manufacture of pharmaceutical compositions in oral dosage form can be any of the usual pharmaceutical media. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, you can use suitable carriers and additives include water, glycols, oils, alcohols, corrigentov, preservatives, coloring agents and the like. For solid oral preparations such as powders, tablets, capsules, and for such hard drugs as suppositories that you use the suitable carriers and additives, including starches, sugar media, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricating agents, binding agents, loosening agents and the like. If desired, the tablets or capsules using standard techniques can be covered intersolubility shell or manufactured in the form of continued release.

Carrier for parenteral preparations will typically contain sterile water or an aqueous solution of sodium chloride, although you can include other ingredients, including those that contribute to the dispersion. Of course, where it is necessary to use sterile water and maintain it in a sterile condition, composition, and media should also be sterilized. You can also prepare injectable solutions, and in this case you can use the appropriate liquid carriers, suspendresume agents and the like.

1. A method of treating infections by hepatitis C virus (HCV) or infection with hepatitis b virus (HBV), which enter carboxamidine formula 1 or its pharmaceutically acceptable salt

where this connection is in the D-configuration.

2. The method according to claim 1 where the pharmaceutically acceptable salt is a hydrochloride according to the formula 1.

3. The method according to claim 1 or 2, where viral the infection is an infection with hepatitis C.

4. The method according to claim 1 or 2, where the compound is administered orally.

5. The method according to claim 1 or 2, where the compound is administered at a dose of between 0.1 mg per kg of body weight of the patient, and 40 mg / kg of body weight of the patient.

6. The method according to claim 1 or 2, which additionally injected interferon.

7. The method according to claim 6, where the interferon is an interferon alpha.



 

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6 cl, 1 tbl, 7 ex

FIELD: medicine.

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FIELD: medicine, oncourology.

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1 ex

FIELD: veterinary science.

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1 ex

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2 cl, 1 tbl

FIELD: medicine, veterinary science.

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5 cl, 5 tbl

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7 cl, 3 tbl, 8 ex

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wherein R1 means one of radicals:

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12 cl, 3 tbl, 3 ex

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2 ex, 2 tbl

FIELD: veterinary science.

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2 cl, 2 ex

FIELD: veterinary science.

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EFFECT: higher efficiency.

3 ex, 2 tbl

FIELD: veterinary science.

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EFFECT: higher efficiency.

3 ex, 2 tbl

FIELD: veterinary science.

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1 cl, 2 dwg, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives if azaindole of the formula (I)

or its pharmaceutically acceptable salts wherein the formula is taken among the group consisting of , , and and wherein each among R1, R2, R3 and R4 is taken independently among the group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen atom, cyano-group (CN), phenyl, nitro-group, -OC(O)R15, -C(O)R15, -C(O)OR16, -OR19, -SR20 and NR21R22 wherein R15 is taken independently among the group including hydrogen atom (H),(C1-C6)-alkyl and (C2-C6)-alkenyl; each among R16, R19 and R0 is taken independently among the group including hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-alkyl substituted with from 1 to 3 halogen atoms; each among R21 and R22 is taken among the group including hydrogen atom(H), hydroxy-group (OH), (C1-C6)-alkyl; R5 represents the group (O)m wherein m = 0 or 1; n = 1 or 2; R6 is taken among the group including hydrogen atom (H), (C1-C6)-alkyl, -C(O)R24 and -C(O)OR5 under condition that carbon atoms comprising carbon-carbon double bond of indicated (C3-C6)-alkenyl are not the addition point to nitrogen atom to which R6 is joined; R24 is taken among the group consisting of hydrogen atom (H), and (C1-C6)-alkyl; R25 represents (C1-C6)-alkyl; each among R7, R8, R9, R10, R11, R12, R13 and R14 is taken independently among the group including hydrogen atom (H) and (C1-C6)-alkyl; Ar is taken among the group including:

, and . Compounds of the formula (I) inhibit HIV-1 that allows proposing their applying in medicine.

EFFECT: valuable medicinal and antiviral properties of compounds.

22 cl, 13 sch, 2 tbl

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