The derived 3-methoxybenzamide, method thereof and pharmaceutical composition having inhibitory activity to the development of blood vessels and metastasis

 

(57) Abstract:

The invention relates to 3-deoxy-derivatives of D-mannosamine formula specified in the description, where R is-NH2C2-C5alkanoyl-NH-group, each of R1and R2independently is C1-C4by alkyl; or R1is hydrogen, halogen, C1-C4the alkyl or C1-C4alkoxy group, and R2is hydrogen; or R1and R2both are Fermi; and if R1is methoxy group, and R2is hydrogen, R is different from the NH2or their pharmaceutically suitable salts, which are useful as inhibitors of the development of blood vessels, in particular inhibitors of the development of metastases. 5 S. and 2 C.p. f-crystals, 1 table.

The invention relates to 3-deoxy-derivatives of D-mannosamine, the method of their derivation, containing pharmaceutical compositions and therapeutic applications. The first object of the present invention are new compounds of the following formula (I)

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where R is-NH2C2-C5alkanoyl-NH -, or-CF3CONH-; each of R1and R2independently is C1-C4the alkyl, or R1is hydrogen, halogen, C1/SUB> are Fermi; and when R1is methoxy group, and R2hydrogen, R is different from the-NH2and their pharmaceutically suitable salts.

From the above formulas (I) it is clear that the hydroxyl group attached to C-1, can be both below and above the plane of the ring. In accordance with this present invention and includes both anomeric forms of the compounds of this invention and their mixture.

Objects of the present invention are also metabolites and the metabolic precursors or bioresistance (known as prodrugs of compounds of formula (I).

Alkyl, alkoxy and alcoholnye group can have a branched or linear chain, preferably linear.

C1-C4An alkyl group is, for example, stands, ethyl, propylene or isopropyl, preferably the stands or ethyl, and especially the stands.

C1-C4The alkoxy group is, for example, methoxy, ethoxy - or propoxy group, preferably methoxy or ethoxy group.

C2-C5Alcoolica group is preferably acetyl group.

The halogen atom is, for example, fluorine or iodine. Seies suitable salts of the compounds of the invention include salts with an attached acid: inorganic, for example, nitric, hydrochloric, Hydrobromic, sulphuric, perchloric and phosphoric, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, almond and salicylic.

As stated above, the present invention also includes pharmaceutically suitable bioresistance (otherwise known as prodrugs of compounds of formula (I), for example, compounds that have the formula other than the formula (I) above, but which, however, when hiring a person become directly or indirectly in vivo into a compound of formula (I).

The above-mentioned condition excludes from the scope of compounds of formula (I) of the hydrochloride of 2-amino-2-deoxy-3-O-methyl-D-mannopyranose, known from J. Org. Chem. so 26, SS. 2455-2458 (1961), however, the biological activity of such compounds has not been described.

Accordingly, as the subject of the present invention is to provide pharmaceutical compositions comprising as active agent the compounds of formula (I).

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where R is-NH2C2-C5alkanoyl-NH -; each of R1and R2independently is C1-C4Ala is Oh, and R2is hydrogen; or both R1and R2are Fermi, or its pharmaceutically suitable salt and a pharmaceutically suitable carrier and/or diluent.

The new compounds of formula (I) and the active agents in pharmaceutical compositions in accordance with the present invention are referred to here as "compounds of the invention".

Preferred compounds of the invention are the compounds of formula (I), in which in accordance with the above condition R is-NH2or C2-C5alkanoyl-NH - group; each of R1and R2independently is C1-C4the alkyl, or R1is hydrogen, halogen, C1-C4the alkyl or C1-C4alkoxy group, and R2is hydrogen; or both R1and R2are Fermi; and their pharmaceutically suitable salts. Specific examples of the preferred new compounds in accordance with the present invention are: 2-amino-2,3-dideoxy-D-mannopyranose; 2-acetamido-2,3-dideoxy-D-mannopyranose; 2-amino-2,3-dideoxy-3-iodo-D-mannopyranose; 2-acetamido-2,3-dideoxy-3-iodine-D-mannopyranose; 2-acetamido-2-deoxy-3-O-methyl-D-mannopyranose; 2-amino-2,3-dideoxy-3-FPO-acetamido-2,3-dideoxy-3-C-methyl-D-mannopyranose; 2-amino-2,3-dideoxy-3-C-ethyl-D-mannopyranose; 2-acetamido-2,3-dideoxy-3-C-ethyl-D-mannopyranose; 2-amino-2,3-dideoxy-3,3-C-dimethyl-D-mannopyranose; 2-acetamido-2,3-dideoxy-3,3-C-dimethyl-D-mannopyranose; 2-amino-2,3-dideoxy-3,3-debtor-D-mannopyranose; 2-acetamido-2,3-dideoxy-3,3-debtor-mannopyranose and, if necessary, their pharmaceutically suitable salts, in particular hydrochloride. Compounds of the invention and their salts can be obtained by the following method including:

a) hydrolysis of compounds of formula (II)

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where R2and R2such as defined above, R3is acyl-NH-group, and R4the protective group for hydroxyl, resulting in a gain of compounds of formula (I) in which R is-NH2; or

b) hydrolysis of compounds of formula (III)

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where R7is fluorine, R2hydrogen or fluorine, R3-R4such as defined above, and R5and R6together form a protective group for C-4 and C-6 hydroxyl, resulting in the receive connection of the formula (I) in which R is-NH2, R1fluorine, and R2hydrogen or fluorine; or

C) acylation of compounds of formula (IV)

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where R1and R2such as defined above, a compound formularie the compounds of formula (I) into another compound of formula (I) and/or, if you obtain salts of the compounds of formula (I) and/or, if desired, obtaining a free compound from its salts.

Hydrolize compounds of the formula (II) or (III) as well as the acylation of compounds of formula (IV) are the same processes that can be carried out in accordance with known of the chemistry of carbohydrates methods. Therefore, the following description of processes a), b) and C) above are given as a priority for such processes without limiting the scope of the present invention.

In the compounds of formula (II) or (III) R3as the acyl-NH-group is, for example, C2-C5alkanoyl-NH - group, usually NHCOCH3or HCOCF3or benzyloxycarbonyl-NH-group.

If in the compound of formula (II) R1is iodine, the preferred R3is HCOCF3group, while if R1such as defined above, but other than iodine, the preferred R3is C2-C5alkanoyl-NH-group, in particular-NHCOCH3.

In the compound of formula (II) or (III) R4as a protective group for hydroxyl is, for example, C1-C4alkyl group, typically the stands, ethyl or isopropyl or b is PU for C-4 and C-6 hydroxyl, such a protective group may be one commonly used in the chemistry of sugars, benzylidene group.

The hydrolysis of compounds of formula (II) or (III) can be performed when processing a mineral acid, for example HCl or H2SO4. It is preferable to carry out the processing of 5N HCl or 2.5% H2SO4in the temperature range of from about 50oC to about 110oC.

The acylation of compounds of formula (IV) can be performed when processing a suitable allermuir agent, for example, a suitable anhydride. For example, if you compound of formula (I), where R is-NHCOCH3group, conduct the reaction of the compound of formula (IV) with acetic anhydride in a lower alcohol, preferably methanol at room temperature.

As stated above, the compound of formula (I) can be converted into another compound of formula (I). The acylation of compounds of formula (IV) can be seen as an example of such a transformation. Indeed, the compound of formula (IV) is a compound of formula (I) in which P is NH2.

Obtaining salts of the compounds of formula (I), where R is-NH2that can be known in the art methods. The compound of formula (II), a known or new, you can receive the - -NHCOCH3and R4the stands can be obtained in accordance with the method described in Arg. Biol. Chem. 33 (5), 748-754 (1969). Similarly, the compound of formula (II), where R1is a methoxy group, R2is hydrogen, R3-NHCOCH3and R4the stands can be obtained following the method described in Carbohydrates Research, 38, 205-216 (1974).

In accordance with the basic method of the present invention the compound of formula (II) can be obtained by removing the protective group with C-4 and C-6 hydroxyl in the compound of formula (V)

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where R1, R2, R3, R4, R5and R6such as defined above, by hydrolysis. It is preferable to hydrolysis under mild conditions with a mineral acid such as HCl or H2SO4for example, as described in Tetrahechon Letters, 18, 2271 (1968). The compounds of formula (III) are new compounds of the formula (V) with R1therefore, as described above, i.e., fluorine, R2hydrogen or fluorine, and R4, R5and R6as defined in the formula (V).

The compound of formula (V), where R1such as defined above, but not iodine, can be obtained by acylation of compounds of formula (VI)

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where R2, R5and R6such as defined above, and R8so, carbolit under the same conditions, as described above for the acylation of compounds of formula (IV). The compound of formula (V), where R1is iodine, and R2, R3, R4, R5and R6such as defined above, can be obtained from the compounds of formula (VII),

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where R3, R4, R5and R6such as defined above, and R9is easily leaving group, such as Totila, mesila or triftoratsetofenona, preferably by Totila, by treatment with alkali metal iodide, preferably an excess NaJ in the ketone, for example, dimethylketone while boiling under reflux.

The compounds of formula (VII) can be obtained by known methods from the corresponding C-3 hydroxyl derivatives that are either known or can be obtained by known methods from known compounds.

The compound of formula (VI) can be obtained by reduction of compound of formula (VIII)

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where R2, R4, R5, R6and R8such as defined above.

The recovery of the compounds of formula (VIII) can be performed by known methods, for example by catalytic hydrogenation, preferably with 10% Pd/C as catalyst and a pressure of from about 10 to about 20 Atmos, can be obtained from the compounds of formula (IX)

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where each of R10and R2independently is C1-C4the alkyl or R10is hydrogen, C1-C4the alkyl or C1-C4alkoxy group, and R2is hydrogen, and R4, R5, R6and R9such as defined above, by treating the appropriate azido-derivative, such as sodium azide. The reaction of the compound of formula (IX) with sodium azide can be, for example, in dimethylformamide with an excess of sodium azide in boiling under reflux.

The compound of formula (VIII), where R8is fluorine, and R2is hydrogen, can be obtained as described in J. Org. Chem. 51, 4558-4564 (1986). In another way it can be obtained from compounds of formula (X)

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where R4, R5and R6such as defined above, by reacting with diethylaminosulfur (DAST) in dichlorethylene at room temperature.

The compound of formula (VIII), where R2and R8are Fermi, can be obtained by oxidation of compounds of formula (X), as defined above, and subsequent treatment of the thus obtained ketone DAST in dry benzene at room temperature.

Connection Formenti. The compounds of formula (IX), where R2and R10such as defined above, can be obtained by known methods from the corresponding C-2 hydroxyl derivatives that are either known or can be obtained from known compounds.

For example, a derivative compound of formula (IX) with C-2 free hydroxyl, in which R2and R10are C1-C4alkilani, or R10is hydrogen or C1-C4the alkyl, and R2is hydrogen, can be obtained by reduction of compound of formula (XI)

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where R4, R5and R6such as defined above, and R2and R11are C1-C4the alkyl, and R2is hydrogen, by reacting with a suitable reducing agent, such as LiAlH4in accordance with known methods.

The compound of formula (IX) in which R10is C1-C4alkoxy group, and R2hydrogen, and R4, R5and R6such as defined above, can be obtained, for example, from compounds of formula (XII)

where R4, R5, R6and R9such as defined above, by known methods, for example, by reaction with a suitable C1-C4alkylhalogenide, particularly the iodide is AMI, and R4, R5and R6such as defined above, are known or can be obtained by the method described in Agr. Biol. Chem. 33 (5) 748-754 (1969).

The compounds of formula (XI) in which R2and R11both are C1-C4alkilani, can be obtained by alkylation of the other compounds of formula (XI) in which R2and R11both are hydrogens.

Alkylation of compounds of formula (XI) in which R2and R11both are hydrogens, to obtain new compounds of the formula (XI) in which R2and R11both are metelli, and R4, R5and R6such as defined above, can be accomplished by interaction with methyliodide and hydrodam sodium in anhydrous dimethylformamide at room temperature.

The compounds of formula (XI) in which R11is C1-C4the alkyl, and R2hydrogen can be obtained, for example, by the method described in J. Chem. Res. (M). 0186-0196 (1982).

The compounds of formula (XII) are either known or can be obtained by known methods from known compounds.

The compounds of formula (II) in which R1and R2independently are C1-C4by alkyl; or R1is halogen, C1-C4is defined above, this new connection and therefore are the objects of the present invention. In addition, objects of the present invention are also the compounds of formula (III), which, as here shown, are also new.

Pharmacology

It has been found that compounds of the invention are active as inhibitors of the development of blood vessels and, in particular, inhibitors of the development of metastases.

Inhibitors of the development of blood vessels are agents able to inhibit the growth of new blood vessels. Therefore, the compounds of the present invention are useful in the treatment of certain pathologies in mammals, including humans, when the growth of new blood vessels is crucial, for example, chronic inflammation, diabetic retinopathy, psoriasis, rheumatoid arthritis, tumor formation and development of metastases.

In particular, the compounds of the invention can be used in cancer therapy alone or in combination with anticancer agents such as doxorubicin (doxorabicin), etoposide (etoposide), fluorouracil (fluorouracil), matalan (mephalan), cyclophosphamide (cyclophosphamide), bleomycin (bleomycin), vinblastine (vinblastin) or mitomycin (mitomycin).

On the inhibitory activity of sedlo found, that these compounds are active in the test with membranes (charioallantoic membrane test) according to the method Jolkman, Nature, 297, 307 (1982).

The activity of compounds of the invention, in particular, the inhibition of the development of metastases also confirm the activity of these compounds against metastases, experimentally injected into mice. Thus, one of the compounds of the invention 2-acetamido-2,3-dideoxy-D-mannopyranose was tested for activity against metastatic cell line B16F10 melanoma experimentally injected into mice.

Cells B16F10 (510-4) injected into the tail vein of mice C3H zero day (day 0).

The test compound is administered daily six times a day, starting with the first day (day 1). Animals killed on day 14 and determine lung metastases. Control animals have an average of 47 metastatic centers (35-57), and animals with the drug 0 (0-2).

Compounds of the invention can be taken in the usual way, for example, parenterally in the form of intravenous injection or infusion, intramuscularly, subcutaneously, either locally or orally.

The dosage depends on age, weight and condition of the patient and route of administration. For example, for an adult, a suitable dose of a compound 2-acetanilides compositions of the invention may contain the compound of the invention as the active substance in combination with one or more pharmaceutically suitable excipients and/or carriers.

Specific examples of the preferred compounds of the invention are used as active ingredients in the preparation of pharmaceutical compositions of the present invention are: 2-amino-2-deoxy-3-O-methyl-D-mannopyranose; 2-amino-2,3-dideoxy-D-mannopyranose; 2-acetamido-2,3-dideoxy-D-mannopyranose; 2-amino-2,3-dideoxy-3-iodine-D-mannopyranose; 2-acetamido-2,3-dideoxy-3-iodine-D-mannopyranose; 2-acetamido-2-deoxy-3-O-methyl-D-mannopyranose; 2-amino-2,3-dideoxy-3-fluoro-D-mannopyranose; 2-acetamido-2,3-dideoxy-3-fluoro-D-mannopyranose; 2-amino-2,3-dideoxy-3-C-methyl-D-mannopyranose; 2-acetamido-2,3-dideoxy-3-C-methyl-D-mannopyranose; 2-amino-2,3-dideoxy-3-C-ethyl-D-mannopyranose; 2-acetamido-2,3-dideoxy-3-C-ethyl-D-mannopyranose; 2-Amina-2,3-dideoxy-3,3-C-dimethyl-D-mannopyranose; 2-acetamido-2,3-dideoxy-3,3-dimethyl-D-mannopyranose; 2-amino-2,3-dideoxy-3,3-debtor-D-mannopyranose; 2-acetamido-2,3-dideoxy-3,3-debtor-D-mannopyranose and, if necessary, their pharmaceutically suitable salts, in particular hydrochloride.

The pharmaceutical compositions of the invention are usually prepared following conventional methods and take in a pharmaceutically suitable form.

For example, the solution for nutrion to be in the form of a sterile aqueous isotonic saline solution.

The suspensions or solutions for intramuscular injections may contain, together with the active compound in pharmaceutically suitable carrier, e.g. sterile water, olive oil, etiloleat, glycols, e.g. propylene glycol, and, if required, an appropriate number of ignorance.related.

Forms for local application, such as creams, lotions or pastes for the treatment of skin diseases, the active ingredient can be mixed with conventional oleoresinous or emulsifying fillers.

Solid forms for oral administration such as tablets and capsules, may contain together with the active compound diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch and potato starch lubricants, for example silica, talc, stearic acid, magnesium stearate or calcium and/or polyethylene glycols; binding agents, for example starches, gum Arabic, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone; loosening agents, for example starch, alginic acid, alginates, glycolate sodium and starch; gas mixtures; dyestuffs; sweeteners; moisturizing agents, for example lecithin, Polysorbate, such recipes. These pharmaceutical preparations can be obtained in the usual way, for example by mixing, granulating, manufacture of tablets, coated with sugar or shell. In addition, in accordance with the invention, it is reported a method for the treatment of pathological States in which injury causes the development of new blood vessels, for example, chronic inflammation, diabetic retinopathy, psoriasis, rheumatoid arthritis, tumor development and metastasis in mammals, including humans; and the method includes receiving mammals compositions of the invention.

In addition, the object of the invention is a product containing the compound of the invention or its pharmaceutically suitable salt and one or more anticancer agents as combination products for simultaneous, separate or sequential use in the treatment of cancer.

The term "combined" treatment means include separate, and, significantly, simultaneous administration of compositions containing a compound of the formula (I) or its pharmaceutically suitable salt, and pharmaceutical compositions containing various pharmaceutically active agents.

Agents, is drawn from the state of the disease, you want to treat, and are, for example, such: doxorubicin (doxorubicin), etoposide (etoposide), fluorouracil (flourouracil), matalan (mephalan), cyclophosphamide (cyclophosphamide), bleomycin (bleomycin), vinblastine (vinblastin) and mitomycin (mitomycin).

The following examples illustrate the invention but do not restrict it.

Example 1. Hydrochloride of 2-amino-2,3-dideoxy-3-iodine-D-mannopyranose (compound 1, R NH2; R1J; R2H) -FCE27062. To a solution of 5N hydrochloric acid (150 ml) is added methyl-2,3-dideoxy-3-iodine-2-triptoreline-D-mannopyranose (1 g). The solution is heated for 2 hours at 100oC. the Aqueous phase discolor activated charcoal and evaporated. The addition of methanol and evaporation of the resulting syrup gives 0.5 g of the compounds in the form of white crystalline powder so pl. 122-123oC []2D5-7,5 (0.1, H2); IR (KBr) 3400-3200 cm-1(OH, NH+3), 2130, 1630 and 1500 cm-1NH+3.

In doing likewise, you can receive hydrochloride following compounds: 2-amino-2,3-dideoxy-D-mannopyranose, 2-amino-2,3-dideoxy-3-fluoro-D-mannopyranose, 2-amino-2,3-dideoxy-3-C-methyl-D-mannopyranose, 2-amino-2,3-dideoxy-3-C-ethyl-D-mannopyranose, 2-amino-2,3-dideoxy-3,3-C-Dima is>D0-23,3oend (C, 5, water).

Example 2. Methyl-2,3-dideoxy-3-iodine-2-triptoreline-D-mannopyranose (compound II, R1J, R2H, R3NHCOCF3, R4CH3).

A solution of methyl 4,6-0-benzylidene-2,3-dideoxy-3-iodine-2 - trifurcated--D-mannopyranoside 0.5 N methanolic solution of hydrogen chloride (50 ml) is stirred for 2 hours at 20oC, then concentrated to half volume and diluted with ether. The product (1.2 g), the connection specified in the form of a white solid is washed with dry ether and evaporated in vacuum. Mass spectrometry with a field desorption: 399 (H+), so pl. 171-172oC (decomposition).

Example 3. Methyl 4,6-0-benzylidene-2,3-dideoxy-3-iodine - 2-triptoreline-a-D-mannopyranose (compound V, R1J, R2H, R3NHCOCF3, R4CH3, R5+ R6benzylidene group).

Methyl-4,6-O-benzylidene-2-desoxy-3-O-p-toluensulfonyl-2-triptoreline-a-D-mannopyranose (1.5 g) is dissolved in 70 ml of dry butanone with sodium iodide (2 g). The mixture is refluxed for 1 hour and concentrated. The residue is extracted with methylene chloride and washed with water until neutral, then concencanada connection: so pl. 152-153oC (decomposition).

Example 4. 2-Acetamido-2,3-dideoxy-D-mannopyranose (compound I, R NCOCH3, R1R2H)-FCE 26950. Amino-12,3-dideoxy-D-mannopyranose (0.8 g) is dissolved in dry methanol (30 ml) and acetic anhydride (3 ml), the mixture is stirred over night. Evaporation of solvent gives a crystalline mass which is recrystallized from a mixture of ethanol and acetone, receiving of 0.60 g of the compounds: I. pl. 140-142oC []25D/to-4.5 (C, 0,1, H2O).

Proceeding similarly, we can obtain the following compounds: 2-acetamido-2,3-dideoxy-3-iodine-D-mannopyranose; 2-acetamido-2-deoxy-3-O-methyl-D-mannopyranose (so pl. 155-156oC; 2-acetamido-2,3-dideoxy-3-fluoro-D-mannopyranose (FCE 27519); 1H-NMR (200 MHz, DMCO-D6): 1.86 (s, 3H, CH3-CONH), of 3.4 to 3.8 (m, 4H, H-4, H-5, CH2-OH), 4,25 (m, 1H, H-2 ), 4,48 (t, J 6,1 Hz, 1H, CH2-OH); 4,60 (DDD, J 5.4 Hz, 10.3 Hz, JH-F50.0 Hz, 1H, H-3), is 4.85 (DDD, J 1.9 Hz, 4.3 Hz, JH-F5.6 Hz, 1H, H-1), 5,31 (d, J 5.7 Hz, 1H, OH-4), was 6.73 (d, J 4.3 Hz, 1H, OH-1), 7,46 (d, J a 8.9 Hz, 1H, NH-COCH3).

2-acetamido-2,3-dideoxy-3-C-methyl-D-mannopyranose +45o(C=0.5, methanol)-FCE 27930; 2-acetamido-2,3-dideoxy-3-C-ethyl-D-mannopyranose; 2-acetamido-2,3-dideoxy-3,3-debtor-D-mannopyranose.

Example 5. Methyl-2 is. actor methyl-2-acetamido-4,6-0-benzylidene-2,3-dideoxy-D-mannopyranose (2 g, 7,06 mmole) in dry methanol (50 ml) is stirred with acetylchloride (0.6 ml) for 4 hours at 20oC and then neutralized with sodium bicarbonate, filtered and concentrated. The residue is extracted with hexane, removing benzaldehyde, and then acetone, receiving 1.47 g (95%) of methyl 2-acetamido-2,3-dideoxy--D-mannopyranose in the form of butter.

1H NMR (200 MHz, CDCl3): 2,03 (s, 3H, CH3-CO-NH), 2,12 (m, 2H, CH2-3), 3,40 (s, 3H, CH3O) 3,68 (m, 1H, H-4 in), 3.75 (DD, J 10,0, 10,0 Hz, 1H, CH(H)-6 ), 3,88 (DDD, J 4,0, 10,0, 10,0 Hz, IH, H-5 ), 4,24 (DD, J of 4.0, and 10.0 Hz, IH, CH(H)-6), or 4.31 (m, IH, H-2 ), 4,50 (c, IH, H-1), 5.56mm (c, IH, CH-Ph), 5,80 (d, J 7,6 Hz, IH, H-COCH3), and 7.3-7.5 (m, 5H, Ph).

Example 6. Methyl-2-azido-4,6-0-benzylidene-2,3-dideoxy-3-fluoro-a-D - mannopyranoside (compound VIII, R2H, R4CH3, R5+ R6benzyliden, R8F). To a mixture of methyl-2-azido-4,6-O-benzylidene-a-D-altro-pyranoside (alptropyranoside) (2 g) and 4-dimethylamino-pyridine (DMAP) (1 g) in 40 ml of dry dichloromethane, stirred at -20oC in nitrogen atmosphere, slowly add 1 ml of diethylaminosulfur (DAST). Mixture is allowed to warm up and then left to stand at room temperature for 24 hours. After cooling to -20oC to the mixture slowly dbarefoot under reduced pressure, and the remainder of the chromatographic clean, getting to 1.25 g of the compounds: I. pl. 122-123oC.

Example 7. Methyl 2-acetamido-4,6-0-benzylidene-2,3-dideoxy-3-fluoro-a - D-mannopyranoside (compound III, R2H, R3NHCOCH3, R4CH3, R5+ R6benzylidene group). To a solution of methyl-2-azido-4,6-O - benzylidene-2,3-dideoxy-3-fluoro-a-D-mannopyranoside (1 g) in methanol (100 ml) is added 10% Pd/C (1 g), the mixture hydronaut at 10 atmospheres for 2 hours, filtered and then concentrated to a dry residue. A solution of the obtained syrup in anhydrous pyridine (10 ml) at 0oC is treated with acetic anhydride (5 ml). After 10 hours at room temperature the solution was poured into a mixture of ice/water and extracted the product with dichloromethane. Then the extract was washed with aqueous sodium bicarbonate solution and water and evaporated in vacuum. Then add toluene (25 ml) and evaporated it from the rest. The output of the compounds of 1.15 g: so pl. 85-86oC.

1H NMR (200 MHZ, C6D6): of 1.56 (s, 3H, CH3-SON), 2,82 (s, 3H, CH3O) to 3.49 (DD, J 10,0, 10,0 Hz, 1H, CH(H)-6), to 3.58 (DDD, J of 9.6, 10.0 Hz, 1H, H-4 ), 3,74 (DDD, J 4,4, 10,0, 10,0 Hz, 1H, H-5 ), 4,07 (DDD, J 4,6, 10,0 Hz, JH-Fthe 2.4 Hz, CH(H)-6), 4,63 (DD, J 1.1 Hz, JH-F4.0 Hz, 1H, H-1 ), to 4.87 (m, 1H, H-2), of 5.05 (DDD, J of 5.4 and 9.6 Hz, JH-F<3-fluoro-a-D-mannopyranose (compound II, R1F, R2H, R3NHCOCH3, R4CH3). Methyl 2-acetamido-4,6-0-benzylidene-2,3 - dideoxy-3-fluoro-a-D-mannopyranose (0.2 g) dissolved in 0.5 N methanolic solution of hydrogen chloride (10 ml) and the solution allowed to stand at room temperature for 3 hours. Get the specified compound in the form of oil (0.11 g).

1H NMR (200 MHz, DMCO-D6): to 1.86 (s, 3H, CH3-CONH), 3,2 (s, 3H, CH3O), a 3.2 to 3.8 (m, 4H, H-4, H-5, CH2-OH), 4,35 (m, 1H, H-2), of 4.49 (DD, J 1.4 Hz, JH-F4,8 Hz, H-1 ), a 4.53 (DDD, J 5,2, and 9.2 Hz, J 5,2, and 9.2 Hz, JH-Fto 58.2 Hz, 1H, H-3), br4.61 (t, J 6.0 Hz, CH2-OH), 5,41 (d, J 6.2 Hz, OH-4 ), of 7.90 (d, J 8,8 Hz, NH-COCH3).

Example 9. 2-Amino-2,3-dideoxy-3-fluoro-D-mannopyranose. Methyl 2-acetamido-4,6-0-benzylidene-2,3-dideoxy-3-fluoro-a - D-mannopyranose (1 g) is dissolved in 2.5% aqueous sulfuric acid (70 ml) and the solution allowed to stand at 100oC for 2 hours. Then the aqueous solution is neutralized to ionoobmennoi resin Dowex 1 x 2 (OH-), evaporation of water under vacuum gives the connection specified in the form of syrup.

IR (KB r) n 3400-3200 cm-1(OH, NH+3), 2130, 1630 and 1500 cm-1(NH+3).

Similarly, you can get amino-2,3-dideoxy-3,3-debtor-D-mannopyranose.

Example 10. The following provides a table is-2,3-dideoxy-D-mannopyranose 250 g

lactose 800 g

corn starch 415 g

the talcum powder 30 grams

magnesium stearate 5 g

Mix 2-acetamido-2,3-dideoxy-D-mannose, lactose and half the corn starch, the mixture is then forced through a sieve with openings of 0.5 mm Corn starch (10 g) is suspended in warm water (90 ml) and the resulting paste is used for granulation of powder. The granules are dried, crushed and sieved through a sieve with openings of 1.4 mm, then add the remaining quantity of starch, talc and magnesium stearate are thoroughly mixed and pressed tablets.

Example 11. You can prepare capsules weight each 0,200 g, containing 20 mg of active substance.

The composition of 500 capsules:

2-acetamido-2,3-dideoxy-D-mannopyranose 10 grams

lactose 80 g

corn starch 5 grams

magnesium stearate 5 g

This drug is Packed in capsules of hard gelatin, which consists of two parts, 0,200 g of the mixture into each capsule.

Example 12.

Intravenous infusion of 50 mg/ml

Suitable for injection pharmaceutical preparation obtained by dissolving 50 g of 2-amino-2,3-dideoxy-3-iodo-D-mannopyranose hydrochloride in water for injection (1000 ml) and sealing the ampoule in the amount of 1-10 ml

Example 14.

Conventional pharmaceutical methods of preparing candles containing the following composition:

2-amino-2,3-deoxy-3,3-debtor-D-mannopyranose 50 mg

Lactose 298 mg

Corn starch 50 mg

Magnesium stearate 2 mg

Example 15.

Prepare capsules, each with a dose of 0.5 g, containing 50 mg of active substance.

Composition for 200 capsules:

2-acetamido-2,3-dideoxy-3-C-methyl-D-mannopyranose 10 grams

Lactose 80 g

Corn starch 5 grams

Magnesium stearate 5 g

This composition is placed in a double hard gelatin capsules, measuring 0.5 g each.

The table presents data on the activity of various compounds.

1. The derived 3-methoxybenzamide formula I

< / BR>
where R-NH2C2C5-alkanoyl NH; each of R1and R2independently C1C4- alkyl; or R1hydrogen, halogen, C1C4-alkyl or C1- C4-alkoxygroup, and R2hydrogen; or R1and R

2. Connection on p. 1, selected from the group comprising 2-acetamido-2,3-dideoxy-D-mannopyranose; 2-amino-2,3-dideoxy-3-iodine-D-mannopyranose; 2-acetamido-2-deoxy-3-O-methyl-D-mannopyranose; 2-amino-2,3-dideoxy-3-fluoro-D-mannopyranose; 2-acetamido-2,3-dideoxy-3-fluoro-D-mannopyranose; 2-acetamido-2,3-dideoxy-3-C-methyl-D-mannopyranose; 2-acetamido-2,3-dideoxy-3-C-ethyl-D-mannopyranose or, if appropriate, their pharmaceutically acceptable salts.

3. The method of obtaining the compounds of formula I on p. 1 or its pharmaceutically acceptable salts, characterized in that the method is carried out by hydrolysis of the compounds of formula II

< / BR>
where R1and R2such, as defined in paragraph 1, R3- acyl-NH-group, R4C1C4-alkyl, resulting in the receive connection of the formula I, in which R NH2or its salt and, if necessary, carry out the acylation of this compound with obtaining the compounds of formula I or its salts, in which R (C2- C5)alkanoyl-NH.

4. Pharmaceutical composition having inhibitory activity to the development of blood vessels and metastasis, containing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient is S="ptx2">

5. The composition according to p. 4, characterized in that the active ingredient is selected from the group comprising 2-acetamido-2,3-dideoxy-D-mannopyranose; 2-amino-2,3-dideoxy-3-iodine-D-mannopyranose; 2-acetamido-2,3-dideoxy-3-fluoro-D-mannopyranose, 2-acetamido-2,3-dideoxy-3-O-methyl-D-mannopyranose, or their pharmaceutically acceptable salts.

6. The derived 3-methoxybenzamide formula II

< / BR>
where R1halogen, R2hydrogen, R3acyl-NH-group, and R4lower alkyl.

7. The derived 3-methoxybenzophenone formula III

< / BR>
where R7fluorine, R2hydrogen, R3acyl-NH-group, R4lower alkyl, R5and R6together form benzyliden.

 

Same patents:

The invention relates to new chemical compound, namely 3-(4-methyl-2-thiazolyl)-6-proper-7-(1-methyl-1-etoxycarbonyl)metaxia - Mona, of the formula I

< / BR>
which has analepticheskih, hypoglycemic and hypolipidemic effect

The invention relates to methods of producing furan 1,3-dioxanes, which are used as the physiologically active substances

The invention relates to a new use some diphenylmethyl-piperazinecarboxamide, in particular amperozide, 4 [4,4-bis(forfinal)butyl] N-ethyl-1-piperazinecarboxamide and their salts in the treatment of substance abuse

The invention relates to pharmaceutical industry concerns (l)-(-)-2(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl) -4-[5,6-bis(4-forfinal)pentyl]-1-piperazineethanol, its pharmaceutically acceptable acid additive salt or hydrate and method of its production

Imidazopyridine // 2092487
The invention relates to certain imidazoquinolines that selectively bind to the GABA-a receptors

The invention relates to animal husbandry, in particular to the means immune stimulation and prevention of gastrointestinal diseases of newborn calves

The invention relates to heterocyclic compounds, specifically to piperazine derivatives, in which the piperazine one nitrogen atom is linked to a fragment of aryloxy or aaltio link oxypropylene or alkanoyloxy, and through another nitrogen atom with the rest of acetanilide

The invention relates to 9-amino-1,2,3,4-tetrahydropyridines and related compounds of the formula I

< / BR>
in which Y is C= O or CHOH; R1is hydrogen or lower alkyl; R2is hydrogen, lower alkyl or phenyl-lower alkyl; R3is hydrogen, OR4in which R4is hydrogen, COR5in which R5is lower alkyl, X is hydrogen, lower alkyl, halogen, lower alkoxy-, hydroxy-group or trifluoromethyl, their geometric or optical isomers, N-oxides, or their pharmaceutically acceptable salts and accessions acids (acid additive salts), which are useful in reducing dysfunction in memory and are thus indicative for the treatment of disease Allgamer

The invention relates to a new monohydrate 5- (2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3 - dihydro-2H-indol-2-he hydrochloride, containing pharmaceutical compositions, and method of neuroleptic treatment of diseases with the use of the specified monohydrate

The invention relates to medicine, namely to psychiatry and neurology

The invention relates to new biologically active compounds 2-piperazinone, namely 3-(21-naphthylmethyl)-piperazine-2-ONU (I) and 1-N-ventilationperfusion-2-ONU (II) formula:

< / BR>
I R 2-naphthyl; RI=H;

II R C6H5; RIC6H5

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine, cardiology.

SUBSTANCE: it is suggested to apply cortisol antagonists in addition to clonidine while manufacturing preparation to treat heart failure. Moreover, one should introduce cortisol antagonist or a product that includes cortisol antagonist along with the second medicinal preparation being a combined preparation to be applied either simultaneously, separately or successively. The present innovation provides decreased symptoms of heart failure at decreasing cardiac muscle's fibrosis and heart sizes due to preferable impact upon glucocorticoid receptors in patient's heart and/or kidneys.

EFFECT: higher efficiency of application.

12 cl, 2 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with medicinal preparations designed as solution and indicated for therapeutic needs. Eye drops contain ciprofloxacin hydrochloride monohydrate being equivalent to 0.3% free foundation, a buffer system that keeps pH within 3.5-5.5 interval, as a conserving agent - benzalconium chloride and a s a stabilizer - the salt of disodium ethylenediamine tetraacetic acid, moreover, their range of osmolality values correspond to 150-450 mM/kg H2O. Eye drops should be obtained by preparing buffer system in which mannitol should be dissolved followed by the salt of disodium ethylenediamine tetraacetic acid, benzalconium chloride, ciprofloxacin hydrochloride. Then one should perform the control for the quality of obtained solution to be then filtered by applying sterilizing elements and packed. This innovation provides treatment of eyes at creating the pressure in an eye and at certain desired osmolality.

EFFECT: higher efficiency of therapy.

4 cl, 1 ex

Endoparasitic agent // 2250779

FIELD: medicine.

SUBSTANCE: invention relates to endoparasitic agent containing cyclic depsipeptide of general formula 1 and piperazine of formula 2 .

EFFECT: endoparasitic agent with synergetic agent.

6 cl, 7 ex, 7 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating oncological diseases. It is suggested to apply bisdioxopiperazine (previously known as cardioprotector) to either treat or prevent tissue lesions caused due to sporadic transudation of cytotoxic poison for topoisomerase II (represented by anthracyclines, etoposide, teniposide, mitoxantrone daunorubicin, doxorubicin, etc.), medicinal remedies and pharmaceutical set of the same indication. It is, also, suggested to apply the method to treat or prevent tissue lesions caused by sporadic transudation of topoisomerase II poison. BisdioxopiperazineICRF-187 has impact due to catalytic inhibiting topo II. Signs for possible transudation of topoisomerase II poison (of local toxicity) usually include the availability of acute pain, erythema, development of ulcerations in area of transudation; due to the action of ICRF-187 the quantity of wounds is reduced, or the development of side effects is not observed.

EFFECT: higher efficiency of therapy.

59 cl, 12 dwg, 13 ex, 10 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

EFFECT: improved method for preparing and treatment, valuable medicinal properties of compounds.

13 cl, 88 ex

FIELD: medicine.

SUBSTANCE: at performing curative endoscopy one should apply pneumoapplication of granulated sorbent - diovine at the quantity of 0.2 g, the pressure being 15 atm. at the distance of 1.5 cm against the defect onto the surface of bleeding rupture of gastric mucosa. Diovine's coarse-grained structure enables to keep the integrity of mucous-bicarbonate barrier due to providing normal vapor exchange and moisture medium in the defect. Moreover, diovine's antimicrobial action helps to suppress gram-positive and gram-negative microflora that enables to shorten terms for defects healing and decrease the frequency of repeated hemorrhages.

EFFECT: higher efficiency of therapy.

1 ex

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