The way to obtain cis-nucleoside analogues, their salts and esters

 

(57) Abstract:

Describes how to obtain CIS-nucleoside analogues of General formula II, where X = S or O; Y = S and R2- the remainder of the purine or pyrimidine base or analogue or derivative, including interaction desired pre-similarvideo or similarvideo in situ purine or pyrimidine base or analogue or derivative with a compound of formula III, where X and Y are defined above; Z = S or 0; and this interaction is carried out in solution using a Lewis acid of the formula V, where R3, R4and R5independently selected from the group including hydrogen, C1-20alkyl (e.g. methyl, ethyl, t-butyl), optionally substituted by halogen (F, CL, Br, I)1-20>alkoxy (e.g. methoxy) or (C6-20aryloxy (for example, phenoxy);7-20aralkyl (e.g., benzyl), optionally substituted with halogen WITH1-20the alkyl or C1-20alkoxy (for example, p - methoxybenzyl);6-20aryl (e.g. phenyl), optionally substituted by halogen; C1-20the alkyl or C1-20alkoxy, trialkylsilyl; halogen (F, CL, Br, I); R6selected from the group consisting of halogen (F, CL, Br, I);1-204)(R5), where R3, R4and R5above: naydennyh or unsaturated compounds WITH6-20arrow, substituted or unsubstituted WITH6-20arylsulfonyl, substituted or unsubstituted WITH1-20alkoxyalkyl and trialkylsilanes. Target products possess antiviral activity. The technical result is to simplify the process of obtaining the above-mentioned compounds with a high yield. 3 C. and 16 h.p. f-crystals.

The invention relates to a stereoselective process for the preparation of analogues and derivatives of nucleosides. In particular, the invention relates to a process for the preparation of analogues and derivatives of nucleosides, which are mostly in their CIS-isomeric configuration.

Analogues and derivatives of nucleosides are an important class of drugs: for example, a number of nucleoside analogues showed antiviral activity against retroviruses such as human immunodeficiency virus (HIV), hepatitis B virus and T-lymphotropic virus man (ed. "PCT WO 89/04662 and Heb. patent, ed. 0 2',3'-dideoxycytidine and 2'-deoxy 3'-thiacytidine [(-)-2-hydroxymethyl-5-(cytosine-1'-y1)- 1,3-oxathiolan] (Heb. patent, ed. 0382526 A2).

Most of the analogues and derivatives of nucleosides contain at least two chiral center (marked with "*" in the formula (A), and each isomer can exist in two pairs of optical isomers (enantiomers) (i.e., two in the CIS-configuration and two in the TRANS configuration). However, biologically beneficial effects usually detect CIS-isomers.

Purine or pyrimidine base

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Many of the known processes for the production of analogues and derivatives of nucleosides to add sugar to a purine or pyrimidine base rely on conventional methods of glycosylation. This method always gives diastereomeric mixture of CIS - and TRANS-isomers, which require laborious separation and result in a lower yield of desired biologically active CIS-nucleoside analogues. Improved methodology for output only CIS-nucleosides requires you to add in sugar, preferably in position 2'-, aryl or acyl-Deputy. As Deputy 2'-useful only for CIS-nucleoside synthesis in one configuration (when the Deputy 2'-located in the position of the CIS in relation to the Deputy 4'-), this Deputy preen to be removed, that requires extra steps. [L Wilson and D. Liotta. "A general method for controlling stereochemistry in the synthesis of 2'-dcoxyribose nucleoside", Tetrahedron Lett.31, pp, 1815-1818 (1990).]

Therefore, an important task of finding a common and promising from an economic point of view stereoselective synthesis of biologically active CIS-nucleoside analogues.

The advantage described in the present invention process is that it allows the preparation of analogues and derivatives of CIS-nucleoside through fewer stages, using inexpensive and easily available starting materials and eliminating the need for laborious stages of giving and deprivation protective properties. Moreover, as described in the present invention, the process allows to obtain a good yield of desired analogs and derivatives of CIS-nucleosides.

In the present invention attempts to find an improved process of obtaining predominantly CIS-nucleoside analogues and derivatives of f-crystals I and their salts and false esters suitable for use in the technology of medicinal forms:

,

where X Is S or O; Y Is S, CH2or CH(R), where R is azido or halogen, and R2- purine or pyrimidine base or an analogue or Pro 1:

introduction in the reaction of the compound f-ly IV:

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with soft desiccant;

stage 2:

interaction is desirable previously subjected to siciliani (or siciliani in place) purine or pyrimidine base (R2) or its analogue or derivative with a new bicyclic intermediate product f-crystals III:

,

where X and Y are defined above; Z Is S or O;

moreover, the interaction is carried out by applying the appropriate Lisovoy acid in a suitable solvent a; to exit nucleoside intermediate product 2 - carboxylic or thiocarbonic acids f-crystals II:

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stage 3:

the recovery of the intermediate product f-ly III in connection f-ly I by applying a suitable reducing agent in a suitable solvent b.

Figure 1 depicts the preferred process in the form in which it is applicable to any of the nucleoside analogue in General, and especially 1,3-oxathiolane, 1,3-dioxolane, 1,3-dithiolane, ashdodite - or 2',3'-dideoxynucleosides counterparts.

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where X Is S or O; Y Is S, CH2, O or CH(R), where R is azido or run; Z Is O or S; and R2- purine or pyrimidine base or analogue or derivative.

Opican, where X Is O, Y Is S and Z is O.

Shown in figure 1 the different stages can be briefly described as follows:

Stage 1. 2-carboxylic or thiocarbonate acid sugar derivatives f-ly IV can be prepared by any known at the present level of technology development (e.g., ed. "PCT WO 92/20669, which is incorporated herein by reference). Bicyclic intermediate product f-ly III is obtained by joining reaction of sugar-derived f-IV crystals in the presence of a suitable soft desiccant, among which preferred soft desiccant is triethylorthoformate.

Stage 2. Previously subjected to siciliani (or siciliani in place) purine or pyrimidine base or analogue or derivative then interacts with the new bicyclic intermediate product f-ly III in the presence of varying Lisovoy acid, e.g. idolisation or triftoratsetata of trimethylsilyl for 2-carboxylic or thiocarbonic acids nucleoside analogue of f-crystals II, mainly in the CIS-configuration.

In a preferred embodiment of the present invention R2- preferably p is the version of the implementation of the present invention R2- preferably a purine or pyrimidine base or analogue or derivative is selected from the group consisting of fortitudine, cytosine and uracil.

Among the preferred lisovich acids used in the interaction purine or pyrimidine base or analogue or derivative are idolreplicas, triftorbyenzola t-butyl-dimethylsilane or trimethylsilyl.

Preferred Lisovyi acid used in the interaction of pyrimidine bases with bicyclic intermediate product f-crystals II - triftorbyenzola t-butyl-dimethylsilane and trimethylsilyl.

Among the preferred solvents suitable for use in the interaction of purine or pyrimidine base or analogue or derivative, at least one halogenated organic solvent. More preferred among the preferred solvent is dichloromethane.

In a more preferred embodiment of the present invention the base R2previously subject to siciliani with the appropriate cilleruelo substance selected from the group comprising exam the substance, selected from the group comprising triftorbyenzola t-butyl-dimethylsilane and trimethylsilyl.

Stage 3. CIS-2-carboxylic or thiocarbonate acid nucleoside analogue of f-crystals II can be recovered using a suitable reducing agent in a suitable solvent to obtain the final compounds of f-crystals I. Optional, the output of the latter stage of recovery can be improved if the connection f-crystals II initially converted into an ester, e.g. ethyl ester, any known at the present level of technology development method, after which followed the restoration using a suitable reagent as described above.

Among the preferred reducing agent is sodium borohydride, triethylborohydride lithium, alumoweld lithium, borane, and the mixture barometrul sulfide and trimethylborane.

Among the preferred solvents is at least one solvent, which has been independently selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, simple ether and dichloromethane.

Scheme 1a shows the use of the process in scheme 1 for the synthesis of a racemic mixture of CIS-2-hydroxymethyl-5-(5'-fertilizin-1'-uhodnye materials, the specialist in this area it is clear that for the preparation of similar compounds can be used similar suitable reagents and starting materials.

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Shown in scheme 1a, the various stages can be briefly described as follows:

Stage 1. TRANS-5-hydroxy-1,3-oxathiolan-2-carboxylic acid f-crystals IVa can be obtained by any known at the present level of technology development method. TRANS-5-hydroxy-1,3-oxathiolan-2 - carboxylic acid f-crystals IVa boiling under reflux reacts with triethylorthoformate, resulting in a new bicyclic intermediate product f-crystals IIIa - 2,7-dioxa-3-oxo-5 - diabetico[2.2.1]heptane.

Stage 2. New bicyclic intermediate product f-crystals IIIa - 2,7-dioxa-3-oxo-5-diabetico[2.2.1]heptane - reacts with 5-fortitudinem previously subjected to siciliani with this Lisovoy acid, as hexamethyldisilazane or siciliani on the spot with this Lisovoy acid, as triftorbyenzola of trimethylsilyl, in such a suitable solvent like dichloromethane containing 2,6 lutidine. Then added Lisova acid, preferably edotreotide or triftorbyenzola trim is the notes - vysokoustoychivy way and with a high ratio of CIS.TRANS.

Stage 3a. CIS-nucleoside analogue of f-crystals IIa - CIS-5-(5'- fertilizin-1'-y1)-1,3-oksanalan-2-carboxylic acid is then processed by the corresponding Converter, such as a mixture of CsF and iodoethane in such a suitable solvent like N,N-dimethylformamide, to obtain a complex ester f-crystals IIb - CIS-ethyl-5-(5'-fertilizin-1'-y1)- 1,3-oxathiolan-2-carboxyla.

The preferred Converter is a mixture of CsF and iodoethane.

The preferred solvent is dimethylformamide.

Stage 3b. Ethyl ester of CIS-nucleoside analogue of f-crystals IIIb - CIS-ethyl-5-(5'-fertilizin-1'-y1)-1,3-oxathiolan-2-carboxyl is then reduced using a suitable reducing agent, e.g., sodium borohydride in an appropriate solvent, e.g., ethanol, to obtain the final compounds f-ly Ia - CIS-2-hydroxymethyl-5-(5'-fertilizin-1'-y1)-1,3-oxathiolane.

Analogues of nucleoside f-ly I, synthesized with the use described in the invention process preferably include 1,3-oxathiolane, 1,3-dioxolane, 1,3-dithiolane and 2',3'-dideoxy analogs that have been modified by any of the following ways (or their combina isostere group (e.g., 7-deazaadenosine): change of sugar, e.g. substitution of hydroxyl groups (C-2' and C-C' in any Deputy, including halogen, azido or hydrogen (e.g., 2',3'-dideoxynucleoside); modification of the sugar binding site to site N-1 may, e.g., to be attached to the N-3 or C-6. and usually attached to the N-9 purine, can, e.g., to be attached to the N-7; configuration change communication Foundation sugars (e.g., CIS - and TRANS-configuration).

The term "purine" or "pyrimidine base" means a base, which can be found in nucleosides found in natural form. Similar base - base, which mimics the naturally occurring bases in the sense that their structures (the kinds of atoms and their arrangement) are similar to those found in nature, however, possess additional functional properties of naturally occurring bases (or, on the contrary, in some other functional properties may be missing). Such analogues include obtained by the substitution component CH a nitrogen atom (e.g., 5-isoperimetry as 5-azacytosine), or by substitution of the nitrogen atom component of CH (e.g., such 7-deazapurine as 7-deazaadenosine or 7-deazaguanine), and the other is that the substituents in the cycle are included in the regular, known in the present state of technology substituents, e.g., halogen, hydroxyl, amino, C1-6alkyl, - hatshepsuts or modified them. Such purine or pyrimidine base, analogs and derivatives of well - known specialists in this area, as it occurs in M. J. Robins, "Chemistry of naturally occurring pyrimidine nucleoside and analogues" Analogue Nucleosides, (R. T. Walker et al., Eds.) Plenum Press, pp 165-192 (1979) and Nasr et al., Antiviral Reg., 14 pp 125-148 (1990).

Lisova acid, the use of which is to facilitate the interaction of the intermediate product f-ly III previously subjected to siciliani (or siciliani in place) purine or pyrimidine base or analogue, has a total f-Loy V:

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where R3, R4and R5is independently selected from the group consisting of hydrogen, C1-6of alkyl (e.g. revenged, ethyl, t-butyl), with optional substitution by halogen (F, Cl, Br, I) C1-20alkoxy (e.g., methoxy), or C6-20aryloxy (e.g. phenoxy); C7-20aralkyl (e.g., benzyl) with optional substitution by halogen, C1-20the alkyl or C1-20alkoxy (e.g. p-methoxybenzyl); C6-20aryl (e.g. , phenyl), with optional substitution by halogen, C1-20the alkyl or C1-20alcox the 1-20 sulphonate esters with optional substitution by halogen (e.g., triftorbyenzola); C1-20alilovic esters with optional substitution by halogen (e.g. triptorelin); polyvalent halides (e.g., triiodide); three times substituted cyrilovich groups total f-crystals: (R3) (R4) (R5) Si (where R3, R4and R5defined above); saturated or unsaturated seleninyl C6-20aryl; substituted or unsubstituted C6-20arylsulfonyl; substituted or unsubstituted C1-20alkoxyalkyl; and trialkylsilanes.

Preferred groups R3, R4and R5- independently methyl or iodine. The most preferred group R3, R4and R5is methyl. Preferred groups R6are iodine, chlorine, bromine or sulphonate esters. The most preferred groups R6are iodine and triftorbyenzola.

In the most preferred embodiment, Lisova acid is selected from the group consisting of iodotrifluoromethane; triftoratsetata t-butyl-dimethylsilane and triftoratsetata of trimethylsilyl.

Under salts and esters suitable for use in the technology of the medicament the project in the technology of medicinal forms, connection f-crystals I. Such a salt, ester or salt of such a complex ester suitable for use in the technology of dosage forms also include any other compound, which, with the introduction of its recipient is capable of providing (directly or indirectly) the compound f-ly I, or possessing antiviral activity of the metabolite or residue.

Specialists in this field will understand that the connection f-ly I can be changed to obtain its derivatives suitable for use in pharmaceutical, functional groups in both components of the base R2and also hydroxymethyl C-2 of the sugar ring. Changes in all of these functional groups are covered by the present invention processes. However, of particular interest are acceptable derivatives (e.g. , esters) obtained by modifying group 2-hydroxymethyl sugar rings.

Preferred esters f-ly I, produced by the process of the present invention include the compound in which IT is replaced by the function carboxyla R1(CO)O-, in which R1is selected from hydrogen; alkyl straight or branched chain (e.g., methyl, halogen, C1-4alkyl or C1-4alkoxy); substituted dihydropyridines (e.g., N-methyldihydromorphine). R1(CO)O - may also be replaced by such sulphonate esters as alkyl - or aralkylamines (e.g., methanesulfonyl); sulphonate esters, esters of amino acids (e.g., L-poured or L-isoleucine); and mono -, di - or trifosfatnogo esters. Also included in the range of such esters esters derived from such multifunctional acids like phosphoric acid or carboxylic acid containing more than one group of carboxyl, e.g. , dicarboxylic acid f-crystals HOOC(CH2)qCOOH, where q is an integer from 0 to 10 (e.g., succinic acid).

Suitable for use in pharmaceutical salts of compounds f-ly I include salts derived from suitable for use in pharmaceutical inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, Hydrobromic, sulphuric, nitric, perchloro, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, p-toluensulfonate, tartaric, acetic, citric, methansulfonate, formic, benzoic, malonic, naphthalene-2 - sulfonic, Bezdna for use in pharmaceutical, can be useful in the preparation of salts useful as intermediates in obtaining described in the present invention compounds and their with the addition of acid salts suitable for use in the technology of medicinal forms.

Salts derived from appropriate bases include alkali metal (e.g. , sodium), alkaline earth metals (e.g., magnesium), ammonium, and salts of N(R')4(where R' - C1-4alkyl).

The following examples illustrate the present invention in such a way that it can be applied in practice, however, by themselves, should not be construed as limitations on the overall scope of the present invention.

Example 1.

2,7-dioxa-3-oxo-5-diabetico[2.2.1]heptane

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A solution of TRANS-5-hydroxy-1,3-oxathiolan-2-carboxylic acid (200 mg, of 1.33 mmol) and triethylorthoformate (15 ml) was heated for 2 hours in a graphite bath at 120oC. After removal of solvent the crude reaction mixture was purified by silica gel-chromatography, elyuirovaniya with ethyl acetate:hexane (1:4) to obtain 64 mg (35%) of the desired product;1H NMR (DMSO): to 3.33 (dd, 1H, J=11.2 Hz), 3,42 (d, 1H, J=11 Hz), 6,53 (s, 1H), 6,83 (d, 1H, J=2 Hz);13C NMR and

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Triftorbyenzola of trimethylsilyl (0,164 ml, services, 0.844 mmol) and 2,6-lutidine (0,098 ml, services, 0.844 mmol) were added to 5-ferritin (54,4 mg, 0,422 mmol) in dichloromethane (1 ml) at room temperature in an argon atmosphere. The mixture immediately became bright. Was added a solution of 2,7-dioxa-3-oxo-5-diabetico[2.2.1] heptane (example 1) (56 mg, 0,422 mmol) in dichloromethane (1 ml), then edotreotide (0.06 ml, 0,422 mmol). The yellow solution stirred at room temperature for 16 hours. Was added an additional amount of 2,6-lutidine (0.05 ml, 0,422 mmol) then methanol (0,034 ml, services, 0.844 mmol). After 5 min stirring, the mixture was concentrated and the residue was rastered simple ether/dichloromethane to achieve a mixture of CIS - and TRANS-products of interaction in the ratio of 10: 1 (99,7 mg, yield of 90.6%). This mixture was further restorana methanol at room temperature to obtain almost pure CIS-product (78 mg, yield 72,7%).1H NMR (DMSO-d6): 3,20 (1H, dd, J=2,9, 9,3), 3,53 (1H, dd, J=2.5 a, 9,3); 5,61 (1H, s) 6,25 (m); of 7.69 (1H, bs); of 7.90 (1H, bs); of 8.28 (1H, d, 7,21).13C NMR (DMSO-d6): 36,07, 78,38, 89,46, 125,76 (d, J=32,8), 136,29 (d, J=284,9), 153,28, 157,93 (d, J=18,0), 171,29.

The 3rd example

CIS-ethyl-5-(5'-fertilizin-1'-y1)-1,3-oxathiolan-2 - carboxylate

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CIS-5-(5'-Florcita,7 mg, 0,057 mmol) and iodoethane (5 l, or 0.57 mmol). The solution is stirred at room temperature overnight and N,N-dimethylformamide was removed. The residue was treated with ethyl acetate/dichloromethane (1: 1.8 ml) and filtered. The filtrate was concentrated and the residue was washed several times with simple ether to obtain the product as a white solid (8 mg, yield 72%).1H NMR (CD3OD): of 1.13 (3H, t), a 3.01 (1H, dd), to 3.36 (1H, dd), 5,43 (1H, s), 6,16 (1H, m), 8,30 (1H, d).

Example 4.

CIS-2-hydroxymethyl-5-(5'-fertilizin-1'-y1)-1,3 - oxathiolane (VSN-330)

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CIS-ethyl-5-(5'-fertilizin-1'-y1)-1,3-oxathiolan-2-carboxylate (example 3) (5,5 mg, 0.019 mmol) in ethanol (0.5 ml) was treated with sodium borohydride (2 mg, 0,057 mmol) at 0oC. the starting material was not completely dissolved. After it was mixed at room temperature for 2 hours, methanol (0.2 ml) was added and stirring continued for 1.5 hours. The solvents were removed and the mixture was purified by silica gel-chromatography with methanol/ethyl acetate as eluents to achieve the pure product as a white solid (4.2 mg, yield 89%). 1H NMR (CD3OD): 2,97 (1H, dd), of 3.32 (1H, dd), 3,66 (1H, dd), with 3.79 (1H, dd), 5,07 (1H, t), 6,03 (1H, m), 8,15 (1H, dd).

Example 5.

Example 6.

CIS-ethyl-5-(cytosine-1'-y1)-1,3-oxathiolan-2-carboxylate

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Iodoethane (0,02 ml, 0.25 mmol) was added to a suspension of CIS-5- (cytosine-1'-y1)-1,3-oxathiolan-2-carboxylic acid (example 5) (38 mg, initial solution was mixed for 18 hours. The dimethylformamide was removed under vacuum to obtain a white solid, which was subjected to column chromatography (ethyl acetate/hexane/methanol/2: 2:1) to obtain 31 mg (yield 72%) of product as white granules. 1H NMR (DMSO-d6): 1,3 (t, 3H, J=7,1 Hz), of 3.12 (dd, 1H, J= 6.7 and 12 Hz), 3,52 (dd, 1H, J=5.1 and 12 Hz), is 4.21 (q, 2H, J=7,1 Hz), 5,7 (s, 1H), 5,79 (d, 1H, J=7.5 Hz), 6,34 (dd, 1H, J=5.1 and 12 Hz), 7,28-7,32 (bd, 1H), 7,95 (d, IH, J=7.5 Hz).

Example 7.

CIS-2-hydroxymethyl-5-(cytosine-1'-y1)-1,3-oxathiolane (VSN-189)

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Borohydride sodium (6 mg, 0.16 mmol) was added to a suspension of CIS-ethyl-5-(cytosine-1'-y1)-1,3-oxathiolan-2-caraccilo (example 6) (15 mg, by 0.055 mmol) in a mixture of methanol (1 ml) and dichloromethane (1 ml) at room temperature. The resulting solution was stirred for 2 hours and the solvents were removed under vacuum to obtain a white solid, which was passed through a silica compound-short path column (ethyl acetate/hexane/methanol) to obtain output 12.5 mg (yield 100%) of product.1H NMR (DMSO-d6): 2,99 (dd, 1H), 3,40 (dd, 1H), 3,71 (m, 2H), 5,14 (t, 1H), 5,70 (d, 1H), 6,18 (t, 1H), 7,20 (d, 2H), 7,80 (d, 1H).13C NMR (DMSO-d6): 36,22, 62,79, 85,75, 86,47 93,86, 140,91, 154,63, 165,59.

Example 8.

CIS-5-(uracil-1'-y1)-1,3-oxathiolan-2-carboxylic acid

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Jodatime the bis-trimethylsilylmethyl (140 mg, 0,545 mmol) in anhydrous dichloromethane at room temperature in an argon atmosphere. The resulting solution was stirred for 20 hours. The reaction was abruptly cooled by adding a mixture of 1: 1 saturated solution of sodium thiosulfate-sodium bicarbonate, then dilute with dichloromethane. The mixture was mixed for 10 minutes to obtain a white suspension. White solid was collected by filtration, then dried under vacuum to obtain 21 mg of a white powder. Analysis1H NMR showed a mixture of 6:1 desired product and uracil. The aqueous portion of the filtrate was acidified with 1 M HCl at pH 4, then saturated with sodium chloride. This solution was extracted by adding tetrahydrofuran. The combined extracts were dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to achieve 73 mg of a white solid. Analysis1H NMR showed a mixture of 5:2 desired product and u, on the basis of the analysis1H NMR total yield was 64% and isomeric purity was estimated as 95% of the CIS isomer.1H NMR (DMSO-d6): of 2.26 (dd, 1H, J=4,9, 12.3 Hz), 3,49 (dd, 1H, J=5,2, and 12.4 Hz), 5,57 (9, 1H), 5,71 (dd, 1H, J=2,2, 8.0 Hz); [this signal is collapsed to a doublet in the processing of D2O (J=8,2 Hz)], of 6.29 (t, 1H, J=5,2 Hz), 8,07 (d, 1H, J

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Barometry sulfide is added to CIS-5-(uracil-1'-y1)-1,3 - oxathiolan-2-carboxylic acid and trimethylboron in tetrahydrofuran. The repair is performed at room temperature. The final product was isolated by J. L. Kraus and G. Attardo. Synthesis. 1991, 1046.

1. The way to obtain CIS-nucleoside analogs of formula II, mostly in the form of the CIS isomer

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where X = S or O;

Y = S, O;

R2- the remainder of the purine or pyrimidine base,

including interaction desired pre-similarvideo or similarvideo in situ purine or pyrimidine base or analogue or derivative with a compound of formula III

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where X and Y are defined above; Z = S or O,

moreover, this interaction is carried out in solution using a Lewis acid of the formula V

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where R3, R4and R5independently selected from the group including hydrogen, C1-20alkyl (e.g. methyl, ethyl, t-butyl), optionally substituted by halogen (F, Cl, Br, J), C1-20alkoxy (e.g. methoxy) or C6-20aryloxy (for example, phenoxy); C7-20aralkyl (e.g., benzyl), optionally substituted with halogen, C1-20the alkyl or C1-20alkoxy-alkyl or C1-20alkoxy; trialkylsilyl or halogen (F, Cl, Br, J);

R6selected from the group consisting of halogen (F, Cl, Br, J); C1-20sulphonate esters, optionally substituted by halogen (for example, triftorbyenzola); C1-20alilovic esters, optionally substituted by halogen (for example, triptorelin); polyvalent halides (for example, triiodide); three times substituted silyl groups of the General formula: (R3) (R4) (R5) Si (where R3, R4and R5defined above); saturated or unsaturated seleninyl C6-20arrow; substituted or unsubstituted C6-20arylsulfonyl; substituted or unsubstituted C1-20alkoxyalkyl and trialkylsilanes.

2. The method according to p. 1, where R2is a pyrimidine base.

3. The method according to p. 1, where R2selected from the group consisting of fortitudine, cytosine and uracil.

4. The method according to any of the preceding paragraphs, where X = O; Y = S and Z = 0.

5. The method according to any of the preceding paragraphs, where the interaction is carried out in a solution comprising at least one halogenated organic solvent.

6. The method according to p. 5, where the solvent submitted group, composed of iodotrifluoromethane; t-butyl-dimethylsilane triftoratsetata and trimethylsilyl triftoratsetata.

8. The method according to any of the preceding paragraphs, where the purine or pyrimidine base is subjected to siciliani with the appropriate cilleruelo agent selected from the group which includes 1,1,1,3,3,3,-hexamethyldisilazane and trimethylsilyl triftoratsetata or siciliani in situ using cilleruelo agent selected from the group which includes t-butyl-dimethylsilane triftorbyenzola and trimethylsilyl triftorbyenzola.

9. The method of obtaining the compounds of formula I

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where X, Y and R2have the values listed in paragraph 1,

includes recovering the obtained compound of formula II.

10. The method according to p. 9, where the recovery is carried out in the presence of at least one solvent, is independently selected from methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran and simple ether.

11. The method according to p. 9 or 10, where the recovery is carried out using a reducing agent selected from sodium borohydride, triethylborohydride lithium, lithium aluminum hydride, borane, and mixtures barometers the scientists of the compounds of formula II to obtain the compounds of formula IIb

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where X, Y, Z, and R2defined according to any one of paragraphs.1 to 3 and R1= C1-6alkyl,

and recovery of the compounds of formula IIb with obtaining the compounds of formula I in a suitable solvent.

13. The method according to p. 12, where the esterification is carried out in the presence of dimethylformamide as solvent.

14. The method according to p. 12 or 13, where the esterification is performed with the use of a mixture of CSF and iodata as tarifitsiruemih agent.

15. The method according to any of paragraphs.12 - 14, where the recovery is carried out in the presence of at least one solvent, is independently selected from methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran and simple ether.

16. The method according to any of paragraphs.12 - 15, where the recovery is carried out using a reducing agent selected from sodium borohydride, triethylborohydride lithium, lithium aluminum hydride, borane, and mixtures brometalia and trimethylborane.

17. The method of obtaining the compounds of formula I, mainly in the form of the CIS isomer

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where X, Y and R2defined above according to any one of paragraphs.1 - 4,

including interaction desired pre-similarvideo or similarvideo in situ purine Il and Z are defined above under item 1 or 4,

moreover, this interaction is done according to the method specified in any of paragraphs. 1 and 5 to 8, in order to obtain the compound of formula II, with subsequent recovery of the compounds of formula II to obtain the compounds of formula I by the method defined in any of paragraphs.9 - 16.

18. The method according to any of the preceding paragraphs, where the compound of formula III is produced by interaction of the compounds of formula IV

< / BR>
where X, Y and Z have the above values,

with a mild dehydrating agent.

19. The method according to p. 18, where the dehydrating agent is triethylorthoformate.

20. The method according to any of the preceding paragraphs, where X and Y both are not grey.

 

Same patents:

The invention relates to new nucleoside analogues of 1,3-oxathiolane and their use for treating viral infections, HIV infection, hepatitis b, more specifically to the (-)-4-amino-5-fluoro-1-(2-oxymethyl-1,3-oxathiolan-5-yl)-(1H )-pyrimidine-2-ONU (I) and its pharmaceutically acceptable derivative containing pharmaceutical compositions

The invention relates to new substituted cyclic derivatives of 1,3-oxathiolane having pharmacological activity, to processes for their preparation and intermediate compounds used for their production, to containing these derivatives, pharmaceutical compositions and to the use of these derivatives for the treatment of viral diseases in mammals

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to substituted derivative asalaam, which is an effective anti-Helicobacter tools that can be used as monotherapy for eradication of Helicobacter pylori and related species

The invention relates to crystals containing water of crystallization (hereinafter referred to as hydrated form or simply hydrate), and the crystals without water of crystallization (hereinafter referred to as the anhydrous form or simply anhydrous), to a method for selective receipt of these crystals and, in addition, to pharmaceutical preparations containing such crystalline form

FIELD: organic chemistry, biochemistry, pharmacy.

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

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes using 4,6-bis-(diethylamino)-2-[(2'-tetrazol-(2'H)-5'yl]-1,3,5-triazine of the formula: as an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on sunflower germinated seeds. The proposed substance shows the enhanced effectiveness in increasing roots and hypocotyls length of seedlings and to expand assortment of the known antidotes.

EFFECT: valuable properties of antidote.

2 cl, 2 tbl, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of N-heterocyclic compounds of the formula: , wherein n and m mean independently a whole number from 1 to 4; A means -C(O)OR1 or -C(O)N(R1)R2; W means -CH; R1 means hydrogen atom or (C1-C8)-alkyl; R means hydrogen atom, (C1-C8)-alkyl, heterocyclyl-(C1-C4)-alkyl chosen from the group comprising benzodioxolyl-, benzodioxanyl- or dihydrobenzofuranylalkyl or phenyl-(C1-C4)-alkyl substituted possibly with alkoxy-group; R4 means cyano-group or heterocyclyl chosen from the group comprising pyridinyl, morpholinyl, benzodioxolyl or benzodioxanyl-radical if m = 1; if m means from 2 to 4 then R4 can mean additionally hydroxy-group, -NR1R2 wherein R1 and R2 mean independently hydrogen atom, (C1-C8)-alkyl or benzyl-radical, -N(R1)-C(O)-R1, -N(R1)-C(O)-OR1, -N(R1)-S(O)t-R1 wherein R1 means hydrogen atom or (C1-C8)-alkyl, -N(R1)-C(O)-N(R1)2 wherein R1 means hydrogen atom; R5 means (C1-C8)-alkyl; t = 2, and their stereoisomers and pharmaceutically acceptable salts, pharmaceutical composition based on thereof and a method for treatment of diseases, in particular, rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and composition.

12 cl

FIELD: herbicides.

SUBSTANCE: invention relates to application of 2-diethylamino-6-methoxy-4-[(4'-ethoxycarnonyl-5'-methyl-1',2',3'-triazole)-1'yl]1,3,5,-triazine of formula as antidote against phytotoxic action of 2,4-dichlorophenoxyacetic acid herbicide onto germinated sunflower seeds.

EFFECT: more effective sunflower germ root length and hypocotyl elongation on background of phytotoxic 2,4-D herbicide action.

2 tbl, 3 ex

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