Nitroethane with pharmacological activity, and methods for their production

 

(57) Abstract:

Nitroethene General formula I, where a and b is hydrogen, substituted or unsubstituted alkyl, R is a residue of formula (a-K), R2is hydrogen, methyl, ethyl,3-12-alkyl, Y is oxygen, NH, NR1where R1-alkyl, n = 1-10, have anti-inflammatory and/or antiplatelet activity. It is established that the introduction end nitroethanol group in the General formula derivatives of 1 leads to an increase in pharmacological activity of nonsteroidal anti-inflammatory agents and at the same time destroys dysfunctional reactions that appear in the treatment of these agents. 2 S. and 9 C.p. f-crystals, 1 PL.

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The object of the present invention are nitroethane with anti-inflammatory and/or antiplatelet activity, their pharmaceutical use and the way they are received.

Prior knowledge

Some derivatives of propionic acid, such as, for example 2-(3-benzoylphenyl)propionic acid, commonly known as Ketoprofen for a long time used as pharmaceutical drugs with anti-inflammatory activity and promoted on various spare parts of the African patent N 68 00.524, the corresponding U.S. patent 3.641.127; in French patent N M6444, and S. A. 75.5528 m (1971); G. A. PINNA et al., Farmaco Ed. Sci. 35,684 (1980); and the pharmacokinetics of a person described in T. ISHIZAKI et. al., Eur. J. Clin. Pharmacol. 18,407 (1980). The use of propionic acid derivatives, such as, for example, Ketoprofen, known as well as the use of other products that are used as anti-inflammatory agents, includes, as is well known, strongly adverse reactions, for example, in the gastrointestinal system, as well as possible damage to the liver and kidneys.

There are a lot of experimental evidence [S. MONCADA, R. M. J. PALMER, and E. A. HIGGS, Pharmacological Reviews, 43(2), 109 (1991); T. H. LUSHER, C. M. BOULANGER, Y. DOHI, Z. YANG, Hypertension, 19, 117 (1992)], based on which the integrity of the vascular endothelium, as suggested, is the main barrier against the attack of pathological processes in some organs and units from the adverse reactions that are typical of anti-inflammatory agents.

This protective barrier and, in addition, the integrity of the vascular endothelium physiologically is due to the presence of nitric oxide and prostacyclin.

Treatment non-steroidal compounds having anti-inflammatory activity, such as 2-(the th synthesizes the precursor of prostacyclin.

In conclusion, if you inhibit the formation of prostacyclin, his stock in tissues significantly depleted, and, in addition, the integrity of the vascular endothelium exposed.

As mentioned above, due to endothelial damage, caused by the reduction of prostacyclin, the distribution of diffuse pathological process affects the gastrointestinal system, liver and kidneys.

The objects of the invention

The object of the present invention is a group of products that provide a high level of pharmacological activity anti-inflammatory agents, but at the same time capable of suppressing the adverse reactions caused in the treatment of the aforementioned agents. Another object of the present invention is the implementation of the process of preparing a group of products having anti-inflammatory activity, but at the same time free from adverse reactions, are typical of anti-inflammatory agents.

Description of the invention.

These and other objects and advantages, which will be shown in the subsequent description, are obtained with the help of nitrofuran having the following General formula:

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where A and B is selected from hydrogen, linear>BR>
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R2selected from hydrogen, methyl, ethyl, alkyl linear or branched, with 3 to 12 carbon atoms, substituted or unsubstituted, Y is selected from oxygen, NH, NR1where R1- linear or branched alkyl and n is from 1 to 10.

In fact, it is established that the introduction end nitroethanol group in derivatives of General formula (I) leads to an increase in pharmacological activity of nonsteroidal anti-inflammatory agents, and at the same time destroys dysfunctional reactions that appear in the treatment of these agents.

In addition, it was found that derivatives (I) are also useful in such painful conditions, such as rheumatic diseases of a General nature, immunological disorders, and to relieve painful conditions of mild and moderate severity of any nature.

Moreover, derivatives (I), which is the subject of this invention, used in the treatment of diseases of the cardiovascular system, and in particular in the treatment of infarction and ischemia, as well as arterial thrombosis as antiplatelet agents.

In accordance with this invention is extremely useful nitroethyl Oan as Y and n equal to 4 according to the following formula:

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Also particularly useful according to this invention, is nitrofur General formula (I), where: hydrogen is selected as A and B, R is selected as

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methyl selected as R, Y is selected as oxygen and n is equal to four, according to the following formula:

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Moreover, according to the present invention, particularly useful nitroethene General formula (I) where: hydrogen is selected as A and B, R is selected as

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methyl, ethyl and hydrogen is chosen as R2oxygen is selected as Y and n is four, according to the following formula:

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To obtain nitroethanol General formula (I), object of the present invention, are particularly important in the first process, which, according to the invention, includes the following stages:

- Obtaining the sodium salt product having the following General formula:

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where R2selected from hydrogen, methyl, ethyl, alkyl linear or branched, with 3 to 12 carbon atoms, substituted or unsubstituted, R is selected from: (II), (III), (IV), (VI), (VII), (VIII), (IX), (X), (XXI), (XXXV), or obtaining derivative (XIV), substituted by carboxyl group, such as acid chlorides, anhydrides, etc.;

- The reaction of the sodium salt of the above derivative (XIV) or above derivative (XIV), substituted by CA, bromine, other6where R6selected from hydrogen, linear or branched alkyl, A and B is selected from hydrogen, linear or branched, substituted or unsubstituted alkyl, R3selected from chlorine, bromine, iodine, and n is from 1 to 10, obtaining in this way the corresponding esters or the corresponding amides;

The reaction of the abovementioned ethers or above amides with nitrous agent such as AgNO3or similar to get nitroethanol (I).

The second process, which is also very important, according to the present invention includes the following stages:

- Obtaining the sodium salt derivatives having the following General formula:

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where R is selected from: (II), (III), (IV), (VI), (VII), (VIII), (IX), (X), (XXI), (XXXV), R2selected from hydrogen, methyl, ethyl, linear or branched alkyl with 3 to 12 carbon atoms, substituted or unsubstituted, or obtaining derivative (XIV), substituted by carboxyl group, such as acid chlorides, anhydrides, or etc.;

The reaction of the sodium salt of the above derivative (XIV) or above derivative (XIV), substituted by carboxyl group, with a compound of General formula:

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where R4selected from chlorine, bromine, other6where R6about the, substituted or unsubstituted alkyl, and n is from 1 to 10, obtaining in this way the corresponding esters or amides;

The reaction of the abovementioned ethers or above amides with palodiruyut connection PBr3and/or the like, to provide the above esters or above amides with halide end group;

The reaction of the abovementioned ethers or above amides having a terminal halogen group, with nitrous agent AgNO3or similar to get nitroethanol (I).

The solvents used in the processes, which are the subject of the present invention, preferably selected from chloroform, methylene chloride, acetonitrile, dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like.

Methods of obtaining derivatives (I) which are the subject of the present invention, consist of several stages and allow you to get the products of the above processes for a short time and with good outputs even in the industrial plan.

According to the methods described in this invention have nitroethyl having the following formula:

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which is particularly useful, and which is obtained as described in the next is-alpha-methyl-4-diphenyloxazole acid added to the solution, containing 10 ml of methanol and 0.23 g of Na. The reaction mixture is stirred for 5 minutes, then the solvent is evaporated under reduced pressure, obtaining the sodium salt of 2-fluoro-alpha-methyl-4-diphenyloxazole acid.

b) Sodium salt of 2-fluoro-alpha-methyl-4-diphenyloxazole acid, is obtained in this way are suspended in 20 ml of dimethylformamide and 3 ml of 1,4-dibromobutane, which add precapitalism to this suspension. The reaction mixture is stirred for 22 hours at room temperature, then NaBr formed is filtered off and the solvent evaporated under reduced pressure. The resulting residue is treated with methylene chloride and, after separation by filtration of the insoluble residue, methylene chloride is evaporated under reduced pressure, obtaining 3 g of dry residue, which is purified chromatographically on silica gel, using as eluent a mixture of hexane/methylene chloride 1/1 (by volume). The main fraction is collected, the solvent evaporated under reduced pressure and obtain 1.86 g of 2-fluoro-alpha-methyl-4-diphenylacetate 4-bromobutyl (XXII).

IR (cm-1): C = 0,1470

1H-NMR (300 MHz) (CDCl3): 1,51 M. D. (d, 3H); 1.56 to M. D. (m, 4H); 3,35 m DV (t, 2H); 3,61 M. D. (q, 1H); 4,1 m DV (t, 2H), 7,05 M. D. (m, 1H); 7,17 memorial plaques (s, 1H); 7.3 to 7,55 M. D. (m, aromatic)

IR (cm-1): C = 0,1737; ONO2, 1623, 1274.

1H-NMR (300 MHz) (CDCl3): 1,53 m D. (d, 3H); 1,72 M. D. (m, 4H); 3,74 M. D. (q, 1H); 4,13 m DV (t, 2H); 4,4 m DV (t, 2H); 7,13 m DV (t, 2H, aromatic); 7,32 - 7,42 M. D. (m, 4H, aromatic); 7,53 M. D. (m. 2H, aromatic).

Mass spectrometry: (M+1) 361; (M+1 - NO2) 316; 243; 199.

According to the method which is the subject of the present invention also receive nitroethyl having the following formula:

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which is especially useful, its getting described in the example here below, and which is given for illustration of the present invention, nwlat to the solution, containing 1.19 g Na in 80 ml of methanol. The reaction mixture is stirred for 15 minutes, then the solvent is evaporated under reduced pressure, the obtained residue is a sodium salt of 2-(3-benzoylphenyl)propionic acid.

b) 100 ml of dimethylformamide and 28.1 g of 1,4-dibromobutane added to the residue, thus obtained. The reaction mixture was kept for 24 hours at room temperature, and then evaporated the solvent under reduced pressure. Add 40 ml of water and 60 ml of ethylene chloride to the residue, thus obtained, the organic phase is extracted, dried over sodium sulfate and the solvent evaporated under reduced pressure to obtain a dry residue. The residue is purified chromatographically on silica gel, using as eluent a mixture of diethyl ether/hexane in a ratio of 1/1 by volume). The main fraction is collected, the solvent evaporated under reduced pressure and obtain 8.8 g of 2-(3-benzoylphenyl)propionate, 4-bromobutyl (XXIII).

1H-NMR (200 MHz) (CDCl3): 1,53 m D. (d, 3H); 1,84 M. D. (m, 4H); 3,32 m DV (t, 2H), 3,78, M. D. (q, 1H), 4.09 to memorial plaques (t, 2H); 7,27 M. D. (m. 1H, aromatic); 7,38 - 7,99 M. D. (m, 8H, aromatic).

Mass spectrometry: 388 (M+); 309 (M+- Br); 209.

(C) 5.5 g AgNO3, lactonitrile. The reaction mixture was stirred 24 hours at room temperature and adding 1,76 g AgNO3, stirred for further 24 hours at room temperature and then filtered. From the resulting solution evaporated the solvent under reduced pressure to obtain the residue, which is treated with methylene chloride.

The mixture, thus obtained, again filtered and the organic phase is purified chromatographically on silica gel under pressure, using as eluent a mixture of ether/hexane in a ratio of 3/7 (by volume)

The fraction containing the product are collected, the solvent evaporated under reduced pressure and obtain 3.4 g of nitrofura 2-(3-benzoylphenyl)propionate 4-oxobutyl (XVIII).

IR (cm-1): C = 0,1737; ONO2, 1632, 1288; OCO, 1660.

1H-NMR (80 MHz) (CDCl3): 1,48 m D. (d, 3H); 1,64 M. D. (m, 4H); 3,78 M. D. (q, 1H), 4,08 M. D. (m, 2H); 4,3 M. D. (m, 2H); 7.3 to 7,81 M. D. (m, aromatic).

Mass spectrometry: 371 (M+); 309 (M+- ONO2); 255.

Anti-inflammatory and antiplatelet activity, as well as gastrointestinal ulcerogenesis, were studied in the biological testing with the following formula:

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Anti-inflammatory activity yovanny carrageenan swelling, as described by C. A. WINTER, E. RISLEY and G. W. NUSS, Proc. Soc. Exp. Biol. Med. 111, 544 (1962), while the antiplatelet activity of the above derivatives has been studied in human platelets stimulated arachidonic acid, according to the method described by V. BERTELE et al., Science 220, 517 (1983).

Gastrointestinal ulceration was determined by an oral introduction to the rats.

Anti-inflammatory and antiplatelet activity, as well as gastrointestinal azwoobrazovania activity of the above compounds are given in table 1, and show for each of the listed nitrofura relatively high compared with the corresponding acids, are not related to the compounds of General formula (I) according to the present invention. Each score represents the average value obtained in the processing of 10 animals.

In particular, derivative (XVIII) and (XII), are presented for additional study pharmacodynamic properties, gave the results shown in the following examples.

- Impact-induced carrageenan edema in rats. Both compounds (XVIII) and (XII) showed the best results compared to the mentioned drugs of Ketop is C. Animals treated for 19 consecutive days (from 3 to 21 days after adjuvant injection) at a dose of 3 mg/kg or (XVIII) or (XII) and the corresponding referenced compounds, showed a significant reduction in arthritis symptoms compared to control.

- Seizures in mice induced by familienaam. At doses ranging from 3 to 10 mg/kg, the compounds (XVIII) and (XII) are quite effective and their effectiveness is almost comparable with the corresponding mentioned compounds.

Platelet aggregation in vivo. If both compounds (XVIII) and Flurbiprofen was injected dose of 20 mg/kg in the rat, inhibited collagenbinding platelet aggregation, and the first (66% inhibition compared to control) was significantly more effective than the latter (40%).

Biochemistry.

- Synthesis of prostaglandins in the inflammatory exudate. Subcutaneous implantation karraginovym sponge causes infiltration of inflamed cells, as reported in Nature 284, 271 (1980). Both compounds (XVIII) and (XII) at a dose of 20 mg/kg inhibited the formation of prostaglandin E2 in the exudate more than 75% in comparison with control and indicate the comparative efficacy with the corresponding above-mentioned compounds by Ketoprofen and Flurries at the same doses (5 - 20 mg/kg), as and for the study of gastric lesions. They significantly inhibited the synthesis of prostaglandin E2, like the above-mentioned respective compounds Ketoprofen and Flurbiprofen, and the degree of inhibition of greater than 90% at the maximum dose.

Without allocating. Proof that the compounds (XVIII) and (XII) were isolated nitric oxide after their introduction was obtained from measurement of nitrate/nitrite plasma levels, as reported in J. Clin. Invest., 85, 264 (1990). Within 1 hour after administration, or (XVIII) or (XII) compounds nitrate/nitrite plasma levels were significantly increased by more than 50%. Ketoprofen or Flurbiprofen had no significant effect on the nitrate/nitrite levels.

In addition, additional biological studies were performed on derivatives (XII) and (XVIII); the above studies showed the following results.

Gastrointestinal tolerance.

- Mucosal damage in rats. (XVIII) and (XII) were studied when compared with those of the above-mentioned compounds by Ketoprofen and Flurbiprofen at doses of 3 to 30 mg/kg, both compounds (XII) and (XVIII) are much better tolerated than the above-mentioned compounds. Ketoprofen or f is independent of the dose, while (XVIII) and (XII) was well tolerated even at the dose of 30 mg/kg

Histological examination confirmed these data. Similar differences in the ability of these compounds to cause gastric and small intestinal damage was also observed with the reintroduction of the compounds.

Leukocyte adhesion/ diameter vessels of the stomach. An early step in the pathogenesis of NSAID-indutsirovannogo lesions of the mucous membrane is the adhesion of leukocytes to the endothelium of postcapillary venules, as reported in Gastroenterology 103, 146 (1992); Trends Pharmacol. Sci. 13, 129 (1992); Am. J. Physiol. 262, G903 (1992). When using intravital microscopy adhesion of leukocytes in mesentericus postcapillary venules may initially be quantified within 1 hour after application of NSAID. Unlike Ketoprofen or Flurbiprofen (XVIII) or (XII) does not cause significant leukocyte adhesion, significantly increasing the diameter of blood vessels. Changes in blood pressure were not found.

General pharmacology.

Secondary pharmacological examination of the compounds (XVIII) or (XII) was performed when compared with Ketoprofen or Flurbiprofen. We detected no adverse reactions adhesion that affect the Central nervous system, geekologie in rodents. Acute toxicity of the above derivative (XVIII), (XXIV), (XXV), (XII) and (XXVI) was then evaluated by using individual doses of each compound (XVIII), (XXIV), (XXV), (XII) and (XXVI), using for each derived group of 10 mice breed Suisse. The evidence of death and the onset of symptoms of intoxication was described for a period of 14 days.

Even after applying a dose of 100 mg/kg of each compound (XVIII), (XXIV), (XXV), (XII) and (XXVI) not have obvious symptoms of their toxicity in the study on animals.

In particular, preliminary studies of the compounds (XVIII) or (XII) were presented on mice in the two methods of administration. Evidence of toxicity was not detected in animals treated by oral or intraperitoneal the introduction of each connection at a dose of 300 mg/kg

- Maximum tolerated dose in rodents. Preliminary studies show that the compounds (XVIII) and (XII) were well tolerated by those species, which are known to be particularly sensitive to this class of compounds. Animals were applied gradually increasing doses up to 30 mg/kg of each compound, and found no obvious symptoms, while the use of compounds of Ketoprofen and Flurrie as signals13CNMR specific carbon atoms (identified by small letters) in the molecule of the following compounds:

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13CNMR typical signals, C-a 73,84, C-b 64,86, C-C 173,22, C-d 195,22, C-e 125,05.

for compounds XXV (see above) description:

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for compounds XXVI (see above) description:

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13CNMR typical signals, C-a 74,02, C-b 64,78, C-C 173,95, C-d 135,51, C-e 122,12.

The connection is obtained through the radical (X) group CH2COO(CH2NO2in prescribed positions:

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13CNMR typical signals, C-a 73,84, C-65,00 b, C-C 172,80, C-d 194,73, C-e 141,42.

The connection obtained by radical (XXI) group CH2(CH3)COO(CH2)4NO2in prescribed positions:

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13CNMR typical signals, C-a 73,96, C-b 64,92, C-C 173,35, C-d 139,68, C-e 118,04.

In position e the phenyl ring to the left there is no Deputy chlorine atom for detecting carbon atoms, issuing a signal13C.

The connection obtained by radical (XXXV) of the same aliphatic groups of the radical (XXI) in the specified position:

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13CNMR typical signals, C-a 74,02, C-b 64,96, C-C 172,93, C-d 194,87, C-e 132,92.

The connection obtained by radical (VII) of the same aliphatic groups of the radical (XXI) in the specified position:


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13CNMR typical signals, C-a 73,91, C-b 64,88, C-C 174,78, C-d 195,89, C-e 145,31.

Range13CNMR was reproduced at room temperature (C) spectrometer Varian Gemini 200 at a frequency to 50.3 MHz, equipped with dual pilot head 5 mm Deuteromony chloroform was used as solvent. Chemical loading of the investigated compounds was related to the chloroform (of 77.0 ppm), Range13CNMR was reproduced using a solution of 0.1 M with a range of 14000 Hz, with pulse 8s (45oC) duration of 0.6 s with dot indicator 16K and with a relaxation delay of 0.5 sec.

Example 3.

Synthesis of N-(2-nitroxyethyl)-2-fluoro--methyl[1,1-biphenyl]-4-ndimethylacetamide

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N-(2-chloroethyl)-2-fluoro-alpha-methyl-[1,1-biphenyl]-4-ndimethylacetamide.

To a solution of 1,1'-carbonyldiimidazole (of 3.32 g of 20.4 mmol) in chloroform (50 ml) is added at room temperature flurbiprofen (5 g, of 20.4 mmol). The resulting mixture is treated with 2 parts-chloroethylamine hydrochloride (2.36 in) of 20.4 mmol) and then triethylamine (2,84 ml of 20.4 mmol). The mixture was stirred at room temperature for 1 hour, diluted with chloroform and washed with water. The organic layer is dried with sodium sulfate and evaporated under vacuum and the pure (5 g) as a white solid and used for subsequent reactions.

N-(2-nitroxyethyl)-2-fluoro----methyl-[1,1-biphenyl]-4-ndimethylacetamide.

A mixture of N-(2-chloroethyl)-2-fluoro----methyl-[1,1-biphenyl]-4-ndimethylacetamide (3.4 g, 11,12 mmol) and silver nitrate (5.7 g, 33,35 mmol) in acetonitrile (90 ml) water for 2 hours. After cooling, the solid is filtered and the solvent is evaporated. The precipitate purified in a chromatography column (eluent hexane-ethyl acetate 7-3). The resulting substance is isolated in pure form as a light yellow oil (1.8 g).

1H-NMR (CDCl3, ppm) 7,76 - 7,27 (8H, m), 7,10 (1H, t) to 4.52 (2H, m), 3,60 (3H, m), of 1.85 (3H, d).

Example 4.

Synthesis of 2-fluoro--methyl-[1,1-biphenyl] -4-acetic acid 1-nitroxy-2-methyl-2-propyl ether.

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2-fluoro--methyl-[1,1-biphenyl]-4-chloride acetic acid.

The solution flurbiprofen (5 g, of 20.4 mmol) in toluene (20 ml) is treated at room temperature with dimethylformamide (2 ml). After cooling, add drops of chloride of oxalyl (5,2 g of 40.9 mmol) and the resulting solution was stirred at room temperature for 4 hours. The solvent is evaporated and the crude acid chloride (lower than the 5.37 g) is used for subsequent reactions.

2-fluoro--methyl-[1,1-biphenyl] -4-acetic acid-1-chloro-2-methyl-2-propyl ether.

A solution of 2-fluoro--methyl-[1,1-Biff the obtained mixture is treated at a temperature of 0oC, adding drops of 1-chloro-2-methyl-2-propanol (3.33 g). The mixture was stirred at room temperature for 3 days and washed with water. The organic layer is dried with sodium sulfate and evaporated under vacuum. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 9-1). The intermediate product is isolated in pure form (3.7 g) and used for subsequent reactions.

2-fluoro--methyl[1,1-biphenyl] -4-acetic acid 1-nitroxy-2-methyl-2-propyl ether.

A mixture of 2-fluoro--methyl-[1,1-biphenyl] -4-acetic acid 1-chloro-2-methyl-2-propyl ether (3,36 g, 10 mmol) and silver nitrate (2,39 g, 14 mmol) in acetonitrile (30 ml) water 2 days. After cooling, the solid is filtered and the solvent is evaporated. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 9-1). The resulting substance is isolated in pure form as a light yellow oil (1.1 g).

1H-NMR (CDCl3, ppm) 7,52 (2H, m), 7,40 - to 7.35 (4H, m), 7,11 (2H, t), 4,30 (2H, s), 3,74 (1H, q) of 1.50 (3H, d), of 1.26 (6H, s).

1. Nitroethene General formula I

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where a and b are selected from hydrogen, linear or branched, substituted or unsubstituted alkyl;

R is selected from:

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R2selected from hydrogen, ethyl, alkyl LINEST NR1where R1means a linear or branched alkyl;

n = 1 to 10.

2. Nitroethane under item 1, where R is

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R2means methyl; a and b denote hydrogen; Y represents oxygen, and n = 4.

3. Nitroethane under item 1, where R is

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R2means methyl; Y represents oxygen; a and b denote hydrogen and n = 4.

4. Nitroethane under item 1, where R is

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R2means methyl; a and b denote hydrogen; Y represents oxygen, and n = 4.

5. Nitroethane under item 1, where R is

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R2means ethyl; a and b denote hydrogen; Y represents oxygen, and n = 4.

6. Nitroethane under item 1, where R is

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R2means hydrogen; a and b denote hydrogen; Y represents oxygen, and n = 4.

7. Nitroethane under item 1, characterized in that they can be used in the pharmaceutical industry as anti-inflammatory agents.

8. Nitroethane under item 1, characterized in that they can be used in the treatment of rheumatic diseases and pain States weak and moderate.

9. Nitroethane under item 1, characterized in that they can be used for the treatment of infarction and ischemia, and in cases of arterial thrombosis as antiplatelet agents.

 

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SUBSTANCE: invention relates to a new method for preparing naproxen nitroxyalkyl esters. Invention describes a method for preparing 2-(S)-(6-methoxy-2-naphthyl)-propanoic acid nitroxyalkyl with enantiomeric excess exceeding or equal to 97% but preferably exceeding or equal to 98%. Method involves interaction of 2-(S)-(6-methoxy-2-naphthyl)-propanoic acid halogen anhydride of the formula A-Hal wherein A represents acyl residue of indicated acid with aliphatic nitroxyalkyl alcohol of the formula HO-Y-ONO2 wherein Y means linear or optionally branched (C2-C5)-alkylene in inert organic solvent in the presence of inorganic base to obtain the corresponding 2-(S)-(6-methoxy-2-naphthyl)-propanoic acid nitroxyalkyl ester of the formula A-O-Y-ONO2 wherein A and Y are given above. Also, invention describes 2-(S)-(6-methoxy-2-naphthyl)-propanoic acid 4-nitroxybutyl ester with enantiomeric excess of (S)-form in limits from 97% to 98% but preferably above 98%. Invention provides the development of a new method for preparing naproxen nitroxyalkyl esters with enhanced level of enantiomeric excess.

EFFECT: improved preparing method.

6 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutical composition eliciting anti-inflammatory and analgetic activity for oral administration and containing compound of the formula (I): A-X1-NO2 wherein A and X1 are given in cl. 1 of the invention claim and representing in the amorphous state or partially amorphous state. Method involves the following steps: stirring compound of the formula (I) with at least one filling agent that is able to confer the amorphous state to obtained mixture wherein this filling agent is taken among group consisting of (C5-C6)-polyalcohols, mono- and disaccharides and their derivatives, oligosaccharides comprising from 3 to 10 monosaccharide units, polysaccharides, their derivatives involving their salts, cyclodextrins and their derivatives, noncyclic derivatives of β-cyclodextrin, polymers and copolymers based on vinyl monomeric links, and/or comprising the carboxyl function, or methacrylic monomers wherein the mass ratio between amount of compound of the formula (I) and the amount of at least one filling agent is in the range = (1:20)-(1:0.5), and providing the amorphous state of obtained mixture by combined grinding, stirring, spraying drying and lyophilization. Also, invention relates to a pharmaceutical composition eliciting an anti-inflammatory and analgetic activity. Invention provides preparing a pharmaceutical composition for oral administration and medicinal agents based on thereof for treatment of inflammatory diseases.

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

10 cl, 1 tbl, 10 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention proposes a method for preparing 2-ethylhexyl nitrate by continuous method. Method involves interaction of 2-ethylhexanol with sulfuric-nitric acid mixtures of the following composition, wt.-%: sulfuric acid (H2SO4), 60-45; nitric acid (HNO3), 10-25; nitrogen oxides, 0.0001-0.1, and water, the balance, up to 100. Mixtures are prepared from 20% fumic sulfuric acid (oleum) and 52% of nitric acid. Nitration reaction is carried out in reactor of the ideal displacing at temperature 15-40°C, time reaction for 2-5 min and at the modulus (volume) acid mixture/2-ethylhexanol = (1.6:1)-(2.3:1) followed by isolation of the end product by centrifugation. Method provides enhancing yield of the basic substance, reducing reaction time of reaction mass and availability of the raw.

EFFECT: improved preparing method, enhanced yield.

1 ex

FIELD: organic chemistry, medicine, gastroenterology, oncology.

SUBSTANCE: invention relates to a new agent used in treatment of gastroenteric tumors. Invention describes an agent for treatment of gastroenteric tumors representing compounds of the general formula: A-X1-NO2 or their salts wherein A means -RCO(X)t wherein t represents a whole number from 0 to 1; X means oxygen atom (O); R is taken among the following groups: (IA), (IIA), (IIIA), (IVA), (VA) and (VIA) such as given in the invention claim; X1 in the formula A-X1-NO2 means a bivalent binding bridge taken among the following: -YO- wherein Y means a liner or when possible a branched (C1-C20)-alkylene comprising preferably from 2 to 5 carbon atoms, or possibly a substituted cycloalkylene comprising from 5 to 7 carbon atoms of the formula: wherein n3 means a whole number from 0 to 3; wherein nf means a whole number from 1 to 6 but preferably from 2 to 4; wherein R1f means hydrogen atom (H), -CH3; nf means a whole number from 1 to 6 but preferably from 2 to 4. Invention provides a new medicinal agent used in treatment of gastroenteric tumors.

EFFECT: valuable medicinal properties of agent.

2 cl, 11 tbl, 18 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of nitrooxy-derivatives of naproxen. Invention describes a method for synthesis of compound of the general formula (A)

wherein R means compound of the formula: wherein R' means hydrogen atom or bromine (Br) atom; R1-R12 are similar or different and mean independently hydrogen atom, linear or branched (C1-C6)-alkyl optionally substituted with aryl; each among m, n, o, p, q, r and s means independently a whole number from 0 to 6; p = 0 or 1; X means oxygen atom (O), sulfur (S) atom, -SO, -SO2, -NR13 or -PR13 wherein R13 means hydrogen atom, (C1-C6)-alkyl; or X is chosen from group including: -cycloalkylene with 5-7 carbon atoms in cycloalkylene ring wherein ring is optionally substituted with side chains T wherein T means linear or branched alkyl with 1-10 carbon atoms; -arylene optionally substituted with one or more halogen atoms, linear or branched alkyl groups comprising from 1 to 4 carbon atoms, or linear or branched (C1-C3)-perfluoroalkyl; -5 or 6-membered saturated, unsaturated or aromatic heterocyclic ring chosen from formula X1-X13:

. Indicated method involves: (i) adding reaction of compound of the formula (B): R-COOZ wherein R is given above; Z means hydrogen atom or cation chosen from Li+, Na+, Ca++, Mg++, tetraalkyl ammonium, tetraalkyl phosphonium with compound of the following formula (C):

wherein R1-R2 and m, n, o, p, q, r and s are given above; Y is chosen from halogen atom, -BF4, -SbF6, FSO3-, RASO3- wherein RA means linear or branched (C1-C6)-alkyl optionally substituted with one or more halogen atoms, or (C1-C6)-alkylaryl; -RBCOO- wherein RB means linear or branched (C1-C6)-alkyl, aryl optionally substituted with one or more halogen atoms or NO2-groups, (C4-C10)-heteroaryl and comprising one or more heteroatoms that are similar or different and chosen from nitrogen, oxygen, sulfur or phosphorus atoms; -aryloxy-group optionally substituted with one or more halogen atoms or NO2-groups, or heteroaryloxy-group, and (ii) conversion if necessary compound of the formula (A) wherein R' means Br atom to compound of the formula (A) wherein R' means hydrogen atom.

EFFECT: improved method of synthesis.

9 cl, 4 ex

FIELD: explosives.

SUBSTANCE: invention relates to technology of preparing components of gun powders, mixed solid propellants, and mixed blasting materials. Nitroisobutylglycerol nitrate is prepared via nitration of nitroisobutylglycerol with sulfuric acid/nitric acid mixture. Particularly, nitroisobutylglycerol is dissolved in acid mixture enriched with nitric acid and thus formed nitroisobutylglycerol trinitrate is treated with sulfuric acid or oleum and then stabilized in inert solvent (dichloromethane or dichloroethane) with anhydrous neutralizing agent: calcium oxide or calcium carbonate. Product is characterized by density at least 1.63 g/cc and high heat resistance with initial intensive decomposition temperature not below that that of standard nitroglycerin (135-140°C).

EFFECT: improved quality characteristics of product.

1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to method of producing monohydric alcohol nitric acid esters. According to the method monohydric alcohol or mixed monohydric alcohols reacts with nitric acid in adiabatic conditions with sulphuric acid added.

EFFECT: there is developed new method of producing the specified esters.

2 ex, 10 cl

FIELD: explosives.

SUBSTANCE: invention relates to a technology of explosive substances (ES) and may be used in detonators and other explosive devices using a process of ES burning changeover into explosion. The method consists in production of tetranitropentaerytrite solution in acetone, deposition of tetranitropentaerytrite crystals by addition of the produced solution while it is mixed into a precipitator at the ratio of 1:(2-3), further filtration of the produced residue and drying, at the same time the precipitator is the solution of isopropyl alcohol in water at the ratio of (2-9):1. The tetranitropentaerytrite solution prior to addition into the precipitator is heated to the temperature of 35-45C. An ultradispersed aluminium powder may be added to the precipitator. The needle shape of tetranitropentaerytrite produced by the stated method makes it possible to improve conditions of transition processes when forming detonation in an ES charge.

EFFECT: method is safe, there are no operations of intensive mechanical exposure at ES and no toxic dissolvents heated to temperatures close to temperature of their boiling.

3 cl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-ethylhexyl nitrate by nitration of 2-ethylhexanol with a mixture of sulphuric acid and nitric acid having the following composition (wt %): HNO3 - 20-30%, H2SO4 - 55-61%, H2O - 10-20% and washing the end product at temperature of 65-75C first with water and then with 10-15% NaOH solution, characterised by that washing is carried out small volumes (weight ratio of 2-ethylhexyl nitrate:water equal to 1:0.075, 2-ethylhexyl nitrate: alkaline solution equal to 1:0.025), followed by coagulation of the suspension of mixtures with a small amount of a strong (75-82%) solution of ammonium nitrate. The invention also relates to a method of producing 2-ethylhexyl nitrate by nitration with a mixture of sulphuric acid and nitric acid having the following composition (wt %): HNO3 - 20-30%, H2SO4 -55-61%, H2O - 10-20% 2-ethylhexanol, characterised by that the end product is washed at temperature of 15-25C with water; the layer of acid water is separated and anhydrous sodium sulphate is then added to the end product while also adding a small amount of soda, the mixture is stirred and the ready product is separated from suspended solids. In another version, the obtained 2-ethylhexyl nitrate is washed at temperature of 15-25C with water; the layer of acid water is separated and the end product is passed through a layer of anhydrous sodium sulphate while adding a small amount of soda.

EFFECT: novel methods of producing 2-ethylhexyl nitrate, characterised by a shorter time for washing the end product and high efficiency of the apparatus.

3 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing nitroethers of monoatomic alcohols which can be used as efficient cetane number-increasing additives for diesel fuel. Disclosed is a method of producing esters of monoatomic alcohols by treatment thereof with a sulphuric acid and nitric acid mixture in the presence of a carbamide, separating the acidic nitroester and washing thereof, wherein the monoatomic alcohol used is 2-ethylhexanol and/or isoamyl alcohol, the sulphuric acid and nitric acid mixture has the composition, wt %: HNO3 - 18.0-21.0 H2SO4 -62.0-65.0, water - the balance up to 100, and is prepared from 99.8% HNO3, 93.4% H2SO4 and spend acid obtained during the nitration process; the sulphuric acid and nitric acid mixture is treated at temperature not higher than 25-30C for 25-30 minutes, and the acidic nitroester is washed first with flush water with the ratio of the product to flush water equal to 1:0.5, and then with 2% sodium hydroxide solution in ratio of 1:0.3.

EFFECT: method of producing nitroesters of monoatomic alcohols enables to obtain an end product with output of not less than 98,5% with content of the basic substance of 99,5-99,8%, with short duration of the method and number of flushing cycles; the method enables to use up to 50% spent acids in the process and considerably reduces the amount of flush water.

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

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