Nitroethane, which has anti-inflammatory and/or analgesic activity, methods for their preparation, pharmaceutical compositions

 

(57) Abstract:

Nitroethene formula M-CO-Y-(C)nAB-ONO2where a and b are hydrogen or methyl; M is chosen from compounds of formulas I-IV

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R is a residue of formula V-VII

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Y IS O, NH, NR1; R1- alkyl, n = 1-6, suitable for the treatment of severe conditions requiring concurrent use of anti-inflammatory and analgesic drugs, or rheumatic diseases of a General nature. 5 C. and 12 C.p. f-crystals, 2 ill., 5 table.

The present invention relates to nitroform a derivative of propionic acid, 1-(p-chlorbenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid, 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a] pyrrole-1-carboxylic acid, 6-methoxy-2-naphthylacetic acid, their pharmaceutical use and the way they are received. The present invention also relates to pharmaceutical compositions containing at least one of the above nitroethanol as the active ingredient.

Some derivatives of propionic acid, such as for example, 2-(6-methoxy-2-naphthyl) propionic acid, 2-(4-isobutylphenyl)propionic acid or alpha-methyl-4-[(2-oxocyclopent)methyl] venzolasca was collaterally in various international markets for many years. The method of obtaining 2-(6-methoxy-2-naphthyl)propionic acid was described in South African Patent 6707 N, 597, in German Patent No. 1 934,460 corresponding to US Patent N 3,637,767, and S. A. 71,91162 j (1969); HARRISON et. al. J. Med. Chem. 13, 203 (1970); the method of obtaining 2-(4-isobutylphenyl)propionic acid was described in the patent GB N 971,700, US N 3,228,831 and US N 3,385,886, and T. SHIORI, N. KAWAJ. J. Org. Chem. 43, 2936 (1978); J. T. PINHEY, B. A. ROWE, Tetragedron Letters 21, 965 (1980); at the same time, the method of obtaining alpha-methyl-4-[(2-oxocyclopent)methyl] benzooxazol acid has been described in the German Patent N 2,814,556 and in US Patent N 4,161,538.

In the case of 2-(6-methoxy-2-naphthyl)propionic acid, pharmacological data described in ROSZNOWSKI et.al., J. Pharmacol. Exp. Ther. 179,114 (1971), at the same time, the pharmacological data of 2-(4-isobutylphenyl)propionic acid is described in ADAMS et. al. Arch. Pharmacodyn. Ther. 178,115 (1969).

The use of these derivatives of propionic acid as anti-inflammatory agents, as is known, is accompanied by a strongly adverse reactions, for example, in the gastrointestinal system, and also possible damage to the liver and kidneys.

Others, especially toxic products, for example, 5-benzoyl-2-dihydro-3H-pyrrolo [1,2-a]pyrrole-1-carboxylic acid or Ketorolac [W. H. ROOKS et.al. Agents Actions 12,67 (1976)]. In particular, in some countries, Ketorolac was withdrawn from the market due to gastrointestinal toxicity, at the same time, Indomethacin is one of the drugs, which was the reason for the high mortality rate during the years of its application on the market. In comparison with other known anti-inflammatory and/or analgesic drugs Ketorolac, Indomethacin cause - because of the already described adverse reactions - very extensive damage and, in particular, in relation to gastrointestinal toxicity, and, as installed, was the cause of death even in children.

Therefore, a clear need for drugs, possessing good anti-inflammatory and/or analgesic activity, but not with overall toxicity.

The aim of the present invention to provide products that are at least provide a high level of pharmacological activity, which is characteristic of the known anti-inflammatory and/or analgesic agents, but at the same time capable of suppressing the adverse reactions that are caused by the action of the tools mentioned above and have a good tolerance.

Another purpose oil)-5-methoxy-2-methyl-1-indolylacetic acid, 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a]pyrrole-1-carboxylic acid, 6-methoxy-2-naphthylacetic acid, which has anti-inflammatory and/or analgesic activity, with good tolerance and free from adverse reactions, are typical of the anti-inflammatory and analgesic agents.

Another objective of the present invention to provide pharmaceutical compositions having anti-inflammatory and/or analgesic activity and good tolerance.

These and other objectives and advantages, which will be shown from the following description, are achieved derivatives of propionic acid, 1-(p-chlorbenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid, 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, 6-methoxy-2-naphthylacetic acid, which according to the present invention have the following General formula:

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where A and B is selected from hydrogen, linear or branched, substituted or unsubstituted alkyl, M is selected from:

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where R is selected from:

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Y is selected from oxygen, NH, NR1where R1means a linear or branched alkyl group, and n is from 1 to 10.

Naimi C2-C10.

In fact, it is established that the introduction of a group, such as limit nitrofura group, derivative of formula (IA) leads to an increase in pharmacological activity, which is typical for non-steroidal anti-inflammatory and/or analgesic agents, leads to products with good tolerance, and at the same time destroys the adverse reactions that occur in the treatment of these drugs. In addition, the introduction of end nitroethanol group in derivatives of propionic acid leads to increased anti-inflammatory effect compared with the well-known non-steroidal anti-inflammatory drugs; this increase is achieved end nitroethanol group, which can be considered as a source of nitrogen oxide and which may further enhance the anti-inflammatory effects.

It was also observed that derivatives (IA) is suitable for the treatment of various severe conditions, such as severe conditions requiring concurrent use of anti-inflammatory and analgesic drugs, or rheumatic diseases of a General nature, immunological disorders, and they are lausiaca the subject of the present invention, can be used in the treatment of diseases of the cardiovascular system and Central nervous system, especially in the treatment of myocardial and cerebral ischemia, and in the case of arterial thrombosis and in the case of senile dementia.

In accordance with this invention is particularly useful is nitrocefin (IA), where hydrogen is selected as A and B, M is selected as

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where R is selected as

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NH is selected as Y, and n is equal to four, according to the following formula:

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Also particularly useful according to the present invention nitrocefin (IA), where hydrogen is selected as A and B, M is selected as

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where R is selected as

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

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Also particularly useful according to the present invention nitroamine derivatives of 2-(4-isobutylphenyl)propionic acid having the following formula:

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Also particularly useful according to the present invention nitroethene (IA) having the following formula;

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Also according to the present invention nitroethene (IA), where M is selected as

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oxygen is selected as Y, hydrogen is selected as A and B, and n is equal to four according to the following formula:

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show a very good Toler the NGOs an important first method, which according to the present invention, includes the following stages:

Obtaining sodium salt derivatives having the following General formula:

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where M is selected from (XXX), (XXXI), (XXXII),

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where R is selected from the following structures:

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or deriving (VIA), substituted by carboxyl group, such as acid chlorides, anhydrides or similar.

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

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where R4selected from chlorine, bromine, other5with R5is hydrogen, a 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, which results in nitroethanol (IA).

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

P IS,

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where R is selected from the following structures:

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when deriving (VIA), substituted by carboxyl group, such as acid chlorides, anhydrides or similar.

The reaction of the sodium salt of the above derivative (VIA) or above derivative (VIA), substituted by carboxyl group, with a compound having the following General formula.

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where R4selected from chlorine, bromine, other5with R5is hydrogen, a linear or branched alkyl, A and B is selected from hydrogen, linear or branched, substituted or unsubstituted alkyl, 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 palodiruyut connection, such as PBr3or similar, with the receipt of the products of the abovementioned ethers or above amides characterized by the presence of halide end group.

The reaction of the abovementioned ethers or above amides characterized by the presence of halide end groups, with nitrous agent such as AgNO3or similar, with getting nitrofuran derivatives (IA).

Solvents that ispoljzuemo methylene, acetonitrile, dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the like.

Such methods for obtaining derivatives (IA), which is the subject of the present invention consist of a limited number of stages and allow you to get the products of these processes for a short time with good yields and in large quantities even in the industrial plan.

According to methods which are the subject of the present invention, the receiving nitrofura propionic acid derivative having the following formula:

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particularly useful and are described in the following example, illustrating, but not limiting the invention.

Example 1

a) 0,59 g EtONa, dissolved in 10 ml of ethanol, was added slowly prokopeva, to a solution of 2 g of 2-(6-methoxy-2-naphthyl) propionic acid is dissolved in 20 ml of ethanol. The reaction mixture was stirred 5 minutes at room temperature, then evaporated under reduced pressure, obtaining 2.1 g of sodium salt of 2-(6-methoxy-2-naphthyl)propionic acid.

2.1 g of sodium salt of 2-(6-methoxy-2-naphthyl)propionic acid, thus obtained, was dispersible in 40 ml of dimethylformamide and 1.5 g of 1-Br-4-Cl-butane dissolved in 30 ml dimethylformamide, then diluted with water and was extracted with methylene chloride. The organic phase, proektirovaniya thus, dried with sodium sulfate and evaporated the solvent under reduced pressure until until received 2 g of dry residue.

The residue was purified by chromatography on silica gel, using as eluent a mixture of hexane/ether 7/3 (by volume).

The head fractions were collected, the solvent was evaporated under reduced pressure received 1 g of 2-(6-methoxy-2-naphthyl)propionate 4-chlorobutyl (IX).

IR (cm-1): C=O, 1669

1H-NMR (300 MHz) (CDCl3): 1,6 M. D. (d, 3H); 1,75 M. D. (m, 4H); 3,45 M. D. (m, 2H); 3,88 M. D. (q, 1H); 3,91 M. D. (l, 3H); 4,1 M. D. (m, 2H); 7,1 - 7,7 M. D. (m, aromatic).

Mass spectrometry: M+320.

b) 0,79 g AgNO3dissolved in 1.3 ml of acetonitrile was to bury 1 g (IX), obtained as described in (a), dissolved in 4.5 ml of acetonitrile. The reaction mixture was stirred 12 hours at a temperature of 85oC and then filtered.

From the obtained solution was one stripped off the solvent under reduced pressure and the obtained residue was added 10 ml of methylene chloride. The mixture, thus obtained, was filtered again, the organic phase is washed with water and then dried over sulphomethate on silica gel, using as eluent a mixture of hexane/ether 7/3 (by volume). The fractions containing the product were collected, the solvent was evaporated under reduced pressure and obtained 1.5 g of nitrofura 2-(6-methoxy-2-naphthyl) propionate 4-hydroxybutyl (V).

IR (cm-1): C=O, 1733; ONO2, 1637.

1H-NMR (300 MHz) (CDCl3): 1,6 M. D. (d, 3H); 1,65 M. D. (m, 4H); 3,8 M. D. (q, 1H); 3.9 to memorial plaques (s, 3H); 4,1 M. D. (m, 2H); 4,3 M. D. (m, 2H); 7,1 - 7,7 M. D. (m, aromatic).

Mass spectrometry: M+347.

According to the method which is the subject of the present invention also receive nitroethyl derivative of propionic acid, which is especially useful and has the following formula:

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who received, as described in the following example, which is given to illustrate this invention, but not limit its scope.

Example 2

a) of 23.9 g phthalimide potassium dispersed in 200 ml of anhydrous dimethylformamide was added to a solution of 55.7 g of 1,4-di-bromobutane dissolved in 300 ml of anhydrous dimethylformamide. The reaction mixture was stirred for 12 hours at room temperature, then diluted with water and was extracted with methylene chloride. Methylene chloride was evaporated from the thus obtained organic is washed with water and Proektirovanie methylene chloride. The organic phase thus obtained was dried and the solvent was distilled under reduced pressure, obtaining 14.8 g of 1-phthalimido-4-bromobutane, which was treated with isopropyl ether and then separated. So pl. = 77oC.

b) 32 ml idiscovered acid is carefully added to 8,25 g 1 phthalimido-4-bradatan; the mixture is then heated and kept at a rapid boil for 24 hours.

After cooling, the mixture was diluted with water and after filtration was evaporated the solvent under reduced pressure, the obtained residue was recrystallize once from ethyl ether and received 6 g of 4-ibutilide.

So pl. = 103oC.

c) 7 ml of thionyl chloride was carefully added to a solution of 2.3 g of 2-(6-methoxy-2-naphthyl) propionic acid in 15 ml of anhydrous chloroform. The reaction mixture was stirred 40 minutes at room temperature and then evaporated the solvent under reduced pressure, obtaining of 2.23 g of 2-(6-methoxy-2-naphthyl) Propionaldehyde.

2.3 g of 2-(6-methoxy-2-naphthyl) propionitrile dissolved in pyridine and the solution cooled to a temperature of 0oC.

of 3.27 g of 4-ibutilide added to this solution, and the mixture thus obtained was stirred 1 hour at 0oC and winters way, first washed with 10% hydrochloric acid solution, and then saturated sodium bicarbonate solution, then evaporated the solvent under reduced pressure, obtaining 3.2 g of dry residue. The residue was purified by chromatography on silica gel, using as eluent methylene chloride.

The intermediate fraction was collected, evaporated the solvent under reduced pressure and obtained 1.6 g of 2-(6-methoxy-2-naphthyl)-4-iodothyronamine (XX).

IR (cm-1): NH, 3294; C=O, 1651.

1H-NMR (300 MHz) (CDCl3): 1,1 - 1,75 m doctor of medicine (m, 4H); 1,6 M. D. (d, 3H); 3,1 m DV (t, 2H); 3,2 M. D. (q, 2H); 3,7 M. D. (q, 1H); 3.9 to memorial plaques (s, 3H); 5.35 m doctor of medicine (m, NH); 7,1 - 7,7 M. D. (m, aromatic).

d) a Suspension of 1.6 g of 2-(6-methoxy-2-naphthyl)-4-iodothyronamine in 20 ml of acetonitrile was heated to a temperature of about 40oC and stirred until 1.0 g AgNO3added.

The mixture was stirred 1 hour at room temperature, then filtered and evaporated under reduced pressure. The obtained residue was mixed with methylene chloride, the resulting mixture was filtered and evaporated the solvent under reduced pressure, and the obtained 0.8 g of dry residue, which was purified by chromatography on silica gel, using as eluent a mixture of methylene chloride/ethyl acetate 9/1 (objetiva 2-(6-methoxy-2-naphthyl)-4 - hydroxybutyrophenone (IV).

IR (cm-1): C=O, 1672; NH, 3294; ONO2, 1637.

Mass spectrometry: M+346.

1H-NMR (80 MHz) (CDCl3): 1,3 - 1,6 M. D. (m, 4H); 1.7 to M. D. (d, 3H); 3,1 M. D. (q, 2H); 3,7 M. D. (q, 1H); 3.9 to memorial plaques (s, 3H); 4,3 M. D. (m, 2H); 5,6 M. D. (m, NH); 7,05 - 7,8 M. D. (m, aromatic).

According to the present invention nitroethyl having the following formula:

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which is especially useful was obtained as described in the example below, which is given to illustrate this invention, but not limit its scope.

Example 3

Obtaining compounds having the formula:

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a) a suspension of 80% sodium hydride (0.16 g) in DMF (15 ml) cautiously with stirring, pricipal of 1.15 g of Ketorolac, dissolved in 20 ml of DMF.

The reaction mixture was kept under stirring at 40oC for 15 minutes, then added 1 ml of 1,4-dibromobutane and the mixture was stirred at room temperature overnight.

Then he evaporated the solvent under reduced pressure and the residue was treated with water and methylene chloride. The organic phase was separated, dried over sodium sulfate and solvent removed under reduced pressure, the obtained residue was purified by chromatography on silica gel, using as eluent a mixture of petrocelli 0.75 g of product, having the formula:

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1H-NMR (80 MHz) (CDCl3): to 1.83 (6H, m); of 2.81 (2H, m); to 3.38 (2H, t); of 4.12 (2H, t); 4,48 (1H, m); 6,03 (1H, d); is 6.78 (1H, d); 7,41 (3H, m); 7,73 (2H, m).

b) a Solution of AgNO3(0.5 g) in 5 ml of acetonitrile was added to a solution of (XXXV) in 20 ml of acetonitrile. The reaction mixture was kept under stirring at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was treated with water and methylene chloride. The organic phase was separated, dried over sodium sulfate and solvent removed under reduced pressure. The residue was purified by chromatography on silicagel, using as eluent a mixture of petroleum ether /ether 4/ 6 (by volume). The head fractions were collected, the solvent was evaporated under reduced pressure and obtained 0.35 g (XXXIV).

1H-NMR (80 MHz) (CDCl3) (M. D.): 1.78 (6H, m); 2.82 (2H, m); 4.14 (2H, m); 4.47 (3H, m); 6.03 (1H, d); 6,79 (1H, d); 7,46 (3H,m); 7.77 (2H, m).

Biological tests anti-inflammatory and analgesic activity was determined, for example, nitroethanol (LA), having the following formula:

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Anti-inflammatory activity of the above nitrofuran derivatives of propionic acid was studied on rats species Wistar using the method of influence on inducir the economic activity of the above derivatives was studied on mice breed Suisse, as described L. C. HENDERSHOT and J. FORSAITH, J. Pharmacol. Exp. Ter. 125, 237 - 249 (1959).

Anti-inflammatory and analgesic activity of the above derivatives obtained in comparison with 2-(6-methoxy-2-naphthyl)propionic acid, taken as the standard.

Antiplatelet activity of the above derivatives has been studied in human platelets. Thrombocytes were incubated with the compounds for 10 minutes at 37oC to stimulation by thrombin. Antitrombozitarnae activity above derivatives obtained in comparison with 2-(6-methoxy-2-naphthyl) propionic acid, taken as the standard.

Then the acute toxicity of the above derivative (IV) and (V) was evaluated for oral use separate doses of each compound (IV) and (V), using for each derived group of 10 mice breed Suisse.

The frequency of mortality and the onset of symptoms of intoxication have been described for a period of 14 days.

Even after applying a dose of 750 mg/kg of the compound (IV) or compound (V) is not set their symptoms of toxicity in the treated animals.

Further biological studies have been conducted in relation to pharmacotoxicological profile of the studied compounds, in particular compounds which Skye activity.

Sharp model.

Impact-induced carrageenan edema in rats. Based on preliminary experiments, the compound (V) and 2-(6-methoxy-2-naphthyl) propionic acid show comparable effectiveness; effective dose is in the range from 1 to 10 mg/kg

Subacute model.

Adjuvant arthritis rats. Animals treated for 19 days (from 3 to 20 days after injection) of the compound (V) or 2-(6-methoxy-2-naphthyl) propionic acid, both at a dose of 3 mg/kg showed a significant reduction in arthritis symptoms compared to control.

C. Gastrointestinal tolerance.

Mucosal damage in rats. The compound (V) was studied in comparison with 2-(6-methoxy-2-naphthyl) propionic acid, taken as a reference, each at a dose in the range from 3 to 30 mg/kg; compound (V) showed significantly better tolerance than 2-(6-methoxy-2-naphthyl) propionic acid. 2-(6-methoxy-2-naphthyl) propionic acid already at 3 mg/kg caused damage to the mucous membrane, and this effect was dose dependent, whereas the compound (V) showed a good tolerance even at doses of 30 mg/kg

C. General pharmacology.

Secondary farmakologicheskaya Eugene significant side effects, with regard to pharmacological activity in action on the Central nervous system, autonomic nervous system, cardiovascular, respiratory and gastrointestinal system.

D. Toxicology.

Acute toxicology in rodents. Preliminary studies were conducted in mice using two techniques. No overt symptoms of toxicity was not detected in treated animals during oral or intraperitoneal introduction at the dose of 300 mg/kg

The maximum tolerated dose in rodents. Preliminary studies showed that the compound (V) is well tolerated by the dog, the animal species, which are known to be particularly sensitive to ulcerogenic activity of anti-inflammatory drugs. Animals receiving oral dose of compound (V) 30 mg/kg, did not show the above symptoms. In comparison, 2-(6-methoxy-2-naphthyl) propionic acid in a dose of 10 mg/kg caused the death of animals.

Were also conducted biological research related to nitroform (IA) having the following formula:

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Then was determined anti-inflammatory activity, gastrointestinal tolerantia activity was determined in rats by the method of impact-induced carrageenan swelling, as described in C. A. WINTER and others (1962) Proc. The Aoc. Exp. Biol. Med. III, 544. Gastrointestinal tolerance was determined by an oral introduction of rats. Platelet antiaggregatory activity was determined in human platelets stimulated arachidonic acid according to the method described in V. BERTELE and others (1983) Science 220, 517.

The results are shown in table. 1 assessment related to anti-inflammatory, antiaggregatory activity and gastrointestinal tolerance below the investigated compounds show a relatively high degree as compared with the product, taken as the standard.

Acute toxicity of these compounds was evaluated by oral use of individual doses for each derived group of 10 mice. 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, the animals showed no signs of overt toxicity.

Example 4.

Synthesis of (S) - 6-methoxy -- methyl-2-naftiluksusnoi acid 1-nitroxy-2-methyl-2-propyl ether /HCT3017/:

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(S)-6-metoki -- methyl-2-naphthalenyloxy acid 1-chloro-2-methyl-2-propyl ether.

To a solution of (S)-6-metoki -- methyl-2-naphtol (1.89 g, 17 mmol, N,N'-dicyclohexylcarbodiimide (3,59 g, 17 moles) and 4-dimethylaminopyridine (0.11 g, 0.09 mmol). The mixture is stirred at room temperature for 24 hours. The solid mass was filtered and a solution of chloroform washed with water. The organic layer is separated, dried with sodium sulfate and evaporated in vacuum. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 8-2). Produce an intermediate product in the form of a white solid mass (3,34 g, melting point 48-51oC) and used for subsequent reactions.

(S)-6-methoxy -- methyl-2-naphthalenyloxy acid 1-nitroxy-2-methyl-2-propyl ether.

A mixture of (S)-6-metoki -- methyl-2-naphthalenyloxy acid 1-chloro-2-methyl-2-propyl ester (3.2 g, 10 mmol) and silver nitrate (2,39 g, 14 mmol) in acetonitrile (30 ml) water in the dark for 2 days. After cooling, the solid mass was filtered and the solvent is evaporated. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 8-2). The target compound is isolated in pure form as a light yellow oil (1.5 g).

1H-NMR(CDCl3, ppm): 7,84-7,73 (3H, m), 7,50 (1H,dd), 7,21-to 7.18 (2H,m), is 4.15 (2H,s), 3,90 (4H,m) to 1.48 (3H,d) of 1.29 (6H,s).

Example 5.

Synthesis of (S)-6-methoxy -- methyl-2-naftiluksusnoi acid 6-(nitro the ptx2">

A solution of (S)-6-methoxy -- methyl-2-naftiluksusnoi acid (6 g, 24 mmol) in chloroform (50 ml) cooled to a temperature of 0oC and treated with drops of triethylamine (4,88 g, 48 mmol). To the resulting cooled mixture is added in drops a solution of 6-chloro-1-hexanol (4.94 g, 36 moles) in chloroform (15 ml). The mixture is stirred at room temperature for 2 hours and then washed with water. The organic layer is separated, dried with sodium sulfate and evaporated in vacuum. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 8-2). Produce an intermediate product in the form of a light yellow oil (5,54 g) and used for the next reaction.

(S)-6-methoxy -- methyl-2-naphthalenyloxy acid 6-(nitroxy)hexyl ether.

A mixture of (S)-6-methoxy -- methyl-2-naftiluksusnoi acid 6-chlorhex ether (are 5.36 g, 15 mmol) and silver nitrate (5,48 g, 32 mmol) in acetonitrile (50 ml) water in the dark for 7 days. After cooling, the solid mass was filtered and the solvent is evaporated. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 9-1). The target compound is isolated in pure form as a light yellow oil (5.2 g).

1H-NMR(CDCl3, ppm): 7,74-of 7.70 (3H,m), 7,44 (1H,dd), 7,20-7,13 (2H,m), 4.26 deaths (2H, t), 4,10 (2H,m), 3,abstracts -- -methyl-4-(2-methylpropyl) benzisoxazol acid 3-(nitrooxide)propyl ether [NCX 322]

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- -methyl-4-(2-methylpropyl) benzonana acid 3-chloropropyl ether.

To the solution-methyl-4-(2-methylpropyl) benzisoxazol acid (4.1 g, 20 mmol) in chloroform (45 ml) is added at room temperature, 1-chloro-3-propanol (1.89 g, 20 mmol), N,N'-DICYCLOHEXYL carbodiimide (4.1 g, 20 mmol) and 4 dimethylaminopyridine (0.11 g, 0.9 mmol). The mixture is stirred at room temperature for 4 hours. The solid mass was filtered and a solution of chloroform washed with water. The organic layer is separated, dried with sodium sulfate and evaporated in vacuum. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 1-1). Produce an intermediate product in the form of a light yellow oil (4.8 g) and used for the next reaction.

- -methyl-4-(2-methylpropyl) benzonana acid 3-(nitroxy) propyl ether.

Mixture-methyl-4-(2-methylpropyl) benzisoxazol acid 3-chloropropyl ether (4,47 g, 15.8 mmol) and silver nitrate (5.3g, and 31.7 mmol) in acetonitrile (20 ml) irrigate in the dark for 36 hours. After cooling, the solid mass was filtered and the solvent is evaporated. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 18-1). The target substance is isolated in pure form as a light yellow m is), of 0.94 (6H,d).

Example 7.

Synthesis of methyl-4-(2-methylpropyl) benzisoxazol acid 6-(nitroxy) hexyl ether [NCX 321]

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chlorine-methyl-4-(2-methylpropyl) benzisoxazol acid.

Solution-methyl-4-(2-methylpropyl) in benzisoxazol acid (6,97 g, 33.8 mmol) in toluene (20 ml) and dimethylformamide (2 ml) cooled to 0oC and treated with drops of oxalyl chloride (8.6 g, 67.8 mmol). The mixture is stirred for 24 hours at room temperature and then evaporated in vacuum. The solid mass is used for subsequent reactions.

-methyl-4-(2-methylpropyl) benzonana acid 6-chlorhex ether.

Solution mass of chloride-methyl-4-(2-methylpropyl) benzisoxazol acid (33.8 mmol) in chloroform (35 ml) is treated at room temperature with triethylamine (6,87 g, with 67.9 mmol). The mixture is cooled to a temperature of 0oC and treated with drops of a solution of 6-chloro-1-hexanol (6,95 g, 50,9 moles). The mixture is stirred at room temperature for 5 hours and washed with water. The organic layer is dried with sodium sulfate and evaporated in vacuum. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 7-3). Produce an intermediate product in the form of a light yellow oil (9,9 g) and use the ether.

Mix-methyl-4-(2-methylpropyl) benzisoxazol acid 6-chlorhex ether (5,58 g, 17.2 mmol) and silver nitrate (4.09 g, 24.1 mmol) in acetonitrile (20 ml). irrigate in the dark for 40 hours. After cooling the mass is filtered and the solvent is evaporated in vacuum. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 27-1). The final product is isolated in pure form as a light yellow oil (2.4 g).

1H-MNR (CDCl3, ppm): 7,18 (2H, d), 7,07 (2H, d), 4,36 (2H, t), of 4.05 (2H, m) to 3.67 (1H, q), 2,43 (2H, d) and 1.83 (1H, m), 1,60 (4H, m) of 1.46 (3H, d), 1,36 is 1.23 (4H, m) to 0.88 (6H, d).

Derivatives loxoprofen

Example 8.

Synthesis of methyl-4-[(2-oxocyclopent)methyl] benzisoxazol acid 4-(nitroxy)butyl ether [NCX 628]

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methyl-4-[(2-oxocyclopent)methyl]Besenova acid 4-bromobutyl ether.

To a solution of 1,4-dibromobutane (7,3 g, 33,79 mmol) in dimethylformamide (30 ml) is added in drops at room temperature a solution of sodium methyl-4-[(2-oxocyclopent)methyl]benzisoxazol acid (3.03 g, 11.3 mmol) in dimethylformamide (60 ml). The mixture is stirred at room temperature for 15 hours, the solution is evaporated in vacuum and the residue washed with water and diethyl ether. The organic phase is allocated, washed with water, dried su 8 - 2). The intermediate product is isolated in the form of a light yellow oil (3.9 g) and used for subsequent reactions.

methyl-4-[(2-oxocyclopent)methyl] benzonana acid 4-(nitroxy)butyl ether.

A mixture of methyl-4-[(2-oxocyclopent)methyl] benzisoxazol acid 4-bromobutyl ester (3.0 g, 10.2 mmol) and silver nitrate (4,69 g, 27.6 mmol) in acetonitrile (20 ml) irrigate in the dark for 18 hours. Then cooled, the mass is filtered and the solution evaporated in vacuo. Sediment transported into the chromatographic column (eluent hexane-ethyl acetate 8 - 2). The final product is isolated in pure form as a light yellow oil (2,84 g).

1H-NMR (CDCl3, ppm): 7,19 - 7,06 (4H, m), 4,34 (2H, t) 4,06 (2H, s), the 3.65 (1H, q), of 3.07 (1H, dd), 2,47 (1H, dd), 2,42 - 1,43 (11H, m) of 1.23 (3H, d).

Indomethacin.

Synthesis of 1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid 4-(nitroxy)butyl ester (NCX 534).

1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-acetic acid 4-chlorobutyl ether.

To a solution of 1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indole - 3-acetic acid (5,04 g, 14 mmol) in chloroform (50 ml) is added at room temperature, 1-chloro-4-butanol (1.4 ml, 14 mmol), N,N1-dicyclohexylcarbodiimide (2,87 g, 14 mmol) and 4-dimethylaminopyridine (0.11 g, 0.09 chloroform washed with water. The organic layer emit, dried in vacuum.

Sediment transported into the chromatographic column (eluent n-hexane/ethyl acetate 9/1). The intermediate product is isolated in the form of a yellow oil (5.2 g) and used for subsequent reactions.

1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid 4-(nitroxy)butyl ether.

A mixture of 1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid 4-chlorobutyl ester (5 g, 11 mmol) and silver nitrate (3.8 g, 22 mmol) in acetonitrile (25 ml) water in the dark for 48 hours.

After cooling the mass is filtered and the solvent is evaporated in vacuum. Sediment transported into the chromatographic column (eluent n-hexane/ethyl acetate 9/1). The final product is isolated in the form of oil (4,2 g).

1H-NMR (CDCl3, ppm): the 7.65 (2H, m), 7,45 (2H, m), to 6.95 (1H, d), at 6.84 (1H, d), of 6.66 (1H, dd), 4,10 (2H, t), 3,82 (3H, s), the 3.65 (2H, s), the 3.35 (2H, t), 2,39 (3H, s), of 1.80 (4H, m).

The obtained substances are listed in the following table. 2, in which reference is made to the formula (1A), paragraph 1 of the claims:

< / BR>
These pellets were prepared in the laboratory by the method of wet granulation. The following describes the preparation of a granulate comprising a compound XXXVI.

In solution were mixed 10 g of compound XXXVI with the e as long until there was a very thin consistency. A solution of 4 g of carboxymethylcellulose sodium in 50 ml of water was added in portions to a powder in a mortar, mixing at intermediate drying at a temperature of 60oC in vacuum again grinding and drying. The obtained granules were driving through a sieve 6-mesh.

p. Animal models of inflammation.

To test the effectiveness of these new compounds, we used two models of acute (edema caused by carrageenan) and chronic (adjuvant arthritis) inflammation in rats.

Swelling caused by injection of 0.1 ml of 1% carrageenan, suspended in sterile physiological solution (solvent) in plantar space in the right hind foot of each rat. The volume of the foot was measured after 3 and 5 hours after injection of carrageenan and analyzed swelling from the point of view of increasing the volume of the foot in relation to the volume of the foot to irritating injections. The measurements were carried out water plethysmometer (mod. 7150, Ugo Basile, Milan, Italy). Diclofenac, nitrofen, naproxen and nitrosoproline (nitrosoproline corresponds nitrocellulose ether of naproxen) a dose of 5 and 10 mg/kg, suspended in 0.5% carboxymethylcellulose, was administered orally one hour before injection caregiverstanning solvent. Adjuvant arthritis was caused by injection into the tail 0.6 ml killed by heating cells of Mycobacterium butyricum suspended in 0.1 ml mineral oil. After 14, 21 and 28 days the development of arthritis was evaluated by the same observer. Primary and secondary arthritic lesions was evaluated by nominal scale as follows: left and right rear feet each 0 to 7, left and right front feet each 0 - 4,5, tail 0 5 ears 0 - 2, nose and eyes every 0 - 1. Deflating was administered at doses of 0.3 and 3 mg/kg of body weight, naproxen and nitrosoproline was given in doses of 4 and 8 mg/kg body weight, respectively; drugs administered orally daily from 3 to 21 days after inducing arthritis, following preventive Protocol. For 14, 21 and 28 days anti-inflammatory activity of drugs was expressed as percentage inhibition values assessment of arthritis on a scale against a control group.

As the original medication, and nitro-derivatives in both doses caused a significant decrease in edema of the feet in three hours, whereas five hours only diclofenac and nitrosoproline at higher doses provided a significant decrease, probably due to its pharmacokinetic properties. In each case the activity of drugs, is vidies three hours for diclofenac and nitrogenase at the dose of 10 mg/kg, the average value of about 27% in three hours for naproxen and nitrosoproline at the dose of 10 mg/kg (table. 3).

Diclofenac and nitrofen at high doses (3 mg/kg) and naproxen and nitrosoproline at both doses (4 and 8 mg/kg) significantly inhibited arthritis.

The impact of releasing nitric oxide derivative of naproxen on hypertension and the defeat of the stomach caused by chronic inhibition of nitric oxide in rats. Mrcelo N. Muscara, Webb McKnight, Piero Del Soldato & John L. Wallace Department of Pharmacology and Therapeutics, University of Calgary, Alberta, Canada; NicOx S.A., Paris, France. (Submtter December 4, 1997; accepted January 21, 1998; received in final Form Janyary 22, 1998)

Summary: NSAIDs may increase blood pressure by mechanisms such as renal vasoconstriction (narrowing of blood vessels and the retention of sodium. This influence is most obvious in hypertensive individuals. As shown, releasing the oxide oxygen NSAID derivatives have significantly reduced toxicity in the gastrointestinal tract and kidneys. In addition, we evaluated the effects of 4-week treatment or naproxen, or release nitric oxide and derived NO-naproxen) on total blood pressure and on the defeat of the stomach in rats, in which hypertension was caused by L-NAME. Kr is naproxen (10 mg/kg) or equimolar dose of NO-naproxen (14.5 mg/kg) was administered orally on a daily basis. After 4 weeks was measured by blood pressure, take blood samples to measure the synthesis of thromboxane and evaluated the defeat of the stomach through the blind macroscopic evaluation. And naproxen, and NO-naproxen inhibited total cyclooxygenase activity > 90%. In rats treated with NO-naproxen, did not manifest significant damage to the stomach. The defeat of the stomach, caused by one L-NAME increased by naproxen, but was prevented NO-naproxen. The treatment with L-NAME significantly increased blood pressure. In the absence of L-NAME group, who received naproxen, had significantly higher blood pressure than in the control group and in the group that received NO-naproxen. For rats that received L-NAME applies the same results, but the concomitant introduction of NO-naproxen resulted in a significant reduction in blood pressure compared with the introduction of only L-NAME. Based on these results, we conclude that NO-naproxen can be a safer alternative compared with standard NSAIDs in the treatment of inflammatory conditions in hypertensive patients.

Key words: non-steroidal anti-inflammatory medication, hypertension, nitric oxide, cyclooxygenase.

Weakly occurs by inhibition of cyclooxygenase, resulting in reduced production of vasodilator prostanoids (mainly PGE2and PGI2), which, together with other mediators such as angiotensin II, atrial naturethese peptide and arginine-vasopressin) directly involved in the control of renal homeostasis (1,2). The excretion of sodium, secretion of renin and sympathetic tone indirectly controlled by prostaglandins (3,4), inhibition of which leads to an increase in the overall blood pressure (KD). However, in humans the effects of NSAIDs on blood pressure (KD) cannot clearly assess when discrepancies arise from differences in age, ethnic origin and/or health status among study subjects (5). More elderly, blacks and low renin hypertensive patients described as particularly susceptible to hypertension caused by NSAID (6). Indomethacin and naproxen are NSAIDs that cause the hypertensive population is not only a significant increase in KD, but also have a strong antagonism to the positive effects of antihypertensive drugs, such as triazine and - blockers (6).

Ulceration of the stomach caused by taking NSAIDs, appears to be associated with a decrease in current crengine of prostaglandin synthesis (see overview in reference 7). Assume that such effects of NSAIDs are basic in their ulcerogenic action (7). Was recently described a new group of NSAID derivatives with significantly reduced adverse effects on the gastric mucosa. Such derivatives are called "NO-NSAIDs", because they have the ability to release nitric oxide (NO), a well-known vasodilator (8,9,10) with inhibitory effects on the adhesion of platelets (11,12) and leukocytes (13). Adding releasing nitric oxide part to NSAIDs have not led to the loss of the ability of these drugs to inhibit cyclooxygenase. Among the NO-NSAIDs, which recently characterized in this way, are NO-flurbiprofen and NO-Ketoprofen (14), NO-diclofenac (15), NO-naproxen (16) and NO-aspirin (17). When NO-NSAIDs were given to rats with normal CD, they had no significant effect on total blood pressure (14, 17). However, studies of such compounds in hypertensive animals have not been conducted.

In this study, we studied the probability that NO-NSAIDs may have less vazopressornye impact on hypertensive rats than standard NSAID. Thus, we tested the effect of treatment with naproxen or NO-naproxen over a period of time is m L-NAME, inhibitor of NO synthesis.

Methods.

Treatment. Male Wistar rats, weighing approximately 250 g, were obtained from Charles River Breeding Farms (Montreal, Quebec). They were kept in polypropylene cages in groups of two or three animals in a cage, and they received laboratory food ad libitum. Groups of rats (n=10 in each group) received daily oral dose of solvent (1 ml/kg), naproxen (10 mg/kg) or equimolar dose of NO-naproxen (14.5 mg/kg) for four weeks. In each group half of the animals received N- nitro-L-arginine methyl ester (L-NAME; Sigma Chemical Co. 400 mg/l drinking water) ad libium within four weeks of the study period, whereas the remaining rats received tap water. Based on individual daily fluid intake, the concentration of L-NAME resulted in a dose of about 45 mg/kg/day. The solvent contained 0.5% carboxymethylcellulose/dimethyl sulfoxide (95/5, V/V). Naproxen (Sigma) and NO-naproxen (NicOx) was dissolved in this solution to 10 mg/ml and 14.5 mg/ml, respectively.

Blood pressure measurement. After weeks of treatment, the animals had a systolic blood pressure measured by tail through the cuff for measuring blood pressure (Harvard apparatus), as described RAS is m Hg, and recorded the average value. The person who conducts the measurement did not know about the effects, which were rats.

The synthesis of thromboxane. At the end of the fourth week of treatment period and after about 20 hours after the last dose of the solvent, naproxen and NO-naproxen rats analizirovali the sodium pentobarbital and determined the synthesis of thromboxane B2in whole blood, as described previously (17). Briefly, blood samples were taken from the descending abdominal aorta, and an aliquot of 1 ml immediately transferred into glass test tube and incubated at 37oC for 45 minutes. At the end of the incubation period was added 10 mg of indomethacin and the tubes were centrifuged (2,000 g, 10 min). Serum was separated and kept at -20oC, then analyzed the concentration of thromboxane B2using commercial kit enzyme-linked immunosorbent assay (Cayman Chemical Company, Ann Arbor, MI). In a separate experiment, three groups of rats (n=6 in each group) were treated daily for five days with a solvent, naproxen or NO-naproxen, as in the study described above. Two hours after the last dose of the test drug was taking whole blood to measure the synthesis of thromboxane B2as explained above.

stomach. Macroscopically visible lesion of the mucosa was estimated by the observer, not knowing about the treatment, as described previously (19).

The statistical analysis. All data are presented as the mean SEM. Differences between groups were analyzed using one-way analysis of variance, followed by test Student-Neuman-Keuls for multiple comparisons. Values with a probability of less than 5% (p < 0.05) was taken as significant.

The synthesis of thromboxane: PL. 5 shows that the differences in the synthesis TXB2not detected in all groups, when blood samples were collected after 20 h after the last dose NSAID (or solvent). However, in blood samples taken 2 hours after the last dose of NSAID, naproxen, and NO-naproxen inhibit the synthesis of thromboxane about > 90% (p < 0.001 vs group treated with the solvent). Suppression thromboxane synthesis found for naproxen was more significant than the suppression found for NO-naproxen (p < 0.05).

Blood pressure: As shown in Fig. 1, treatment of L-NAME caused a significant increase in KD values in animals treated with the solvent (1272 against 1622, p < 0.001), naproxen (1484 against 1734 p < 0.001) or NO-naproxen (1373 compared with values in animals solvent-treated (p < 0.001 and p < 0.05, respectively), but vazopressornye effect of naproxen was shown more significantly, what caused the NO-naproxen (p < 0.05). While vazopressornye effect of L-NAME significantly increased with concomitant introduction of naproxen (p < 0.05), NO-naproxen significantly reduce hypertension caused by L-NAME (p < 0.05).

Injury of stomach Injury of the gastric mucosa was detected in rats treated or control, or NO-naproxen, whereas all rats treated with naproxen, were found damaged (Fig. 2). The introduction of L-NAME also led to the development of hemorrhagic lesions in the stomach. The introduction of naproxen in rats treated with L-NAME in drinking water has led to a significant increase in the severity of lesions of the gastric mucosa. On the contrary, the introduction of NO-naproxen prevented damage of the gastric mucosa associated with the introduction of L-NAME in drinking water.

Discussion.

Chronic inhibition of NO synthesis by the introduction of L-arginine analogues provides a useful model of hypertension (20, 21). This model shows some similarities with clinical pathologies associated with endothelial disrotatory demonstrated that hypertensive effect of L-arginine analogues may be reversible or weakened by the introduction of a large number of L-arginine, and that the kidneys are one of the target organs responsible for the hemodynamic effects of inhibition of NO synthesis (20, 21, 25-27). Vasodilator prostaglandins represent another group of mediators of fundamental importance in the maintenance of renal homeostasis (1, 2). Inhibition of renal Cox by NSAIDs leads to disruption of kidney control KD, especially in hypertensive patients (6).

Our results show that naproxen, and its NO-releasing derivative significantly increase KD, and the impact of NO-naproxen more discretely than the impact caused by the original connection. We also showed that naproxen strengthens hypertension induced by L-NAME, thus mimicking the clinical situation (6). On the other hand, NO-naproxen is not only not increase, but even partially inhibits hypertension caused by L-NAME. As shown, flurbiprofen or NO-flurbiprofen did not show vazopressornye effects in normal rats during the period of one hour after nutrigold what about the introduction of (17). Thus, we should assume that vazopressornye effect of NSAIDs is seen only after prolonged treatment period. Moreover, these results confirm that NO and prostaglandins act in synergy in the control of KD, and that in the absence of endogenous NO significant increase in sensitivity to NO-naproxen, releasing NO, which is manifested in a variety of impacts NO-naproxen in the absence and presence of concomitant treatment with L-NAME.

The introduction of naproxen or L-NAME caused a significant damage to the stomach, which is significantly increased when these two compounds were administered together. These observations are in accordance with the described protective effects of NO and prostaglandins in the intestinal mucosa (29). Despite the fact that NO-naproxen reduced the total cyclooxygenase activity by more than 90%, it did not cause damage to the stomach when administered to normal or hypertensive rats. In the latter case, NO-naproxen protect the stomach from damage usually caused by chronic L-NAME. The ability of some NO-NSAIDs to protect the stomach from damage, while at the same effective suppression of prostaglandin synthesis in the research, reviewer gastrointestinal safety of NO-NSAIDs, consisted of introducing them for short periods of time. Thus, these data reduced the damage of the stomach within 4 weeks of daily therapy reinforce the statement about the relative safety of this new group of drugs compared to the original drug.

From table. 5 can clearly understand that naproxen and NO-naproxen caused a significant inhibition thromboxane generation in whole blood, when blood samples were taken 2 h after the last dose. However, the synthesis TXB2was significantly lower in the group treated with naproxen than in the group treated with NO-naproxen. Despite these differences, NO-naproxen inhibit the synthesis of thromboxane 92%; therefore, NO protective effect of naproxen, or when the increase in KD, or if the damage of the gastric mucosa cannot be described by pure inhibition of COX. In a previous study, NO-naproxen did not cause significant damage to the stomach at a higher dose than was used in this study.

It should also be noted that, as was previously demonstrated, NO-naproxen exhibits anti-inflammatory activity, traveline 20 million people in the United States are simultaneously anti-hypertensive and NSAID therapy (6), thus undergoing cardio-renal and gastrointestinal risk discussed above. The results presented in this article confirm that NO-naproxen may represent a safer alternative to standard NSAIDs for the treatment of inflammatory diseases in hypertensive patients.

This work was supported by a grant from the Heart and Stroke Foundation of Canada, Dr. Wallace is a representative of the Medical Research Council of Canada Senior Scientist and an Alberta Heritage Foundation for Medical Research Scientist. Dr. Muscara supported Pharmacology, Merck Fellowship.

Comparison of NO-naproxen with naproxen: ulcerogenic, analgesic and anti-inflammatory effects. N. Davies, A. G. Roseth*C. B. Appleyard, W. McKnight, P. Del Soldato , A. Calignano , Cirino & J. L. Wallace Intestinal Disease Research Unit, Faculty of Medicine, University of Calgary, Calgari Alberta, Canada;*Department of Medicine, Aker University Hospital, Oslo, Norway; Nicox SA. Paris, France; and Department of Experimental Pharmacology? Univercity of Naples, Naples, Italy

Accepted for printing September 3, 1996

Summary

Prerequisites: was Recently described a new class of releasing nitric oxide non-steroidal anti-inflammatory drugs (NO-NSAIDs) derivative, which exhibits anti-inflammatory activity, but it is clearly less gastrointestinal damage than the original NSAID, from which it gets light is of naproxen less ulcerogenic against gastro-intestinal tract, than the original NSAID, and shows whether it is analgesic and anti-inflammatory properties of the original NSAID.

Methods: Both drugs were compared to models with acute damage to the stomach, on the model with antral ulcer, and after daily injection twice a day for 18 days (model with small intestinal damage). Anti-inflammatory activity was tested in the model caused by carrageenan swelling of the legs, whereas the analgesic activity was tested on model induced by acetic acid painful cramps. The pharmacokinetic profiles of naproxen versus NO-naproxen compared HPLC analysis.

Results: it Was found that NO-naoroxen causes significantly less damage to the stomach, although causes an increase in TNFa plasma like naproxen. Chronic introduction of NO-naproxen small intestinal damage was considerably less than the introduction of the original NSAID. However, NO-naproxen showed increased comparable analgesic and anti-inflammatory effects compared to naproxen.

NO-naproxen is not fully developed in naproxen, but decreased levels in blood were not the main cause of reduced jeludochny tract derivative NSAID with elevated comparable analgesic and anti-inflammatory properties compared with naproxen.

Introduction.

NSAIDs have widespread clinical use due to its anti-inflammatory, protivogipertonicheskoe, analgesic and antithrombotic properties. However, the use of these drugs is limited due to their ability to cause damage to the mucous throughout the gastrointestinal tract. NSAID-related gastrointestinal side effects explain more than 70,000 hospitalizations and 7000 deaths annually in the United States. Naproxen is pure stereochemical 2-arylpropionic acid NSAID and, as has been shown to cause damage to the mucous throughout the gastrointestinal tract. In USA naproxen recently sold as over-the-counter drug. With the increasing use of over-the-counter NSAIDs there is a possibility of increasing the spread of the harmful effects caused by these medicines.

We recently described a new class of releasing nitric oxide non-steroidal anti-inflammatory drug (NO-NSAID), which causes significantly reduced gastrointestinal reactions.

1. Nitroethane, which have the following General formula:

< / BR>
where a and b are selected from throughout the oxygen, NH, NR1where R1means a linear or branched alkyl group, and n is from 1 to 6.

2. Nitroethane under item 1, characterized in that M is equal to

< / BR>
where R means

< / BR>
A and b are equal to hydrogen, Y is oxygen and n is equal to four.

3. Nitroethane under item 1, characterized in that M is equal to

< / BR>
where R is equal to

< / BR>
A and b are equal to hydrogen, Y is NH and n is equal to four.

4. Nitroethane under item 1, characterized in that M is equal to

< / BR>
where R is equal to

< / BR>
Y is oxygen, a and b are equal to hydrogen, and n is equal to four.

5. Nitroethane under item 1, characterized in that M is equal to

< / BR>
where R is equal to

< / BR>
Y is NH, a and b are equal to hydrogen, and n is equal to four.

6. Nitroethane under item 1, characterized in that M is equal to

< / BR>
where R is equal to

< / BR>
A and b are equal to hydrogen, Y is oxygen and n is equal to four.

7. Nitroethane under item 1, characterized in that M is equal to

< / BR>
where R is equal to

< / BR>
A and b are equal to hydrogen, Y is NH and n is equal to four.

8. Nitroethane under item 1, characterized in that M is equal to

< / BR>
A and b are equal to hydrogen, Y is oxygen and n is equal to four.

9. Nitroethane under item 1, characterized in that M is equal to

< / BR>
A and b equal fedorovgott.

11. Nitroethane under item 1, having analgesic activity.

12. Nitroethane under item 1, characterized in that they can be used to treat rheumatic diseases, for treating disorders of the immune system, and weak and medium pains.

13. Nitroethane under item 1, characterized in that they can be used to treat diseases of the cardiovascular system, for the treatment of senile dementia, for the treatment of ischemia of the heart and brain, and in the case of arterial thrombosis.

14. The method of producing nitroethanol under item 1, having the following General formula:

< / BR>
where a and b are selected from hydrogen or methyl, M is selected from

< / BR>
< / BR>
< / BR>
< / BR>
where R is selected from

< / BR>
< / BR>
< / BR>
Y is selected from oxygen, NH, NR1where R1means a linear or branched alkyl, and n is from 1 to 10, characterized in that it comprises the following stages: - obtaining the sodium salt derivatives having the following General formula:

< / BR>
where M is selected from (XXX), (XXXI), (XXXII),

< / BR>
where R is selected from the following structures:

< / BR>
< / BR>
< / BR>
or deriving (VIA), substituted by carboxyl group, such as acid chlorides, anhydrides or the like; the reaction is Noah group, with a compound having the following General formula:

< / BR>
where R4selected from chlorine, bromine, other5where R5is hydrogen, a 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, which results in nitroethanol (IA).

15. The method of producing nitroethanol under item 1, having the following General formula:

< / BR>
where a and b are selected from hydrogen or methyl, M is selected from

< / BR>
< / BR>
< / BR>
< / BR>
where R is selected from

< / BR>
< / BR>
< / BR>
Y is selected from oxygen, NH, NR1where R1means a linear or branched alkyl group, and n is from 1 to 10, characterized in that it comprises the following stages: obtaining the sodium salt derivatives having the following General formula:

< / BR>
where M is selected from (XXX), (XXXI), (XXXII),

< / BR>
where R is selected from the following structures:

< / BR>
< / BR>
< / BR>
or deriving (VIA), substituted by carboxyl group, such as loranger the data (VIA), substituted by carboxyl group, with a compound having the following General formula:

< / BR>
where R4selected from chlorine, bromine, other5where R5is hydrogen, a linear or branched alkyl, a and b is selected from hydrogen, linear or branched, substituted or unsubstituted alkyl, and n is from 1 to 10, obtaining thus the corresponding esters or the corresponding amides; the reaction of the abovementioned ethers or above amides with palodiruyut connection, such as PBr3or similar, obtaining thus the products of the abovementioned ethers or above amides characterized by the presence of halide end group; the reaction of the abovementioned ethers or above amides characterized by the presence of halide end groups, with nitrious agent such as AgNO3or similar, obtaining thus nitroethanol (IA).

16. Pharmaceutical composition having anti-inflammatory activity, characterized in that they comprise at least one nitroethyl under item 1 as an active ingredient.

17. Pharmaceutical composition having analgesic activity, characterized in that they comprise at least odataset a

10.05.94 for all other values radicals.

 

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The invention relates to a new protected bicyclic to amidines formula I, where a is chosen from the group

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< / BR>
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