Nitrate salts of heterocyclic compounds, method of their production and pharmaceutical compositions based on them

 

(57) Abstract:

The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention. Compounds of formulas (a) and (b) and compositions on their basis have antiulcer activity and can be used in medicine. 4 C. and 3 h.p. f-crystals, 2 PL.

The present invention relates to compositions used in the treatment and prevention of ulcer recurrence and mainly dyspepsia. More specifically this invention relates to compositions having improved gastro-protective activity, combined with the ability to inhibit high acid secretion.

The products known in the art and commercially available, are compounds having antisecretory activity (inhibition of acid secretion). See, for example,esteem, show high antisecretory activity and are used as emergency treatment and long-term therapy. The disadvantage of these products is that they are in his presence have bad gastro-protective activity. From a practical point of view this means that the protection of the stomach is not optimal and causes of anxiety, especially when long-term therapy. In this case, the presence of frequent relapses due to the weakening of the mucous membrane of the stomach.

In the art it is known that in order to overcome these disadvantages, the above medicines add other antiulcer drugs with gastro-protective action: prostaglandin, salts of bismuth (e.g., citrate of bismuth and antibiotics. This approach is achieved remission of peptic ulcer disease. However, these combinations are not satisfactory mainly because of their tolerance. For example, it is well known that prostaglandins may cause side effects (diarrhea) in intestinal tract; salts of bismuth often cause nausea and heartburn. Antibiotics cause undesirable gastrointestinal effects.

Felt the need for dostupniye and tolerance, General and local, in particular, have improved gastro-protective activity in combination with high antisecretory activity.

The applicant has unexpectedly and surprisingly found anti-ulcer pharmaceutical composition having the above-mentioned required properties.

The object of the present invention are pharmaceutical compositions containing as the main component of the nitrate salt of one or more components selected from the following classes of compounds:

where (A) the class of compounds:

R=H, OCH3, OCHF2;

R1=CH3THE CO3;

R2=N, CH3;

R3=CH3CH2-CF3, (CH2)3-OCH3;

where () is the class of compounds:

RI3, RI4equal to or different from each other and mean respectively the free valence, hydrogen, -N=C(NH2)2, -CH2-N(CH3)2;

Y=S,N-RI6,CRI7RI8;

X=O, S, N-RI1;

RI2=N,CH3;

n=0,1;

Z=N-CN, N-SO2NH2CH-NO2or

, RI1equal to or different from each other represent hydrogen, the free valency.

Preferred nitrate salt precursors of formula (A) are as follows:

when R=och3, R1=CH3, R2=CH3, R3=CH3this balance of omeprazole;

how to omeprazole, but with R=OCHF2, R1=CO3, R2=N, is the remainder of pantoprazole;

how to omeprazole, but with R=H, R2=N, R3=(CH2)3-OCH3this balance rabeprazole;

as in rabeprozole, but with R3=CH2-CF3is the rest of lansoprazole.

In (A) the class of compounds also includes those compounds that contain intramolecular ring, obtained by processing the precursor in an acidic aqueous medium ("A Textbook of Drug Design and Development", Hardwood Academic Publisher, 1991, p.140):

where NAIandAIImean, respectively, the nitrogen atoms and carbon atoms in positions 1 and 2 of the pyridine ring of the formula A, andB2and NB3mean respectively the atoms of carbon and nitrogen in the 2 and 3 positions imidazole ring (1 position of the imidazole ring is protonated nitrogen).

Preferred nitrate salt preds the means the free valence, Y=N-RI6where RI6=N, RI3=H, RI4means the free valence and forms with RI1double bond, RI2=CH3n=1, RI5=-NH-CH3Z=N-CN, is the remainder of cimetidine;

when X=N-RI1where RI1means the free valence, Y=S, RI3=-N=C(NH2)2, RI4means the free valence and forms with RI1double bond, RI2=N, n=l, RI5=N, Z=(VIIA), is the remainder of aprotinine;

as in aprotinine, but with n=0, RI5=NH2and Z=N-SO2NH2this balance famotidine;

as in aprotinine, but with RI3=-CH2-N(CH3)2, RI5=-NH-CH3and Z=CH-NO2is the rest of nizatidine;

as in nizatidine, but with X, indicating oxygen, Y=CRI7RI8where RI7is hydrogen and RI8means the free valence, RI4means the free valence and forms with RI8double bond, it is the remnant of ranitidine.

In the compositions according to the present invention can also use the finding of salt compounds of the above classes contain at least one mole of nitrate ion/mol compounds. Preferably the ratio between the moles of nitrate ions and the precursor is equal to one. Salt having a higher molar ratio receive, when in the molecule there are other basic amino group in a sufficient amount to form a salt.

Precursor salts corresponding to the above classes, receive according to the methods described in "The Merck Index 12aEd." (1996), fully incorporated into this description by reference.

Salt of the present invention can be obtained according to one of the following methods.

When the substance from which salt is available as a free base or as the corresponding soluble salt in an organic solvent, which preferably does not contain hydroxyl groups, for example acetonitrile, ethyl acetate, tetrahydrofuran, etc., salt is obtained by dissolving the substance in a solvent at a concentration of, preferably equal to or higher than 10% wt./about., the addition amount of concentrated nitric acid corresponding to the moles of forming a salt of the amine groups present in this compound. Nitric acid is preferably diluted Ah 20-0C. The product is usually isolated by filtration and washed with solvent.

When the substance is not very soluble or available as a soluble salt in the above-mentioned solvents can be used with an appropriate mixture of gidroksilirovanii solvents. Examples of such solvents are methyl alcohol, ethyl alcohol and water. The precipitation can be accelerated by diluting the thus obtained mixture after adding nitric acid non-polar solvent.

When the original product forms a salt with hydrochloric acid, can be obtained salt with nitric acid, directly adding silver nitrate to a solution of compounds. After filtering off the silver chloride solution is concentrated and cooled to obtain a nitrate salt.

When the original product is a salt, it is possible to release the corresponding base by treatment with a saturated solution of carbonate or bicarbonate of sodium or potassium or a diluted solution of sodium hydroxide or potassium. The base is then extracted with a suitable organic solvent (for example, halogenated solvents, esters, ethers), which is then dehydrated. Organisasie in acetonitrile or other of the above-mentioned solvents.

Surprisingly it was found that the compositions of the present invention allow to comprehensively improve in comparison with the known above-mentioned combinations pharmacotoxicological situation predecessors, increasing therapeutic efficacy and their General and local tolerance in the treatment of ulcers and stomach disorders, in combination with improved gastro-protective activity.

Of the compositions of the present invention are prepared the corresponding pharmaceutical compositions in accordance with well known techniques in this field together with standard excipients, see, for example, that “Remington's Pharmaceutical Sciences 15a Ed.”

Dose of salts of the present invention are standard doses of their predecessors (a) and (b) classes.

It is also an object of the present invention are compositions obtained by combining one or more nitrate salts of the compounds (a) and (b) classes, or their pharmaceutical compositions with standard gastro-protective properties. As examples can be mentioned prostaglandins, salts of bismuth, antibiotics, active against pathogenic microorganisms in the gastrointestinal mucosa. With udivleni the ka. This avoids adverse effects known gastroprotection when they are used in combination with the compounds or pharmaceutical compositions of the present invention. Indeed, it was found that the number of known gastroprotection in combination of the present invention compared with known quantities and does not cause unwanted effects. Specialist in the art can easily determine the maximum number of standard gastroprotection, which are combined with the pharmaceutical compositions of the present invention, since it indicates that there is no typical side effects known gastroprotection. In any case, the number of standard gastroprotection, which is used in combination, lower than the amount used in the combinations described at this level of technology.

The following examples are presented to illustrate this invention and should not be construed as limiting it.

Example 1.

Receiving nitrate of cimetidine.

10 g of cimetidine dissolved in 100 ml of a mixture of acetonitrile/tetrahydrofuran/water 1:1:2 (by volume), cooled to +4C. rum, maintaining the temperature at +4C, prior to the deposition of the product in the sediment. After a few hours of rest precipitated solid is filtered, washed with ethyl ether and dried. Get to 12.1 g of salt Mononitrate cimetidine with so pl. 158-C (with decomposition).

1H-NMR (D2O): 8,55 (1H, s), 3,83 (2H, s), 3,32 (2H, s), 2,77 (3H, s), 2,68 (2H, t), 2,32 (3H, s).

Elemental analysis:

Rasch. (%) 38,09 N 5,43 N 31,09 S 10,17

The detection. (%) 37,99 N 5,41 N 31,16 S OF 10.25

Example 2.

Receiving nitrate of ranitidine.

5 g of ranitidine hydrochloride is dissolved in 140 ml of a mixture of acetonitrile/methanol 6:1 at +20C. Add to 4.2 g of powder of silver nitrate. The precipitate of silver chloride is filtered, the residue washed with a solution of acetonitrile/methanol 6:1, the combined organic phases together, dried and processed to obtain a dry residue. Obtain 3.5 g of amorphous solids, corresponding to Mononitrate of ranitidine.

1H-NMR (D2O): 6,70 (1H, d), 6,40 (1H, d), 4,34 (2H, s), 3,83 (2H, s), of 3.43 (2H, t), with 2.93 (2H, m), 2,87 (N, s).

Elemental analysis:

Rasch. (%) 41,37 N 6,14 N 18,56 S 8,50

The detection. (%) 41,12 N 6,20 N 18,44 S SCORED 8.38

PHARMACOLOGICAL TESTS

Example 3.

The animals were observed for 14 days. In none of the groups of animals were not marked symptoms of toxicity.

Example 4.

Antiulcer activity.

Antiulcer activity was evaluated according to the experimental model described in the article by A. Robert et al. “Cytoprotection by prostaglandins in rats. Prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl and thermal injury (Cytotoxity by prostaglandins in rats. Prevention of necrosis of the stomach caused by alcohol, HCl, NaOH, hypertonic NaCl, and thermal damage) Gastroenterology 77, 433-43, 1979.

5 groups of 10 rats each, stomach which has remained empty since the previous night, 15 minutes before injection of absolute ethanol (1 ml) oral route you entered:

5 ml/kg of a 2% aqueous suspension of carboxymethylcellulose.

50 mg/kg of cimetidine in 5 ml/kg of a 2% aqueous suspension of carboxymethylcellulose.

- 62.5 mg/kg nitrate cimetidine (which corresponds to 50 mg/kg of cimetidine) in 5 ml/kg of a 2% aqueous suspension of carboxymethylcellulose.

50 mg/kg which corresponds to 60 mg/kg of ranitidine) in 5 ml/kg of a 2% aqueous suspension of carboxymethylcellulose.

An hour later, animals were killed and assessed the degree of gastric lesions. The results are presented in table I, and they show that the nitrate salt of cimetidine and ranitidine have improved gastro-protective activity compared to the original products.

Example 5.

Obtaining compounds nitrate salt with the remainder of omeprazole

6 g of omeprazole was dissolved in 180 ml of an organic solution with the composition (calculated by volume) acetonitrile/methanol/tetrahydrofuran 1/1/3. The resulting solution was cooled to a temperature of 0C. 10 ml of an organic solution of nitric acid, which is obtained by mixing 10 ml volumetric flask times the amount of acetonitrile from 1.22 ml of 65% nitric acid and then mixing with a volume of organic solvent was added in drops under stirring, while maintaining the temperature at 0C. The solution is then stirred for one hour, then the precipitate was filtered. The obtained residue was washed with ethyl ether and dried. Received 6,64 g salt Mononitrate omeprazole.

T. D.: 162-164 ° C.

1HNMR (DMSO): 9,12 (1H, d), 7,66 (1H, dd), 7,22 (1H, d),? 7.04 baby mortality (1H, m), 4,60 (2H, s), 4.26 deaths (3H, s), 3,85 (3H, s), of 2.54 (6H, s).

Analysis C, H, N, S:

Rasschitannoi activity.

Antiulcer experiment has been performed in accordance with example 4.

Omeprazole was administered to 10 rats with doses of 50 mg/kg in 5 ml/kg of carboxymethylcellulose in water suspension (2% w/v.

Nitrate salt was administered doses of 59 mg/kg, respectively, in the 50 mg/kg of omeprazole in 5 ml/kg of carboxymethylcellulose in water suspension (2% w/v.

The results are presented in table II.

Damage to the stomach is expressed in the right column of the table in % of the number of rats showing the defeat of the stomach from 10 rats of this group.

The data in the table show that nitrate salt with the remainder of omeprazole has improved gastro-protective activity compared with omeprazole.

Examples of pharmaceutical compositions

Tablet containing nitrate ranitidine:

Nitrate 360 mg ranitidine

The micro-granulate cellulose 260 mg

Magnesium stearate 4 mg

The hypromellose 15 mg

Titanium dioxide 6 mg

Tablet containing nitrate of cimetidine

Nitrate cimetidine 240 mg

The micro-granulate cellulose 50 mg

Corn starch 10 mg

Polyvinylpyrrolidone 10 mg

The sodium sulfate 1 mitral omeprazole

Nitrate omeprazole 100 mg

The micro-granulate cellulose 240 mg

Magnesium stearate 2 mg

The hypromellose 30 mg

Titanium dioxide 4 mg

Preparation of a powder containing nitrate cimetidine + salt of bismuth (mixed in water before use).

Nitrate cimetidine 380 mg

The bismuth aluminate 450 mg

Tragacanth glue 500 mg

Carboxymethylcellulose sodium 100 mg

Aroma 50mg

Sucrose was added to 5 g

1. Nitrate salts of heterocyclic compounds of formulas (a) and (b) selected from the following classes of compounds:

where in the compounds of formula (A)

R - OCH3, R1- CH3, R2- CH3, R3- CH3;

R - F2, R1- OCH3, R2- N, R3- CH3;

R - N, R1- CH3, R2- N, R3- (CH2)3-OCH3;

R - N, R1- CH3, R2- N, R3- (CH2)3-OCH3;

R - N, R1- CH3, R2- N, R3- CH2-CF3;

where in the formula (V)

X - N-RI1where RI1SUB> means the free valence and forms with RI1double bond, RI2- CH3n = 1, RI5- -NH-CH3, Z - N-CN;

X - N-RI1where RI1means the free valence, Y-S;

RI3- N=C(NH2)2, RI4means the free valence and forms with RI1double bond, RI2- N, n=1, RI5- N, Z - (VIIand):

X - N-RI1where RI1means the free valence, Y Is S, RI3- -N=C(NH2)2, RI4means the free valence and forms with RI1double bond, RI2- N, n=0, RI5- NH2and Z - N-SO2NH2;

X - N-RI1where RI1means the free valence, Y Is S, RI3- -CH2-N(CH3)2,

RI4means the free valence and forms with RI1double bond, RI2- N, n=1,

RI3- -NH-CH3Z - CH-NO2;

X is oxygen, Y IS CRI7RI8where RI7means hydrogen and RI8means free and forms with RI7double bond, RI2- N, n=1, RI5- -NH-CH3Z - CH-NO2.

2. The pharmaceutical composition of nitrate salts having antiulcer activity and containing as active substance a compound under item 1.

3. The pharmaceutical composition of nitrate salts having antiulcer activity and containing as active substance a connection on p. 1 and standard gastroprotection.

4. The composition according to PP.2 and 3, where the standard gastroprotective selected from prostaglandins, salts of bismuth and antibiotics.

5. The method of obtaining nitrate salts under item 1, characterized in that, if a substance which forms a salt, available as a free base or as a soluble salt in an organic solvent, which does not contain hydroxyl groups, nitrate salt is obtained by dissolution of the original substance in a solvent and then adding the number of moles of concentrated nitric acid, which corresponds to the number of amino groups in the compound, cooling the reaction mixture to 20-0C while adding nitric acid and isolation of the product by filtration.

6. The method according to p. 5, characterized in that for increasing ofanim solvent and, after the addition of nitric acid, the precipitation of the product can be accelerated by dilution of the mixture of non-polar solvent.

7. The method according to PP.5 and 6, characterized in that, if the original compound forms a salt with hydrochloric acid, a nitric acid salt get direct addition of silver nitrate to a solution of the compound, filtering of silver chloride, followed by concentration of the solution and its cooling.

 

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