BG61302B1 - N-/3-/3-/1-piperidineilmethyl/phenoxypropyl hydroxyacetamide 1,2,3-propenetricarboxilate bismuth /3+/ complex and method for its preparation - Google Patents

Abstract

Compounds having formula (formula) are produced by reaction between n-/3-/3-/piperidinsilmethyl/phenoxypropyl hydroxyacetamide and bismuth citrate in boiling aqueous medium. The salt with the above-mentioned formula has high antisecretion and cytoprotective activity, as well as antibacterial effect towards Hellicobacter pylori and is used for the treatment of gastric and duodenal ulcera. It is applied in the form of tablets and capsulates.

Description

TECHNICAL FIELD

The invention relates to N- (3- (3- (1- (10-piperidinylmethyl) phenoxy) propyl) hydroxyacetamide 1,2,3-propenecarboxylate bismuth / 37 complex / 1: 1: 1), which has antisecretory, cytoprotective and antibacterial activity and finds application for the treatment of 15 gastric and duodenal ulcers, and a method for preparing it.

BACKGROUND OF

TECHNIQUE 20

dream, co, '|

BUT - C - CO, 'in / ¹

CH, CO, · -CH, CHjCHJ4HCOCH ₂ OH (II) having at the same time histamine H ₂ antagonistic activity, cytoprotective and antibacterial activity against Helicobacter pylori and to find application for the treatment of gastric and duodenal ulcers, and to create a method for the preparation and.

SUMMARY OF THE INVENTION

N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) hydroxyacetamide of the formula is known

- CH,

/ I / 'O-CHjCHjCHjNHCOCHjOH in the form of an oxalate salt has high histamine H ₂ 30 antagonistic activity against various experimental ulcer models in experimental animals (EP 0024510; Bickel M. et al., Arzeim-Forsch; Drud Res, 36 (II ), 9, 1358, 1984).

It is also known that some salts of 35 bismuths such as bismuth citrate (in the form of tricalium bismuth dicitrate) and bismuth salicylate are used as antacids for the treatment of hyperacidity and for the treatment of gastric ulcers in humans (Wilson, TR Post- 40 graduate Medical Journal, 51 / suppl 5 /, 18, 1975; Wilson, TR Postgraduate Medical Journal, 51 / Suppl /, 22, 1975; Wagner, S., Gut, 33, 179, 1992).

Bismuth citrate has been shown to have a 45 antibacterial effect on Helicobacter pylori, a microorganism that is one of the important pathological factors for the occurrence of gastric and duodenal ulcers (Marshall B., The American Journal of gasteroenterology, 86/1 /, 50 16, 1991 ).

It is an object of the invention to provide the blueBismuth salt of formula II according to the invention by reacting N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) hydroxyacetamide free base with bismuth citrate, which is a complex of citric acid bismuth. taken in equimolar amounts in an environment of a suitable solvent, for example water.

The reaction between a compound of formula I and bismuth citrate is carried out in a temperature range of 0 to 100 ° C for 3 to 4 hours. The reaction is considered complete when the pH of the reaction mixture reaches 5.5-6. The resulting bismuth salt was isolated from the reaction mixture by filtering the latter and concentrating the aqueous filtrate in vacuo to dryness. The resulting dry residue, representing the crude bismuth salt, is purified from suitable organic solvents such as alcohols (ethanol, isopropanol, butanol), ketones (acetone), preferably absolute ethyl alcohol, by suspending the salt in the organic solvent and stirring the suspension 10 to 20 min. The ethyl alcohol was decanted and the salt was treated with diethyl ether to give a white crystalline product.

The structure of the bismuth salt is demonstrated by elemental analysis data, complexometric determination of bismuth content and potentiometric determination of organic ligand content and 1 H-NMR spectra. According to these data, the ratio of bismuth citrate to the compound of formula I is 1: 1.

The starting piperidine derivative of formula I was prepared by the method described in (EP 024510).

The bismuth salt of a compound of formula I has been found to have antisecretory activity against histamine-induced gastric secretion in rats.

The antibacterial activity of a compound of formula I of the bismuth salt was tested10 in vitro experiments against Helicobacter pylori. The antibacterial effect of the bismuth salt is manifested at a minimum inhibitory concentration (MIC) in the range of 16 to 64 pg / 5 ml.

The cytoprotective effect of the bismuth salt of a compound of formula I was tested in an experimental model of ethanol-induced ulcers in rats by a method described by Konturek, S., Eur.J. Pharmacol, 125, 185, 1986. The histamine H ₂ receptor antagonist Roxatidine was used as a reference. The data from the studies are presented in Table 1.

Table 1

Effects of the bismuth salt of a compound of formula I and of roxatidine on a model of ethanol-induced ulcers in rats

Groups of animals; treatment η Average total length of ulcers (mm) Percent inhibition Number Percent inhibition controls (with water) 18 83.5 ± 7.4 14.0 ± 2.4 experienced Roxatidine 62 mg / kg 100 mg / kg 10 9 40,8 ± 15,2 *** 22,3 ± 9,0 *** -54 -73 8,6 ± 2,3 *** 6.1 ± 1.7 · ** -39 -56 experienced bismuth salt of compd. of formula I 29 mg / kg 58 mg / kg 87 mg / kg 115 mg / kg 13 12 14 14 39.4 ± 10, I *** 48.5 + 18.3 *** 7,9 ± 3,7 *** 14,1 ± 7,9 *** -53 -42 -91 -83 11.2 + 2.5 10.8 ± 3.2 3.7 ± 0.9 *** 6,3 ± 2,1 *** -20 -23 -74 -55

All values are presented as mean values of standard errors; * · - statistical significance at p <0.01 and *** - statistical reliability at p <0.001 compared to controls.

It shows that in the control groups of experimental animals, absolute ethanol caused ulcerative lesions with an average overall length of 83.5 ± 7.4 mm and an average number of ulcers of 14.0 ± 2.4 mm.

Treatment of the experimental animals with the bismuth salt of a compound of formula I at all doses resulted in a statistically significant reduction in the mean total length of the lesions (p <0.001). A statistically significant decrease was also found in the other parameter studied - average number of ulcers. The highest suppression of both length and number of ulcers was reported at a dose of 87 mg / kg - 91% and 74%, respectively.

The results of comparative studies of the bismuth salt of a compound of Formula I and H ₂ receptor antagonist Roxatidine, administered at equimolar doses of 115 mg / kg and 62 mg / kg, respectively, showed that it had a significantly greater cytoprotective effect than Roxatidine , the difference in effects being statistically significant (p <0.001). Thus, at a dose of 115 mg / kg of the bismuth salt, the percentage inhibition of the total ulcer length was 83% versus 54% for the preparation Roxatidine administered at an equivalent dose of 62 mg / kg. A similar effect was observed in the percentage of ulcer suppression, with a dose reduction of 115 mg / kg for the bismuth salt of 55 versus 39% for Roxatidine at a dose of 62 mg / kg.

The bismuth salt of the invention may be administered in the form of pharmaceutical compositions such as tablets or capsules for oral administration.

The preparation of the pharmaceutical compositions is accomplished by known methods by mixing the active substance with the appropriate excipients.

The bismuth salt of 30 to 70% is incorporated into a granulate with a matrix structure containing milk sugar of 20 to 60%, wheat starch of 20 to 50%, microcrystalline cellulose of 15 to 60%, highly dispersed colloidal silica of 5 to 15%, and hydroxypropyl methylcellulose (methocel K4M) as a binding agent of 3 to 15% by weight of the total tablet weight. The hydrophobic excipients that are subsequently added to the granulated mass are microcrystalline cellulose 8 to 20%, talc 1 to 6% and magnesium stearate 0.1-3% by weight of the total tablet weight.

The pharmaceutical composition containing the bismuth salt of a compound of formula I can be prepared according to the invention and by simultaneously homogenizing the active substance and said excipients such as milk sugar, wheat starch, highly dispersed colloidal silica, microcrystalline cellulose, talcropyl magnesium magnesium magnesium magnesium acetate methocel K4M / which are moistened with ethanol to a suitable granulation mass. The resulting mixture was then granulated and dried and, after regranulation, encapsulated in hard gelatin capsules.

The bismuth salt of a compound of formula I can be administered orally to humans at doses of 100 to 600 mg / kg, preferably 150 to 300.

Single daily doses may be administered one to four times daily, preferably one to two times.

The advantages of the bismuth salt of a compound of formula I for treating gastric and duodenal ulcers over known histamine H ₂ receptor antagonists are that it has both antisecretory, cytoprotective and antibacterial effects unlike the known H ₂ receptor antagonists, in which the latter two effects are indicated. are very poorly expressed, and that it dissolves very well in water unlike the oxalate salt of a compound of formula I and bismuth citrate, which is almost insoluble, which property of the salt is a great advantage in oral Her application for the treatment of ulcers.

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

The following examples illustrate the invention without limiting it.

Example 1. Preparation of N- (3- (3 - (- πηperidinylmethyl) phenoxy) -propyl) hydroxyacetamide 1,2,3-propenecarboxylate bismuth / 3 ⁺ / complex

3.84 g / 0.012 M / N- (3- (3- (1-piperidinylmethyl) phenoxy) -propyl) hydroxyacetamide free base was suspended in 64 ml of water. The mixture was heated to 90 ° C and 5 g (0.012 M / bismuth citrate) was added thereto. The reaction mixture was boiled under vigorous stirring for 4 to 5 hours. At the end of the reaction, the pH of the mixture was 5.5-6. Cool to room temperature and filter the mixture with unreacted bismuth citrate. The aqueous filtrate was concentrated in vacuo to give a solid residue. The latter was dissolved in 40 ml of methanol and then the solvent was evaporated to dryness in vacuo. The resulting crystalline residue was suspended in 52 ml of absolute ethanol and the suspension was stirred for 20 min. The organic solvent was decanted and the so washed bismuth salt of a compound of formula I was suspended in 50 ml of diethyl ether. After stirring at room temperature for 1 hour, the crystalline bismuth salt was filtered off, washed further with fresh diethyl ether and dried in vacuo at 50-60 ° C.

3.1 g (35%) of the theoretical / bismuth salt of a compound of formula I are obtained in the form of a white crystalline powder.

Elemental analysis in%: C _and H ₃₁ M ₂ 0 ₁₀ VH ₂ 0 Calculated: C 38.18 H 4.56 N 3.87 Bi 29.66 Found: C 37.78 H 4.76 N 4.20 Bi 28 , 40 Water content 2.6%

The bismuth citrate content of the salt is above 98% determined by complexometric titration.

The content of the compound of formula I as the base in the salt is over 98% determined by potentiometric titration.

1 H-NMR (DMSO-d ₆ ): δ = 1.54 (solid m, 6H, 3xCH ₂ of the piperidine ring), 1.82 (m, 2H, C-CH ₂ -C), 2.44 (s , 4H, 2xCH ₂ of citrate), 2.68 (dense m, 4H, N- (CH ₂ ) ₂ of the piperidine ring), 3.24 (m, 2H, CH ₂ NH), 3.72 (s, 2H , Ar-CH ₂ -N), 3.84 and 3.90 (two s, 4H, OCH ₂ -C and COCH ₂ O), 6.68-7.28 (t, 4H, o-C ₆ H ₄ ), 7.70 (broad s, 1H CONH /, 11.80 (broad s, 1H).

EXAMPLE 2 Effect of the Bismuth Seal of a Compound of Formula I on a Model of Ethanol-Induced Gastric Ulcers in Rats.

114 male white Wistar rats with an average body weight of 236 g were used. The test substances are administered 1 hour before the ulcerative action. The test animals were orally treated with aqueous solutions of the bismuth salt or the comparator Roxatidine, and the controls with water under the same experimental conditions.

Animals were previously fasted under free access to water for 38 h. Ethanol-induced lesions are induced by oral administration of absolute ethanol at a dose of 0.3 ml per 100 g body weight. After 1 h the animals were killed by intraperitoneal administration of urethane overdose. The stomachs are then removed, opened over the large curvature and placed in a 5% formaldehyde solution for 20 min and examined macroscopically for destructive mucosal changes. The degree of damage was estimated using the average total length of lesions and the average total number of ulcerative lesions.

Statistical processing of the results obtained

Statistical processing is performed by the method of variational analysis, and the data are presented by means of averages and standard errors.

Example 3. Preparation of tablets Exemplary composition

Bismuth salt of a compound of formula I 0.150g

Lactose 0.030g

Wheat starch 0,022g

Microcrystalline cellulose 0,044g

Highly dispersed colloidal silica 0,010g

Methocel K 4M 0,010g

The ingredients after sieving and homogenization are granulated with 95% ethanol, the resulting mixture is dried and, after regranulation, dusted with the following excipients:

Microcrystalline cellulose 0.015 g

Talc 0.006 g

Magnesium stearate 0.003 g

The tableting is carried out on a rotary tablet machine with a diameter of 10 mm with a mechanical strength of the tablets from 4.5 to 6 kg.

Example 4. Preparation of capsules Bismuth salt of a compound of formula I 0,150 g Milk sugar 0,040 g Wheat starch 0,027 g Microcrystalline cellulose 0,055 g Highly dispersed silicon dioxide 0,010 g Talc 0,005 g Magnesium stearate 0,003 g Methocel K4M 0,010 g Ingredients after sieving and homogeneous-

wetting with 95% ethanol to give a suitable granulation mass. After drying and regranulation, the resulting mixture was encapsulated in hard gelatin capsules No. 1.

Claims (4)

Claims 5 1. N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) hydroxyacetamide 1,2,3-propenecarboxylate bismuth / 3 ⁺ / complex of formula A process for the preparation of the bismuth salt of formula II according to claim 1, characterized in that N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) hydroxyacetamide is reacted with an equimolar amount of bismuth citrate in aqueous medium at a temperature of from 80 to 100 ° C. A method for preparing the bismuth salt according to claim 2, characterized in that the bismuth salt is purified by suspension in organic solvents such as alcohols or ketones, preferably absolute alcohol and subsequent treatment with diethyl ether. A pharmaceutical composition comprising the bismuth salt of a compound of formula I together with organic or inorganic excipients in the form of tablets or capsules.