SA90100090B1 - Ranitidine salts and bismuth complexes with carboxylic acids and their pharmaceutical compositions - Google Patents

Abstract

The invention relates to salts formed between ranitidine and bismuth complexed with a carboxylic acid, and the dissolution products of these salts. Examples of suitable carboxylic acids include citric acid, tartaric acid, and agaricic acid. The salts are useful in the treatment of disorders of the digestive system, especially in cases of gastroduodenal disorders. The salts exhibit antisecretory activity associated with the administration of ranitidine in combination with antibacterial activity against Campylobacter pylori, and also have cytoprotective properties.

Description

Ranitidine salts and bismuth complexes with carboxylic acids and their pharmaceutical compositions Full description Background of the invention: This invention relates to furan derivative salts that have an effect on histamine receptors and a method for preparing them and Adana compounds containing them and using them in therapeutic materials. With bismuth complexes of M carboxylic acids. Ranitidine is the common name N-[2-[[[[5-[(dimethylamino)-methyl]-2-furanylJmethyl]thio]ethyl]-N'-methyl-2- nitro-1,1-ethenediamine Described with its physiologically acceptable salts in the complete description of British Patent Specification No. 1565966 0 191589150 and its claims. In the full description of British Patent No. 1,569955, it refers to physiologically acceptable salts formed using inorganic acids and organic acids. These salts include 1 hydrochlorides, chydrobromides, and sulfates. And the salts formed using mono- and di-carboxlic acids, such as SEE aliphatic mono- and di-carboxlic acids, acetates, cacetates, cmaleates, and fumarates. hydrochloride salt; It is widely used in the treatment of cases characterized by a decrease in stomach acidity. These cases include ten ulcers (BY), duodenal and gastric ulceratin, reflux oesophagetis, and symptoms of Zollinger-Ellison attacks. Ranitidine is also used for prophylactic treatment in surgical procedures and in the treatment of allergic and inflammatory conditions, where histamine acts as a mediator to cause these conditions. Bismuth salts and preparations such as bismuth citrate, chismuth ammonium citrate, csodium bismuthyl tartarate, and bismuth acid solution of bismuth and the acid solution have been used for a long time. For bismuth cacid bismuth sodium tartrate and a concentrated solution of bismuth and a concentrated solution of bismuth described for example in the Pharmacopoeia (solution of bismuth and ammonium citrate and ammonium as antacids) (British Pharmaceutical Codex (1949) ) 144 British In addition to that; and before (dyspepsia digestion sue 5 hyperacidity treatment of excessive acidity 0 2 the advent of antihistamines; these preparations of bismuth were also useful in the treatment of ulcers of the stomach and intestines. sly Evidence that the bacteria Campylobacter mm in recent years; Bizgoft is associated with disorders and inflammation of the stomach wall; indigestion; which is not accompanied by campylobacter pylori presence of ulcers; and lack of secretion of hydrochloric acid. This may be associated with the disease of ulcers of the stomach and duodenum > 0 of bacterial origin. Campylobacter pylori is affected by bismuth compounds such as bismuth subcitrate, bismuth subsalicylate AB (in the form of tripotassium bismuth 068: for example) and is sensitive to bismuth salicylate ctripotassium dicitrato 180016 bismuth subsalicylate There are a number of bismuth compounds referred to above such as acid complexes formed between 0 and tartaric acid 01010 acid bismuth and a carboxylic acid such as citric acid or alkali metal. It has now been found that ammonia ranitidine or their salts with ammonia, tartaric acid, which antagonizes the histamine receptor, will be salts with these complexes; The resulting ranitidine 2 products have a distinct and beneficial side of activity. oy. GENERAL DESCRIPTION OF THE INVENTION The present invention provides new salts formed between ranitidine and bismuth complexed with a carboxylic acid; and the products of the dissolution of these salts. Of the suitable carboxylic acids, we can mention the salts that are able to form a compound with bismuth, and they are the compounds that are able, therefore, to form a salt with opal on a grain.

¢ Carboxylic acids capable of forming complexes, for example, with bismuth to give bismuth-carboxylic acid complexes for use according to the invention OL fa may be carboxylic acids containing at least three functional groups in addition to the carboxyl group available to form salts with ranitidine and from the remaining three functional groups or more than 0; Three of them, for example, are carboxyl and/or hydroxy groups capable of forming complexes with trivalent bismuth to give trivalent bismuth complex: eal, and where the carboxylic acid appears optical isomerism: and Geometric isomerism / or geometric isomerism, the invention is intended to include all optical isomers including racemates and / or geometric isomers. The decomposition products comprising hydrates comprising Lad are within the scope of the invention. Examples of suitable carboxylic acids capable of forming complexes with bismuth for use are: According to the invention; Citric, tartaric, and ethylenediaminetetraacetic acids can be mentioned. Other examples of suitable carboxylic acids 20109 10 are propyleitric and agaricic acids 0.6. Tartaric acid 560 is preferred, especially ; citric acid. 4d agaricic acid is another acid that may be used according to the invention. a | the special salts according to the invention; Can be stated: N-[2-[[[5-[(dimethylamino)-methyl] -2-furanylJmethyl]thio]ethyl]-N'-methyl-2- nitro-1,1-ethenediamine 2-hydroxy -1,2,3-propanetricarboxylate bismuth (3%) Y. * complex, also known as ¢ranitidine bismuth citrate N-[2-[[[5-[(dimethylamino)-methyl) ] -2-furanyl]methyl]thio]ethyl]-N'-nitro-1,1- ethenediamine [(R-R*R¥)]-2,3-dihydroxybutanedioate bismuth (3%) complex, Yo known as ranitidine bismuth tartrate 11

° N-[2-[[[5-[(dimethylamino)-methyl]-2-furanylJmethyl]thio]ethyl]-N'-methyl-2- nitro-1,1-ethenediamine 2-hydroxy-1 ,2,3-nonadecane tricarboxylate bismuth (3+) complex, | Also known as 'ranitidine bismuth agaricicate' and six N-[2-[[[[5-[(dimethylamino)-methyl]-2-furanylJmethyl]thio]ethyl]-N'-methyl-2- ° nitro-1,1-ethenediamine N,N'-ethanediylbis[N-(carboxymethyl)-glycine]bismuth complex, (3%) also known as ranitidine bismuth-EDTA. The preferred salts according to the invention may be mentioned: N-[2-[[[5-[(dimethylamino)-methyl]-2-furanylJmethyl]thio]ethyl]-N'-methyl-2- 1 nitro-1, 1-ethenediamine 2-hydroxy-1,2,3-propanetricarboxylate bismuth (3+) complex; and N-[2-[[[5-[(dimethylamino)-methyl]-2-furanylJmethyl]thio] ethyl]-N'-nitro-1,1- ethenediamine [(R-R*R*)]-2,3-dihydroxybutanedioate bismuth (3+) complex. vo A preferred salt AT according to the invention is: N-[2-[[[5-[(dimethylamino)-methyl]-2-furanylJmethyl]thio]ethyl]-N'-methyl-2- : npitro-1,1-ethenediamine 2-hydroxy-1 2,3-nonadecane tricarboxylate bismuth (3%) * complex. | Bismuth ranitidine citrate represents a particularly preferred compound according to the invention. Ye: The salts, according to the invention, have a set of distinctive properties, A ald, for the treatment of stomach and intestinal disorders. Especially the disease of stomach ulcers and cases of ulcers of the stomach and duodenum, for example, inflammation of the stomach wall and indigestion for reasons other than ulcers. The salts according to the invention have antisecretory and antihistamine properties associated with ranitidine with antibacterial activity against bacteria of the genus and species Campylobacter. In addition. The salts of invention Ye have cytoprotective properties - they also show activity against pepsins 60 in the human stomach; With inhibition of the pepsin 1 enzyme, the pepsin isozyme associated with gastric ulcers.

. He portrayed the activity of the compounds according to the invention, the antisecretory activity, in experiments on living organisms to test the secretion of stomach acids induced by histamine in the Heidenhein pouch dog. Dyspepsia in humans by testing on 0 organisms. In addition, he portrayed the anti-activity of microorganisms similar to Campylobacter bacteria by conducting tests in experimental animals of the genus ferrets - he depicted the protective activity of cells in experimental animals by studying the ability of salts to hinder the decomposition of stomach tissue in rats induced by Cds Road | Another aspect of the salts according to the invention is that they are ALE water soluble and give stable 0 aqueous solutions. Under normal conditions, many of the salts of bismuth and its compounds, including the salts formed by using carboxylic acids of the kind used in the formation of the salts of the invention, are insoluble in water. bismuth citrate; e.g. a solubility rate (in neutral water) of 750.7 on a weight-to-volume basis (w/v); While ranitidine bismuth citrate is soluble in water to an extent greater than 759 0 (w/v). Vo and so forth the observed properties of the salts according to the invention; Such ranitidine-bismuth citrate emphasizes the fact that they are distinct chemical entities that can be clearly distinguished from simple mixtures (eg, mixtures of equimolecular proportions) of ranitidine and a complex formed between bismuth and a-carboxylic acid. Some salts according to the invention may also be distinguished from simple mixtures of ranitidine and a complex of bismuth and a carboxylic acid on the basis of infra-red spectroscopy. . The infrared spectrum of a simple natural mixture of ranitidine bismuth citrate is characterized by; Dla with major peaks at Lyon 171 aa 1:7 AAA values that dominate the infrared spectrum and disappear in the spectrum of ranitidine bismuth citrate. 7 Yo The salts according to the invention may be prepared by reacting ranitidine with a suitable bismuth-carboxylic acid complex (eg, bismuth citrate or bismuth-ammonium citrate); in a suitable solvent such as water; And separate the salt formed in this way from the solution. z

other clad ida; The invention provides a salt formed between ranitidine and a complex of bismuth with a carboxylic acid; containing the products of the dissolution of these salts.” The aforementioned salt is prepared by reacting ranitidine with a complex of carboxylic acid and bismuth. According to ald AT, the invention contains ranitidine-bismuth citrate salt Dida has two products: 0 its dissolution when prepared by reacting ranitidine with a complex of bismuth with citric acid. The reaction between ranitidine and a suitable bismuth-carboxylic acid complex to give a salt according to the invention is preferably carried out at an elevated temperature; For example; at a temperature in the range from ∼ to 100°C. Once the reaction is complete (when the mixture has reached 3 pH neutrality and/or dissolution), the suspension or solution is cooled and filtered; The required ranitidine salt may be obtained from the filtrate by evaporation, followed by extraction and grinding of the resulting stagnant substance using an alcohol such as methanol or ethanol1 clarified; and a ketone such as acetone or ether cether e.g. “Jal: Diethyl ether” Alternatively, the reaction mixture may be evaporated directly followed by extraction and grinding of the resulting sludge. Alternative processes also for separation of the desired salt include the vo filtrate drying process hl or adding the filtrate (optionally after dilution with water) to a suitable counter solvent (eg an alcohol such as ethanol) at such a high temperature (eg the reflux of Li of the counter solvent) that the product precipitates. ... | - z >01 Intermediate bismuth-carboxylic acid complexes may usually be prepared by the processes described in the 1944 (1949) British Pharmaceutical Codex (British Pharmaceutical Codex) Thus a suspension of a suitable bismuth salt (Sa) may be heated methylation of bismuth oxynitrate and a suitable carboxylic acid (Ole (citric or tartaric acid)) in a solvent such as water at 98 to 0C io and the completion of the reaction is judged when one drop of the mixture is added to an ammonia solution in dilute water; to result in a clear solution. then the suspension is optionally diluted with water; The desired bismuth-carboxylic acid complex may be recovered by filtration. Bismuth citrate vo and ammonium may be prepared immediately as desired by treating the bismuth citrate with an appropriate amount of ammonia solution in water. z n ms

A

The salts may be synthesized according to the invention for use on any occasion; The invention includes in its scope human or pharmaceutical compositions containing salt according to the invention prepared for use in human medicine (oral). These compositions intended to be used primarily for veterinary oral administration may be approved pharmaceutically excipients or carriers are traditionally formulated using carriers of the preferred type for the composition. tablets © for oral administration; Pharmaceutical compositions may take the form of tablets, for example (which may include capsules, chewable capsules, or chewable capsules (Ka may be sucked on tablets) with Jota factors. These compositions are prepared by conventional method with acceptable excipients Pharmaceutical or “pregelatinised maize starch” (for example; pregelatinized starch 33 binding agents) or hydroxypropyl methyl cellulose epolyvinylpyrrolidone polyvinylpyrrolidone 1. or clactose cellulose (such as milk sugar fillers fillers (hydroxypropyl-methylcellulose or calcium hydrogen phosphate 0010005581106 cellulose microcrystalline . Moisengml stearate Ola) 150160158 or lubricants (calcium hydrogen phosphate (eg disintegrants or disintegrants ¢) silica or talc or talc cmagnesium stearate or “sodium strach glycollate” or “potato starch” sodium lauryl sulphate by pS (examples Wetting agents Jb factor the tablets by well-known methods in this profession.Liquid preparations for administration may take an aid, for example, or an oral suspension or solution may be presented in the form of appropriate solutions or syrups before use. This vehicle may be prepared as a dry product to form with water or as an excipient Bia suspension agents Liquid formulations by conventional method with pharmaceutically acceptable additives© or cellulose derivatives; food fats, esorbitol (for example; sorbitol suspending agents or dlecithin (for example, lecithin, emulsifying agents, hydrogenated Jal se); or oil esters; alcohol, almond oil and excipients Anhydrous (eg; almond oil (acacia - or ethyl methyl-propyl-bar; fractionated vegetable oils) and preservatives (eg methyl sorbic acid or propyl-p-hydroxybenzoates) Yo «flavoring and flavoring materials cbuffer salts The preparations also contain buffer salts: whenever appropriate. Of the salts of the invention that are taken internally by humans from 1 mg of the active ingredient per dose SS REDS to 800 mg; especially 100 g; preferably 1 once to four times a day; preferably once Sle unit. The unit dose is administered;

Ea one to two times. The exact dose depends on the nature and severity of the condition being treated; It will also be necessary to make routine variations in dose based on the age and weight of the patient. Thin-layer chromatography was performed on silica 0 with a flush wash by a mixture of dichloromethane: ethanol: cthin layer chromatography ammonia: 1.88 ammonia at a ratio of 8:70: (System A); or a mixture of ethyl acetate: isopropanol: 88 iodoplatinate (ULV light (System B); UV Yi) 0:70 water at a ratio of detection unless otherwise specified potassium permanganate and potassium permanganate ©0016 Contradictory. 1 Preparation 2-Hydroxy-1,2.3-propanetricarboxylic acid. bismuth (3%) complex (1:1) ("Bismuth citrate) x g) and acid YY,47) bismuth oxynitrate Heat a mixture of bismuth oxynitrate

EE Tr on a steam bath with continuous stirring for (Ja Ar) g) in citric water (TY) ia, and then a drop of the suspension was added to a dilute ammonia solution in water to give a clear solution. The mixture with water; nominated; The separated material was washed well with water until it was free of nitrates and excess citric acid. The stagnant material was dried under vacuum to give the compound entitled gm).

OY (Bi (YALA © 1.74 H VA, AC) Analysis found: rh (Bi tYA,£€ 7t 0 T (H ¢VA, +) C requires C¢H;BiO; . 0.11H,0 mol. 6,11 = Water analysis showed the presence of 70,49 11.0

Preparation [R-(R*R*)1-2,3-Dihydroxybutanedioic acid, bismuth ( 3%) complex, (2:1) ("Bismuth - tartrate") 1AH

Ye g) in water (ATTY g) and bismuth oxynitrate (YY) a mixture of (+)- tartaric is heated for a minute; A small part of Te was then dissolved, stirring occasionally, for a period of ome (Ayia) ml) at 5) the product completely in a dilute ammonia-water solution. The mixture was cooled to room temperature and then filtered;

Tie The filtrate was washed well with water until it became free of dissolved substances in the water. The stagnant material was dried (g. VEYA) #CV in a vacuum atmosphere to give the compound entitled 1-00 mMkL 0 VAY CH YA EEC Existing analysis: Apple BI all 6,4 Wu for brother OAV 6 my hatchet CsHyBiO,, . 0.43H,0 mol. EY = 11:0 11,94 Water analysis indicated the presence of the preparation?: 2-Hydroxy-1,2,3-nonadecanetricarboxylic acid, bismuth (3%) complex, (1: 1) 1 ("Bismuth agaricicate") ((-)-2-hydroxy-1 ,2,3-nonadecanetricarboxylic acid Heat the mixture of a = g) and bismuth oxynitrate (5.74 g) in water (50 ml) at 9.16 cli for £ hours. The acidic mixture was filtered and the stagnant material was washed well with water until it became dys, then dried to give (Ja 00 XY) the filtrate was neutral. The stagnant substance was washed well with hot methanol The compound entitled (17,785 g). ,007.0.11H,0 : 6 Bi Y.mol. 1,11 = 11.0 760.71 Water analysis revealed the presence of 4 of the preparation N.N'-1 2-Fthanediylbis[N-(carboxymethyl)glycinelbismuth (3) *) complex (1:1) ("Bismuth-EDTA"). g) in water (VY,0V) NIN'-1 ,2-ethanediylbis[N-(carboxymethyl)glycine] (EDTA) Yo for 2 hours. nominate the hot commentator; The separated material was reheated in ml (edo) at 001: : all solids melted. At (Ja (da Vex) 4-49 °C) using water again at 0 at

11 During each extraction process, the suspension was filtered and the acidic flakes were vigorously evaporated in an airless atmosphere, to a volume of approximately 1 ml. The mixture resulting from the extractions was cooled to 80%, filtered using nitric acid as the precipitated solid, and washed until it became free of nitric acid with cold water, then with ethanol and ether, and dried to give the titled compound (18.57 g). (Bi Farha «0 0,8) (N ¢Y,84 ¢H YY,YY 0) E Analysis found: 61

Bi YLA number and (NY, YA) Each YA 0 smelt requires 00.50

JE

H,0 = 1.5 71,814 molecule. The analysis of the water showed the presence of 1 then 0

N-[2-[[[5-[(Dimethylamino)-methyl |-2-furanyllmethyl]thiolethyl]-N'-methyl-2- nitro-1,1-ethenediamine 2-hydroxy-1.2.3-propanetricarboxylate bismuth ( 37) complex (1:1:1) ("Ranitidine bismuth citrate")

N-[2- [[[5-[(dimethylamino)-methyl]-2-furanyl]methyl]thio] ethyl]-N'-methyl-2- Vo nitro-1,1-ethenediamine 0 dl g) in water (10 ml) at 9-049°C until the suspension became neutral (VOY cml (min). The mixture was cooled to temperature Yo (about pH z to pH detection paper). The filtrate was evaporated to dryness, 0 room temperature; the unreacted bismuth citrate (0.1517 g) was filtered to give a hardening resin. Methanol (00 ml) was added to the vacuumed In vacuo (sal in 0 ml) and cooled. filtered Vr) the resin; The mixture was evaporated to give a residue which was heated with methanol and the suspension was filtered. (Ja 0) the cloudy floating liquid and the separated material was ground into powder with methanol. The filter material was washed with methanol and dried to give the titled compound (1.58 g). The mobility value was After purification by thin-layer chromatography +, TO = for ranitidine (RE) reference product for bismuth citrate = zero after (RE) (flush wash system A); Type of thin layers and use of flush wash (System A).

B. Existing analysis: 0 HY to make each without a net to another. YY 1 C1oH7BiN,O,S, 0.1 CgHsBiO;, 0.16 C,H;0H, 0.48H,0 And based on §5.0V Bi 771.1, water analysis revealed the presence of 71.056 1120 - EA molecules. The nuclear magnetic resonance revealed the presence of VT as an ethanol molecule. : -0071-2-“for [line] and [T] Al-Jassaa and [Al-Jissah 2-507] [Abjata-0 (M. states A BG 01-5] 11-12-11 ‎nitro-1,1-ethenediamine 2-hydroxy-1,2.3 -propanetricarboxylate bismuth (3%) 1 complex (1:1:1) ("Ranitidine bismuth citrate") was added to a mixture of bismuth citrate (7.94 g) with water (do 10 ammonia solution in water Its concentration is 1.878 in an amount sufficient to dissolve the solid. The solution is filtered through a “Hyflo” filter and the filtrate and combined liquid washing products are evaporated in a vacuum atmosphere. The solution is re-evaporated with water until the vapor no longer ve The float on top of the stagnant is alkaline when detected by CAS pH paper (VEY pH) (use water for washing in 7075 ml portions). ranitidine (TE) g); and evaporate the solution to dryness in a vacuum atmosphere The stagnant dissolved in water was re-evaporated with water until no more detectable alkaline vapor (AX ml) dried © material residual via rotary evaporator 120187 under vacuum at Loaded Ar and the powdered residue was removed with the help of ether. The residue was ground to a fine powder, suspended in ether, and filtered. The resulting product was dried to give the compound labeled TAYE (g). The reference mobility of the ranitidine product was = 1.7 using thin layer chromatography and using system (A) flush wash; And the value of reference movement of bismuth citrate product = zero. (DMSO-dg) 2.57 (2H,d, 1/2 AB OF CH,CO), 2.8-2.9 (m, CH; NH, Yo) HONEY - CH,CH,S and 1/2 AB OF CH ,CO), 2.87 (s, (CH;),N"), 3.47(2H,t, CH,CH,NH), furan = CH's). bc + 3.86(2H,s, CH,S ), 4.35(2H,s,CH,N"), 6.10 and 6.67(2H,d) E711

l Infrared Spectrum LT. (Togol (((-OH) 404 (Nujol Nt 5 701 Mtt f 08 « Laglo -CO,-) 1761 + -1111(and 01110-)11110- ) “am Found Analysis: 0 Intel TMCPICKL AY and Ly 77 Ks YA (Bi 0H 0.34H,0 05.21:10 BLATTERY Requires YY, Yo (C tel ¢Y,AA) Cal bagra 0 0 “S ¢YY, 76.87 779.1 (Bi) Water analysis revealed the presence of 11.0 10.88 = 1.74 mole. Example? N-[2-[[] 5-[(Dimethylamino)-methyl]-2-furanyljmethyl]thio]ethyl]-N'-methyl-2- Ve nitro-1,1-ethenediamine 2-hydroxy-1.2.3-propanetricarboxylate bismuth (3%) complex (1:1:1) ("Ranitidine bismuth citrate") Heat a mixture of ranitidine (0.4 lb) and bismuth citrate (5050 g) in water (Qe Vo) at 5 45-4* C for yy min. Filter the hazy solution; dilute with water (Yo ml) then add during yy min 6 with stirring to synthetic methyl alcohol (7.4 L); heat under condensation rad.: Heat the resulting suspension for 11 min; then cooled to ambient temperature. The compound titled TT (g) was prepared by cad A and washed with industrial alcohol (700<79 ml) © and dried in a vacuum at 50 C. The reference mobility of the ranitidine product was C= 4 using thin layer chromatography with flush wash by system (b); WCATH© - Reference Mobility of bismuth citrate product = 0 and detected by UV and iodine. Example ; Z N-[2-[[[5-[( Dimethylamino)-methyl]-2-furanyllmethyl]thiolethyl]-N'-methyl-2- nitro-1,1-ethenediamine 2-hydroxy-1,2.3 -propanetricarboxylate bismuth (3%) complex (1:1:1) ("Ranitidine bismuth citrate") Yo ranitidine (£50 g) was added to a suspension of bismuth citrate (p00) in 0.1 mol grams of aqueous ammonia solution (07 ml); and water (97 ml). He heated the suspension when he died

minutes; then the resulting hazy solution was filtered and diluted with water (01 ml); the compound titled YoY (g) was separated by spray-drying the resulting solution (£0 ml of total volume = 146 ml). The value of the reference movement id of ranitidine by chromatography (type of layers: |thin) and using system (B) as a flush wash = 0.44 and the value of the reference movement of the product of m-bismuth citrate = yellow and the detection of the labeled compound by ultraviolet radiation and iodine.Example ° N-[2-[[[5-[(dimethylamino)-methyl] -2-furanyllmethyl]thio]ethyl}-N'-methyl-2- nitro-1,1 ethenediamine 1 R -R*R *)] 2 3-dihydroxybutanedioate bismuth (3+) complex (1:1:1) ("Ranitidine bismuth tartrate") 1 ranitidine (Y) 0.0 g) was added to a slurry of bismuth tartrate ( 7.07 g) in water (Vo) ml); the mixture was warmed gently with stirring to form a solution. The solution was filtered through a Hi-Flu filtration media; the filtrate and the combined liquid wash products were evaporated in a vacuum atmosphere to give a thick resinous substance. The solid material swells with increasing evaporation The product was re-evaporated with methanol (Je4%Y) » The gummy residue was extracted with hot methanol (00 ml YX) The semi-solid residue 1 was pulverized with methanol (+ ¥ ml) until It forms a fine suspension that has a creamy color, which is then filtered out. The residue was dissolved into a fine suspension by trituration with methanol (Yo (mL); then nominated; The material was washed. stagnant with methylcellulose and then with ether” and dried to give the entitled compound. The value of the reference movement of the ranitidine product by chromatography (thin layer type) and washing it with a jet of the system ( ) - 8 and the value of the reference movement of the bismuth citrate product = zero. a Infrared spectrum - maximum Nojoule values 0000-01+7” (RBI) (complex group of bands; 000-1750 ((-OH- + -NH-) (band group. au (-NHC)) =CHNO,)NH-) 1777 ((-NHC(=CHNONH- + -CO,- + -CO,H) Abstract Analysis: | © (H YAY) CgHyBiO;,.0.15 CH;0H 0.33 two systems C,3H,,N,40;S.Yo requires Nick NEY, EY GH YAYY 1.10 0 YE,90 in JYAY The nuclear magnetic resonance spectrum indicated the presence of 116 momol gram methanol Example > z \Yo

Ye

N-[2-[[[5-[(dimethylamino)-methyl]-2-furanyl]methyl]thio]ethyl]-N'-methyl-2- nitro-1,1-ethenediamine 2-hydroxy-1.2.3 nonadecane tricarboxylate bismuth (3+) complex (1:1:1) ("Ranitidine bismuth agaricicate") and water; 7 g); ranitidine (7,797 g) in water (01 ml) at 40-450"C for 2 hours. The solution was diluted with 10 (de) water and heated for one hour. Heated and evaporated the filtrate to dryness with the help of ethanol.The resinous residue was evaporated again from ethanol (Je Vo XY) to give a resin.This substance was dissolved in ethanol (©ml); and the solution was filtered through a Hi-Flu filter media. A Leachate and liquid washing products in a vacuum atmosphere to give a resin, mixed with hot acetone (Ja 701), and after heating the mixture for 10 minutes, the floating liquid was filtered. +0 (Ja) to give a fine suspension. The suspension was filtered and the remaining material was washed well with acetone and dried to give the titled compound (£.19 g) as a yellow-orange solid. ve Abstract analysis: © 7 p every 1.00 N Carve and Lad Gy CX, C35HsoN;0;0SBi.0.05C,,Hy007.0.5130 EE Ao requires each NET (NET) spray and AVAT 177 A. Water analysis showed the presence of 71.04 water = 1.8 mol. The value of the reference movement of the ranitidine product by chromatography (thin-layer type) was 0 © and using system (a) as a flush wash solution = 1.75 and the value of the reference movement of the bismuth agarisicate / agaricic acid mixture = zero and when using a solution Washing GHA (chloroform: methanol: acetic acid: water at a ratio of 1:1:9:19) in chromatography had reference mobility of the ranitidine product = 0.1; UV detection; iodoplatinate and potassium permanganate; bromocresol green reagent; vo coefficient of in situ movement = 1:7 (agarisic acid); Detection: Bromocresol green dye as No. D11

‎N-[2-[[[5-[(dimethylamino)-methyl]-2 -furanyl]methyl]thio]ethyl]-N'-methyl-2- ‎nitro-1.1-ethenediamine N.N'-ethanediylbis [N-(carboxymethyl)-glycine]bismuth ‎complex (1:1:1) ("Ranitidine bismuth- EDTA"): 0 | (*3) added to a mixture of bismuth-EDTA (?94,?g) and ranitidine (7.7 g); sla (10 ml); The mixture was heated to complete dissolution. Filter a small amount of the precipitate formed through a Hi-Flow filter media. evaporate the solution to dryness in a vacuum; The remaining material was evaporated again with 15<7 (ml) methanol. Cad residue in hot methanol (Yr (mL)); The solution was filtered through a Hi-Flow filtration medium. The filtrate was evaporated to dryness to give a semi-solid substance that was dissolved in methanol (01 ml). The cooling caused an oil to precipitate; and after being left still for Te an hour; Substance formed

0 is a white solid. This material was filtered and the stagnant material was washed with methanol. The solid was resuspended

ethanol” and filtered; The remaining material was washed with methanol. The solid was resuspended in ethanol

nominated; The residue was washed with ethanol and then with ether and dried to give the titled compound (0 743 g). The value of the reference mobility of the ranitidine product using chromatography (thin layer type) using system (1) as a flush wash solution = To

vo is the reference kinetic factor of the bismuth-EDTA product = zero.

Abstract analysis: © Amkl 5,60 (N lobe of lazo YE CoH; BiN, 05 H,0 | Bi analysis of the water revealed the presence of 4 17.7 0.1 = H,0 molecules.

7 Examples (a) to (d) that follow depict pharmaceutical compositions according to the invention in which the active ingredient is specifically ranitidine-bismuth citrate. Other compounds of the invention may be synthesized in a similar manner. like () . tablets

Tablets can be prepared by the usual methods, fie compression method or wet granulation: : Yo The tablets may be covered with a thin layer of suitable materials; As hydroxypropyl methyl ola using standard technical methods. First (direct compression) mg/tablet

L Active Ingredient 0 mg milk sugar (lactose) | 8 mg microcrystalline cellulose © : 06 mg cross-linked polyvinylpyrrolidone YA mg © 7 0 mg magnesium stearate mcbw 0 mg The active ingredient, microcrystalline cellulose, is sifted; , milk sugar (lactose) and cross-linked polyvinylpyrrolidone through a micron sieve and blended in a suitable mixer. The magnesium stearate is filtered through a micron sieve; And synthesize with the energetic blend. Press the tofu into 0 discs using a suitable rotary punch. WG (wet granulation) mg/tablet Active ingredient 0 mg galactose (lactose) mg active pregelatinized Vs mg ve cross-linked polydid pyrrolidone A mg magnesium stearate a mg oo Al Makbous | 0 mg to make up the ingredient (capil) and milk sugar (lactose); The activity is pre-gelled together and granulated using water. The dewy (wet) mass is dried and ground. Magnesium stearate and cross-linked polyvinyl 0 pyrrolidone are sieved through a YOu micron sieve and combined with the granule. The resulting mixture was pressed using a suitable rotary auger for tablets. Example (b). Suckable/Chewable Tablets mg/tablet A (first) Active ingredient 0 mg ve Polyvinylpyrrolidone YA mg Sweetener/Flavor Sufficient quantity Magnesium stearate V mg: E11

Ya

05 mg mannitol to 00 mg compressed weight The active ingredient, the sweetener / repellent for taste, aroma and mannitol are synthesized together and granulated using a solution of polyvinylpyrrolidone. the wet mass is dried; and grind; and lubricated with micron stearates) press the resulting granule into tablets using a drill YOu = magnesium (granular size © and a rotor for the tablets. mg / pinch 0 mg 0 0 (Secondly) the active ingredient is mg 001 Hydroxypropyl methylcellulose : Magnesium stearate No mg ye Flavoring and aroma Adequate quantity Vor . xylitol mg to 00 mg Pressed weight Synthesize the active ingredient; xylitol; flavoring (Taste and odor) were prepared and granulated all using a solution of hydroxypropyl methyl cellulose in aqueous ethanol, dried, ground (1 micron) and pressed into tablets using 50 and lubricated with magnesium stearate (granular size, appropriate drill and rotary. Example (2) capsules μ mg / capsule } 0 mg (I) ACTIVE INGREDIENT © pregelatinized starch © mg magnesium stearate © mg mg 0 filled weight μm; They are rolled together and greased 50. Sift the active ingredient and the pre-gelatinized starch through a sieve (micron). The mixture is filled in hard gelatin capsules 750 mg of magnesium stearate (granular size Yo of a suitable size. D mg / capsule per

(II) ACTIVE INGREDIENT 00 mg milk sugar (lactose). VO mg polyvinylpyrrolidone Y 0 mg cross-linked polyvinylpyrrolidone 0 mg magnesium stearate © mg filled weight O00 mg The active ingredient and galactose (lactose) are synthesized together and a hydrated AES is formed from them using a solution of polyvinyl pyrrolidone. The mass was dried, ground and synthesized using cross-linked polyvinylpyrrolidone and magnesium stearate (particle size 750 micron). Fill the resulting mixture into 0 hard gelatin capsules of suitable size. Example (D) Syrup for intake by Al mg/capsule Z Active ingredient 0 mg Hydroxypropyl methylcellulose: £0 mg Ve Propyl hydroxybenzoate 8 mg Butyl Hydroxybenzoate 8 0 mg saccharine sodium 0 mg sorbitol solution ml: suitable buffer solutions sufficient amount Ye flavors and aroma suitable sufficient quantity purified water to 0 ml hydroxypropyl methyl cellulose dispersion in a portion of heated purified water with hydroxybenzoate and allow the solution to cool to room temperature. sodium saccharin is added; flavors, aroma and sorbitol solution to the bulk solution as a whole. The active ingredient is dissolved in part of the remaining water and added to the Jana solution. Suitable buffer solutions may be added to adjust the pH in the maximum stability zone. The solution is supplemented to the required volume, filtered and filled into suitable containers.

Claims (1)

And 7 protective elements 1-1 is a salt formed between ranitidine 6 and the bismuth complex with Y-carboxylic acid or a dissolved form of this salt. 0 ?- salt according to claim 1, where the aforementioned carboxylic acid contains 0 at least three functional groups in the molecule in addition to the existing carboxyl group to form v ranitidine salt = F salt According to claim 1, where the aforementioned carboxylic acid is selected from the group Y, which consists of “citric acid” and “tartaric acid v” cethylenediaminetetraacetic acid propyleitric acid and .agaricic acid 1 ?- salt according to claim 1 where the aforementioned carboxylic acid is selected from Group Y (All consist of citric acid ccitric acid and tartaric acid 01 #- A compound selected from the group consisting of the formula N-[2-[[[[5-[(dimethylamino)-methyl]-2-furanylJmethyl]thio]ethyl] -N'-methyl-2- Y nitro-1,1-ethenediamine 2-hydroxy-1,2,3-propanetricarboxylate bismuth v0: (trivalent) and their solutes. From the group consisting of the formula N-[2-[[[5-[(dimethylamino)-methyl]-2-furanylJmethyl]thio]ethyl]-N'-methyl-2- Y nitro-1,1- ethenediamine [(R-R*R*)]-2,3-dihydroxybutanedioate bismuth v (trivalent) and its solutes. A-17 1 Pharmaceutical compound for the treatment of serious gastrointestinal disorders An effective amount of 7 for the treatment of the aforementioned disorders consists of a salt composed of ranitidine and bismuth v complex with carboxylic acid or dissolved solvate ¢ of this salt with at least one pharmaceutically acceptable carrier or diluent. =A 1 Pharmaceutical compound according to claim element A, where carboxylic acid Y is selected from the group consisting of citric acid and tartaric acid ¥ 7 M1 4- Pharmaceutical compound according to claim 7; In a blended formulation for oral use. Nua-1-01 for the treatment of gastrointestinal disorders includes x effective amount for the treatment of the mentioned disorders from the combination N-[2- 15 -[(dimethylamino)-methyl] -2-furanylmethyl] thiolethyl]-N'-methyl-2- v nitro-1,1-ethenediamine 2-hydroxy-1,2,3-propanetricarboxylate bismuth ¢° (trivalent) and their solutes with carrier Jala or one diluent Pharmaceutical acceptable at least 1. 1-11 pharmaceutical compound according to claim 10; in a dosage form containing 1001 milligram to 1 gram of the compound mentioned in the dose 1-1 ball Pharmaceutical Wy of claim 10; in a dosage form containing 001 mg to Ave Y mg of said compound in one dose. SIV 1 pharmaceutical compound according to claim dO) dosage form containing 101 Milligrams to Too Y milligrams of said compound per dose. -16-1 Pharmaceutical compound according to claim 101 in a blended formulation for oral use. -100© 1 Napa compound according to claim VE in tablet form. -11-1 A salt formed between ranitidine and a bismuth complex with 00 “carboxylic acid” or a dissolved of this salt; provided that the said salt is ©: oT | Preparation of Ranitidine Jel ranitidine and bismuth carboxylic acid composition .bismuth carboxylic acid complex ¢ oo -17 1 Ranitidine bismuth citrate or solutes “ld” when prepared * Y by the reaction of ranitidine with complex bismuth with citric acid 'ye