WO1995012579A1

WO1995012579A1 - Bismuth salt of carbostyril derivatives for the treatment of peptic ulcers

Info

Publication number: WO1995012579A1
Application number: PCT/JP1994/001805
Authority: WO
Inventors: Makoto Komatsu; Minoru Uchida; Takao Nishi
Original assignee: Otsuka Pharmaceutical Company, Limited
Priority date: 1993-11-05
Filing date: 1994-10-27
Publication date: 1995-05-11
Also published as: AU8003194A

Abstract

Bismuth salt of carbostyril derivatives of formula (I) wherein R is a halogen atom, the propionic acid substituent is substituted at 3- or 4-position on the carbostyril nucleus, and the bond between 3- and 4-positions is single or double bond, which is useful for the prevention and treatment of peptic ulcer and peptic inflammatory diseases.

Description

DESCRIPTION

BISMUTH SALT OF CARBOSTYRIL DERIVATIVES FOR THE TREATMENT OF PEPTIC ULCERS

Technical Field

This invention relates to a novel bismuth salt of carbostyril derivatives useful as a medicament. More particularly, it relates to a bismuth salt of carbostyril derivatives of the formula:

wherein R is a halogen atom, and the propionic acid substituent is substituted at 3- or 4-position on the carbostyril nucleus, and the bond between 3- and 4-positions is single or double bond, preferably a bismuth salt of 2-(4-ch'lOrobenzoylamino)-3- (2-quinolon-4-yl)propionic acid.

Background Art

The carbostyril derivatives of the formula (I) and processes for the preparation thereof are disclosed in Japanese Patent Second Publication (Kokoku) No. 35623/1988. It is disclosed that the carbostyril derivatives are useful as an anti-ulcer drug (Japanese Patent Second Publication (Kokoku) No. 61923/1990). It is also known that these carbostyril derivatives are useful as an agent for the treatment of gastritis (Japanese Patent First Publication (Kokai) No. 74329/1991) and further as an anti-diabetic (WO 92/21342 and Japanese Patent First Publication (Kokai) No. 148143/1993), as an agent for increasing somatostatin or for inhibiting decrease of somatostatin (WO 93/23043), and as an agent for protecting intestinal mucous membrane disorder or for treating ulcerative colitis (Japanese Patent First Publication (Kokai) No. 211662/1994) .

It has recently been found that a Gram-negative bacteria, Helicobacter pylori participates significantly in induction of various diseases such as chronic gastritis, stomach ulcer, duodenal ulcer, etc. [cf. Masaaki TOMOI, Pharmacia, Vol. 29, No. 8 (1993), pp. 873-876]. For example, in patients suffering from an active chronic gastritis, Helicobacter pylori has been detected in such a high ratio as 88 % in average, and it has been found that the number of cells of Helicobacter pylori is correlative with the degree of the symptom of chronic gastritis accompanied with increase of neutrophil and permeation of lymphocytes (which are index for the activity of the gastritis). It is also disclosed in the above literature that in case of patients suffering from duodenal ulcer, the infectious ratio of Helicobacter pylori is in such a high ratio as 85 % in average, and hence, this bacteria participates significantly in said disease. It is also known that when these patients stop to take a drug, the diseases will again appear. When an antibacterial agent is administered to the patients, the recurrence of the diseases is significantly decreased. Accordingly, it will be considered that Helicobacter pylori participates in the recurrence of gastritis, duodenal ulcer, etc.

It is known that the infection of Helicobacter pylori can be remedied by administering the patients a bismuth salt (e.g. colloidal bismuth subcitrate or bismuth subsalicylate) or an antibacterial agent (e.g. amoxicillin, tetracycline, etc.) alone, or a combination of a bismuth salt, an antibacterial agent and an antiprozoal (e.g. metronidazole) . (Journal of Antimicrobial Chemotherapy (1986) Vol. 17, pp. 309- 314). It is also known that bismuth or some bismuth salts are useful for the treatment of gastrointestinal disorders (EP-A₂- 0206626, EP-E₂-026627, Japanese Patent First Publication

(Kokai) No. 48624/1987).

Summary of the Invention

The present inventors have studied to develop a new drug having a specifically high inhibitory activity against Helicobacter pylori with less side effects and have found that the novel bismuth salt of carbostyril derivatives of the formula (I), particularly 2-(4-chlorobenzoylamino)-3-(2- guinolon-4-yl)propionic acid bismuth salt, show superior antibacterial activity against Helicobacter pylori and are useful as a drug for the treatment of peptic ulcers (e.g. gastric ulcer, duodenal ulcer, etc.) and for the treatment of peptic inflammation diseases (e.g. gastritis) and further that the compounds of this invention show excellent preventive or therapeutic effects on chronic ulcer models such as experimental ulcer induced by acetic acid or thermal ulcer, or on various other experimental ulcer models and also therapeutic effects on gastric inflammation with less toxicity and less side effects and hence are useful as an agent for the prevention or treatment of chronic ulcers. Thus, an object of the invention is to provide a novel bismuth salt of carbostyril derivatives (I) useful as a drug. Another object of the invention is to provide an antibacterial agent for the treatment of Helicobacter pylori infectious diseases, or an anti-peptic ulcer agent, or an anti-peptic inflammatory agent. A further object of the invention is to provide a drug for the prevention and treatment of various inflammatroy diseases and various chronic ulcers .

Brief Description of Drawings

Fig. 1 shows a chart of IR spectrum of the compound of this invention prepared in Example 1.

Fig. 2 shows a chart of IR spectrum of the compound of this invention prepared in Example 2.

Disclosure of the Invention

The bismuth salt of the carbostyril derivatives (I) of this invention has an inhibitory activity against H. pylori which would participate in occurrence or recurrence of gastric mucouse membrance disorders, for example, inhibitory activities against the promotion of IL-8 production in IL-8--producing cells (e.g. peripheral blood monocyte, tissue macrophase, large granular lymphocyte, T-lymphocyte, neutrophile, fibroblast, vascular endogenic cells, cutaneous keratinocyte, hepatic cells, astrocyte, epithelial cells, gastric carcinoma cells, etc.), inhibition of neutrophile activation, or inhibition of adhesive factor-increasing activity. Thus, the compounds of this invention will be useful for the prevention of occurrence or recurrence of gastric mucous membrane disorders which are induced by H. pyroli . Besides, H. pyroli has not only the action of inducing the activation of neutrophile but also the action of promoting the expression of ICAM-1 (ligand of CDllb) in vascular endogenic cells and gastric mucous membrance cells, and hence, the compounds of this invention are also effective for inhibiting the promotion of expression of ICAM-1 by H. pyroli .

The compounds of this invention have also an antiulcer activity, an activity of increasing endogenic prostaglandin E₂, an activity for removing or inhibiting active oxygen, an IL-8 production inhibitory activity, an activity for inhibiting activation of granulocytes, an activity for inhibiting expression of adhesive factor of granulocytes, and are useful as an antiulcer agent, an agent for exhibiting activity owing to prostaglandin E₂ (e>g< prevention and treatment of ulcers), an antioxidant, an agent for prevention, protection and treatment of acute or chronic inflammatory diseases . The compounds are also useful for enhancing bio- compatibility of artificial organs and artificial blood vessel. The compounds are further effective for the prevention of recurrence of peptic ulcer and peptic inflammation.

The inflammatory diseases include inflammatory skin diseases such as inflammatory keratosis (e.g. psoriasis, etc.), atopic dermatitis, contact dermatitis, and the like; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), Behcet's disease, which are chronic inflammatory diseases; inflammatory hepatic diseases such as hepatitis B, hepatitis C, alcoholic hepatitis, chemical allergic hepatitis; inflammatory kidney diseases such as nephritis, glomerulonephritis; inflammatory respiratory diseases such as bronchitis; aphtha; laryngitis; vocal fold inflammation; voice disorders; inflammatory diseases occurred during using artificial organs or artificial blood vessel; mucous membrane disorders of digestive tract which is induced by non-steroidal antiinflammatories or intestinal mucous membrane disorders; and the like, but are not limited thereto.

The intestinal mucous membrane disorders include simple primary small intestinal ulcer, nonspecific colonic ulcer, ulcerative colitis induced by nonspecific inflammation, Crohn's disease, the cause of which are not yet known, and further includes various disorders induced by infection with microorganisms, disturbances of circulation, collagen disease, irradiation of isotope, or chemicals.

Moreover, the compounds of this invention have inhibitory activity for decrease of secretion of somatostatin, anti-diabetic activity, and urease-inhibitory activity, and hence are also useful as a somatostatin decrease inhibitor, anti-diabetic and urease inhibitor. Owing to the urease- inhibitory activity, the compounds are useful for the prevention and treatment of gastric mucouse membrane disorder caused by production of ammonia induced by H. pyroli and further useful for the improvement and treatment of hyper ammonemia or symptoms accompanied with hyper ammonemia by their inhibitory activity against production of ammonia within the intestinal tract, more specifically for the prevention and treatment of hepatic encephalopathy, psychoneurotic disorders, abnormal electroencephalogram, tremor of hand and fingers which appear in hepatic diseases such as hepatitis, cirrhosis. The compounds of this invention can be prepared by various processes, for example, by the processes as shown in the following reaction schemes . [Reaction Scheme-1]

(2a) (la) wherein M is an alkali metal such as sodium, potassium, and R, the substituting position of the propionic acid substituent and the bond between 3- and 4-positions are the same as defined above.

That is, the compound (2a) is reacted with bismuth nitrate in an appropriate solvent to give the desired compound (la). The solvent used therein includes, for example, water, alcohols (e.g. glycerin), preferably a mixture of water and an alcohol. The compound (2a) is used in an amount of at least 3 moles, preferably 3 to 5 moles, to 1 mole of the- bismuth nitrate. The reaction is usually carried out at a temperature of about 0°C to 100°C, preferably at about 0°C to 70°C, for about 0.5 to 5 hours .

[Reaction Scheme-2]

(2b) (lb) wherein R, the substituting position of the propionic acid substituent and the bond between 3- and 4-positions are the same as defined above.

That is, the compound (2b) is reacted with bismuth hydroxide in an appropriate solvent to give the desired compound (lb). The solvent used therein includes, for example, water. The bismuth hydroxide is used in an amount of at least 1 mole, preferably 1 to 2 moles, to 1 mole of the compound (2b). The reaction is usually carried out at a temperature of about 0°C to 150°C, preferably at room temperature to 100°C, for about 0.5 to 5 hours .

The bismuth salt of carbostyril derivatives of this invention is usually in the form of conventional pharmaceutical preparations, for example, preparations suitable for oral administration such as tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, and preparations for parenteral administration such as suppositories and injections (e.g. solutions, suspensions, etc.). These preparations can be prepared by a conventional method with conventional pharmaceutically acceptable carriers or diluents, such as fillers, thickening agents, binders, wetting agents, disintegrators, surfactants, lubricants, and the like.

In order to form in tablets, there are used conventional pharmaceutically acceptable carriers such as vehicles (e.g. lactose, white sugar, sodium chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.), binders (e.g. water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrators (e.g. dry starch, sodium arginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl- sulfate, stearic monoglyceride, starches, lactose, etc.), disintegration inhibitors (e.g. white sugar, stearin, cacao butter, hydrogenated oils, etc.), absorption promoters (e.g. quaternary ammonium base, sodium laurylsulfate, etc.), wetting agents (e.g. glycerin, starches, etc.), adsorbents (starches, lactose, kaolin, bentonite, colloidal silicates, etc.), lubricants (e.g. purified talc, stearates, boric acid powder, polyethylene glycol, etc.), and the like. Moreover, the tablets may also be in the form of a conventional coated tablet, such as sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film coating tablets, or double or multiple layer tablets .

In the preparation of pills, the carriers include vehicles (e- - glucose, lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (e.g. gum arable powder, tragacanth powder, gelatin, ethanol, etc.), disintegrators (e.g. laminaran, agar, etc.), and the like.

In the preparation of suppositories, the carriers include, for example, polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides, and the like.

Capsules can be prepared by charging a mixture of the compound of this invention with the above carriers into hard gelatin capsules or soft capsules in a usual manner.

In the preparation of injections, -the solutions, emulsions or suspensions are sterilized and are preferably mad isotonic with the blood. In the preparation of these solutions emulsions and suspensions, there are used conventional diluents such as water, ethyl alcohol, propylene glycol, ethoxylate isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxy ethylene sorbitan fatty acid esters, and the like. In thi case, the pharmaceutical preparations may also be incorporate with sodium chloride, glucose, or glycerin in an amoun sufficient to make them isotonic, and may also be incorporate with conventional solubilizers, buffers, anesthetizing agents Besides, the pharmaceutical preparations may optionally b incorporated with coloring agents, preservatives, perfumes flavors, sweeting agents, and other medicaments, if required

The amount of the active component, bismuth salt o carbostyril derivatives, of this invention to be incorporate into the preparations is not specified but may be selected fro a broad range, but it is usually in the range of from 1 to 7 % by weight, preferably in the range of 5 to 50 % by weight.

The agent of this invention may be administered in an method, and suitable method for administration may be determine in accordance with various forms of preparation, ages, sexes an other conditions of the patients, the degree of severity o diseases, and the like. For instance, tablets, pills solutions, suspensions, emulsions, granules and capsules ar administered orally. The injections are intraveneousl administered alone or together with a conventinal auxiliar liquid (e.g. glucose, amino acid solutions), and further ar optionally administered alone in intramuscular, intracutaneous subcutaneous, or intraperitoneal route, if required, supposi¬ tories are administered in intrarectal route.

The dosage of the agent of this invention may b selected in accordance with the usage, ages, sexes and othe conditions of the patients, the degree of severity of the diseases, and the like, but is usually in the range of about 0.6 to 50 mg of the active bismuth salt of this invention per 1 kg of body weight of the patient per day. The active compound is preferably contained in the pharmaceutical preparations in an amount of 10 to 1000 mg per the dosage unit.

Examples

The active compounds and agents of this invention are illustrated by the following Examples, Preparations and Pharmacological experiments.

Example 1

2-(4-Chlorobenzoylamino)-3-(2-quinolon-4-yl) ropionic acid (3.7 g) is suspended in water (50 ml) and glycerin (38 ml), and thereto is added sodium hydroxide (400 mg) . The. mixture is stirred to dissolve to give sodium 2-(4-chlorobenzoylamino)-3- (2-quinolon-4-yl)propionate. To the mixture is added dropwise a solution of bismuth nitrate pentahydrate (1.6 g) in glycerin (8 ml) and water (10 ml). After the addition, the mixture is stirred at room temperature for one hour. After adding water to the reaction mixture, the precipitates are separated by filtration, washed with water, and then dried to give bismuth 2-(4-chlorobenzoylamino)-3-(2-quinolon-4-yl)propionate (i.e. the compound of the formula (la) wherein R is 4-C1, the bond between the 3- and 4-positions is double bond, and the- propionic acid substituent is substituted at 4-position) (4.1 g) as whit powders .

M.p.: 248 - 257°C (decomp.)

Elementary analysis for C₅₇H_/,₂N₆0₁₂Cl₃Bi.2H₂0:

Calcd.: C,50.55; H,3.42; N,6.21; Bi₂O₃,17.20 Found: C,49.06; H,3.31; N,5.58; Bi₂0₃,16.27.

IR spectrum: as shown in the attached Fig. 1. Example 2

Bismuth nitrate pentahydrate (4.9 g) is dissolved i acetic acid (20 ml), and the solution is diluted with water (20 ml). The mixture is made alkaline by adding dropwise 25 aqueous ammonia with stirring. The resulting suspension i centrifuged, and the supernatant is removed off by decantation To the residue is added water, and the mixture is stirred an again centrifuged. This procedure is repeated three times t give precipitates of bismuth hydroxide. The precipitates o bismuth hydroxide thus obtained are suspended in water (100 ml and thereto is added 2-(4-chlorobenzoylamino)-3-(2-quinolon-4 yl)propionic acid (3.6 g) . The mixture is stirred for 2 minutes at room temperature and further for one hour at 60°C. After cooling the reaction mixture, the precipitates ar separated by filtration, washed with water, and then dried t give bismuth 2-(4-chlorobenzoylamino)-3-( 2-quinolon-4 yl)propionate (i.e. the compound of the formula (lb) wherein is 4-Cl, the bond between the 3- and 4-positions is double bond, and the propionic acid substituent is substituted at 4-position) (5.7 g) as white powders.

M.p.: 264 - 269°C (decomp.) Elementary analysis for C₁₉H N₂0₅ClBi .2/3H₂0:

Calcd.: C,37.61; H,2.55; N,4.62; Bi₂O₃,38.40

Found: C,35.71; H,2.69; N,4.11; Bi₂O₃,34.20.

IR spectrum: as shown in the attached Fig. 2.

Preparation 1

Film coated tablets are prepared from the followin components .

Components Amount

2-(4-Chlorobenzoylamino)-3-(2-quinolon-4-yl)- propionic acid bismuth salt 150 g

Abicel (tradename of microcrystalline cellulose, manufactured by Asahi Chemical Industry Co., Ltd., Japan) 40 g

Corn starch 30 g

Magnesium stearate 2 g

Hydroxypropyl methylcellulose 10 g

Polyethylene glycol-6000 3 g

Castor oil 40 g

Ethanol 40 g

The active component of this invention, Avicel, cor starch and magnesium stearate are mixed and kneaded and th mixture is tabletted using a conventional pounder (R 10 mm) fo sugar coating. The tablets thus obtained are coated with a fil coating agent consisting of hydroxypropyl methylcellulose, poly ethylene glycol-6000, castor oil and ethanol to give film coate tablets .

Preparation 2

Tablets are prepared from the following components . Components Amount

2-(4-Chlorobenzoylamino)-3-( 2-quinolon-4-yl)- propionic acid bismuth salt 150 g

Citric acid 1 . 0 g

Lactose 33 . 5 g

Dicalcium phosphate 70 . 0 g

Pluronic F-68 30 , . 0 g

Sodium laurylsulfate 15 . . 0 g

Polyvinylpyrrolidone 15 , . 0 g

Polyethylene glycol (Carbowax 1500) 4 , , 5 g

Polyethylene glycol (Carbowax 6000) 45 , , 0 g

Corn starch 30 . , 0 g

Dry sodium laurylsulfate 3 . . 0 g

Dry magnesium stearate 3 . , 0 g

Ethanol q < , s .

The active compound of this invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodiu laurylsulfate are mixed. The mixture is screened with No. 60 screen and is granulated in wet with an alcohol solutio containing polyvinylpyrrolidone, carbowax 1500 and 6000. If required, an alcohol is added thereto so that the powder mixture is made a paste-like mass . Corn starch is added to the mixture and the mixture is continuously mixed to form uniform particles.

The resulting particles are passed through No. 10 screen and entered into a tray and then dried in an oven at 100°C for 12 to 14 hours. The dried particles are screened with No. 16 screen and thereto are added dry sodium laurylsulfate and dr magnesium stearate, and the mixtue is tabletted to form the desired shape. The core tablets thus prepared are vanished and dusted with talc in order to guard from wetting. Undercoating is applied to the core tablets . In order to administer the tablets orally, the core tablets are vanished several times. In order to give round shape and smooth surface to the tablets, further undercoating and coating with lubricant are applied thereto. The tablets are further coated with a coloring coating material until the desired colored tablets are obtained. After drying, the coated tablets are polished to obtain the desired tablets having uniform gloss .

Preparation 3

An injection preparation is prepared from the following components.

Components Amount

2-(4-Chlorobenzoylamino)-3-(2-quinolon-4-yl)- propionic acid bismuth salt 5 g

Polyethylene glycol (molecular weight: 4000) 0 , . 3 g

Sodium chloride 0 , . 9 g

Polyoxyethylene sorbitan monooleate 0 , . 4 g

Sodium metabisulfite 0 , . 1 g

Methyl-paraben 0 , . I E i g

Propyl-paraben 0 , . o: ! g

Distilled water for injection 10 . . 0 ml

The above parabens, sodium metabisulfite and sodium chloride are dissolved in distilled water of half volume of the above with stirring at 80°C. The solution thus obtained is cooled to 40°C, and the active compound of this invention and further polyethylene glycol and polyoxyethylene sorbitan mono¬ oleate are dissolved in the above solution. To the solution is added distilled water for injection to adjust to the desired volume, and the solution is sterilized by filtering with an appropriate filter paper to give an injection preparation. Pharmacological Test 1

1. Strain used in the experiment:

Standard strains: Helicobacter pylori ATCC 43504 and

Helicobacter pylori ATCC 43526

Clinically isolated strains:

Helicobacter pylori C0001, Helicobacter pylori C0002, and Helicobacter pylori CO003

2. Merhod for measuring the antibacterial activity:

The antibacterial activity of the test compound (compound of Example 1) was measured by an agar plate dilution method. That is, the test compound was weighed, dissolved in distilled water and then diluted with distilled water to prepare a series of fold-diluted solutions. The diluted solution was mixed with Brucella agar medium supplemented with -7 % bovine fetal serum (13.5 ml) to prepare a plate medium containing a test compound. Onto the plate medium containing a test compound was inoculated the test strain (1.8 x 10 , 1.8 x lO⁶ CFU/ml, 5 μl) by a point inoculator. It was cultured at 37°C for 3 days under faint aerobic condition. The minimum inhibitory concentration (MIC, μg/ l) was determined when any growth of the bacteria was entirely not observed. The MIC was expressed by converting into the content of bismuth of the test compound.

The results are shown in the following Table 1. Table 1

Claims

CLAIMS 1. A bismuth salt of a carbostyril derivative of th formula:

wherein R is a halogen atom, the propionic acid substituent is substituted at 3- or 4-position on the carbostyril nucleus, an the bond between 3- and 4-positions is single or double bond.

2. A bismuth salt of 2-(4-chlorobenzoylamino)-3-(2 quinolon-4-yl)propionic acid.

3. A bismuth salt of 2-(4-chlorobenzoylamino)-3-(2- quinolon-4-yl)propionic acid having an IR spectrum as shown i Fig. 1 which is prepared by reacting sodium 2-(4-chlorobenzoyl- amino)-3-(2-quinolon-4-yl)propionate with bismuth nitrate.

4. A bismuth salt of 2-(4-chlorobenzoylamino)-3-(2- quinolon-4-yl)propionic acid having an IR spectrum as shown in Fig. 2 which is prepared by reacting 2-(4-chlorobenzoylamino)-3- (2-quinolon-4-yl)propionic acid with bismuth hydroxide.

5. An antibacterial agent against Helicobacte pylori , which comprises as an active ingredient the compound as set forth in claim 1.

6. An agent for the prevention and treatment of peptic ulcer, which comprises as an active ingredient the compound as set forth in claim 1.

7. An agent for the prevention and treatment of peptic inflammatory diseases, which comprises as an active ingredient the compound as set forth in claim 1-.

8. A process for preparing a bismuth salt of a carbostyril derivative of the formula:

wherein R is a halogen atom, the propionic acid substituent is substituted at 3- or 4-position on the carbostyril nucleus, and the bond between 3- and 4-positions is single or double bond, which comprises reacting a carbostyril compound of the formula:

wherein M is an alkali metal, and R, the substituting position of the propionic acid substituent and the bond between 3- and

4-positions are as defined above, with bismuth nitrate.

9. A process for preparing a bismuth salt of a carbostyril derivative of the formula:

wherein R is a halogen atom, the propionic acid substituent is substituted at 3- or 4-position on the carbostyril nucleus, and the bond between 3- and 4-positions is single or double bond, which comprises reacting a carbostyril derivative of the formula:

(2b)

wherein R, the substituting position of the propionic aci substituent and the bond between 3- and 4-positions are a defined above, with bismuth hydroxide.