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WO1995012579A1 - Sel de bismuth de derives de carbostyrile destines au traitement des ulceres gastro-duodenaux - Google Patents

Sel de bismuth de derives de carbostyrile destines au traitement des ulceres gastro-duodenaux Download PDF

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Publication number
WO1995012579A1
WO1995012579A1 PCT/JP1994/001805 JP9401805W WO9512579A1 WO 1995012579 A1 WO1995012579 A1 WO 1995012579A1 JP 9401805 W JP9401805 W JP 9401805W WO 9512579 A1 WO9512579 A1 WO 9512579A1
Authority
WO
WIPO (PCT)
Prior art keywords
propionic acid
bismuth
bismuth salt
carbostyril
bond
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1994/001805
Other languages
English (en)
Inventor
Makoto Komatsu
Minoru Uchida
Takao Nishi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Priority to AU80031/94A priority Critical patent/AU8003194A/en
Publication of WO1995012579A1 publication Critical patent/WO1995012579A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2

Definitions

  • 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:
  • 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, preferably a bismuth salt of 2-(4-ch'lOrobenzoylamino)-3- (2-quinolon-4-yl)propionic acid.
  • 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.
  • 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].
  • Hcobacter 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).
  • 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.
  • peptic ulcers e.g. gastric ulcer, duodenal ulcer, etc.
  • peptic inflammation diseases e.g.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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 E 2 , 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 E 2 (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.
  • inflammatory skin diseases
  • 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.
  • 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.
  • 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]
  • 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 .
  • 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.).
  • 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.).
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • 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.
  • the solutions, emulsions or suspensions are sterilized and are preferably mad isotonic with the blood.
  • conventional diluents such as water, ethyl alcohol, propylene glycol, ethoxylate isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxy ethylene sorbitan fatty acid esters, and the like.
  • 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.
  • a conventinal auxiliar liquid e.g. glucose, amino acid solutions
  • 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.
  • 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) .
  • Film coated tablets are prepared from the followin components .
  • 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 .
  • Tablets are prepared from the following components .
  • 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 .
  • the core tablets are vanished several times.
  • 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 .
  • An injection preparation is prepared from the following components.
  • Polyethylene glycol (molecular weight: 4000) 0 , . 3 g
  • the antibacterial activity of the test compound 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 lO 6 CFU/ml, 5 ⁇ l) by a point inoculator. It was cultured at 37°C for 3 days under faint aerobic condition. The minimum inhibitory concentration (MIC, ⁇ g/ 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit un sel de bismuth de dérivés de carbostyrile de formule (I) où R représente un atome halogène, où le substituant acide propionique est substitué en position 3 ou 4 du noyau carbostyrile, et où la liaison entre les positions 3 et 4 est simple ou double. Ce sel est utile dans la prévention et le traitement de l'ulcère gastro-duodénal et des troubles inflammatoires gastro-duodénaux.
PCT/JP1994/001805 1993-11-05 1994-10-27 Sel de bismuth de derives de carbostyrile destines au traitement des ulceres gastro-duodenaux Ceased WO1995012579A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU80031/94A AU8003194A (en) 1993-11-05 1994-10-27 Bismuth salt of carbostyril derivatives for the treatment of peptic ulcers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5/276745 1993-11-05
JP27674593 1993-11-05

Publications (1)

Publication Number Publication Date
WO1995012579A1 true WO1995012579A1 (fr) 1995-05-11

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PCT/JP1994/001805 Ceased WO1995012579A1 (fr) 1993-11-05 1994-10-27 Sel de bismuth de derives de carbostyrile destines au traitement des ulceres gastro-duodenaux

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AU (1) AU8003194A (fr)
WO (1) WO1995012579A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998026769A1 (fr) * 1996-12-16 1998-06-25 Otsuka Pharmaceutical Co., Ltd. Inhibiteur d'adp-ribosyltransferase
WO2005070892A1 (fr) 2004-01-21 2005-08-04 Otsuka Pharmaceutical Co., Ltd. Sel amine d'un derive de carbostyrile

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3324034A1 (de) * 1982-07-05 1984-01-05 Otsuka Pharmaceutical Co. Ltd., Tokyo Carbostyrilderivate, verfahren zu deren herstellung und arzneimittel, welche diese enthalten
EP0206626A2 (fr) * 1985-06-13 1986-12-30 Barry James Dr. Marshall Utilisation de bismuth pour la fabrication d'un médicament destiné au traitement des désordres gastrointestinaux dûs à Campylobacter polyridis
WO1992021342A1 (fr) * 1991-06-07 1992-12-10 Otsuka Pharmaceutical Co., Ltd. Antidiabetique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3324034A1 (de) * 1982-07-05 1984-01-05 Otsuka Pharmaceutical Co. Ltd., Tokyo Carbostyrilderivate, verfahren zu deren herstellung und arzneimittel, welche diese enthalten
EP0206626A2 (fr) * 1985-06-13 1986-12-30 Barry James Dr. Marshall Utilisation de bismuth pour la fabrication d'un médicament destiné au traitement des désordres gastrointestinaux dûs à Campylobacter polyridis
WO1992021342A1 (fr) * 1991-06-07 1992-12-10 Otsuka Pharmaceutical Co., Ltd. Antidiabetique

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998026769A1 (fr) * 1996-12-16 1998-06-25 Otsuka Pharmaceutical Co., Ltd. Inhibiteur d'adp-ribosyltransferase
WO2005070892A1 (fr) 2004-01-21 2005-08-04 Otsuka Pharmaceutical Co., Ltd. Sel amine d'un derive de carbostyrile
US7732611B2 (en) 2004-01-21 2010-06-08 Otsuka Pharmaceutical Co., Ltd. Amine salt of carbostyril derivative
EP2253619A1 (fr) 2004-01-21 2010-11-24 Otsuka Pharmaceutical Co., Ltd. Sel amine d'un derive de carbostyrile
US8222276B2 (en) 2004-01-21 2012-07-17 Otsuka Pharmaceutical Co., Ltd. Amine salt of carbostyril derivative

Also Published As

Publication number Publication date
AU8003194A (en) 1995-05-23

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