Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4704—2-Quinolinones, e.g. carbostyril
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to an agent for inhibiting carcinogenesis, specifically, it relates to an agent for inhibiting carcinogenesis of the digestive tract cancer. More particularly, the invention relates to an agent for inhibiting carcinogenesis comprising, as the active ingredient, a carbostyril derivative represented by the following general formula (I),
• R is a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom) ; the substituted position of the substituent in the carbostyril skeleton is 3- or 4-position in the carbostyril skeleton; and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is a single bond or a double bond]; or a salt thereof, preferably 2-(4-chlorobenzoylamino)-3-(2-quinolon-4- yl)propionic acid or salt thereof.
• Patent Application Kokai (Laid-open) No. 3-74329, and processes for producing those carbostyril derivatives having optical activities are described in Japanese
• Patent Application Kokai (Laid-open) No. 3-145468.
• carbostyril derivatives of the present invention inhibitory effect of carbostyril derivatives of the present invention on reactive oxygen metabolites is described in Japan. J. Pharmacol., Vol. 49, pp. 441-448 (1969), and the protectability of gastric mucous membrane by carbostyril derivatives of the present invention is described in Folia Pharmacol. Japon., Vol. 97, pp. 371-380 (1991). Furthermore, the usefulness of carbostyril derivatives as agents for curing diabetes mellitus is described in International Publication No. WO 92/21342, the usefulness of carbostyril derivatives as agents for protecting intestinal mucosa from disorders is described in International Publication No.
• cancers means cancers originated from the epitheliums existed in various parts of the body, for example, cancers originated from epitheliums of the skin, the tongue, the pharynx, the trachea, as well as cancers of the digestive tracts, such as the esophagus, the stomach, the duodenum, the small intestine and the large intestine.
• the agents for inhibiting carcinogenesis of the present invention can be prepared into various forms of common pharmaceutical preparations by formulating the carbostyril derivative represented by the general formula (I) or a salt thereof.
• the pharmaceutical preparations are prepared by formulating with commonly employed diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants and the like.
• the pharmaceutical preparations can be shaped into various forms depending upon the curing purposes, thus, typical examples of the forms are tablets, pills, powders, liquid medicines, suspensions, emulsions, granules, capsules, suppositories, injection preparations (liquid, suspension and the like), aerosol preparations, syrup preparations and preparations for external use and the like. Further, sustained release preparations can also be prepared by formulating with suitable resins.
• any known carriers which are used widely in this field can be applied, for example, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidone and the like; disintegrators such as dry starch, sodium alginate, agar powder, laminarin powder, sodium hydrogen-carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglycerides of stearic acid, starch, lactose and the like; disintegration inhibitors such as white sugar, stearin, cacao butter, hydrogenated oils and the like; absorption accelerators such as quaternary
• the tablets can be prepared in the form of common coated tablets, for example, sugar-coated tablets, gelatin film-coated tablets, enteric film- coated tablets, film-coated tablets, or in the form of double-layers tablets, multiple-layers tablets and the like.
• any known carriers which are widely used in this field can be applied, for example, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and the like; binders such as arabic gum powder, tragacanth gum powder, gelatin, ethanol and the like; and disintegrators such as laminarin, agar-agar and the like can be exemplified.
• excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and the like
• binders such as arabic gum powder, tragacanth gum powder, gelatin, ethanol and the like
• disintegrators such as laminarin, agar-agar and the like can be exemplified.
• any known carriers which are widely used in this field can be applied, for example, polyethylene glycols, cacao butter, higher alcohols, esters of higher alcohol, gelatin, semi-synthesized glycerides and the like can be exemplified.
• any known diluents which are widely used in this field can be applied.
• water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, fatty acid esters of polyoxyethylene sorbitan and the like can be exemplified.
• sodium chloride, glucose or glycerin may be contained therein.
• a dissolving adjuvant, a buffer solution, an analgesic agent and the like which are commonly used may be contained therein.
• a coloring agent, a preservatives, a perfume, a flavoring agent, a sweetening agent and other medicines may be contained therein.
• External preparations are prepared in the form of common pharmaceutical preparations for external use.
• common pharmaceutical preparations for external use are including, for example, a liquid medicine, a medicinal oil, a lotion, a liniment, an oleoginous ointment, an emulsion type ointment, such as O/W type hydrophilic ointment and W/O type water-absorbing ointment, a water-soluble ointment, a pasta, a plaster, a patch, a cream, an emulsion and the like, and these forms of pharmaceutical preparations for external use are not restricted within the scope of these examples.
• Each one of these forms of pharmaceutical preparations for external use can be prepared by common methods.
• various base materials which are widely used in this field can be also applied.
• at least one oleoginous base can be used singly, or mixture of two or more of them can be used widely; or at least one water- soluble ointment base can be used singly, or mixture of two or more of them can be used widely.
• these ointment base are fats and oils such as peanut oil, sesame oil, soybean oil, safflower oil, avogado oil, sunflower oil, corn oil, rapeseed oil, cotton seed oil, castor oil, camellia oil, coconut oil, olive oil, poppy seed oil, cacao butter, beef tallow, lard, wool fat and the like; modified bases obtained by subjecting these fats and oils to chemical changes such as hydrogenation; mineral oils such as petrolatum, paraffin, silicone oil, squalane and the like; higher fatty acid esters such as isopropyl myristate, n-butyl myristate, isopropyl linoleate, acetyl ricinoleate, stearyl ricinoleate, propyl ricinoleate, isopropyl ricinoleate, isobutyl ricinoleate, heptyl ricinoleate, diethyl sebac
• a geling agent such as a preservative, an antioxidant, a buffer solution, a pH controlling agent, a wetting agent, an antiseptic agent, a coloring agent, a flavoring agent, a pigment, a thickening agent, a metal chelating agent and the like.
• Aerosol type preparations can be prepared generally by formulating a sterilized solution or suspension of the carbostyril derivative of the general formula (I) with a propellant.
• a propellant for example, any one of known diluents which are commonly used in this field can also be used, thus the diluents which are exemplified in formulating the injection preparations can be used.
• any one of the propellants which are commonly used in this field can also be used, thus, liquefied gas propellants such as chlorofluorocarbons like Flon-12 (general term of dichlorodifluoromethane) or Flon-123 (general term of trifluorodichloroethane) ; compressed gas propellants such as nitrogen gas, carbon dioxide gas and the like can be exemplified.
• the aerosol type preparations may further contain a common solubilizing adjuvant, a buffering agent, and the like, and if necessary, a coloring agent, a preservative, a perfume, a flavoring agent, a sweetening agent may be added thereto.
• the amount of the carbostyril derivative of the general formula (I) or salt thereof to be contained in the agent for inhibiting carcinogenesis according to the present invention is not particularly restricted and can be selected from a wide range, and the amount may be generally selected within the range of 1-70% by weight, preferably 5-50 % by weight.
• Method for administering the agent of the present invention is not particularly restricted except that the case selected to the specific treating purpose.
• the method is decided depending upon the form of pre ⁇ paration, the age of patient, the distinction of sex and other conditions, the degree of disease condition of the patient and others.
• tablets, pills, a liquid medicine, a suspension, an emulsion, granules, a syrup and capsules are administered orally.
• An injec ⁇ tion preparation is intravenously administered singly or in combination with common auxiliary solutions such as glucose solution and/or amino acid solution, in case of necessity, it is singly administered intramuscularly, intradermally, subcutaneously or intraperitoneally.
• a suppository is administered intrarectally.
• An external preparation is coated on the diseased part.
• Dosage of the agent for inhibiting carcino- genesis of the present invention may be suitably selected depend upon the age of patient, the distinction of sex and other conditions, as well as the degree of disease condition of the patient and other related factors, and generally the amount of carbostyril derivative of the general formula (I) or salt thereof may be 0.6 to 50 mg per 1 kg of the body weight per day.
• the desirable content of the effective ingredient in each unit of administration form may be 10 to 1,000 mg.
• Citric acid 1. .0 g
• Polyethylene glycol (Carbowax 6000) 45. .0 g
• the mixture was sieved through a No. 60 screen.
• the resulting sieved mixture was wet-granulated with an ethanol solution containing polyvinyl pyrro ⁇ lidone, Carbowax 1500 and Carbowax 6000.
• ethanol was added to convert the mixture into a paste-like mass.
• Corn starch was added, and mixing operation was continued until uniform particles were formed.
• the resulting particles were passed through a No. 10 screen, then placed in a tray, and were dried in an oven at 100°C for 12-14 hours. The dried particles were sieved through a No. 16 screen. Next, dry sodium lauryl sulfate and dry magnesium stearate were added to the resulting particles.
• the mixture was compressed into core tablets of the desired shape by using a tablet machine.
• the resulting core tablets were treated with a varnish and then talc was sprayed thereon for preventing from moisture absorption.
• undercoat layer was coated. Sufficient number of varnish coatings were conducted to the core tablets so as to make them suitable for internal use. Formation of undercoat layer and smooth coating were conducted to make the coated tablets having completely round and smooth surface. Color coating was conducted until the desired color surface was obtained. After drying, the coated tablets were polished to obtain tablets of uniform gloss.
• Polyethylene glycol (mol. wt.: 4000) 0.3 g
• N-Ethyl-N'-nitro-N-nitrosoguanidine which is known as a carcinogenic substance, was administered to the mice to produce cancer of the duodenum, then 2-(4-chlorobenzoylamino)-3- (2-quinolon-4-yl)propionic acid (general name: Rebamipide) was administered as test compound to the test mice to examine the activity for inhibiting carcinogenesis.
• the test mice were classified into three groups of A, B and C (each one of the groups is con- sisting of 30 mice). The all of the test mice were given freely the drinking water which contains ENNG in the concentration of 100 mg/liter for 4 weeks. Thereafter, one solid feed in which the amount of test compound of Rebamipide is controlled to keep in the rate of 20 mg/kg/day were given to the mice of Group A from 5th to 16th week, and another solid feed in which the amount of test compound of Rebamipide is controlled to keep in the rate of 50 mg/kg/day were given to the mice of Group B for from 5th to 16th week.
• test mice of Groups of A, B and C were given tap water freely, then the duodenums of the test mice were sacrificed on the 16th week after the administration of the test compound, and the effect for inhibiting carcinogenesis performed by the test compound were examined.
• the average incidences of carcinogenesis were 0.84 ⁇ 0.86 in Group A, 0.68 ⁇ 0.87 in Group B and 1.21 ⁇ 1.27 in Group C, respec- tively, thus the carcinogenesis were inhibited in the test mice of Groups A and B which were administered with carbostyril derivative of the present invention.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Quinoline Compounds (AREA)

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• 1995
  • 1995-09-06 JP JP7228889A patent/JPH0971532A/ja active Pending
• 1996
  • 1996-08-20 WO PCT/JP1996/002319 patent/WO1997009045A1/en not_active Application Discontinuation
  • 1996-08-20 KR KR1019980701227A patent/KR19990043995A/ko not_active Application Discontinuation
  • 1996-08-20 EP EP96927200A patent/EP0848610A1/en not_active Withdrawn
  • 1996-08-20 CN CN96196805A patent/CN1195987A/zh active Pending
  • 1996-08-20 AU AU67100/96A patent/AU705751B2/en not_active Ceased
  • 1996-08-20 CA CA002228898A patent/CA2228898A1/en not_active Abandoned

Non-Patent Citations (1)

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