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WO1990009794A1 - Remede contre le diabete - Google Patents

Remede contre le diabete Download PDF

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Publication number
WO1990009794A1
WO1990009794A1 PCT/JP1990/000250 JP9000250W WO9009794A1 WO 1990009794 A1 WO1990009794 A1 WO 1990009794A1 JP 9000250 W JP9000250 W JP 9000250W WO 9009794 A1 WO9009794 A1 WO 9009794A1
Authority
WO
WIPO (PCT)
Prior art keywords
administration
group
diabetes
thiazine
streptozotocin
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/JP1990/000250
Other languages
English (en)
Japanese (ja)
Inventor
Toshio Satoh
Hitoshi Matsumoto
Hisao Kakegawa
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.)
Nippon Hypox Laboratories Inc
Original Assignee
Nippon Hypox Laboratories Inc
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 Nippon Hypox Laboratories Inc filed Critical Nippon Hypox Laboratories Inc
Publication of WO1990009794A1 publication Critical patent/WO1990009794A1/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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a therapeutic agent for diabetes, and particularly to a pharmaceutical agent suitable as a therapeutic agent for insulin-dependent diabetes.
  • Insulin-dependent diabetes mellitus impairs the uptake of glucose from the blood into cells by the absolute or relative lack of insulin secreted from three cells in the islets of Langerhans of the knee. It is a disease that impairs carbohydrate metabolism, as well as protein metabolism and lipid metabolism. The cause of this absolute or relative lack of insulin has not yet been determined, but may be due to genetic factors, excessive sugar intake, inflammation or destruction of three cells.
  • symptomatic treatment methods such as diet, administration of hypoglycemic agents, and injection of insulin have been used.
  • symptomatic treatment methods such as diet, administration of hypoglycemic agents, and injection of insulin.
  • the treatment of insulin-dependent diabetes is symptomatic, and the affected individual must continue dieting, taking hypoglycemic drugs, or injecting insulin for a lifetime.
  • the financial and psychological burden of the affected individuals was significant.
  • an object of the present invention is to provide a fundamental therapeutic agent for inulin-dependent diabetes mellitus, and particularly for the treatment of diabetes having an action of suppressing inflammation of three cells and a function of repairing broken three cells.
  • the therapeutic agent for diabetes of the present invention has the following general formula
  • FIG. 1 shows the time course of the serum glucose concentration of the control group of the aloxane diabetic rat used in Example 1 and the specific thiazine 1.1,1-dioxide (SC-200) administration group. It is a graph.
  • Fig. 2 shows the glucose concentration in the serum of the control group of the streptozotocin-induced diabetic rat used in Example 2 and the specific thiazine 1,1-dioxide (SC-200) administration group.
  • 6 is a graph showing a change with time of the graph.
  • the therapeutic agent for diabetes of the present invention contains a thiazine-11,1 dioxide derivative represented by the above general formula (I) as an active ingredient.
  • Ar represents a benzene ring or a naphthalene ring fused to the thiazine ring in the general formula (I), and examples of the compound of the general formula (I) are as follows. .
  • Examples of the dosage form of the therapeutic agent for diabetes of the present invention include powders, fine granules, granules, tablets, coated tablets, capsules, etc., oral solid preparations such as syrups, and injections. In the case of formulation, it can be produced by a conventional method using a usual pharmaceutical carrier.
  • an excipient is added to the above active ingredients, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, and a flavoring agent are added. Powders, fine granules, granules, tablets, coated tablets, capsules, etc. in the usual manner.
  • lactose corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc.
  • a binder polyvinyl alcohol, polyvinyl ether, Tilcellulose, methylcellulose, arabia gum, tragacanth, gelatin, shellac, hydroxypropinoresenololose, hydroxypropyl pilstarch, polyvinylpyrrolidone, and the like can be used.
  • the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, etc.
  • Magnesium stearate, talc, po It is possible to use polyethylene diol, silica, hydrogenated vegetable oil and the like.
  • coloring agents use substances that are permitted to be added to pharmaceuticals.For flavoring agents, cocoa powder, heart-shaped brain, aromatic acid, heart-shaped oil, dragon brain, cinnamon powder, etc. can be used. . In the case of oral solid preparations, it goes without saying that coating with sugar coating, gelatin coating, etc. will not work.
  • liquid preparation for oral use for example, ordinary syrups (solutions) add sucrose, sorbitol, etc. as sweeteners, and sorbitan fatty acid esters, polysorbates, polysorbates as solubilizers.
  • a suspension syrup it can be obtained by adding arabia gum, tragacanth, sodium carboxymethylcellulose, methylcellulose, etc. as a suspending agent in addition to the above-mentioned raw materials for the preparation. .
  • aqueous solvents such as distilled water for injection, physiological saline, Ringer's solution, vegetable oils (sesame oil, laccase oil, olive oil, corn oil, etc.), fatty acid esters
  • Non-aqueous solvents such as ethanol, propylene glycol, and glycerin, or non-aqueous solvents and alcoholic non-aqueous
  • a solvent mixed with a solvent and add a stabilizer, dissolution aid, suspending agent, emulsifier, buffer (pH regulator), isotonic agent, soothing agent, preservative, etc.
  • antioxidants such as L-ascorbic acid, sodium pyrosulfite, sodium bisulfite, and longgarite can be used.
  • Polyoxyethylene hydrogenated castor oil, ethanol, sodium hydroxide, sodium hydrogen carbonate, ethylene diamine and the like can be used.
  • the suspending agent carboxymethylcellulose sodium, aluminum monostearate, or the like can be used.
  • the emulsifier polyoxyethylene hydrogenated castor oil or the like can be used.
  • Benzyl alcohol, procaine hydrochloride, dibu strength hydrochloride, lidocaine hydrochloride, glucose, inositol and the like can be used as a soothing agent, and as a preservative, sodium paraoxybenzoate can be used.
  • Tritium, benzyl alcohol, chlorobutanol, phenol, cresol, etc. can be used.
  • the dose may vary depending on the severity of the disease, the age of the affected patient, the health condition, and the like.
  • the desired effect can be obtained by administering the active ingredient thiazine-1,1-dioxide derivative at a rate of 10 to 1,000 mg / kgZ day o
  • the rats are divided into groups of 5
  • the group was a control group, and blood was collected at 24 hours, 47 hours and 71 hours after administration of aroxane, and the serum glucose concentration was measured, respectively.
  • the other group was the SC-200 administration group, and 24 hours and 48 hours after administration of aloxane, 100 mg of SC-200 was orally administered, respectively, in the same manner as the control group.
  • Blood was collected 24 hours after administration of aloxane (immediately after administration of SC-200), 47 hours and 71 hours later, and the glucose concentration in serum was measured.
  • the glucose concentration before administration of aroxane was 123.3 mg / dl on average, and the glucose concentration 24 hours after administration of aroxane was 388.6 on average in the control group.
  • the average glucose concentration at 37 hours after administration of 71.4 mg Zd was 74.8 mg / dK SC—2 in the control group.
  • the average of 50.8 mg / dl in the 00 group and the average glucose concentration 71 hours after aroxane administration was 62.38 mg / d KSC in the control group, and the average in the 200 group.
  • the glucose concentration in the SC-200-administered group at 47 and 71 hours after administration of aroxane was significantly lower than that in the control group.
  • streptozotocin dissolved in citrate buffer at pH 5.0 was added to each rat at 3 Omg / kg (however, (Trebutozotocin amount) was injected twice via the tail vein to destroy Langerhans islet cells and to develop small levbutozotocin-induced diabetes. The second administration of streptozotocin was performed 10 days after the first administration.
  • the rats were divided into four groups of 5 animals each, one group consisting of a single oral group, and 7 days after the first administration of streptozotocin, 10 Blood samples were collected on days (immediately after the second administration of streptozotocin) and on day 13, and blood glucose levels were measured.
  • the other three groups were the SC-200 administration group to which SC-200 obtained by the same method as in Example 1 was administered, and the group to which SC-200 was administered at a rate of 5 mgZkgZ day (SC-200 5tngZkg administration group), 3 OmgZkgZ days administration group (3 (-200 30mgZkg administration group), and 20 OmgZkgZ days administration group (SC-200 200mgZkg administration group) 3 days after the first administration of streptozotocin, SC-200 was orally administered continuously for 11 days, and 7 days and 10 days after the first administration of streptozotocin (2 days). Blood was collected from each rat immediately after the first streptozotocin administration) and 13 days later, and the glucose concentration in the serum was measured.
  • the glucose concentration 7 days after the first administration of streptozotocin was 158.3 mg / dU SC-200 on average in the control group and 5 mgZkg in the administration group.
  • the mean glucose concentration in the control group was 362.1 mg / dU SC- averaged 273.5 mg / dK SC in the 200 mg 5 kg Z kg group.
  • the glucose concentration in the group administered with kg and the group administered with 200 mg of SC-200 was significantly lower than the glucose concentration in the control group.
  • the glucose concentration 13 days after the first administration of streptozotocin was 48.7 mg / dl.
  • the average dose in the control group was 284.6 mg / dl, and the glucose concentration in the SC—200 / 300 group and 3C—200 / 200 nig / kg group was It was significantly lower than that of the trol group.
  • the therapeutic agent for diabetes of the present invention has no effect with the conventional hypoglycemic agent Aloxane diabetic distreptozotocin also shows a hypoglycemic effect against streptozotocin-induced diabetes.
  • the antidiabetic agent of the present invention shows that streptozotocin-induced three-cell inflammation This was probably due to its effect on repairing ⁇ cells that were disrupted by streptozotocin.
  • the therapeutic agent for diabetes of the present invention has an inhibitory action on inflammation of three cells and a repair action on broken ⁇ cells.

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

Abstract

L'invention concerne un remède contre le diabète comprenant comme ingrédient actif un dérivé de thiazine 1,1-dioxyde ayant la formule générale (I), dans laquelle Ar représente un anneau de benzène ou de naphtalène fusionné avec l'anneau de thiazine.
PCT/JP1990/000250 1989-02-28 1990-02-28 Remede contre le diabete Ceased WO1990009794A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1/46805 1989-02-28
JP4680589 1989-02-28

Publications (1)

Publication Number Publication Date
WO1990009794A1 true WO1990009794A1 (fr) 1990-09-07

Family

ID=12757548

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1990/000250 Ceased WO1990009794A1 (fr) 1989-02-28 1990-02-28 Remede contre le diabete

Country Status (1)

Country Link
WO (1) WO1990009794A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0455830A4 (en) * 1989-11-30 1993-01-27 Nippon Hypox Laboratories Incorporated Medicine containing thiazine dioxide derivative

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3674876A (en) * 1969-06-09 1972-07-04 Pfizer Benzothiazine dioxides as lipid regulating agents
US3892740A (en) * 1974-10-15 1975-07-01 Pfizer Process for the production of carboxamides of oxo-1,2-benzothiazine-1,1-dioxides
DE2452996A1 (de) * 1974-11-08 1976-05-20 Thomae Gmbh Dr K Neue 4-hydroxy-2h-naphtho- eckige klammer auf 2,1-e eckige klammer zu -1,2thiazin-3-carboxamid-1,1-dioxide, verfahren zu ihrer herstellung und diese enthaltende arzneimittel
DE2539112A1 (de) * 1975-09-03 1977-03-17 Thomae Gmbh Dr K Neue 4-hydroxy-2h-naphtho eckige klammer auf 2,1-e eckige klammer zu -1,2- thiazin-3-carboxamid-1,1-dioxide, verfahren zu ihrer herstellung und diese enthaltende arzneimittel

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3674876A (en) * 1969-06-09 1972-07-04 Pfizer Benzothiazine dioxides as lipid regulating agents
US3892740A (en) * 1974-10-15 1975-07-01 Pfizer Process for the production of carboxamides of oxo-1,2-benzothiazine-1,1-dioxides
DE2452996A1 (de) * 1974-11-08 1976-05-20 Thomae Gmbh Dr K Neue 4-hydroxy-2h-naphtho- eckige klammer auf 2,1-e eckige klammer zu -1,2thiazin-3-carboxamid-1,1-dioxide, verfahren zu ihrer herstellung und diese enthaltende arzneimittel
DE2539112A1 (de) * 1975-09-03 1977-03-17 Thomae Gmbh Dr K Neue 4-hydroxy-2h-naphtho eckige klammer auf 2,1-e eckige klammer zu -1,2- thiazin-3-carboxamid-1,1-dioxide, verfahren zu ihrer herstellung und diese enthaltende arzneimittel

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 76(17): 94614X, (J. MED. CHEM., 14(12), 1171-5(1971), LOMBARDINO et al.). *
CHEMICAL ABSTRACTS, 78(15): 92403V, (J. MED. CHEM., 16(1), 44-8(1973), ZINNES et al.). *
CHEMICAL ABSTRACTS, 89(13): 109314U, (Justus Liebigs ANN. CHEM., (4), 635-42 (1978), STEINER). *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0455830A4 (en) * 1989-11-30 1993-01-27 Nippon Hypox Laboratories Incorporated Medicine containing thiazine dioxide derivative

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