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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis

Definitions

• the present invention relates to the field of diabetes mellitus therapy. More particularly, this invention relates to the use of compounds having aldose reductase inhibiting activity (hereinafter referred to as "aldose reductase inhibitors”) to correct an abnormal metabolic pathway associated with diabetes mellitus, thereby enhancing and/or restoring insulin sensitivity.
• aldose reductase inhibitors compounds having aldose reductase inhibiting activity
• diabetes mellitus is used to describe chronic hyperglycemia and the side effects of glucose toxicity.
• diabetes mellitus There are two general classifications of diabetes mellitus: (1) insulin-dependent (Type I), and (2) noninsul in-dependent (Type II).
• Type I insulin-dependent
• Type II noninsul in-dependent
• the present invention is directed to the treatment of both Type I and Type II diabetes mellitus, particularly Type II.
• Type I diabetes mellitus is generally attributable to an insulin deficiency.
• simple insulin deficiency cannot entirely account for the diabetic syndrome seen in Type II diabetes mellitus. This conclusion is supported by the following observations: (1) in many Type II diabetics, insulin deficiency is not present; and (2) even in Type II diabetics who have impaired insulin secretion leading to an insulin deficiency, insulin resistance can be demonstrated to be responsible for their hyperglycemic state.
• insulin receptor function in Type II diabetes mellitus patients can be modified by sustained, rigorous caloric and/or carbohydrate restriction, oral hypoglycemic drug therapy, insulin injections, and/or physical exercise which results in weight Toss.
• these therapeutic approaches taken either alone or in combination (i.e., diet, exercise, insulin, and/or oral hypoglycemics), the net overall effect is to lower blood glucose over a sustained time.
• induced hypoglycemia This effect is called “induced hypoglycemia.”
• the following articles may be referred to for further background in connection with known therapeutic methods of inducing hypoglycemia, and the resulting modification of insulin receptor function: Savag et al., "Diet induced improvement of abnormalities in insulin and glucagon secretion and in insulin receptor binding in diabetes mellitus," Diabetes Care, Vol. 5, pages 999-1007 (1979); Beck-Nielsen et al., “Normalization of the insulin sensitivity and the cellular insulin binding during treatment of obese patients following treatment with glibencl amide,” Acta Endocrinology, Vol.
• Type II diabetes mellitus It follows that frequent episodes of hyperglycemia in adults induced, for example, by a high calorie diet and lack of exercise, will eventually diminish insulin sensitivity and induce Type II diabetes mellitus.
• the aforementioned chronic process may be described as an insidious change in the glucose "set point" induced by improper life style and aging.
• the biochemical mechanism underlying a loss of insulin sensitivity and concomitant changes in glucose metabolism in connection with Type II diabetes mellitus is believed to involve the energetically expensive enzymatic conversion of the aldose sugar, glucose, to sorbitol at the cost of NADPH. This loss of NADPH co-factor substantially suppresses the very dynamic reduction of oxidized glutathione into reduced glutathione.
• Reduced glutathione is believed to be involved in maintaining normal insulin receptor function at the target cells. It has been previously demonstrated that insulin release in response to glucose is related to the redox state of islet cell thiols, and that reduced glutathione enhances the capacity of glucose to induce insulin release. See Hallman et al., "Stimulation of insulin release by thiols,” Biochem. Biophys. Acta, Vol. 392, pages 101-109 (1975); and Ammon et al., "Cysteine analogues potentiate glucose-induced insulin release in vitro," Diabetes, Vol. 35, pages 1390-1396 (1986), respectively.
• the present invention is directed to enhancing insulin sensitivity at or within target tissues by administering one or more aldose reductase inhibitors to patients who are either afflicted with diabetes mellitus or predisposed to acquiring this disease.
• An appropriate aldose rethictase inhibitor regimen will prevent and/or reverse loss of insulin sensitivity.
• This treatment with aldose reductase inhibitors results in a gradual decrease in insulin resistance by enhancing normal insulin receptor function at the target cells.
• This positive effect on insulin receptor function is believed to be the result of normalization of the redox state of the affected cells (i.e., normalization of the conversion of intracellular oxidized glutathione to reduced glutathione); more specifically, the enhancement of insulin receptor sensitivity is believed to result directly from increased cellular levels of reduced glutathione.
• glutathione metabolism is the indirect result of interruption of an abnormal metabolic pathway by aldose reductase inhibitors. More particularly, diabetes mellitus is believed to involve an abnormal metabolic pathway wherein the aldose sugar, glucose, is converted to sorbitol at the expense of NADPH. This loss of NADPH affects the cellular redox state in a manner such that the conversion of oxidized glutathione to reduced glutathione is decreased, thereby decreasing the amount of reduced glutathione available at the insulin receptors. Reduced glutathione either directly or indirectly (e.g., via a transferase) maintains the insulin receptor in a reduced thiol state.
• An insulin receptor active site must be in a reduced thiol state in order for a mixed disulfide bond or an activated complex to form between insulin and the insulin receptor.
• Aldose reductase inhibitors prevent the above-described depletion of NADPH and resulting decrease in cellular reduced glutathione levels and thiol reduction potential by inhibiting glucose reducing enzymes, such as aldose reductase and L-hexonate dehydrogenase, and thereby promote the binding of both endogenous and exogenous insulin to insulin receptor sites.
• the methods of the present invention are applicable to treatment of both Type I and Type II diabetes mellitus, and to reversal and prevention of Type II diabetes mellitus, and comprise administering a therapeutically effective amount of an aldose reductase inhibitor.
• the administration of an appropriate aldose reductase inhibitor regimen effectively lowers blood glucose levels in Type I and Type II diabetes mellitus patients by enhancing the action of endogenous and exogenous insulin.
• the amount of insulin required to maintain a normal blood glucose level may be reduced.
• a similar result will be expected in Type II diabetes mellitus patients who are receiving insulin therapy.
• Type II patients receiving a combination of insulin and an aldose reductase inhibitor it may be possible to discontinue insulin use after a relatively short course of therapy (e.g., several weeks) with this combination, and to maintain a normal blood glucose level thereafter using only aldose reductase inhibitor therapy.
• the present invention also provides a method of preventing, or at least retarding, the onset of Type II diabetes mellitus in patients who are predisposed to acquiring this disease.
• a fasting blood glucose level of greater than 140 mg of glucose per deciliter of blood is generally associated with a clinical diagnosis of Type II diabetes mellitus.
• a patient having a fasting blood glucose level of greater than 100 mg per deciliter of blood but less than 140 mg per deciliter is considered to be "hyperglycemic.”
• aldose dose reductase inhibitors which may be employed in the present invention comprise any compound having aldose reductase inhibiting activity which is therapeutically effective in enhancing insulin sensitivity, and is safe for use in humans and other mammals.
• Aldose reductase inhibitors which are particularly suitable for use in the method of the present invention are disclosed in commonly assigned U.S. Patent Nos. 4,537,892; 4,436,745; and 4,438,272.
• the following patents disclose additional examples of aldose reductase inhibitors which may be used in the present invention: U.S. Patent Nos. 3,821,383; 4,117,230; 4,130,714; and 4,181,728.
• the entire contents of the abovecited patents are hereby incorporated by reference in the present specification.
• the following compounds represent particularly preferred aldose reductase inhibitors: a.
• [3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazin-1-yl]acetic acid also called “STATIL®”
• patients afflicted with diabetes mellitus and patients predisposed to acquiring diabetes mellitus are treated with one or- more aldose reductase inhibitors in an amount effective to enhance insulin sensitivity (i.e., a "therapeutically effective” amount).
• the aldose reductase inhibitor(s) may be administered to the patient by means of a variety of dosage forms and routes of administration, as will be readily appreciated by those skilled in the art. Oral administration is generally preferred, but topical administration and administration by injection may be found preferable in some instances.
• Dosage regimens i.e., amount and frequency

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• 1988
  • 1988-03-18 JP JP63503190A patent/JPH01503460A/ja active Pending
  • 1988-03-18 AU AU15490/88A patent/AU598366B2/en not_active Ceased
  • 1988-03-18 EP EP19880903550 patent/EP0306525A4/en not_active Withdrawn
  • 1988-03-18 WO PCT/US1988/000814 patent/WO1988006887A1/en not_active Application Discontinuation
  • 1988-03-18 CA CA000561908A patent/CA1310269C/en not_active Expired - Fee Related
  • 1988-11-19 KR KR1019880701502A patent/KR890700346A/ko not_active Application Discontinuation

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