AU598366B2 - Use of aldose reductase inhibitors to enhance insulin sensitivity in diabetes - Google Patents

Description

:i:Lei~ AU-AI-15490/88 WORLD INTELLECTUA'iaOPrY OI NIZ N PCT Interna li *-a INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 88/ 06887 A61K 31/50, 31/44, 31/42 Al A61K 31/541, 311/4, 31/19542 Al (43) International Publication Date: A61K 31/415, 31/40, 31/195 22 September 1988 (22.09.88) (21) International Application Number: PCT/US88/00814 (81) Designated States: AT (European patent), AU, BE (European patent), BR, CH (European patent), DE (Eu- (22) International Filing Date: 18 March 1988 (18.03.88) ropean patent), DK, FI, FR (European patent), GB (European patent), IT (European patent), JP, KR, LU (European patent), NL (European patent), NO, SE (31) Priority Application Number: 028,512 (European patent).

(32) Priority Date: 20 March 1987 (20.03.87) Published (33) Priority Country: US With international search report.

(71) Applicant: ALCON LABORATORIES, INC. [US/US]; 6201 South Freeway, P.O. Box 6600, Fort Worth, TX 76115 17 NOV 1988 (72) Inventor: YORK, Billie, Jr. 3400 Morfeld Drive, Crowley, TX 76036 (US).

(74) Agent: PRICE, Robert, Lowe, Price, Leblanc, Beck-

AUSTRALIAN

er Shur, 427 North Lee Street, Alexandria, VA 10 C 8 22314 1 OC 1988 PATEN.T QtFFCE (54) Title: USE OF ALDOSE REDUCTASE INHIBITORS TO ENHANCE INSULIN SENSITIVITY IN DIABETES

MELLITUS

(57) Abstract A method of enhancing insulin sensitivity in mammals humans) is described. The method is based on the use of aldose reductase inhibitors to restore and preserve intracellular reduced glutathione levels, thereby enhancing the formation of insulin receptor-mixed disulfide bonds.

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II mod^ WO 88/06887 PCT/US88/00814 -1- USE OF ALDOSE REDUCTASE INHIBITORS TO ENHANCE INSULIN SENSITIVITY IN DIABETES MELLITUS Background of the Invention 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.

The term "diabetes mellitus" is used to describe chronic hyperglycemia and the side effects of glucose toxicity. There are two general classifications of diabetes mellitus: insulin-dependent (Type and noninsulin-dependent (Type II). The present invention is directed to the treatment of both Type I and Type II diabetes mellitus, particularly Type II.

The above-cited classifications of diabetes mellitus are based on the role insulin plays in the disease state. Type I diabetes mellitus is generally attributable to an insulin deficiency. In contrast, it is clear that simple insulin deficiency cannot entirely account for the diabetic syndrome seen in Type II diabetes mellitus. This conclusion is supported by the following observations: in many Type II diabetics, insulin deficiency is not present; and 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 hypere ycemic state. Reference is made to the following articles for further background in this regard: Reaven et al., "Nonketotic diabetes mellitus: insulin deficiency or insulin resistance?", A erican Journal of Medicine, Vol. 60, page 80 (1976); Alford Set al., "The significance and interpretation of mildly abnormal oral glucose tolerance," Diabetologia, Vol. 7, page 173 (1971); and DeFronzo et al., "Insulin sensitivity and insulin binding to monocytes in maturity-onset diabetes," Journal of Clinical Investigation, Vol. 63, page 939 (1979).

WO 88/06887 PCT/US88/00814 -2- It is known that the insulin resistance associated with Type II diabetes mellitus patients and consequent hyperglycemia can be partially reversed with frequent insulin injections. Moreover, it is known that 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 loss. With these therapeutic approaches, taken either alone or in combination diet, exercise, insulin, and/or oral hypoglycemics), the net overall effect is to lower blood glucose over a sustained time. 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 glibenclamide," Acta Endocrinology, Vol. pages 103-112 (1979); Beck-Nielsen et al., "Increased insulin sensitivity and cellular insulin binding in obese diabetes following treatment with glibenclamide," Acta Endocrinology, Vol. 90, pages 451-462 (1979); Rizkalla et al., "Insulin receptor changes in Type II diabetes after short-term insulin treatment," Horm. Metabol. Res., Vol. 17, pages 512-517 (1985); Scarlett et al., "Insulin treatment reverses the insulin resistance of Type II diabetes mellitus," Diabetes Care, Vol. 5, pages 353-363 (1982); and Selig, "Hypoglycemia during prolonged exercise in normal men," Endocrinology, Vol. 1983, pages 209-212 (1983).

While applicant is not bound by any theory, it is believed that inducing hypoglycemia will, in time, increase insulin sensitivity in i 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" 1 p 1 1 1 1 1 11 1 1 1 1 WO 88/06887 PCT/US88/00814 -3induced 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. It has also been suggested that metabolic changes in cellular glutathione in diabetes mellitus cause other reversible thiol-disulfide regulated metabolic chages which result in a net increase in cellular gluconeogenesis. See Ziegler, "Role of reversible oxidation-reduction of enzyme thiol-disulfide in metabolic regulation," Annu. Rev.

Biochem., Vol. 54, pages 305-329 (1984).

Summary of the Invention 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 reductase 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 cell s normalization of the 1 1 WO 88/06887 PCT/US88/00814 -4conversion 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.

While applicant is not bound by any theory, it is believed that the above-cited normalization of 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 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 30 mellitus patients by enhancing the action of endogenous and exogenous insulin. As the result of the administration of an appropriate aldose Sreductase inhibitor regimen to a patient afflicted with Type I diabetes mellitus, the amount of insulii required to maintain a normal blood 1 1 1 1 1 'j I WO :88/06887 PCT/US8/00814 glucose level may be reduced. A similar result will be expected in Type II diabetes mellitus patients who are receiving insulin therapy.

In 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 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 11 diabetes mellitus. In contrast, 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." There is a further class of patients who are not yet diabetic in a clinical sense, but are predisposed to acquiring diabetes. These patients are referred to as "latent" or "chemical" diabetics. In accordance with the present invention, it is possible to retard the progression of the underlying disease state in both patients who are hyperglycemic and patients who may be identified as latent or chemical diabetics, thereby preventing the progression of the disease state to a point at which the patients would be clinically diagnosed as having Type II diabetes mellitus.

This prevention or prophylaxis is achieved by enhancing the action of endogenous insulin, as explained above.

Detailed Description of the Invention The aldose dose reductase inhibitors which may be employed in the present T-vention 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 S .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; *1 7 1 1 1 1 1 1 1 WO 88/06887 WO 8806887PCT/US88/008 14 -6- 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,

HNH

7,9-difluoro-2-methylspiro(5H-indeno E 1,2-bjpyridin-5,3'-pyrol idine)b.

7,9-difluoro-2-rnethylspiro(5H-indenb [1,2-blpyridin-5,4' imidazolidine)- 2' WO 8806887-7--PCT/US88/008 14 WO 88/06887 2,7-difluoro-4-methylspiro(9H-fluoren-9,4 -imidazolidirie)-2' 07 7-fluoro-2-methylspiro(5H-indeno[1,2-b1-pyridin-5,4'imidazolidine)- 2' WO 88/06887 e.

PCT/US88/008 14 0 .,2

SCH

3 2,7-difluoro-4-methylthiospiro(9-fluorel-9,4' -iniidaza'iidine) diane; f.

SOH

7,9-if~ora2-mthythiapir(5Hideo C,2-blpyridin-5,4' imidazolidine)-2'

I

I

WO 88/06887 g.

I

PCT/US88/008 14 2 5 7 -trifluoro-4methylspiro(9Hfluore-9,4-imidazolidine)- 2 d ione; h.

HN-{

oJ NH 2 5 7 -trifluoro-4methylthiospiro(9Hfuoren9,4-imidazo'tidine)- 2 dione;

'I

71

I

F.,

WO 88106887 WO 8806887PCT/US88/008 14

H

2C\ 7-methylthiospiro(5H-ideno(1,2-blpyridin-.5,31-pyrolidine)-2',5'-dione; 2,7-difluorospiro(9H-fluoren-9,4' iridazolidin)-2' WO 88/06887 WO 8806887PCT/US88/008 14 -11- 00 2,7-difluorospiro(9H-fluoren-9,5'-oxazolidine)-2'5'dione; 2,7-difluorospiro(9H-fluoren-9,3'-pyrolidine)-2' 2K WO 88/06887 WO 8806887PCT/US88/008 14 -12- (S)-6-flucrospiro(chroman-4,4-irnidazolidine]-2' ,5'dione (also called SORB IN I n 0

CH

N-(r5-(trifluoromethyl)-6-methoxy-i-naphthalenyllthioxomethyl]-nrethylglycine (also called "TOLRESTATS"); and

H

~1 WO 88/06887 PCT/US88/00814 -13- Br [3-(4-bromo-2-fluorobenzyl)-.4-oxo-3H-phthalazin-1-yl]acetic acid (also called "STATIL").

In accordance with the present invention, 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 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 amount and frequency) will be determined by the clinician based on factors such as the patient's physical condition and the duration of action of the pharmaceutical composition employed.

7 7

Claims (4)

1. A method of enhancing insulin sensitivity in a patient afflicted with diabetes mellitus, which comprises administering a therapeutically effective amount of an aldose reductase inhibitor to the patient.

2. A method of preventing or retarding the onset of Type II diabetes mellitus in a patient predisposed to acquiring this condition, which comprises administering a therapeutically effective amount of an aldose reductase inhibitor to the patient. 1 i li :1 i :i 'J i b INTERNATIONAL SEARCH REPORT International Application N cPCT/US88/008 14 I. CLASSIFICATION OF SUBJECT MATTER (it several classification symbols apply, indicate all) 6 i ~I 'I i 'I ;I I _I d d-I, According to International Patent Classification (IPC) or to both National Classification and IPC IPC(4): A61K 31/50, 31/44, 31/42, 31/415, 31/40, 31/195 U.S.Cl.: 514/248, 278, 376, 389, 409, 562 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols U.S. 514/4, 248, 278, 376, 389, 409, 562 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searched a Ill. DOCUMENTS CONSIDERED TO BE RELEVANT a Category Citation of Document, 1i with indication, where approprtate, of the relevant passages 12 Relevant to Claim No. 13 Y A, 4,147,797 (KELBAUGH) 03 April 1-2 1979, see the entire document. Y A, 4,226,875 (SCHNUR) 07 October 1-2 1980, see the entire document, Y A, 4,235,911 (SARGES) 25 November 1-2 1980, see the entire document. Y A, 4,251,258 (BRITTAIN) 17 February 1-2 1981, see the entire document. Y A, 4,254,108 (SESTANJ) 03 March 1-2 1981, see the entire document. Y A, 4,430,337 (HOLLAND) 07 February 1-2 1984, see the entire document. Special categories of cited documents: 1 0 later document published after the international filing date A' document defining the general state of the art which is not or priority date and not in conflict with the application but A"documentdefinnte en r tate the art ich cited to understand the principle or theory underlying the considered to be of particular relevance Invention earlier document but published on or after the international document of particular relevance: the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance: the claimed invention citation or other special reason (as specifed) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 02 MARCH 1988 0 2 JUN 1988 International Searching Authority Signature Authorized Ofcer ISA/US D E WATFT. (1softndh (Rev.-1187) 'I 7 International Application No.PCT/US88/00814 SPCT/US88/00814 FURTHER INFORM,' iON CONTINUED FROM THE SECOND SHEET Y A, 4,537,892 (YORK) 27 August 1985, see the entire document. A, 4,575,507 (LIPINSKI) 11 March 1986, see the entire document. A, 4,604,406 (BELLINI) 05 August 1986, see the entire document. 1-2 1-2 1-2 OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE' This international search report has not been established in respect of certain claims under Article 17(2) for the following reasons: 1.l- Claim numbers because tney relate to subject matter not required to be searched by this Authority, namely: Claim numbers because they relate to parts of the international application that do not comply with the prescribed require- ments to such an extent that no meaningful international search can be carried out specifically:

3. Claim numbers_ because they are dependent claims not drafted in accordance with the second and third sentences of PCT Rule 6.4(a). VI.] OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING 2 This International Searching Authority found multiple inventions In this international application as follows: t1. As all required additional search fees were timely paid by the applicant, this international search report covers ail searchable claims of the international application. As only some of the required additional search fees were timely paid by the applicant, this international searcn report covers only those claims of the international application for vhich fees were paid, specifically claims: 3.7 No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claim numbers:

4 As all searchable claims could be searched without effort ustifying an additional fee, the International Searching Authority did not invite payment of any additional lee. Remark on Protest i The additional search tees were accompanied by applicant's protest. No protest accompanied the payment of additional search fees. Form PCTAISA410 (suplnmsil she (Rev. 11-47)