AU4085799A

AU4085799A - Novel diphenylethylene compounds

Info

Publication number: AU4085799A
Application number: AU40857/99A
Authority: AU
Inventors: Debendranath Dey; Satyanarayana Medicherla; Bishwajit Nag
Original assignee: Calyx Therapeutics Inc
Current assignee: Theracos Inc
Priority date: 1999-05-18
Filing date: 1999-05-18
Publication date: 2000-12-05
Anticipated expiration: 2019-05-18
Also published as: EP1178788A1; AU778767C; CN1354659A; AU778767B2; HK1046642A1; KR100598638B1; KR20020012220A; JP2002544227A; EP1178788A4; WO2000069430A1; MXPA01011760A; HK1046642B; CN1194674C; CA2373603A1

Description

WO00/69430 PCT/US99/11001 NOVEL DIPHENYLETHYLENE COMPOUNDS Field of the Invention 5 The field of the invention is novel diphenylethylene compounds and their use for treatment of diabetes. Background of the Invention Extracts of the leaves, flowers, and gum of the tree Pterocarpus marsupium Roxb. (Leguminosae), also known as the 10 Indian Kino Tree, have been used traditionally for the treatment of diarrhea, toothaches, fever and urinary and skin infections. Extracts of the bark have been long regarded as useful for the therapy of diabetes. Hypoglycemic activity of a naturally occurring 15 pterostilbene, trans-1-(3,5-dimethoxyphenyl)-2-(4 hydroxyphenyl)-ethylene, isolated from the heartwood of pterocarpus marsupium as been reported by Manickam et al., J. Nat. Prod., 1997, 60:609-610. However, this pterostilbene is water insoluble and has not been shown to 20 be efficacious in the treatment of diabetes, particularly in instances where insulin is present but inactive. The cause of diabetes is yet unknown, although both genetics and environment appear to be factors. Insulin dependent (Type I) and non-insulin dependent (Type II) are the types of 25 diabetes. Type I is an autonomic immune disease in which the responsible autoantigen is still unknown. Patients of Type I need to take insulin intravenously to survive. However, Type II diabetes, the more common form of the disease, is a metabolic disorder resulting from the body's 30 inability to make a sufficient amount of insulin or to properly use the insulin that is produced within the body. Insulin secretion and insulin resistance are considered the major defects, however, the precise genetic factors involved in the mechanism remain unknown.

WO00/69430 PCTIUS99/11001 Patients with diabetes usually have one or more of the following defects: less production of insulin by the pancreas; over secretion of glucose by the liver; impairment of glucose uptake by the skeletal muscle; defects in glucose 5 transporters; desensitation of insulin receptors; and defects in the metabolic breakdown of polysaccharides. Other than the intravenous application of insulin, there are four classes of oral hypoglycemic agents in use. Class Approved Mechanisms of Limitations Drugs Action 10 sulfur urea 4 (1st acts on dev. of generation) pancreas to resistance and release more 2 (2nd insulin generation) biguanides metformin reduces liver glucose problems, secretion by lactic liver; acidosis improves insulin sensitivity alpha- acarbose interferes only useful glucosidase with at post inhibitor digestive pradiandio process; level reduces glucose absorption 15 thiazolidin troglipzone reduces "add-on" e-dione insulin with resistancy insulin; not useful for people with heart and liver disease 2 - WO00/69430 PCT/US99/11001 As is apparent from the above table, each of the current agents available for use and treatment of diabetes has certain disadvantages. Accordingly, there is a continuing interest in the identification and development of 5 new agents, particularly, water soluble agents which can be orally administered, for the use of treatment of diabetes. Besides the pterostilbene discussed above, (-)-epicatechin, has also been isolated from pterocarpus marsupium by Sheehan et al., J. Nat. Prod., 1983, 46:232, 10 and has been reported as having a hypoglycemic effect. See also Chakravarthy et al., Life Sciences, 1981, 29:2043-2047. Other phenolic type compounds have been isolated from pterocarpus marsupium by Maurya et al., J. Nat. Prod., 1984, 47:179-181; Jahromi et al., J. Nat. Prod., 1993, 56:989-994; 15 and Maurya et al., Heterocycles, 1982, 19:2103-2107. Summary of the Invention A class of novel diphenylethylenes is provided having the following formula I. RII R wherein R is hydrogen or -COZ, Z is hydrogen or a 20 cation; and R,, R 2 and R 3 are each independently H, -OH or

-OR

4 , wherein R 4 is linear or branched alkyl of 1-12 carbon atoms; with the proviso that when R is hydrogen and R 2 =

R

3 =-OMe, then R. is not -OH. 3 - WO00/69430 PCTIUS99/11001 A novel class of styrenes is also provided of the formula II

R

6 p

R

8 wherein R s is hydrogen or methyl; R 6 and R 7 are independently hydrogen or OMe; R, is hydrogen or hydroxy. 5 Pharmaceutical compositions of compounds of the formula I or II are provided for treatment of diabetes comprising of therapeutically effective amount of the compound in a physiologically acceptable carrier. A method of treating diabetes is also provided 10 comprising step of orally administering to a subject suffering from a diabetic condition a therapeutically effective amount of a compound of formula I or II. Brief Description of the Drawing FIG. 1 shows the effect of administration of the 15 compound in Example 1 on blood glucose level in STZ induced diabetic rats. FIG. 2 shows the effect of the compound in Example 1 on glucose tolerance in hyperinsulinemic and insulin resistant Zucker rats. 20 FIG. 3 shows the effect of the compound in Example 1 on plasma triglyceride levels in Zucker rats. FIG. 4 shows the effect of the compound in Example 1 on glucose tolerance in Zucker rats. - 4 - WO00/69430 PCT/US99/11001 FIGS. 5A, 5B and 5C show, respectively, results of a lethal effect study on Swiss Webster mice by administration of dosages of 16.7, 167, and 333 mg/kg/BW on day zero. Description of the Preferred Embodiments 5 Diphenylethylene of the formula I and styrenes of formula II are provided by synthetic methods generally known in the art. Particularly, preferred are compounds of formula I in which R 2 and R 3 are methoxy. A particularly preferred species is a compound in which R 2 and R 3 are 10 methoxy and R is CO 2 Z, and R, is OH. The cations for Z are typically sodium, lithium, potassium, or any other physiologically acceptable cation which may be introduced orally to a subject. Particularly preferred styrenes of the formula II 15 are those in which R 6 and R 7 are methoxy and R 8 is hydrogen. Another preferred class of the formula II includes compounds wherein R 6 and R 7 are hydrogen and R 8 is hydroxy. The compounds of the formula I and II are made by methods known in the art. In general, for the compounds of 20 formula I, appropriate benzaldehyde and phenylacetic acid starting materials are condensed, then decarboxylated, if required. - 5 - WO 00/69430 PCT/US99/11001 SCHEME I o~on NaOH O CHO OH 130-140oC, 24 hr /Ca OMe CorNH OMe NP9001 Cu, quinoline reflux OMe -6 SUBSTITUTE SHEET (RULE 26) WO 00/69430 PCT/US99/11001 Compounds of the formula II are prepared generally from a benzaldehyde starting material and alkylidenetriphenylphosphorane by the Wittig reaction. SCHEME U + CH2PPh3I 16 hr = CHO

N

2 , HMPA I CH 2 PPh 3 I 1 ous +CH CH 2 Pkh 3 OM

N

2 , IPA + CH 3

CH

2 PPh 3 1 , 16hr m / -7 - WO 00/69430 PCT/US99/11001 Exemplary compounds of the formula I and II are as follows: Oe OeO M e 1 2 OMe OMe OH , OO 3 4 II OH 5 6 MeO MeO I I OMe OMe 7 8 OH 9 -8- WO00/69430 PCT/US99/11001 The compounds according to the present invention may be combined with a physiologically acceptable vehicle in pharmaceutical composition. The particularly preferred form of composition is an orally administrated capsule or 5 solution in which the compound is delivered in water, saline, a phosphate buffer, or lyophilized powder in a form of tablets or capsules which also includes various fillers and binders. The effective dosages of the compound in a composition will be selected by those of ordinary skill in 10 the art and may empirically be determined. The compounds of the present invention are useful for the treatment of diseases such as diabetes characterized by the presence of elevated blood glucose levels, that is, hyperglycemic disorders such as diabetes melitus, including 15 both Type I and II diabetes as well as other hyperglycemic related disorders such as obesity, increased cholesterol, kidney related disorders, and the like. By "treatment", it is meant that the compound is administered at least to reduce the blood glucose level in 20 the patient suffering from the hyperglycemic disorder. The compound is administered in an amount sufficient to reduce blood glucose level to an acceptable range, wherein an acceptable range means ±10%, usually ±8% and usually ±5% of the normal average blood glucose level for the subject. A 25 variety of subjects may be treated with the compounds to reduce blood glucose levels, such as livestock, valuable or rare animals, pets, as well as humans. The compounds may be administered to the subject suffering from the hyperglycemic disorder using a convenient administration technique, 30 including intravenous, intradermal, intramuscular subcutaneous oral and the like. However, the oral route of administration is particularly preferred. The dosage delivered to the host will necessarily depend upon the route - 9 - WO00/69430 PCT/US99/11001 by which the compound is delivered, but generally ranges from 5 to 500 mg/70 kg human body weight or typically from about 50 to 200 mg/70 kg human body weight. Of particular interest are methods of treating human 5 hyperglycemic disorder such as diabetes, including both Type I and II, where the compound is administered to the human suffering from the hyperglycemic disorder to at least reduce the blood glucose level of the subject to about the normal blood glucose range for a human. 10 The following examples are offered by way of illustration and not intended to limit the invention in any way. EXAMPLE 1 Preparation of Sodium 15 2-(4-hydroxyvhenyl)-3-(3,5-dimethoxvphenyl)-propenoate To a mixture of 3,5-dimethoxybenzaldehyde (30 mM) and P-hydroxyphenyl acetic acid (30 mM) was added 5 mL acetic anhydride and 2.5 mL of triethylamine (TEA). After being stirred at 130-140 0 C for 24 hr., the mixture was 20 cooled to room temperature and quenched with 25 mL concentrated HC1 and extracted with CH 2 C1 2 . The organic extract was further extracted with 1N NaOH, then the NaOH extract was washed with water, the aqueous layer was acidified with concentrated HCI and washed with water to 25 obtain the crude product. Crude product was recrystallized from ethanol/water to yield the acid I. To decarboxylate I, ig under N 2 , 3g of Cu powder and 30 mL of quinoline were refluxed, stirring for 4 hrs. The reaction mixture was filtered, diluted with water and 30 extracted with CH 2 C1 2 . The organic layer was dried and concentrated, and the decarboxylated product was purified by flash chromotography. - 10 - WO00/69430 PCT/US99/11001 To convert the acid I to the title compound, to ig of I NaOH solution was added under room temperature. The mixture was shaken and freeze dried to give acid salt title product, 1. 5 EXAMPLE 2 General Procedure for Preparation of Styrene Derivatives General Procedure: To a stirred solution of Wittig salt (1mM) in dry THF at -78 0 C was added potassium 10 (bistrimethylsilyl)amide (1mM). After being stirred under

N

2 for 2 hours at -78 0 C, HMPA (2mM) and aldehyde (1mM) in THF was added and stirred at room temperature for 16 hours. The reaction was quenched with water and extract with diethyl ether. Product was purified by flash 15 chromatography. EXAMPLE 3 Referring to FIG. 1, the streptozotocin (STZ) induced diabetic rats were produced by injecting STZ (40 mg/kg/BW) intravenously. The blood glucose levels were 20 measured 72 hrs. after the injection. Experiments were conducted with rats showing fasting blood glucose levels more than 200 mg/dl. The compound in example 1 was administered at a dose of 20 mg/kg/BW orally to test rats. Simultaneously, a control group received vehicle PBS 25 (phosphate buffered saline). Soon after administration, glucose tolerance tests were conducted by administering glucose (2g/kg/BW) and blood glucose levels were monitored at different time points. The results are shown in FIG. 1. Between 30 and 60 minutes after administration, the blood 30 glucose levels in the rats receiving the test compound began to diminish. - Ii - WO00/69430 PCT/US99/11001 EXAMPLE 4 Referring to FIG. 2, glucose tolerance was measured in Zucker (fa/fa) rats. Hyperinsulinemic and insulin resistant Zucker rats were randomized into two groups 5 designated as a test group and a control group to check the effect of compound in Example 1 on glucose tolerance and insulin levels. Six of the test group rats were given dosages of the compound of Example 1 (20 mg/kg/BW/oral) once per day for period of three days. The control group was 10 gavaged with an equal volume of PBS. An oral glucose (2 g/kg/BW) tolerance test was conducted on overnight-fasted rats soon after administration of test materials on day-3. Referring to FIG. 2, it shows that the compound of Example 1 improves glucose tolerance in insulin resistant obese Zucker 15 rats. EXAMPLE 5 Referring to FIG. 3, twelve insulin resistant hyperinsulinemic obese Zucker (fa/fa) rats were randomized into two groups designated as a test group and a control 20 group. Six of the test group rats received the compound of Example 1 (20 mg/kg/BW) at zero hour. The control group received an equal volume PBS. Plasma triglyceride levels were monitored for a period of 24 hours on fed state. The results are shown in FIG. 3. The compound from Example 1 25 lowers plasma triglyceride levels in obese insulin resistant hyperinsulinemic and triglyceridemic Zucker rats. EXAMPLE 6 Referring to FIG. 4, twelve obese hyperinsulinemic and insulin resistant Zucker (fa/fa) rats were randomized 30 into groups designated as the test group and control group. Six of the test group were kept on the compound of Example 1 - 12 - WO00/69430 PCT/US99/11001 (20 mg/kg/BW/oral) once per day for a period of thirteen days. The control group was gavaged with an equal volume of PBS. Basal plasma insulin levels were monitored intermittently every three or four days during the course of 5 the thirteen day study. The results in FIG. 4 show that the compound has an effect on lowering plasma insulin levels in this animal model. EXAMPLE 7 Nine healthy male Swiss Webster mice were divided 10 into three study groups of three. The first study group (FIG. 5A) received the compound of Example 1 at a dose of 16.7 mg/kg/BW, the second study group (FIG. 5B) received a dose of 167 mg/kg/BW, and the third study group (FIG. 5C) received a dose of 333 mg/kg/BW on day zero of the study. 15 The mice were kept on regular food and water during the entire study period. During the study, the mice were under close observation and their behavior, gross physiology and mortality/survival were monitored. FIGS. 5A, 5B and 5C show that the survival rate in these mice in the course of the 20 study period was 100%. What is claimed is: - 13 -

Claims

1. A compound of the formula I RR R(I) wherein R is hydrogen; and RI, R 2 , R 3 are each independently H, -OH, -OR 4 wherein 5 R 4 is linear or branched alkyl of 1-12 carbon atoms; with the proviso that when R is H and R 2 =R 3 =-OMe, then Ri is not -OH.

2. The compound according to claim 1, wherein R 2 and R 3 are OMe. 10

3. The compound according to claim 2, wherein R. is OMe.

4. The compound according to claim 2, wherein Ri is H.

5. The compound according to claim 1, wherein R 2 15 and R 3 are hydrogen and R, is OH.

6. The compound according to claim 1, wherein R 2 is OMe, R 3 is hydrogen and R, is OH. - 14 - WO 00/69430 PCT/US99/11001

7. The compound according to claim 1, wherein R 2 and R 3 are OH, and R, is OMe.

8. A compound of the formula II R 8 R 7 Or) wherein R s is hydrogen or methyl; R, and R, are each 5 independently hydrogen or -OMe; and R, is H or OH.

9. A compound according to claim 8, wherein R s and R, are hydrogen and R 6 and R 7 are OMe.

10. A compound according to claim 8, wherein R s is methyl, R 6 and R 7 are OMe and R 8 is hydrogen. 10

11. A compound according to claim 8, wherein R s is methyl, R , and R 7 are hydrogen and R 8 is OH.

12. A composition according to any one of claims 19 to 30 which is suitable for oral administration.

13. A method for treating diabetes comprising the 15 step of administering to a subject suffering from a diabetic condition a therapeutically amount of a composition - 15 - WO00/69430 PCTIUS99/11001 according to any one of claims 19 to 30, or mixtures thereof, in a physiologically acceptable carrier.

14. A method according to claim 13 in which said composition is administered orally to said subject. 5

15. A pharmaceutical composition for the treatment of diabetes comprising a therapeutically effective amount of the compound of the formula OH MeO OMe in a physiologically acceptable carrier.

16. A composition according to claim 15, wherein 10 said composition is suitable for oral administration.

17. A method of treating diabetes comprising a step of administering to a subject suffering from a diabetic condition a therapeutically effective amount of a compound - 16 - WO 00/69430 PCTIUS99/11001 ,OH MeO op OMe in a physiologically acceptable carrier.

18. A method according to claim 17, wherein said compound is orally administered to said subject.

19. A pharmaceutical composition for the treatment 5 of diabetes comprising a therapeutically effective amount of a compound, or mixtures compounds of the formula: RR wherein R is hydrogen or -CO 2 Z, Z is H or a cation; and R 1 , R 2 , R 3 are each independently H, -OH, -OR 4 wherein 10 R 4 is linear or branched alkyl of 1-12 carbon atoms; - 17 - WO 00/69430 PCT/US99/11001 with the proviso that when R is H and R 2 =R 3 =-OMe, then R, is not -OH; and a physiologically acceptable carrier.

20. The composition according to claim 19, wherein 5 R 2 and R 3 are OMe.

21. The composition according to claim 20, wherein R is -CO 2 Z and R, is OH.

22. The composition according to claim 20, wherein R is H and RI is OMe. 10

23. The composition according to claim 20, wherein R is H and R I is H.

24. The composition according to claim 19, wherein R 2 and R 3 are hydrogen and R, is OH.

25. The composition according to claim 19, wherein 15 R 2 is OMe, R 3 and R are hydrogen and R, is OH.

26. The composition according to claim 19, wherein R 2 and R, are OH, R is H and R, is OMe.

27. A pharmaceutical composition for the treatment of diabetes comprising a therapeutically effective amount of 20 a compound or mixture of compounds of the formula: - 18 - WO 00/69430 PCT/US99/11001 R 5 R R 7 ) wherein R s is hydrogen or methyl; R s and R, are each independently hydrogen or -OMe; and R, is H or OH; and a physiologically acceptable carrier.

28. A composition according to claim 27, wherein R s 5 and R 8 are hydrogen and R 6 and R 7 are OMe.

29. A composition according to claim 27, wherein R s is methyl, R. and R 7 are OMe and R 8 is hydrogen.

30. A composition according to claim 27, wherein R, is methyl, R 6 and R 7 are hydrogen and R 8 is OH. - 19 -