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WO2000069430A1 - Novel diphenylethylene compounds - Google Patents

Novel diphenylethylene compounds Download PDF

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Publication number
WO2000069430A1
WO2000069430A1 PCT/US1999/011001 US9911001W WO0069430A1 WO 2000069430 A1 WO2000069430 A1 WO 2000069430A1 US 9911001 W US9911001 W US 9911001W WO 0069430 A1 WO0069430 A1 WO 0069430A1
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WIPO (PCT)
Prior art keywords
compound
hydrogen
ome
composition according
diabetes
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Application number
PCT/US1999/011001
Other languages
French (fr)
Inventor
Bishwajit Nag
Satyanarayana Medicherla
Debendranath Dey
Original Assignee
Calyx Therapeutics, Inc.
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Publication date
Application filed by Calyx Therapeutics, Inc. filed Critical Calyx Therapeutics, Inc.
Priority to PCT/US1999/011001 priority Critical patent/WO2000069430A1/en
Priority to CA002373603A priority patent/CA2373603A1/en
Priority to JP2000617889A priority patent/JP2002544227A/en
Priority to AU40857/99A priority patent/AU778767C/en
Priority to CNB998166448A priority patent/CN1194674C/en
Priority to EP99924332A priority patent/EP1178788A4/en
Priority to MXPA01011760A priority patent/MXPA01011760A/en
Priority to KR1020017014590A priority patent/KR100598638B1/en
Publication of WO2000069430A1 publication Critical patent/WO2000069430A1/en
Priority to HK02108244.5A priority patent/HK1046642B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/40—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals
    • C07C15/50—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals polycyclic non-condensed
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • 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
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/15—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with all hydroxy groups on non-condensed rings, e.g. phenylphenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring

Definitions

  • the field of the invention is novel diphenylethylene compounds and their use for treatment of diabetes.
  • Extracts of the leaves, flowers, and gum of the tree Pterocarpus marsupium Roxb. (Leguminosae) , also known as the 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.
  • Type I Insulin dependent
  • Type II non-insulin dependent
  • 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.
  • Type II diabetes the more common form of the disease, is a metabolic disorder resulting from the body's 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.
  • 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 transporters; desensitation of insulin receptors; and defects in the metabolic breakdown of polysaccharides.
  • defects in the intravenous application of insulin there are four classes of oral hypoglycemic agents in use.
  • a novel class of styrenes is also provided of the formula II
  • 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 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.
  • FIG. 1 shows the effect of administration of the 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.
  • 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.
  • 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.
  • 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 methoxy and R is C0 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 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 formula I, appropriate benzaldehyde and phenylacetic acid starting materials are condensed, then decarboxylated, if required.
  • the compounds according to the present invention may be combined with a physiologically acceptable vehicle in pharmaceutical composition.
  • a physiologically acceptable vehicle in pharmaceutical composition.
  • the particularly preferred form of composition is an orally administrated capsule or 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 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 both Type I and II diabetes as well as other hyperglycemic related disorders such as obesity, increased cholesterol, kidney related disorders, and the like.
  • treatment it is meant that the compound is administered at least to reduce the blood glucose level in 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.
  • an acceptable range means ⁇ 10%, usually ⁇ 8% and usually ⁇ 5% of the normal average blood glucose level for the subject.
  • an acceptable range means ⁇ 10%, usually ⁇ 8% and usually ⁇ 5% of the normal average blood glucose level for the subject.
  • a 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, 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 by which the compound is delivered,
  • the organic extract was further extracted with IN NaOH, then the NaOH extract was washed with water, the aqueous layer was acidified with concentrated HCl and washed with water to obtain the crude product. Crude product was recrystallized from ethanol/water to yield the acid I .
  • 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 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 (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.
  • STZ streptozotocin
  • EXAMPLE 4 glucose tolerance was measured in Zucker (fa/fa) rats. Hyperinsulinemic and insulin resistant Zucker rats were randomized into two groups 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 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 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 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 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 into groups designated as the test group and control group. Six of the test group were kept on the compound of Example 1 (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 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 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
  • the third study group (FIG. 5C) received a dose of 333 mg/kg/BW on day zero of the study.
  • 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 study period was 100%.

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Abstract

Novel diphenylethylene and styrenes are provided which are administered orally to decrease blood glucose levels in rats. The glucose tolerance in insulin resistant rats is also shown, as well as lowering of triglyceride levels in serum insulin resistant, hyperinsulinemic and hypertriglycedemic rats. The compounds are orally effective anti-diabetic agents that potentially may reduce abnormality of glucose and lipid metabolism in diabetes.

Description

NOVEL DIPHENYLETHYLENE COMPOUNDS Field of the Invention 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 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 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, £0:609-610. However, this pterostilbene is water insoluble and has not been shown to 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 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 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. 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 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.
Figure imgf000004_0001
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 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, 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, 42:179-181; Jahromi et al . , J. Nat. Prod.. 1993, 56:989-994; 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.
Figure imgf000005_0001
wherein R is hydrogen or -C02Z, Z is hydrogen or a cation; and R,_, R2 and R3 are each independently H, -OH or -0R4, wherein R4 is linear or branched alkyl of 1-12 carbon atoms; with the proviso that when R is hydrogen and R2 = R3=-OMe, then R: is not -OH. A novel class of styrenes is also provided of the formula II
Figure imgf000006_0001
wherein R5 is hydrogen or methyl; Rβ and R7 are independently hydrogen or OMe; R8 is hydrogen or hydroxy. 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 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 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. 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. 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 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 R2 and R3 are methoxy. A particularly preferred species is a compound in which R2 and R3 are methoxy and R is C02Z, 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 are those in which R6 and R7 are methoxy and R8 is hydrogen. Another preferred class of the formula II includes compounds wherein R6 and R7 are hydrogen and R8 is hydroxy.
The compounds of the formula I and II are made by methods known in the art. In general, for the compounds of formula I, appropriate benzaldehyde and phenylacetic acid starting materials are condensed, then decarboxylated, if required.
SCHEME I
Figure imgf000008_0001
Compounds of the formula II are prepared generally from a benzaldehyde starting material and alkylidenetriphenylphosphorane by the Wittig reaction.
SCHEME U
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000009_0003
Exemplary compounds of the formula I and II are as follows :
Figure imgf000010_0001
Figure imgf000010_0002
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 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 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 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 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 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, 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 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 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. The following examples are offered by way of illustration and not intended to limit the invention in any way.
EXAMPLE 1 Preparation of Sodium 2- (4-hydroxyτ»henyl) -3- (3 , 5-dimethoxyphenyl) -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°C for 24 hr., the mixture was cooled to room temperature and quenched with 25 mL concentrated HCl and extracted with CH2C12. The organic extract was further extracted with IN NaOH, then the NaOH extract was washed with water, the aqueous layer was acidified with concentrated HCl and washed with water to obtain the crude product. Crude product was recrystallized from ethanol/water to yield the acid I .
To decarboxylate I, lg under N2, 3g of Cu powder and 30 mL of quinoline were refluxed, stirring for 4 hrs . The reaction mixture was filtered, diluted with water and extracted with CH2C12. The organic layer was dried and concentrated, and the decarboxylated product was purified by flash chromotography . To convert the acid I to the title compound, to lg of I NaOH solution was added under room temperature. The mixture was shaken and freeze dried to give acid salt title product , 1.
EXAMPLE 2
General Procedure for Preparation of Styrene Derivatives General Procedure: To a stirred solution of Wittig salt (ImM) in dry THF at -78 °C was added potassium (bistrimethylsilyl) amide (ImM). After being stirred under N2 for 2 hours at -78°C, HMPA (2τnM) and aldehyde (ImM) 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 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 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 (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 glucose levels in the rats receiving the test compound began to diminish. 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 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 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 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 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 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 into groups designated as the test group and control group. Six of the test group were kept on the compound of Example 1 (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 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 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. 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 study period was 100%.
What is claimed is:

Claims

CLAIMS 1. A compound of the formula I
Figure imgf000016_0001
wherein R is hydrogen; and
R_ , R2 , R3 are each independently H, -OH, -OR4 wherein R4 is linear or branched alkyl of 1-12 carbon atoms; with the proviso that when R is H and R2=R3=-OMe, then R_ is not -OH.
2. The compound according to claim 1, wherein R2 and R3 are OMe .
3. The compound according to claim 2, wherein R_ is OMe.
4. The compound according to claim 2, wherein R1 is H.
5. The compound according to claim 1, wherein R2 and R3 are hydrogen and R_ is OH.
6. The compound according to claim 1, wherein R2 is OMe, R3 is hydrogen and R_ is OH.
7. The compound according to claim 1, wherein R2 and R3 are OH, and R- is OMe.
8. A compound of the formula II
Figure imgf000017_0001
wherein R5 is hydrogen or methyl; R5 and R7 are each independently hydrogen or -OMe; and R8 is H or OH.
9. A compound according to claim 8, wherein R5 and R8 are hydrogen and R6 and R7 are OMe .
10. A compound according to claim 8, wherein R5 is methyl, R6 and R7 are OMe and R8 is hydrogen.
11. A compound according to claim 8, wherein R5 is methyl, R6 and R7 are hydrogen and R8 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 step of administering to a subject suffering from a diabetic condition a therapeutically amount of a composition 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.
15. A pharmaceutical composition for the treatment of diabetes comprising a therapeutically effective amount of the compound of the formula
Figure imgf000018_0001
in a physiologically acceptable carrier.
16. A composition according to claim 15, wherein 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
Figure imgf000019_0001
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 of diabetes comprising a therapeutically effective amount of a compound, or mixtures compounds of the formula:
Figure imgf000019_0002
wherein R is hydrogen or -C02Z, Z is H or a cation; and
R1# R2, R3 are each independently H, -OH, -0R4 wherein R4 is linear or branched alkyl of 1-12 carbon atoms; with the proviso that when R is H and R2=R3=-OMe, then R_ is not -OH; and a physiologically acceptable carrier.
20. The composition according to claim 19, wherein R2 and R3 are OMe.
21. The composition according to claim 20, wherein R is -C02Z and R_ is OH.
22. The composition according to claim 20, wherein R is H and R_ is OMe.
23. The composition according to claim 20, wherein
R is H and R_ is H.
24. The composition according to claim 19, wherein R2 and R3 are hydrogen and R- is OH.
25. The composition according to claim 19, wherein R2 is OMe, R3 and R are hydrogen and R_ is OH.
26. The composition according to claim 19, wherein R2 and R3 are OH, R is H and R_ is OMe.
27. A pharmaceutical composition for the treatment of diabetes comprising a therapeutically effective amount of a compound or mixture of compounds of the formula:
Figure imgf000021_0001
wherein R5 is hydrogen or methyl; R6 and R7 are each independently hydrogen or -OMe; and R8 is H or OH; and a physiologically acceptable carrier.
28. A composition according to claim 27, wherein R5 and R8 are hydrogen and R6 and R7 are OMe .
29. A composition according to claim 27, wherein R5 is methyl, R6 and R7 are OMe and R8 is hydrogen.
30. A composition according to claim 27, wherein R_ is methyl, R6 and R7 are hydrogen and R8 is OH.
PCT/US1999/011001 1999-05-18 1999-05-18 Novel diphenylethylene compounds WO2000069430A1 (en)

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CA002373603A CA2373603A1 (en) 1999-05-18 1999-05-18 Novel diphenylethylene compounds
JP2000617889A JP2002544227A (en) 1999-05-18 1999-05-18 New diphenylethylene compounds
AU40857/99A AU778767C (en) 1999-05-18 1999-05-18 Novel diphenylethylene compounds
CNB998166448A CN1194674C (en) 1999-05-18 1999-05-18 Novel stilbene compounds
EP99924332A EP1178788A4 (en) 1999-05-18 1999-05-18 Novel diphenylethylene compounds
MXPA01011760A MXPA01011760A (en) 1999-05-18 1999-05-18 Novel diphenylethylene compounds.
KR1020017014590A KR100598638B1 (en) 1999-05-18 1999-05-18 Novel Diphenylethylene Compounds
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056382A1 (en) * 2000-02-04 2001-08-09 Calyx Therapeutics, Inc. Novel diphenylethylene compounds
WO2002013811A3 (en) * 2000-08-16 2002-08-15 Insmed Inc Compositions containing hypoglycemically active stilbenoids
WO2002014252A3 (en) * 2000-08-16 2002-09-12 Insmed Inc Compositions containing hypoglycemically active stilbenoids
JP2003095856A (en) * 2001-09-26 2003-04-03 Nonogawa Shoji Kk Skin care preparation
WO2006007794A1 (en) * 2004-07-21 2006-01-26 Institut Of Radiation Medicine, Academy Of Military Medical Sciences, Pla Cis-1,2-substituted stilbene derivates and the use thererof for manufacturing medicaments for treating medicaments for treating and/or preventing diabetes
EP1421933A4 (en) * 2001-07-26 2007-09-05 Inst Radiation Med Amms Pla Use of stilbene compounds in preparing medicaments for treating or preventing diabetes and diseases associated with retrovirus
US7323496B2 (en) 1999-11-08 2008-01-29 Theracos, Inc. Compounds for treatment of inflammation, diabetes and related disorders
US7544497B2 (en) 2003-07-01 2009-06-09 President And Fellows Of Harvard College Compositions for manipulating the lifespan and stress response of cells and organisms
US8101804B2 (en) 2006-07-28 2012-01-24 Clariant Specialty Fine Chemicals (France) Process for the synthesis of (E)-stilbene derivatives which makes it possible to obtain resveratrol and piceatannol
US8242171B2 (en) 2003-12-29 2012-08-14 President And Fellows Of Harvard College Method for reducing the weight of a subject or inhibiting weight gain in a subject
US8399714B2 (en) 2007-10-03 2013-03-19 Clariant Speciality Fine Chemicals (France) Process for the synthesis of polyhydroxystilbene compounds
US8846724B2 (en) 2003-12-29 2014-09-30 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
US9241916B2 (en) 2005-06-14 2016-01-26 President And Fellows Of Harvard College Cognitive performance with sirtuin activators

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100384801C (en) * 2006-06-23 2008-04-30 中国科学院广州化学研究所 (E)-3,5-dimethox-4'-hydroxy diphenyl ethylene synthesis method
CN107324976B (en) * 2017-07-28 2020-06-16 安徽理工大学 Method for preparing (E) - β -alkyl styrene compound

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5314693A (en) * 1992-02-07 1994-05-24 Kioritz Corporation Pest control chemicals against pine wood nematodes
US5430062A (en) * 1992-05-21 1995-07-04 Research Corporation Technologies, Inc. Stilbene derivatives as anticancer agents
US5770620A (en) * 1995-06-19 1998-06-23 Ontogen Corporation Aryl acrylic acid derivatives useful as protein tyrosine phosphatase inhibitors
US5827898A (en) * 1996-10-07 1998-10-27 Shaman Pharmaceuticals, Inc. Use of bisphenolic compounds to treat type II diabetes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2778337B1 (en) * 1998-05-05 2001-08-31 Inst Nat Sante Rech Med ARYLHYDROCARBON RECEPTOR LIGAND ANTAGONISTS

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5314693A (en) * 1992-02-07 1994-05-24 Kioritz Corporation Pest control chemicals against pine wood nematodes
US5430062A (en) * 1992-05-21 1995-07-04 Research Corporation Technologies, Inc. Stilbene derivatives as anticancer agents
US5770620A (en) * 1995-06-19 1998-06-23 Ontogen Corporation Aryl acrylic acid derivatives useful as protein tyrosine phosphatase inhibitors
US5827898A (en) * 1996-10-07 1998-10-27 Shaman Pharmaceuticals, Inc. Use of bisphenolic compounds to treat type II diabetes

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
GREEN R. H.: "Syntheses of Differanisole A", TETRAHEDRON LETTERS, vol. 38, no. 26, 1997, pages 4697 - 4700, XP002919437 *
PETTIT G. R. ET AL: "Isolation, Structure , Synthesis, and Antimitotic Properties of Combretastatins B-3 and B-4 from Combretum Caffrum", J. NAT. PROD., vol. 51, no. 3, 1988, pages 517 - 527, XP002919438 *
REDDY K.L. ET AL: "From Styrenes to Enantiopure Alpha-Arylglycines in Two Steps", J. AM. CHEM. SOC., vol. 120, no. 6, 1998, pages 1207 - 1217, XP002919436 *
See also references of EP1178788A4 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7323496B2 (en) 1999-11-08 2008-01-29 Theracos, Inc. Compounds for treatment of inflammation, diabetes and related disorders
WO2001056382A1 (en) * 2000-02-04 2001-08-09 Calyx Therapeutics, Inc. Novel diphenylethylene compounds
WO2002013811A3 (en) * 2000-08-16 2002-08-15 Insmed Inc Compositions containing hypoglycemically active stilbenoids
WO2002014252A3 (en) * 2000-08-16 2002-09-12 Insmed Inc Compositions containing hypoglycemically active stilbenoids
US6552085B2 (en) 2000-08-16 2003-04-22 Insmed Incorporated Compositions containing hypoglycemically active stilbenoids
US7384920B2 (en) 2001-07-26 2008-06-10 Institute Of Radiation Medicine, Academy Of Military Medical Sciences, Pla Use of stilbene compounds in the manufacture of medicament for the prevention and treatment of diabetes or retrovirus-associated diseases
EP1421933A4 (en) * 2001-07-26 2007-09-05 Inst Radiation Med Amms Pla Use of stilbene compounds in preparing medicaments for treating or preventing diabetes and diseases associated with retrovirus
JP2003095856A (en) * 2001-09-26 2003-04-03 Nonogawa Shoji Kk Skin care preparation
US7544497B2 (en) 2003-07-01 2009-06-09 President And Fellows Of Harvard College Compositions for manipulating the lifespan and stress response of cells and organisms
US8242171B2 (en) 2003-12-29 2012-08-14 President And Fellows Of Harvard College Method for reducing the weight of a subject or inhibiting weight gain in a subject
US8846724B2 (en) 2003-12-29 2014-09-30 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
US9597347B2 (en) 2003-12-29 2017-03-21 President And Fellows Of Harvard College Compositions for treating obesity and insulin resistance disorders
WO2006007794A1 (en) * 2004-07-21 2006-01-26 Institut Of Radiation Medicine, Academy Of Military Medical Sciences, Pla Cis-1,2-substituted stilbene derivates and the use thererof for manufacturing medicaments for treating medicaments for treating and/or preventing diabetes
US8039513B2 (en) * 2004-07-21 2011-10-18 Institute Of Radiation Medicine, Academy Of Military Medical Sciences, Pla Cis-1,2-substituted stilbene derivatives and their use in preparation of drugs for treatment and/or prevention of diabetes
US9241916B2 (en) 2005-06-14 2016-01-26 President And Fellows Of Harvard College Cognitive performance with sirtuin activators
US8101804B2 (en) 2006-07-28 2012-01-24 Clariant Specialty Fine Chemicals (France) Process for the synthesis of (E)-stilbene derivatives which makes it possible to obtain resveratrol and piceatannol
US8399714B2 (en) 2007-10-03 2013-03-19 Clariant Speciality Fine Chemicals (France) Process for the synthesis of polyhydroxystilbene compounds

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AU778767C (en) 2006-09-07
KR100598638B1 (en) 2006-07-07
CN1354659A (en) 2002-06-19
KR20020012220A (en) 2002-02-15
EP1178788A1 (en) 2002-02-13
EP1178788A4 (en) 2005-08-10
AU4085799A (en) 2000-12-05
HK1046642A1 (en) 2003-01-24
HK1046642B (en) 2005-11-25
CN1194674C (en) 2005-03-30

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