CA2373603A1 - Novel diphenylethylene compounds - Google Patents
Novel diphenylethylene compounds Download PDFInfo
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- CA2373603A1 CA2373603A1 CA002373603A CA2373603A CA2373603A1 CA 2373603 A1 CA2373603 A1 CA 2373603A1 CA 002373603 A CA002373603 A CA 002373603A CA 2373603 A CA2373603 A CA 2373603A CA 2373603 A1 CA2373603 A1 CA 2373603A1
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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
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- 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
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, 60:609-610. 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 corm 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.
Class Approved Mechanisms of Limitations Drugs Act ion sulfur urea 4 (1st acts on dev. of generation) pancreas to resistance and release more
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, 60:609-610. 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 corm 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.
Class Approved Mechanisms of Limitations Drugs Act ion 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 thiazolidin troglipzone reduces "add-on"
e-dione insulin with resistancy insulin; not useful for people with heart and liver disease 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, _47:179-181; 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.
R.
wherein R is hydrogen or -CO~Z, Z is hydrogen or a cation;
and R, , R2 and R3 are each independently H, -OH or -OR4, 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.
e-dione insulin with resistancy insulin; not useful for people with heart and liver disease 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, _47:179-181; 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.
R.
wherein R is hydrogen or -CO~Z, Z is hydrogen or a cation;
and R, , R2 and R3 are each independently H, -OH or -OR4, 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.
- 3 A novel class of styrenes is also provided of the formula II
'I
C~ ) wherein RS is hydrogen or methyl; R6 and R, 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 ?0 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 ~5 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.
'I
C~ ) wherein RS is hydrogen or methyl; R6 and R, 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 ?0 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 ~5 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 -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 Rz and R3 are methoxy and R is C02Z, and R1 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 R5 and R, are methoxy and R8 is hydrogen.
Another preferred class of the formula II includes compounds wherein R6 and R, are hydrogen and Re 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.
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 Rz and R3 are methoxy and R is C02Z, and R1 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 R5 and R, are methoxy and R8 is hydrogen.
Another preferred class of the formula II includes compounds wherein R6 and R, are hydrogen and Re 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.
- 5 -SCHEME I
OM, NaOH
cHO off Ac=OrTEA
/ ----., 130~ 140~C, 241 OMe
OM, NaOH
cHO off Ac=OrTEA
/ ----., 130~ 140~C, 241 OMe
- 6 -OH
SUBSTITUTE SHEET (RULE 26) OMe TTp900I
Cu, quinolinc reflex Compounds of the formula II are prepared generally from a benzaldehyde starting material and alkylidenetriphenylphosphorane by the Wittig reaction.
\ CHO NZ~ ~ \
/ + CHZPPh3t 16 hr OMe OM~
\ CHO
Nz, HMPA \ \_ + CH~CHZPPh3I
16 hr /
OMt OMB
\ C~ \ \
+ CH3CHZPPh31 N~'~ _ / /
16 hr M,p Exemplary compounds of the formula I and II are as follows:
/ OH
Me0 \ ' COOnG~
OMe , OMe / OH
~ \ Meo / \ \
_ _ \
_ OMe OMe Me0 / ~ \ HO / ~ \
- ~ v v \ \
OH
Me0 / ~ Me0 OMe OMe OH
_ g _ 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 tie 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 _ g _ 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.
Preparation of Sodium 2-(4-hydroxyphenyl)-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 HC1 and extracted with CH2C12. The organic extract was further extracted with 1N 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, 1g under Nz, 3g of Cu powder and mL of quinoline were refluxed, stirring for 4 hrs. The reaction mixture was filtered, diluted with water and 30 extracted with CHzCl2. 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 1g of I NaOH solution was added under room temperature. The mixture was shaken and freeze dried to give acid salt title product, 1.
General Procedure for Preparation of Styrene Derivatives General Procedure: To a stirred solution of Wittig salt (1mM) in dry THF at -78°C was added potassium (bistrimethylsilyl)amide (1mM). After being stirred under N2 for 2 hours at -78°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 chromatography.
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.
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.
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.
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.
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:
SUBSTITUTE SHEET (RULE 26) OMe TTp900I
Cu, quinolinc reflex Compounds of the formula II are prepared generally from a benzaldehyde starting material and alkylidenetriphenylphosphorane by the Wittig reaction.
\ CHO NZ~ ~ \
/ + CHZPPh3t 16 hr OMe OM~
\ CHO
Nz, HMPA \ \_ + CH~CHZPPh3I
16 hr /
OMt OMB
\ C~ \ \
+ CH3CHZPPh31 N~'~ _ / /
16 hr M,p Exemplary compounds of the formula I and II are as follows:
/ OH
Me0 \ ' COOnG~
OMe , OMe / OH
~ \ Meo / \ \
_ _ \
_ OMe OMe Me0 / ~ \ HO / ~ \
- ~ v v \ \
OH
Me0 / ~ Me0 OMe OMe OH
_ g _ 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 tie 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 _ g _ 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.
Preparation of Sodium 2-(4-hydroxyphenyl)-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 HC1 and extracted with CH2C12. The organic extract was further extracted with 1N 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, 1g under Nz, 3g of Cu powder and mL of quinoline were refluxed, stirring for 4 hrs. The reaction mixture was filtered, diluted with water and 30 extracted with CHzCl2. 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 1g of I NaOH solution was added under room temperature. The mixture was shaken and freeze dried to give acid salt title product, 1.
General Procedure for Preparation of Styrene Derivatives General Procedure: To a stirred solution of Wittig salt (1mM) in dry THF at -78°C was added potassium (bistrimethylsilyl)amide (1mM). After being stirred under N2 for 2 hours at -78°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 chromatography.
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.
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.
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.
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.
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 (30)
1. A compound of the formula I
wherein R is hydrogen; and R1, 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 R1 is not -OH.
wherein R is hydrogen; and R1, 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 R1 is not -OH.
2. The compound according to claim 1, wherein R2 and R3 are OMe.
3. The compound according to claim 2, wherein R1 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 R1 is OH.
6. The compound according to claim 1, wherein R2 i s OMe , R3 i s hydrogen and R1 is OH.
7. The compound according to claim 1, wherein R2 and R3 are OH, and R1 is OMe.
8. A compound of the formula II
wherein R5 is hydrogen or methyl; R6 and R7 are each independently hydrogen or -OMe; and R8 is H or OH.
wherein R5 is hydrogen or methyl; R6 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 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 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:
wherein R is hydrogen or -CO2Z, Z is H or a cation;
and R1, 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 R1 is not -OH; and a physiologically acceptable carrier.
wherein R is hydrogen or -CO2Z, Z is H or a cation;
and R1, 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 R1 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 - CO2Z and R1 is OH.
22. The composition according to claim 20, wherein R is H and R1 is OMe.
23. The composition according to claim 20, wherein R is H and R1 is H.
24. The composition according to claim 19, wherein R2 and R3 are hydrogen and R1 is OH.
25. The composition according to claim 19, wherein R2 is OMe, R3 and R are hydrogen and R1 is OH.
26. The composition according to claim 19, wherein R2 and R3 are OH, R is H and R1 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:
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.
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 R5 is methyl, R6 and R7 are hydrogen and R8 is OH.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1999/011001 WO2000069430A1 (en) | 1999-05-18 | 1999-05-18 | Novel diphenylethylene compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2373603A1 true CA2373603A1 (en) | 2000-11-23 |
Family
ID=22272785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002373603A Abandoned CA2373603A1 (en) | 1999-05-18 | 1999-05-18 | Novel diphenylethylene compounds |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP1178788A4 (en) |
| JP (1) | JP2002544227A (en) |
| KR (1) | KR100598638B1 (en) |
| CN (1) | CN1194674C (en) |
| AU (1) | AU778767C (en) |
| CA (1) | CA2373603A1 (en) |
| HK (1) | HK1046642B (en) |
| MX (1) | MXPA01011760A (en) |
| WO (1) | WO2000069430A1 (en) |
Families Citing this family (14)
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|---|---|---|---|---|
| US7323496B2 (en) | 1999-11-08 | 2008-01-29 | Theracos, Inc. | Compounds for treatment of inflammation, diabetes and related disorders |
| CA2397076A1 (en) * | 2000-02-04 | 2001-08-09 | Calyx Therapeutics, Inc. | Novel diphenylethylene compounds |
| US6552085B2 (en) | 2000-08-16 | 2003-04-22 | Insmed Incorporated | Compositions containing hypoglycemically active stilbenoids |
| US6410596B1 (en) * | 2000-08-16 | 2002-06-25 | Insmed Incorporated | Compositions containing hypoglycemically active stillbenoids |
| CN1398838A (en) | 2001-07-26 | 2003-02-26 | 中国人民解放军军事医学科学院放射医学研究所 | Diphenylethylene compound and its prepn and application in preventing and treating diabetes |
| JP4781580B2 (en) * | 2001-09-26 | 2011-09-28 | 日本メナード化粧品株式会社 | Collagenase inhibitor |
| EP1708689A2 (en) | 2003-12-29 | 2006-10-11 | The President and Fellows of Harvard College | Compositions for treating or preventing obesity and insulin resistance disorders |
| US8017634B2 (en) | 2003-12-29 | 2011-09-13 | President And Fellows Of Harvard College | Compositions for treating obesity and insulin resistance disorders |
| CN1723884A (en) * | 2004-07-21 | 2006-01-25 | 中国人民解放军军事医学科学院放射医学研究所 | Cis-1, the diphenyl ethylene derivatives that 2-replaces are used to prepare the purposes of the medicine of treatment or prevent diabetes |
| WO2006138418A2 (en) | 2005-06-14 | 2006-12-28 | President And Fellows Of Harvard College | Improvement of cognitive performance with sirtuin activators |
| 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 |
| FR2904311B1 (en) | 2006-07-28 | 2013-01-11 | Clariant Specialty Fine Chem F | NEW PROCESS FOR THE SYNTHESIS OF (E) STILBENIC DERIVATIVES PERM TO OBTAIN RESVERATROL AND PICEATANNOL |
| FR2921921B1 (en) | 2007-10-03 | 2011-08-19 | Clariant Specialty Fine Chem F | PROCESS FOR THE SYNTHESIS OF POLYHYDROXYSTILBENIC COMPOUNDS |
| CN107324976B (en) * | 2017-07-28 | 2020-06-16 | 安徽理工大学 | Method for preparing (E) - β -alkyl styrene compound |
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|---|---|---|---|---|
| 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 |
| FR2778337B1 (en) * | 1998-05-05 | 2001-08-31 | Inst Nat Sante Rech Med | ARYLHYDROCARBON RECEPTOR LIGAND ANTAGONISTS |
-
1999
- 1999-05-18 AU AU40857/99A patent/AU778767C/en not_active Ceased
- 1999-05-18 JP JP2000617889A patent/JP2002544227A/en active Pending
- 1999-05-18 KR KR1020017014590A patent/KR100598638B1/en not_active IP Right Cessation
- 1999-05-18 WO PCT/US1999/011001 patent/WO2000069430A1/en active IP Right Grant
- 1999-05-18 EP EP99924332A patent/EP1178788A4/en not_active Withdrawn
- 1999-05-18 CN CNB998166448A patent/CN1194674C/en not_active Expired - Fee Related
- 1999-05-18 CA CA002373603A patent/CA2373603A1/en not_active Abandoned
- 1999-05-18 MX MXPA01011760A patent/MXPA01011760A/en not_active IP Right Cessation
-
2002
- 2002-11-14 HK HK02108244.5A patent/HK1046642B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1178788A1 (en) | 2002-02-13 |
| EP1178788A4 (en) | 2005-08-10 |
| AU778767C (en) | 2006-09-07 |
| HK1046642B (en) | 2005-11-25 |
| WO2000069430A1 (en) | 2000-11-23 |
| HK1046642A1 (en) | 2003-01-24 |
| AU4085799A (en) | 2000-12-05 |
| CN1354659A (en) | 2002-06-19 |
| KR100598638B1 (en) | 2006-07-07 |
| KR20020012220A (en) | 2002-02-15 |
| AU778767B2 (en) | 2004-12-23 |
| MXPA01011760A (en) | 2003-09-04 |
| JP2002544227A (en) | 2002-12-24 |
| CN1194674C (en) | 2005-03-30 |
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