FIELD OF THE INVENTION

The present invention generally relates to pharmaceutical agents and more particularly to hypoglycemic agents which are useful as antidiabetic drugs,

BACKGROUND OF THE INVENTION

Diabetes is characterized by an impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in diabetic patients. The underlying defects lead to a classification of diabetes into two major groups: type 1 diabetes, or insulin dependent diabetes mellitus, which arises when patients lack p-cells producing insulin in their pancreatic glands, and type 2 diabetes, or non-insulin dependent diabetes mellitus, which occurs in patients with an impaired p-cell function besides a range of other abnormalities.

Type 1 diabetic patients are currently treated with insulin, while the majority of type 2 diabetic patients are treated either with agents that stimulate p-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin. Since the agents that stimulate p-cell function or enhance the tissue sensitivity of the patients towards insulin are typically administered orally, these agents are collectively referred to as oral hypoglycemic agents.

It is known that N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (Nateglinide) exhibits an excellent effect of lowering the blood sugar level when it is taken orally and is thus used as a medicine for diabetes. Certain derivative compounds of Nateglinide are known in the prior art where, the modifications have been found to occur on the cyclohexanecarboxylic acid portion in the Nateglinide. However, there is a need for compounds which have better activity in the reduction of blood sugar level and which has enhanced biological activity in comparison to compounds which exist as of date.

OBJECTS OF THE INVENTION

• One object of the invention is to provide a pharmaceutical agent preferably a hypoglycemic agent for the treatment of blood sugar disorders.

• Another object of the invention is to provide a pharmaceutical agent preferably a hypoglycemic agent with enhanced biological activity.

• Yet another object of the invention is to provide a pharmaceutical agent preferably a hypoglycemic agent production of which is cost effective.

DETAILED DESCRIPTION

The embodiments herein and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments that are detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

The foregoing description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the appended claims.

According to one aspect of the invention there is provided a pharmaceutical agent, particularly a hypoglycemic agent for the treatment of blood sugar disorders, represented by the general formula: or a salt thereof, or a precursor which can be converted thereto in the human or animal body, wherein the hypoglycemic agent is in a racemic mixture or an enantiomerically pure form. In the aforesaid general formula:

R1 is an aryl ring preferably a phenyl ring substituted with at least one halogen atom wherein the halogen is selected from the list consisting of Fluorine, Chlorine and Bromine; or

R1 is an aromatic heterocyclic ring with at least one heteroatom wherein the aromatic heterocyclic ring consists of Nitrogen as the heteroatom.

The compounds of the aforementioned general formula having an aromatic heterocyclic ring are preferably converted into Hydrochloride salts. The invention may be used for treating of metabolic disorders such as diabetes, obesity. However, the primary role of the compound in this invention has been found to exist as a hypoglycemic agent.

The compounds used in the present invention are useful as a hypoglycemic agent for treating diabetic mammals including humans. The derivatives can be used for lowering blood sugar by formulating them into a preparation such as tablets, capsules, and elixirs for oral administration and into an aseptic liquid preparation or an aseptic suspension preparation for parenteral administration such as subcutaneous, intramuscular, intravenous injection, and suppositories.

To produce the preparations using the compounds as described above for the present invention, they may be converted to dosage forms such as tablets,
granules, powders, capsules, injections and suppositories by conventional methods.
For the production of oral preparations, there may be added to the derivative as the principal agent, adjuvants such as fillers, binders, disintegrators, lubricants, colors, and correctives, as necessary, and then formed by conventional methods into tablets, coated tablets, granules, powders, capsules and the like.

Examples of specific materials which can be incorporated into tablets, capsules, and so forth are by way of an example and are as follows: fillers such as cornstarch, lactose, white sugar, glucose, sorbitol, and crystalline cellulose; binders such as polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth gelatine, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinyl pyrrolidone; disintegrators such as starch, agar, gelatine powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin and pectin; lubricants such as magnesium stearate, talc, polyethylene glycol, silica, hardened plant oil; colors such as one which is allowed as an additive for the medicines; correctives such as cocoa powder, mentha herb, aromatic acid, mentha oil, borneol, cinnamon bark powder. These tablets and granules may be coated with sugar, gelatine, or the like, as desired.

For the production of the injectable formulations, there may be added to the compounds of general formula (1) as the principal agent, a pH adjusting agent, a buffer agent, a stabilizing agent, preservatives or the like, as necessary to produce a material for subcutaneous, intramuscular or intravenous injection by conventional methods.

EXAMPLES

According to one embodiment, in the general formula R1 is a phenyl ring substituted with at least one halogen atom; wherein the halogen is selected from the list consisting of Fluorine, Chlorine and Bromine which can be produced by the following process:

Example 1 - Preparation of N-[(trans-4-isopropylcyclohexyl) carbonylJ-4- fluorophenylalanine

[IUPAC 3-(4-fluorophenyl)-2-[(4-propan-2-ylcyclohexylcarbonyl)amino]propanoic acid]

To a solution of trans-4-isopropylcyclohexanecarboxylic acid (11g) in dry dichloromethane, oxalyl chloride (7.2mL) is added dropwise at room temperature. The contents are maintained at 40°C for 2 hours and dichloromethane is removed under vacuum to give crude acid chloride which is used without further purification.

A solution of 4-fluorophenylalanine is prepared in 10% aqueous potassium hydroxide and cooled to 0°C. To this solution, the acid chloride obtained in the above process, dissolved in THF is added dropwise and the mixture is stirred for 2V2 hours at 0°C. After quenching into ice, the pH is adjusted to 2 with conc. hydrochloric acid to precipitate the crude product, which is purified by crystallisation from 1:1 methanol-water.

Example 2 - Preparation of N-[(trans-4-isopropylcyclohexyl) carbonyl]-4- chlorophenylalanine

[IUPAC 3-(4-chlorophenyl)-2-[(4-propan-2ylcyclohexylcarbonyl)amino]propanoic acid]

To a solution of trans-4-isopropylcyclohexanecarboxylic acid (11g) in dry dichloromethane, oxalyl chloride (7.2mL) is added dropwise at room temperature. The contents are maintained at 40°C for 2 hours and dichloromethane is removed under vacuum to give crude acid chloride which is used without further purification.

A solution of 4-Chlorophenylalanine is prepared in 10% aqueous potassium hydroxide and cooled to 0°C. To this solution, the acid chloride obtained in the above process, dissolved in THF is added dropwise and the mixture is stirred for 2Vi hours at 0°C. After quenching into ice, the pH is adjusted to 2 with conc. hydrochloric acid to precipitate the crude product, which is purified by crystallisation from 1:1 methanol-water.

The process of making the above compounds is by way of an example as show in examples 1 and 2; and different alternates are possible within the meaning of the invention. Moreover, the substitution of halogen at different positions on the benzene ring is also claimed within the scope of this invention.

Example 3 - Preparation of N-[(trans-4-isopropylcyclohexyl) carbonyl]-3,4- difluorophenylalanine

[IUPAC 3-(3,4-difluorophenyl)-2-[(4-propan-2-ylcyclohexylcarbonyl)amino]propanoic acid]

To a solution of trans-4-isopropylcyclohexanecarboxylic acid (11g) in dry dichloromethane, oxalyl chloride (7.2mL) is added dropwise at room temperature. The contents are maintained at 40°C for 2 hours and dichloromethane is removed under vacuum to give crude acid chloride which is used without further purification.

A solution of 3,4-difluorophenylalanine is prepared in 10% aqueous potassium hydroxide and cooled to 0°C. To this solution, the acid chloride obtained in the above process, dissolved in THF is added dropwise and the mixture is stirred for 2V2 hours at 0°C. After quenching into ice, the pH is adjusted to 2 with conc. hydrochloric acid to precipitate the crude product, which is purified by crystallisation from 1:1 methanol-water.

Example 4 - Preparation of N-[(trans~4-isopropylcyclokexyl) carbonyl]-2,4- difluorophenylalanine

[IUPAC 3-(2,4-difluorophenyl)-2-l(4-propan'2 ylcyclohexylcarbonyl)amino]propanoic acid]

To a solution of trans-4-isopropylcyclohexanecarboxylic acid (11g) in dry dichloromethane, oxalyl chloride (7.2mL) is added dropwise at room temperature. The contents are maintained at 40°C for 2 hours and dichloromethane is removed under vacuum to give crude acid chloride which is used without further purification.

A solution of 2,4-difluorophenylalanine is prepared in 10% aqueous potassium hydroxide and cooled to 0°C. To this solution, the acid chloride obtained in the above process, dissolved in THF is added dropwise and the mixture is stirred for 2XA hours at 0°C.

After quenching into ice, the pH is adjusted to 2 with conc. hydrochloric acid to precipitate the crude product, which is purified by crystallisation from 1:1 methanol-water.

Example 5 - Preparation of N-[(trans-4-isopropylcyclohexyl) carbonyl]-25- difluorophenylalanine

[IUPAC 3-(2,5-difluorophenyl)-2-[(4-propan-2-
ylcyclohexylcarbonyl)amino]propanoic acid]

To a solution of trans-4-isopropylcyclohexanecarboxyIic acid (11g) in dry dichloromethane, oxalyl chloride (7.2mL) is added dropwise at room temperature. The contents are maintained at 40°C for 2 hours and dichloromethane is removed under vacuum to give crude acid chloride which is used without further purification.

A solution of 2,5-difluorophenyIalanine is prepared in 10% aqueous potassium hydroxide and cooled to 0°C. To this solution, the acid chloride obtained in the above process, dissolved in THF is added dropwise and the mixture is stirred for 2Vi hours at 0°C. After quenching into ice, the pH is adjusted to 2 with conc. hydrochloric acid to precipitate the crude product, which is purified by crystallisation from 1:1 methanol-water.

The process of making the above compounds is by way of an example as shown in example 3,4 and 5; and different alternates are possible within the meaning of the invention. Moreover, the substitution of halogen at more than two positions on the benzene ring is also claimed within the scope of this invention.

According to another embodiment, in the general formula R1 is an aromatic heterocyclic ring with at least one heteroatom; wherein the aromatic heterocyclic ring consists of Nitrogen as the heteroatom and can be produced by the following process:

Example 6 - Preparation of N-[(trans-4-isopropylcyclohexyl) carbonyll-4- pyridylalanine

[IUPA C 2-(4-propan-2-ylcyclohexyl)carbonylamino-3-(pyridin-4-yl)propanoic acid]

To solution of trans-4-isopropylcyclohexanecarboxylic acid (11g) in dry dichloromethane, oxalyl chloride (7.2mL) is added dropwise at room temperature. The contents are maintained at 40°C for 2 hours and dichloromethane is removed under vacuum to give crude acid chloride which is used without further purification.

A solution of 4-pyridylalanine is prepared in 10% aqueous potassium hydroxide and cooled to 0°C. To this solution, the acid chloride obtained in the above process, dissolved in THF is added dropwise and the mixture is stirred for 2V2 hours at 0°C. After quenching into ice, the pH is adjusted to 2 with conc. hydrochloric acid to precipitate the crude product, which is purified by crystallisation from 1:1 methanol-water.

Example 7 - Preparation of N-[(trans-4~isopropylcyclohexyl) carbonylJ-3- pyridylalanine

[IUPAC 2-(4-propan-2-ylcyclohexyl)carbonylamino-3-(pyridin-3-
yl)propanoic acid]

To solution of trans-4-isopropylcyclohexanecarboxylic acid (11g) in dry dichloromethane, oxalyl chloride (7.2mL) is added dropwise at room temperature. The contents are maintained at 40°C for 2 hours and dichloromethane is removed under vacuum to give crude acid chloride which is used without further purification.

A solution of 3-pyridylalanine is prepared in 10% aqueous potassium hydroxide and cooled to 0°C. To this solution, the acid chloride obtained in the above process, dissolved in THF is added dropwise and the mixture is stirred for 2Vz hours at 0°C. After quenching into ice, the pH is adjusted to 2 with conc. hydrochloric acid to precipitate the crude product, which is purified by crystallisation from 1:1 methanol-water.

The process of making the above compounds is by way of an example and different alternates are possible by substitution with Nitrogen at one or more positions on the Heterocyclic ring within the meaning of the invention.

Analysis of the said compounds can be carried by a variety of detection methods including HPLC, mass spectroscopy, NMR spectroscopy and IR spectra analysis.

Test

Mice (17 hours of fasting) were used as test subjects for conducting Glucose Tolerance Tests. Glucose Tolerance Tests (GTT's) determine how quickly glucose is cleared from the blood after glucose administration. The test compounds by way of an example and not as a limitation were administered orally to the test subjects with 250mg/100g body weight glucose load. After a predetermined time intervals of 30 minutes up to 120 minutes, the percentage decrease of the blood glucose against the control group and Metformin (a standard drug) was determined. The results are shown in the following table:

It is clear from the foregoing that the aforesaid compounds can be used as an 15 antidiabetic drug for oral administration as well as the more usual parenteral administration.

Wherein:
AD-1 = 3-(4-chlorophenyl)-2-[(4-propan-2-
ylcycIohexyIcarbonyl)amino]propanoic acid.

AD-2 = 3 -(4-fluoropheny l)-2- [(4-propan-2-
ylcyclohexylcarbonyl)amino]propanoic acid,

AD-3 = 2-(4-propan-2-ylcyclohexyl)carbonylamino-3-(pyridin-4-yl)propanoic acid.

AD-4 = 2-(4-propan-2-ylcyclohexyl)carbonylamino-3-(pyridin-3-yl)propanoic acid.

CLAIMS

What is claimed is:

1. A pharmaceutical agent of general formula:

or salts thereof, wherein:

R1 is aryl ring substituted with at least one halogen atom; or

R1 is an aromatic heterocyclic ring with at least one heteroatom.

2. The pharmaceutical agent as claimed in claim 1, wherein the aryl ring substituted halogen atom is selected from the group consisting of Fluorine, Chlorine and Bromine.

3. The pharmaceutical agent as claimed in claim 1, wherein the aryl ring is a phenyl ring.

4. The pharmaceutical agent as claimed in claim 1, wherein the agent is 3- (4-fluorophenyl)-2-[(4-propan-2-ylcyclohexylcarbonyl)amino]propanoic acid; 3-(4-chlorophenyl)-2-[(4- propan-2-ylcyclohexylcarbonyl)amino]propanoic acid; 3-(3,4- difluorophenyl)-2-[(4-propan-2-ylcyclohexylcarbonyl)amino]propanoic acid; 3-(2,4-difluorophenyl)-2-[(4-propan-2-ylcyclohexylcarbonyl)amino]propanoic acid; 3-(2,5-difluorophenyl)-2- [(4-propan-2-ylcyclohexylcarbonyl)amino]propanoic acid; 2-(4- propan-2-ylcyclohexyl)carbonylamino-3-(pyridin-4-yl)propanoic acid; or 2-(4-propan-2-ylcyclohexyl)carbonylamino-3 -(pyridin-3 - yl)propanoic acid.

5. The pharmaceutical agent as claimed in claim 1, wherein the pharmaceutical agent is a racemic mixture.

6. The pharmaceutical agent as claimed in claim 1, wherein the pharmaceutical agent is a hypoglycemic agent.

7. The pharmaceutical agent as claimed in claim 1, wherein the number of heteroatom in the aromatic heterocyclic ring is one.

8. The pharmaceutical agent as claimed in claim 1, wherein the number of heteroatoms in the aromatic heterocyclic ring is two.

9. The pharmaceutical agent as claimed in claim 1, wherein the heteroatom in the aromatic heterocyclic ring is nitrogen.

10. A pharmaceutical composition comprising a pharmaceutical agent as claimed in claim 1 and a pharmaceutical excipient.