Title of Invention	A process for the synthesis of 1-(Aryloxy)Propinoyl-2-Arylsulfonyl Hydrazine useful as hypoglycemic Agents
Abstract	A process for the synthesis of 1-(aryloxy)propionoyl-2-arylsulfonyl hydrazine useful as hypoglycemic agents by reacting an aryloxypropionic acid hydrazide with an arylsulfonyl chloride in dry pyridine in equimolar proportion under reflux for a period ranging from 4-8 hrs, terminating the reaction by pouring the above said reaction mixture over crushed ice followed by filtration to obtain the desired product.

Title of Invention

A process for the synthesis of 1-(Aryloxy)Propinoyl-2-Arylsulfonyl Hydrazine useful as hypoglycemic Agents

Abstract

A process for the synthesis of 1-(aryloxy)propionoyl-2-arylsulfonyl hydrazine useful as hypoglycemic agents by reacting an aryloxypropionic acid hydrazide with an arylsulfonyl chloride in dry pyridine in equimolar proportion under reflux for a period ranging from 4-8 hrs, terminating the reaction by pouring the above said reaction mixture over crushed ice followed by filtration to obtain the desired product.

Full Text	The present invention relates to a process for the synthesis of l-(aryloxy)propionoyl-2-arylsulfonyl hydrazines useful as hypoglycemic agents. The present invention also relates to the synthesis of l-(aryloxy)propionoyl-2arylsulfonyl hydrazines as new hypoglycemic agents which may be useful in the treatment of diabetes. Introduction of more clinically effective hypoglycemic agents has been followed invariably by the rapid emergence of resistant antidiabetic drugs leading to increasing demand for new and potent hypoglycemic drugs. Acquisition of resistance has seriously reduced the therapeutic value of many known drugs including antidiabetics and has become a major stimulus to look for new moieties. Hence, the best approach is to look for new molecules structurally different from the existing drugs. The present invention relates to such an effort in developing title compounds as new hypoglycemic agents. These have not so far been investigated for the hypoglycemic activity and all compounds described are new molecules reported for the first time. Reference may be made to Indian Drugs, 17, 315, 1980, wherein, authors have syhthesized arylsulfonyl hydrazines as hypoglycemic agents. The drawbacks are that no substitutions were made to the hydrazine group which can improve the hppoglycemic activity. Incorporation of aryloxyalkyl substituents to organic moieties has been found to result in compounds which possess enhanced biological profile. Reference may also be made to Indian.J. Chem:27B, 1057-1059, 1988, wherein authors have introduced substitutions by condensation of 4-chlorophenoxyacetic and isobutyric acid hydrazides with arylsulfonyl chlorides. The main object of the present invention is to provide l-(aryloxy)propionoyl-2-arylsulfonyl hydrazines which obviates the drawbacks as detailed above. Another object of the present invention is to provide a process for the synthesis of 1-(aryloxy)propionoyl-2-arylsulfonyl hydrazines as potential hypoglycemic agents. Still another object of the present invention is to unravel new hypoglycemic molecules structurally different from the known drugs such as Glibenclamide, Tolbutamide, Chloropropamide, Phenformin, Metformin, etc. In the present invention, aryloxypropionic acid hydrazides were reacted with arylsulfonyl chlorides to obtain the title compounds as hypoglycemic agents for the first time. Accordingly the present invention provides a process for the synthesis of 1-(aryloxy)propionoyl-2-arylsulfonyl hydrazine of the formula useful as hypoglycemic agents of the formula (Formula Removed) wherein R is 4-C1 or 3-CH3, 4-CI or 2,4-CI2; Ri is selected from H, CI, and CH3, which comprises reacting an aryloxypropionic acid hydrazide with an arylsulfonyl chloride in dry pyridine in equimolar proportion under reflux for a period ranging from 4-8 hrs, terminating the reaction by pouring the above said reaction mixture over crushed ice followed by filtration to obtain the desired product. In an embodiment of the present invention the aryloxy group used is selected from the group consisting of 4-chlorophenoxy, 3-methyl-4-chlorophenoxy and 2, 4-dichlorophenoxy groups. In an another embodiment the aryl group is selected from the group consisting of phenyl, 4-chlorophenyl and 4-tolyl. In yet another embodiment the compounds l-(aryloxy)propionoyl-2-arylsulfonyl hydrazine is useful hypoglycemic agents. In yet another embodiment the compound l-(aryloxy)propionoyl-2-arylsulfonyl hydrazine obtained is comprising the group of l-(4'-chlorophenoxy)propionoyl-2- phenylsulfonyl hydrazine, l-(4'-chlorophenoxy) propionoyl-2-(4"-chlorophenyl)sulfonyl hydrazine 1-(4'-chlorophenoxy) propionoyl-2-(4"-toluene)sulfonyl hydrazine, l-(3'- methyl-4'-chlorophenoxy) propionoyl-2-phenyl sulfonyl hydrazine, l-(3'-methyl-4'- chlorophenoxy) propionoyl-2-(4"-chlorophenyl) sulfonyl hydrazine, 1-(3'-methyl- 4'- chlorophenoxy) propionoyl -2- (4"-tolune) sulfonyl hydrazine, l-(2',4-dichlorophenoxy) propionoyl-2- phenylsulfonylhydrazine,l-(2'-4-dichlorophenoxy) propionoyl-2-(4"-chlorophenyl) sulfonyl hydrazine and l-(2',4'-dichlorophenoxy) propionoyl-2-(4"-tolune)sulfonyl hydrazine. urief description of the accompanying drawings Figure 1 shows the hypoglycemic activity of l-(aryloxy)propionoyl - 2- arylsulfonyl hydrazines in normoglycemic rats. Figure 2 shows the hypoglycemic activity of l-(aryloxy)propionoyl-2-arylsulfonyl hydrazines in Sreptozotocin induced diabetic rats. These l-(aryloxy)propionoy 1-2-arylsulfonyl hydrazines are new molecules synthesized for the first time possessing hypoglycemic activity orally. The hydrazides, i.e. 4-chlorophenoxypropionic acid hydrazide, 3-methyl-4-chlorophenoxypropionic acid hydrazine and 2-4-dichlorophenoxypropionic acid hydrazide which are required for the synthesis of title compounds were prepared from 4-chlorophenol, 3-methyl-4-chlorophenol and 2,4-dichlorophenol respectively. The following examples are given by way of illustration and therefore should not be constructed to limit the scope of the present invention. Example 1: l-(4'-chlorophenoxy)propionoyl-2-phenylsulfonyl hydrazine: To a solution of 4-chlorophenoxypropionic acid hydrazide in dry pyridine, benzenesulfonyl chloride was added dropwise and the reaction mixture refluxed, for 6 hours. The reaction product was poured over crushed ice and the separated organic solid was filtered and crystallized from ethanol to give the title compound which was confirmed by spectroscopic data.m.p. 127-129C. 'HNMR (CDC13 + DMSO-d6): 1.25 (d), 3H, J=8.8Hz), 4.60 (q, IH, J=6.8Hz), 6.70 (d, 2H, J=7.2 Hz), 7.20 (d, 2H, J=7.0 Hz), 7.45 (t, 2H, J=7.0 Hz), 7.60 (t, IH, J=70 Hz), 7.75 (d, 2H, J=7.2 Hz), 9.65 (brs, IH) 10.40 (brs, IH). Example 2: l-(4'-chlorophenoxy)propionoyl-2-(4"-chlorophenyl) sulfonyl hydrazine: 4-Chlorophenoxypropionic acid hydrazide was dissolved in dry pyridine. To this solution, 4-Chlorobenzenesulfonyl chloride was added slowly while stirring. The contents were refluxed for 7 hours. Then cooled and poured over crushed ice when the crude product was obtained. It was filtered, washed with water, dried and crystallized from ethanol to give the title compound, which was confirmed by spectral data. M.p. 132-134C. 'H NMR (CDCI3 + DMSO-d6): 1.60 (d, 3H, J=6.6Hz), 4.75 (1, IH, J=6.6 Hz), 6.90 (d, 2H, J=7.5 Hz), 7.20 (d, 2H, J=7.5 Hz), 7.5 (d, 2H, J=7.6 Hz), 7.90 (d, 2H, J=7.6 Hz), 9.88 (brs. IH) 10.25 (brs. IH). Example 3: l-(4'-chlorophenoxy) propionoyl-2-(4"-toIuene)suIfonyl hydrazine: To a solution of 4-chlorophenoxypropionic acid hydrazide in dry pyridine, 4-toluenesulfonyl chloride was added dropwise and the reaction mixture was refluxed for 5 hours. Crude reaction product was obtained after pouring the contents in ice water. It was filtered, washed with water and crystallized from ethanol to give above compound. Pure product was confirmed by spectroscopic data. m.p.l62-164C. :H NMR (CDCI3 + DMSO- d6): 1.35 (d, 3H, J=6.8 Hz), 2.40 (s, 3H), 4.60 (1, 1H, J=6.8 Hz), 6.80 (d, 2H, J-7.4 Hz), 7,16 (d, 2H, J=7.4 Hz), 7.50 (d, 2H, J=7.5 Hz),7.80 (d,2H,J=7.5Hz), 9.10(brs,lH), 10.20 (brs, 1H). Example 4: l-(3'-methyl-4'-chlorophenoxy) propionoyl-2-phenyIsulfonyl hydrazine: 3-Methyl-4-chlorophenoxypropionic acid hydrazide was added to dry pyridine to make uniform solution. Benzenesulfonyl chloride was added dropwise while stirring. Later, the reaction mixture was refluxed for 6 hours. The crude product was obtained when the reaction mixture was poured over crushed ice. It was filtered, washed with good amount of water, dried and crystallized from ethanol to give the above compound whose structure was confirmed by spectroscopic data. m.p. 148-149C. 'H NM R (CDC13 + DMSO-d6): 1.35 (d, 3H, J=6.8 Hz), 2.34 (s, 3H), 4.52 (q, 1H, J=6.8 Hz), 6.58 (dd, 1H, J=7.3 & 2.1 Hz), 6.78 (d, 1H, J=2.0 Hz), 7.16 (d, 1H, J=7.4 Hz), 7.40 (t, 2H, J=7.3 Hz), 7.55 (t, 1H, J=7.3 Hz), 7.75 (d, 2H, J=7.4 Hz), 9.10 (brs, 1H), 10.15 (brs, 1H). Example 5: l-(3'-methyI-4'-chlorophenoxy)propionoyl-2-(4"-chlorophenyl)su!fonyl hydrazine: To a solution of 3-methyl-4-chlorophenoxypropionic acid hydrazine in hot dry pyridine, 4-chlorobenzenesulfonyl chloride was added slowly while stirring. Then, the reaction mixture was refluxed for 8 hours. The crude product gets separated when the reaction medium was poured over ice water. It was filtered, washed with excess of water, dried and crystallized from ethanol to give the title compound. Structure of the compound was confirmed by spectral data. m.p. 164-166C. !H NM R (CDCI3 + DMSO-d6): 1.36 (d, 3H, J=6.5Hz) 2.35 (s, 3H), 4.60 (1, 1H, J=6.5 Hz), 6.60 (dd, 1H, J-7.0 & 1.8 Hz), 6.78 (d, 1H, J=6.8 Hz), 7.18 (d, 1H, J=7.0 Hz), 7.38 (d, 2H, J-7.8 Hz), 7.70 (d, 2H, J=7.8 Hz), 9.78 (brs, 1H) 10.30 (brs. 1H). Example 6: l-(3'-methyI-4'-chlorophenoxy)propionoyl-2-(4"-toIune)sulfonyI hydrazine: 3-Methyl-R-chlorophenoxypropionic acid hydrazide was dissolved in dry pyridine. 4-tolunesulfonyl choloride was then added dropwise while stirring. Later reaction mixture was refluxed for 6 hours, cooled and poured over ice water. Crude product thus obtained was filtered and crystallized from ethanol to give title compound, was identified by spectroscopic data. m.p. 160-162C . 'HNMR (CDCl3+DMSO-d6):1.30(d,3H,J=6.8Hz), 2.25(s,3H), 2.38(s,3H), 4.50(1,1H, J6.8Hz), 6.52(dd,lH, J-7.5&2.1Hz), 6.70(d,lH, J=2.1Hz), 7.10(dd,lH, J=7.5&0.8Hz), 7.18(d,2H,J-7.5Hz), 7.60(d,2H,J=7.5Hz), 9.40(brs,lH)10.22(brs, 1H). Example 7: l-(2',4-dichIorophenoxy)propionoyI-2-phenylsulfonyIhydrazine: To a stirred solution of 2,4-dichlorophenoxypropionic acid hyudrazide in hot dry pyridine, benezenesulfonyl chloride was added dropwise. The reaction contents were refluexed for 7 hours and cooled. The crude reaction product was separated, when the reaction mixture was poured over crushed ice. It was filtered, washed with water and dried. The product was crystallized from ethanol and its structure was confirmed by spectral data. m.p. 182-183C . 'H NMR (CDC13 + DMSO-d6): 1.38 (d, 3H, J=6.8 Hz), 4.56 (1, 1H, J=6.8 Hz), 6.70 (d, 1H, J=7.6 Hz), 7.10 (dd, 1H, J=7.4 & 2.1 Hz), 7.35 (d, 1H, J=2.0 Hz), 7.40-7.60 (m, 3H), 7.80 (d, 2H, J=7.6 Hz), 9.20 (brs, 1H), 10.10 (brs, 1H). Example 8: l-(2'-4-dichlorophenoxy) propionoyl-2-(4"-chlorophenyl) sulfonyl hydrazine: 2,4-Dichlorophenoxypropionic acid hydrazide was dissolved in required amount of dry pyridine. R-Chlorobezenesulfonyl chloride was added slowly to the above solution while stirring. Then, the reaction mixture was refluxed for 8 hours, cooled and poured over crushed ice when the crude product was obtained. It was filtered, washed with water, dried and crystallized from ethanol to give the title compound, structure of the product was confirmed by spectroscopic data. m.p. 190-192C. 'H N MR (CDCI3 + DMSO-d6): 1.40 (d, 3H, J=6.7 Hz), 4.50 (1, 1H, J=6.6 Hz), 6.65 (d, 1H, J=7.5 Hz), 7.05 (dd, 1H, J-7.5 & 1.9Hz), 7.10 (d, 2H, J=7.8 Hz), 7.35 (d, 1H, J-1.9Hz), 7.60 (d, 2H, J=7.8 Hz), 9.05 (brs, 1H), 10.10 (brs, 1H). Example 9: l-(2',4'-dichlorophenoxy) propionoyl-2-(4"-tolune)sulfonyl hydrazine: To a solution of 2,4-dichlorophenoxypropionic acid hydrazide in dry pyridine, 4-tolunesulfonyl choloride was added slowly while stirring. The reaction mixture was refluxed for 5 hours, cooled and poured over crushed ice. Crude reaction product was filtered, dried and crystallized from ethanol to obtain title compound, which was identified by spectra data. m.p. 176-177C . 'HNMR (CDCI3 + DMSO-d6): 1.40 (d, 3H, J=6.8 Hz), 2.42 (s, 3H), 4.54 (q, 1H, J=6.8 Hz), 6.68 (d, 1H, J=7.5 HzO, 7.08 (dd, 1H, J=7.4 & 2.1 Hz), 7.20 (d, 2H, J=7.8 Hz), 7.32 (d, 1H, J=2.0 Hz), 7.70 (d, 2H, J=7.8 Hz), 9.00 (brs, 1H) 10.10 (brs, 1H). Hypoglycemic activity: Typical representative members of this invention have shown hypoglycemic activity for the first time both in normoglycemic and Streptozotocin induced diabetic rats compared to standard drug. The standard drug used in both the experimental animal evaluation is Glibenclamide. The experimental details are given below. Hypoglycemic activity in normal rats: Wistar rats of either sex weighing 150-180 gms were fasted overnight and divided into control, standard and test groups each consisting of 6 rats. The standard drug, Glibenclamide, was administered in the dose of 5 mg/kg per oral to the rats. All test compounds were administered in the dose of 200 mg/kg per oral to the test groups. Both standard and test drugs were administered as 1% gum acacia suspension. Control group received vehicle only. Blood glucose levels were measured before drugs administration at 0 hr and at 1 hr, 2 hr, 4 hr and 6 hr after drugs administration. Percent reduction of blood glucose levels at different time intervals was calculated with reference to basal glucose levels. All the blood glucose estimations were done using GOD/POD method and were analyzed using Auto Blood Analyzer (Technicon RA-1000, Bayer Diagnostics, Ireland). The standard drug (Glibenclamide) has shown a percent inhibition of glucose 65.1 and all the test compounds (1 to 9 examples) have shown percent inhibition in range of 48.5 to 63.2 (Fig. 1) Hypoglycemic activity in Streptozotocin induced diabetic rats: Wistar rats of either sex weighting 150-180 gms were used in this study and were divided into control, standard and test groups each consisting of 6 rats. Basal glucose levels were taken for all rats. Diabetes was induced by administering Streptozotocin in the dose of 50 mg/kg intravenously to the rats in all the groups. After a period of 48 hrs glucose levels were again measured and rats that have shown glucose levels of 400 i^20 mg/dl were selected. Glibenclamide (lmg/kg) and the test compounds (50 mg/kg) were administered as 1% gum acacia suspension daily for a period of 14 days. At the end of 14 days after the last does, blood glucose levels were again measured and the percent reduction in blood glucose was measured for all the rats in all the groups with respect to the initial reading before drugs administration. The standard drug has shown hypoglycemic activity expressed as percent inhibition of blood glucose levels as 68.2 whereas test compounds (examples 1-9) has shown hypoglycemic activity in the range of 43.5 to 59.3 (Fig. 2). The main advantages of the present invention are: 1. The process is simple and is a single step reaction. 2. Raw material are cheap and the process does not require special chemicals. 3. The total reaction can be completed in a period of 5-8 hrs on lab scale. 4. Since the end product is a solid, this permits the pharmaceutical formulated to make solid oral dosage forms such as tablets, capsules, etc. 5. The compounds may be useful in the management of diabetes as these are potential hypoglycemics. We claim : 1. A process for the synthesis of 1-(aryloxy)propionoyl-2-arylsulfonyl hydrazine of the formula useful as hypoglycemic agents of the formula (Formula Removed) wherein R is 4-C1 or 3-CH3, 4-CI or 2,4-CI2 ; R1 is selected from H, CI, and CH3, which comprises reacting an aryloxypropionic acid hydrazide with an arylsulfonyl chloride in dry pyridine in equimolar proportion under reflux for a period ranging from 4-8 hrs, terminating the reaction by pouring the above said reaction mixture over crushed ice followed by filtration to obtain the desired product. 2. A process as claimed in claim 1, wherein aryloxy group is selected from the group consisting of 4-chlorophenoxy, 3-methyl-4-chlorophenoxy and 2, 4-dichlorophenoxy groups. 3. A process as claimed in claims 1&2, wherein aryl group is selected from the group consisting of phenyl, 4-chlorophenyl and 4-tolyl. 4. A process for the synthesis of l-(aryloxy)propionoyl-2-arylsulfonyl hydrazine substantially as herein described with reference to the examples accompany this specification.

Full Text

The present invention relates to a process for the synthesis of l-(aryloxy)propionoyl-2-arylsulfonyl hydrazines useful as hypoglycemic agents. The present invention also relates to the synthesis of l-(aryloxy)propionoyl-2arylsulfonyl hydrazines as new hypoglycemic agents which may be useful in the treatment of diabetes.
Introduction of more clinically effective hypoglycemic agents has been followed invariably by the rapid emergence of resistant antidiabetic drugs leading to increasing demand for new and potent hypoglycemic drugs. Acquisition of resistance has seriously reduced the therapeutic value of many known drugs including antidiabetics and has become a major stimulus to look for new moieties. Hence, the best approach is to look for new molecules structurally different from the existing drugs. The present invention relates to such an effort in developing title compounds as new hypoglycemic agents. These have not so far been investigated for the hypoglycemic activity and all compounds described are new molecules reported for the first time.
Reference may be made to Indian Drugs, 17, 315, 1980, wherein, authors have syhthesized arylsulfonyl hydrazines as hypoglycemic agents. The drawbacks are that no substitutions were made to the hydrazine group which can improve the hppoglycemic activity. Incorporation of aryloxyalkyl substituents to organic moieties has been found to result in compounds which possess enhanced biological profile. Reference may also be made to Indian.J. Chem:27B, 1057-1059, 1988, wherein authors have introduced substitutions by condensation of 4-chlorophenoxyacetic and isobutyric acid hydrazides with arylsulfonyl chlorides.
The main object of the present invention is to provide l-(aryloxy)propionoyl-2-arylsulfonyl hydrazines which obviates the drawbacks as detailed above.
Another object of the present invention is to provide a process for the synthesis of 1-(aryloxy)propionoyl-2-arylsulfonyl hydrazines as potential hypoglycemic agents.
Still another object of the present invention is to unravel new hypoglycemic molecules structurally different from the known drugs such as Glibenclamide, Tolbutamide, Chloropropamide, Phenformin, Metformin, etc.
In the present invention, aryloxypropionic acid hydrazides were reacted with arylsulfonyl chlorides to obtain the title compounds as hypoglycemic agents for the first time.
Accordingly the present invention provides a process for the synthesis of 1-(aryloxy)propionoyl-2-arylsulfonyl hydrazine of the formula useful as hypoglycemic agents of the formula
(Formula Removed)
wherein R is 4-C1 or 3-CH3, 4-CI or 2,4-CI2; Ri is selected from H, CI, and CH3, which comprises reacting an aryloxypropionic acid hydrazide with an arylsulfonyl chloride in dry pyridine in equimolar proportion under reflux for a period ranging from 4-8 hrs, terminating the reaction by pouring the above said reaction mixture over crushed ice followed by filtration to obtain the desired product.
In an embodiment of the present invention the aryloxy group used is selected from the group consisting of 4-chlorophenoxy, 3-methyl-4-chlorophenoxy and 2, 4-dichlorophenoxy groups.
In an another embodiment the aryl group is selected from the group consisting of phenyl, 4-chlorophenyl and 4-tolyl.
In yet another embodiment the compounds l-(aryloxy)propionoyl-2-arylsulfonyl hydrazine is useful hypoglycemic agents.
In yet another embodiment the compound l-(aryloxy)propionoyl-2-arylsulfonyl
hydrazine obtained is comprising the group of l-(4'-chlorophenoxy)propionoyl-2-
phenylsulfonyl hydrazine, l-(4'-chlorophenoxy) propionoyl-2-(4"-chlorophenyl)sulfonyl
hydrazine 1-(4'-chlorophenoxy) propionoyl-2-(4"-toluene)sulfonyl hydrazine, l-(3'-
methyl-4'-chlorophenoxy) propionoyl-2-phenyl sulfonyl hydrazine, l-(3'-methyl-4'-
chlorophenoxy) propionoyl-2-(4"-chlorophenyl) sulfonyl hydrazine, 1-(3'-methyl-
4'- chlorophenoxy) propionoyl -2- (4"-tolune) sulfonyl hydrazine, l-(2',4-dichlorophenoxy) propionoyl-2- phenylsulfonylhydrazine,l-(2'-4-dichlorophenoxy) propionoyl-2-(4"-chlorophenyl) sulfonyl hydrazine and l-(2',4'-dichlorophenoxy) propionoyl-2-(4"-tolune)sulfonyl hydrazine.
urief description of the accompanying drawings
Figure 1 shows the hypoglycemic activity of l-(aryloxy)propionoyl - 2- arylsulfonyl hydrazines in normoglycemic rats.
Figure 2 shows the hypoglycemic activity of l-(aryloxy)propionoyl-2-arylsulfonyl hydrazines in Sreptozotocin induced diabetic rats.
These l-(aryloxy)propionoy 1-2-arylsulfonyl hydrazines are new molecules synthesized for the first time possessing hypoglycemic activity orally.
The hydrazides, i.e. 4-chlorophenoxypropionic acid hydrazide, 3-methyl-4-chlorophenoxypropionic acid hydrazine and 2-4-dichlorophenoxypropionic acid hydrazide which are required for the synthesis of title compounds were prepared from 4-chlorophenol, 3-methyl-4-chlorophenol and 2,4-dichlorophenol respectively.
The following examples are given by way of illustration and therefore should not be constructed to limit the scope of the present invention. Example 1: l-(4'-chlorophenoxy)propionoyl-2-phenylsulfonyl hydrazine:
To a solution of 4-chlorophenoxypropionic acid hydrazide in dry pyridine, benzenesulfonyl chloride was added dropwise and the reaction mixture refluxed, for 6 hours. The reaction product was poured over crushed ice and the separated organic solid was filtered and crystallized from ethanol to give the title compound which was confirmed by spectroscopic data.m.p. 127-129C. 'HNMR (CDC13 + DMSO-d6): 1.25 (d), 3H, J=8.8Hz), 4.60 (q, IH, J=6.8Hz), 6.70 (d, 2H, J=7.2 Hz), 7.20 (d, 2H, J=7.0 Hz), 7.45 (t, 2H, J=7.0 Hz), 7.60 (t, IH, J=70 Hz), 7.75 (d, 2H, J=7.2 Hz), 9.65 (brs, IH) 10.40 (brs, IH). Example 2: l-(4'-chlorophenoxy)propionoyl-2-(4"-chlorophenyl) sulfonyl hydrazine:
4-Chlorophenoxypropionic acid hydrazide was dissolved in dry pyridine. To this solution, 4-Chlorobenzenesulfonyl chloride was added slowly while stirring. The contents were refluxed for 7 hours. Then cooled and poured over crushed ice when the crude product was obtained. It was filtered, washed with water, dried and crystallized from ethanol to give the title compound, which was confirmed by spectral data. M.p. 132-134C. 'H NMR (CDCI3 + DMSO-d6): 1.60 (d, 3H, J=6.6Hz), 4.75 (1, IH, J=6.6 Hz), 6.90 (d, 2H, J=7.5 Hz), 7.20 (d, 2H, J=7.5 Hz), 7.5 (d, 2H, J=7.6 Hz), 7.90 (d, 2H, J=7.6 Hz), 9.88 (brs. IH) 10.25 (brs. IH). Example 3: l-(4'-chlorophenoxy) propionoyl-2-(4"-toIuene)suIfonyl hydrazine:
To a solution of 4-chlorophenoxypropionic acid hydrazide in dry pyridine, 4-toluenesulfonyl chloride was added dropwise and the reaction mixture was refluxed for 5
hours. Crude reaction product was obtained after pouring the contents in ice water. It was
filtered, washed with water and crystallized from ethanol to give above compound. Pure
product was confirmed by spectroscopic data. m.p.l62-164C. :H NMR (CDCI3 + DMSO-
d6): 1.35 (d, 3H, J=6.8 Hz), 2.40 (s, 3H), 4.60 (1, 1H, J=6.8 Hz), 6.80 (d, 2H, J-7.4 Hz), 7,16
(d, 2H, J=7.4 Hz), 7.50 (d, 2H, J=7.5 Hz),7.80 (d,2H,J=7.5Hz), 9.10(brs,lH), 10.20 (brs, 1H).
Example 4: l-(3'-methyl-4'-chlorophenoxy) propionoyl-2-phenyIsulfonyl hydrazine:
3-Methyl-4-chlorophenoxypropionic acid hydrazide was added to dry pyridine to
make uniform solution. Benzenesulfonyl chloride was added dropwise while stirring. Later,
the reaction mixture was refluxed for 6 hours. The crude product was obtained when the
reaction mixture was poured over crushed ice. It was filtered, washed with good amount of
water, dried and crystallized from ethanol to give the above compound whose structure was
confirmed by spectroscopic data. m.p. 148-149C. 'H NM R (CDC13 + DMSO-d6): 1.35 (d,
3H, J=6.8 Hz), 2.34 (s, 3H), 4.52 (q, 1H, J=6.8 Hz), 6.58 (dd, 1H, J=7.3 & 2.1 Hz), 6.78 (d,
1H, J=2.0 Hz), 7.16 (d, 1H, J=7.4 Hz), 7.40 (t, 2H, J=7.3 Hz), 7.55 (t, 1H, J=7.3 Hz), 7.75 (d,
2H, J=7.4 Hz), 9.10 (brs, 1H), 10.15 (brs, 1H).
Example 5: l-(3'-methyI-4'-chlorophenoxy)propionoyl-2-(4"-chlorophenyl)su!fonyl hydrazine:
To a solution of 3-methyl-4-chlorophenoxypropionic acid hydrazine in hot dry
pyridine, 4-chlorobenzenesulfonyl chloride was added slowly while stirring. Then, the reaction mixture was refluxed for 8 hours. The crude product gets separated when the reaction medium was poured over ice water. It was filtered, washed with excess of water, dried and crystallized from ethanol to give the title compound. Structure of the compound was confirmed by spectral data. m.p. 164-166C. !H NM R (CDCI3 + DMSO-d6): 1.36 (d, 3H, J=6.5Hz) 2.35 (s, 3H), 4.60 (1, 1H, J=6.5 Hz), 6.60 (dd, 1H, J-7.0 & 1.8 Hz), 6.78 (d, 1H, J=6.8 Hz), 7.18 (d, 1H, J=7.0 Hz), 7.38 (d, 2H, J-7.8 Hz), 7.70 (d, 2H, J=7.8 Hz), 9.78 (brs, 1H) 10.30 (brs. 1H).
Example 6: l-(3'-methyI-4'-chlorophenoxy)propionoyl-2-(4"-toIune)sulfonyI hydrazine: 3-Methyl-R-chlorophenoxypropionic acid hydrazide was dissolved in dry pyridine. 4-tolunesulfonyl choloride was then added dropwise while stirring. Later reaction mixture was refluxed for 6 hours, cooled and poured over ice water. Crude product thus obtained was filtered and crystallized from ethanol to give title compound, was identified by spectroscopic data. m.p. 160-162C . 'HNMR (CDCl3+DMSO-d6):1.30(d,3H,J=6.8Hz), 2.25(s,3H), 2.38(s,3H), 4.50(1,1H, J6.8Hz), 6.52(dd,lH, J-7.5&2.1Hz), 6.70(d,lH, J=2.1Hz), 7.10(dd,lH, J=7.5&0.8Hz), 7.18(d,2H,J-7.5Hz), 7.60(d,2H,J=7.5Hz), 9.40(brs,lH)10.22(brs, 1H).
Example 7: l-(2',4-dichIorophenoxy)propionoyI-2-phenylsulfonyIhydrazine:
To a stirred solution of 2,4-dichlorophenoxypropionic acid hyudrazide in hot dry
pyridine, benezenesulfonyl chloride was added dropwise. The reaction contents were
refluexed for 7 hours and cooled. The crude reaction product was separated, when the
reaction mixture was poured over crushed ice. It was filtered, washed with water and dried.
The product was crystallized from ethanol and its structure was confirmed by spectral data.
m.p. 182-183C . 'H NMR (CDC13 + DMSO-d6): 1.38 (d, 3H, J=6.8 Hz), 4.56 (1, 1H, J=6.8
Hz), 6.70 (d, 1H, J=7.6 Hz), 7.10 (dd, 1H, J=7.4 & 2.1 Hz), 7.35 (d, 1H, J=2.0 Hz), 7.40-7.60
(m, 3H), 7.80 (d, 2H, J=7.6 Hz), 9.20 (brs, 1H), 10.10 (brs, 1H).
Example 8: l-(2'-4-dichlorophenoxy) propionoyl-2-(4"-chlorophenyl) sulfonyl hydrazine:
2,4-Dichlorophenoxypropionic acid hydrazide was dissolved in required amount of dry pyridine. R-Chlorobezenesulfonyl chloride was added slowly to the above solution while stirring. Then, the reaction mixture was refluxed for 8 hours, cooled and poured over crushed ice when the crude product was obtained. It was filtered, washed with water, dried and crystallized from ethanol to give the title compound, structure of the product was confirmed by spectroscopic data. m.p. 190-192C. 'H N MR (CDCI3 + DMSO-d6): 1.40 (d, 3H, J=6.7 Hz), 4.50 (1, 1H, J=6.6 Hz), 6.65 (d, 1H, J=7.5 Hz), 7.05 (dd, 1H, J-7.5 & 1.9Hz), 7.10 (d, 2H, J=7.8 Hz), 7.35 (d, 1H, J-1.9Hz), 7.60 (d, 2H, J=7.8 Hz), 9.05 (brs, 1H), 10.10 (brs, 1H). Example 9: l-(2',4'-dichlorophenoxy) propionoyl-2-(4"-tolune)sulfonyl hydrazine:
To a solution of 2,4-dichlorophenoxypropionic acid hydrazide in dry pyridine, 4-tolunesulfonyl choloride was added slowly while stirring. The reaction mixture was refluxed for 5 hours, cooled and poured over crushed ice. Crude reaction product was filtered, dried and crystallized from ethanol to obtain title compound, which was identified by spectra data. m.p. 176-177C . 'HNMR (CDCI3 + DMSO-d6): 1.40 (d, 3H, J=6.8 Hz), 2.42 (s, 3H), 4.54 (q, 1H, J=6.8 Hz), 6.68 (d, 1H, J=7.5 HzO, 7.08 (dd, 1H, J=7.4 & 2.1 Hz), 7.20 (d, 2H, J=7.8 Hz), 7.32 (d, 1H, J=2.0 Hz), 7.70 (d, 2H, J=7.8 Hz), 9.00 (brs, 1H) 10.10 (brs, 1H). Hypoglycemic activity:
Typical representative members of this invention have shown hypoglycemic activity for the first time both in normoglycemic and Streptozotocin induced diabetic rats compared to standard drug. The standard drug used in both the experimental animal evaluation is Glibenclamide. The experimental details are given below.
Hypoglycemic activity in normal rats:
Wistar rats of either sex weighing 150-180 gms were fasted overnight and divided into control, standard and test groups each consisting of 6 rats. The standard drug, Glibenclamide, was administered in the dose of 5 mg/kg per oral to the rats. All test compounds were administered in the dose of 200 mg/kg per oral to the test groups. Both standard and test drugs were administered as 1% gum acacia suspension. Control group received vehicle only. Blood glucose levels were measured before drugs administration at 0 hr and at 1 hr, 2 hr, 4 hr and 6 hr after drugs administration. Percent reduction of blood glucose levels at different time intervals was calculated with reference to basal glucose levels. All the blood glucose estimations were done using GOD/POD method and were analyzed using Auto Blood Analyzer (Technicon RA-1000, Bayer Diagnostics, Ireland). The standard drug (Glibenclamide) has shown a percent inhibition of glucose 65.1 and all the test compounds (1 to 9 examples) have shown percent inhibition in range of 48.5 to 63.2 (Fig. 1) Hypoglycemic activity in Streptozotocin induced diabetic rats:
Wistar rats of either sex weighting 150-180 gms were used in this study and were divided into control, standard and test groups each consisting of 6 rats. Basal glucose levels were taken for all rats. Diabetes was induced by administering Streptozotocin in the dose of 50 mg/kg intravenously to the rats in all the groups. After a period of 48 hrs glucose levels were again measured and rats that have shown glucose levels of 400 i^20 mg/dl were selected. Glibenclamide (lmg/kg) and the test compounds (50 mg/kg) were administered as 1% gum acacia suspension daily for a period of 14 days. At the end of 14 days after the last does, blood glucose levels were again measured and the percent reduction in blood glucose was measured for all the rats in all the groups with respect to the initial reading before drugs administration. The standard drug has shown hypoglycemic activity expressed as percent inhibition of blood glucose levels as 68.2 whereas test compounds (examples 1-9) has shown hypoglycemic activity in the range of 43.5 to 59.3 (Fig. 2).
The main advantages of the present invention are:
1. The process is simple and is a single step reaction.
2. Raw material are cheap and the process does not require special chemicals.
3. The total reaction can be completed in a period of 5-8 hrs on lab scale.
4. Since the end product is a solid, this permits the pharmaceutical formulated to make solid oral dosage forms such as tablets, capsules, etc.
5. The compounds may be useful in the management of diabetes as these are potential hypoglycemics.

We claim :
1. A process for the synthesis of 1-(aryloxy)propionoyl-2-arylsulfonyl hydrazine of the formula useful as hypoglycemic agents of the formula

(Formula Removed)
wherein R is 4-C1 or 3-CH3, 4-CI or 2,4-CI2 ; R1 is selected from H, CI, and CH3, which comprises reacting an aryloxypropionic acid hydrazide with an arylsulfonyl chloride in dry pyridine in equimolar proportion under reflux for a period ranging from 4-8 hrs, terminating the reaction by pouring the above said reaction mixture over crushed ice followed by filtration to obtain the desired product.
2. A process as claimed in claim 1, wherein aryloxy group is selected from the group consisting of 4-chlorophenoxy, 3-methyl-4-chlorophenoxy and 2, 4-dichlorophenoxy groups.
3. A process as claimed in claims 1&2, wherein aryl group is selected from the group consisting of phenyl, 4-chlorophenyl and 4-tolyl.
4. A process for the synthesis of l-(aryloxy)propionoyl-2-arylsulfonyl hydrazine
substantially as herein described with reference to the examples accompany this specification.

Documents:

379-del-2002-abstract.pdf

379-del-2002-claims.pdf

379-del-2002-complete specification (granted).pdf

379-del-2002-correspondence-others.pdf

379-del-2002-correspondence-po.pdf

379-del-2002-description (complete).pdf

379-del-2002-form-1.pdf

379-del-2002-form-2.pdf

379-del-2002-form-3.pdf

379-del-2002-form-4.pdf

379-del-2002-petition-138.pdf

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Patent Number

195185

Indian Patent Application Number

379/DEL/2002

PG Journal Number

36/2008

Publication Date

05-Sep-2008

Grant Date

24-Nov-2006

Date of Filing

28-Mar-2002

Name of Patentee

Council of Scientific and Industrial Research,

Applicant Address

Rafi Marg,

Inventors:

#	Inventor's Name	Inventor's Address
1	Thallapalli Ramalingam	Indian Institute of Chemical Technology, Hyderabad-500007
2	Yadavalli Venkata Durga Nageswar	Indian Institute of Chemical Technology, Hyderabad-500007
3	Adari Bhaskar Rao	Indian Institute of Chemical Technology, Hyderabad-500007
4	Prakash VamanRao Diwan	Indian Institute of Chemical Technology, Hyderabad-500007
5	Jhillu Singh Yadav	Indian Institute of Chemical Technology, Hyderabad-500007
6	Kondapuram Vijaya Raghavan	Indian Institute of Chemical Technology, Hyderabad-500007

PCT International Classification Number

N/A

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA