IE41477B1 - Sulfonylcarbamoyl derivatives - Google Patents

Abstract

1454737 Acylated sulphonamides BRISTOLMYERS CO 6 June 1975 [12 June 1974] 24455/75 Heading C2C Novel compounds (VI) (including salts thereof) wherein R 3 is a hydrogen or halogen atom or a lower alkyl group having from 1 to 4 carbon atoms inclusive, X is a methyl, phenyl or benzyl group, and Y is a methyl group or X and Y taken together form the group (VII) wherein R 1 is a lower alkyl group having from 1 to 5 carbon atoms inclusive or a phenyl group, R 2 is a hydrogen atom or a straight chain alkyl group having from 1 to 3 carbon atoms inclusive or R 1 and R 2 taken together form the group -(CH 2 ) 5 -, are made by reacting (III) or (IV) with Pharmaceutical preparations having hypoglycemic and hyperglycemic actions contain (VI) as active ingredient. Administration is orally or parenterally.

Description

This invention relates to sulfonylcarbamoyl derivatives of 1,3-dicarbonyl compounds which have blood sugar regulating properties.

The present invention provides an arylsulfonyl5 carbamoyl derivative having the general Formula VI VI wherein R is a hydrogen or halogen atom (including chlorine, bromine, fluorine and iodine) or a lower alkyl group having from 1 to 4 carbon atoms inclusive; X is a methyl, phenyl or benzyl group and Y is a methyl group; or X and Y taken together form the group R1 7 CH2~ \ V CH2wherein R-^ is a lower alkyl group having from 1 to 5 carbon atoms inclusive or a phenyl group; R2 is a hydrogen atom or a straight chain alkyl group having from 1 to 3 carbon atoms inclusive or R^ and R2 taken together form the group -(CH2)^-; or a pharmaceutically acceptable basic salt thereof.

The preferred compounds of the present invention are the arylsulfonylcarbamoyl-1,3-cyclohexanediones characterized by Formula I, the arylsulfonylcarbamoyl5 1,3-dicarbonylacyclic compounds of Formula II and the pharmaceutically acceptable basic salts thereof In Formula I above, R^ is a lower alkyl group having from 1 to 5 carbon atoms inclusive or a phenyl group; R2 is a hydrogen atom or a straight chain alkyl group having from 1 to 3 carbon atoms inclusive; or R^ and R2 taken together form the group -(CH2)g-.

Rg in Formulae I and II represents a hydrogen or 13 halogen atom (including chlorine, bromine, fluorine and iodine) or a lower alkyl group having from 1 t o 4 carbon atoms inclusive. In Formula II, R^ represents a methyl, phenyl or benzyl group.

Both chronic hypoglycemic and hyperglycemic states are known but the most prevalent condition found with regard to abnormal levels of blood sugar is that caused by diabetes which produces increased blood glucose levels. Various agents have been developed to lower blood sugar level for treatment of diabetes and among presently available antidiabetic agents there can be mentioned, by way of example, those of the sulfonylurea type such as tolbutamide. S. Hunig, et al. Chem. Ber., 95, 926 (1962) reported the preparation of 2-(N-g-toluenesulfonylcarbamoyl)-cyclohexanone, a compound formally related to the compounds of the present invention, however, they disclose no biological properties thereof.

By the term lower alkyl as used herein is meant both straight and branched chain hydrocarbon radicals containing 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl, tert .-butyl, pentyl and branched chain isomers thereof such as 3-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 2,2-dimethylpropyl, and 1,1-dimethylpropyl.

By the term pharmaceutically acceptable basic salts as used herein is meant salts of the compounds of formula I, II or VI with alkaline agents. The pharmaceutically acceptable basic salts of the above compounds are provided by admixture of the compounds of Formula I, II or VI with substantially one chemical equivalent of an alkaline agent, such as for example, alkali metal alkoxides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates and alkaline earth metal bicarbonates.

A preferred method of sodium salt formation is to treat a compound of Formula I, II or VI with substantially one chemical equivalent of sodium methoxide in methanol - 4 41477 solution. The desired sodium salt precipitates from methanolic solution upon the addition of anhydrous ether or the solvent is removed by distillation.

The arylsulfonylcarbamoyl-l,3-dicarbonyl compounds 5 of the present invention of Formulae I, II and VI are prepared by reacting an alicyclic-1,3-dione or acyclic1,3-dione having the general formula: III IV in a suitable reaction-inert solvent, with a sulfonyl10 isocyanate having the formula wherein R^, R2, R3 and R^ are as previously defined, and, when a pharmaceutically acceptable basic salt is desired, reacting the compound of Formula VI so produced with an alkaline agent.

By the term reaction-inert solvent” as used herein is meant a solvent which functions as a diluent for the reaction and does not interact with the alicyclic or acyclic diketone or sulfonylisocyanate reactant. Benzene is a preferred solvent for carrying out the process; however, other solvents such as toluene, xylene, hexane, dioxane, tetrahydrofuran and 1,1-dichloethane are also satisfactory.

In carrying out the process for the preparation of the compounds of the present invention, approximately equimolar quantities of the reactants are dissolved or suspended in the reaction-inert solvent and the mixture is maintained at a temperature in the range of 0 to 150°C. for a period of time ranging from 1 to 24 hours. The time period required for complete reaction is generally inversely proportional to the temperature at which the reaction is conducted, i.e., the higher the temperature, the shorter the reaction period.

Cyclohexanedione intermediates of Formula III are known or they can be prepared by means of a Michael Condensation involving diethylmaloanate and the appropriate a, fi-unsaturated ketone according to the procedure of R. L. Frank and Η. K. Hall, J. Am. Chem. Soc., 72, 1645 (1950) .

The method of the present invention for regulating blood sugar concentration in a non-human mammal comprises administering to a mammal requiring blood sugar concentration regulation an amount effective to exert a blood sugar regulating effect of a compound of the Formula I, II or VI. The amount of the compound administered is generally in the range of from 3 to 200 mg./kg. body weight of said mammal. The compounds of the present invention are effective as hypoglycemic or hyperglycemic agents.

Oral administration of the compounds of the present invention is particularly preferred. However parenteral routes such as intramuscular, intravenous, intraperitoneal - 6 4147? and subcutaneous administration may also be employed.

The compounds of the invention can be incorporated into pharmaceutical preparations such as tablets and capsules which contain the usual adjuvants and carriers such as talc, starch, lactose and magnesium sterate.

Conventional biological tests are employed to demonstrate blood sugar regulating properties of the compounds of the present invention of the Formulae I, II and VI. For example, the compounds of the invention when administered orally to laboratory mammals such as guinea pig, rat, rabbit and mouse provide a decrease or an increase in blood glucose concentration as determined by standard glucose assay described by W.S. Hoffman, J. Biol. Chem., 120, 51 (1937).

Significant hypoglycemic of hyperglycemic effects are obtained after an induction period of 1 to 2 hours when the compounds of the present invention are administered at a dose Of 100 mg./kg. body weight. These effects are generally well-maintained for more than 8 hours post-drug administration.

Compounds of the present invention preferred for their hypoglycemic activity are: ,5-Dimethyl-2-(N-g-toluenesulfonylcarbamoyl)1,3-cyclohexanedione, -Ethyl-2-(N-g-toluenesulfonylcarbamoyl)-1,3cyclohexanedione, -Isopropyl-2-(N-£-toluenesulfonylcarbamoyl)1.3- cyclohexanedione, -tert.-Butyl-2-(N-jo-toluenesulfonylearbamoyl)1.3- oyclohexanedione, and 2-(N-g-Chlorobenzenesulfonylcarbamoyl)-5,5dimethylcyclohexane-1,3-dione.

At a dose of 100 mg./kg, body weight, the compounds above provided a 20% decrease in blood sugar for a period of more than eight hours after the animals were treated. Compounds particularly preferred for their long-lasting hypoglycemic action are 5-isopropyl-(N-g-toluenesulfonylcarbamoyl)-1,3-cyclohexanedione and 2-(N-g-chlorobenzenesulfonylcarbamoy1)-5,5-dimethyl-cyclohexane-l,3-dione; with these compounds 8 hours after administration, decreased blood sugar level values of 34% and 36% respectively were obtained. Tolbutamide, by comparison, gave a 50% depression of the blood sugar level of rats one hour after dosing; however, 5 hours after dosing, the blood sugar level had recovered to less than 20% below normal. -(1-Ethylpropyl)-2-(N-g-chlorobenzenesulfonylcarbamoy 1) -1, 3-cyclohexanedione is particularly preferred for its hyperglycemic activity. Oral administration of 5-(1-ethylpropyl)-2-(W-g-chlorobenzenesulfonylcarbamoyl)-1,3-cyclohexanedione to rats at a dose of 100 mg./kg. provides a marked hyperglycemic effect with a 25% elevation of blood sugar after 6 hours and a 44% elevation of blood sugar after 8 hours.

The following examples are given only by way of Illustration and are not intended to be limiting in any respect.

Example 1.

A mixture of 7.0 g (0.05 mole) 5,5-dimethyl-l,3cyclohexanedione and 9.86 g (0.05 mole) g-toluenesulfonyl8 isocyanate in 150 ml. of benzene was stirred at 40 to 60°C. for a period of 6 hours. The mixture was then heated on a steam bath for 2 hours and concentrated under reduced pressure providing a semi-solid residue which was taken up in a mixture of 45 ml. of acetone and 5 ml. of methanol. Addition of 10 ml. of water to the acetone-methanol solution provided a quantitative yield of product, m.p. 94 to 1O8°C. Crystallization of the crude product from acetone-water afforded 9.6 g. (56% yield) of 5,5-dimethyl-2-(N-£-toluenesulfonylcarbamoyl)-1,3-cyclohexanedi0ne, m.p. 127.5 to 129.5°C. Analysis.

Calcd. for Ο-^Η-^ΝΟ^δ (percent) : C, 56.96; H, 5.68; S, 9,50.

Found (percent): C, 57.23; H, 5.94; S, 9.61.

Example 2.

Reaction of equimolar amounts of 5-methyl-l,3cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-methyl-2-(N-£-toluenesulfonylcarbamoyl)-1,3-cyclohexanedione, m.p. 121.5-122.5°C. (corr.) Analysis.

Calcd. for Ο-^Η^γΝΟ^δ (percent); C, 55.71; H, 5.30; N, 4.33; S, 9.92.

Found (percent): C, 55.80; H, 5.38; N, 4,52; S, 10.14.

Example 3.

Reaction of 5-ethyl-l,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-ethyl-2-(N-g-toluenesulfonylcarbamoyl)-!,3-cyclohexanedione, m.p. 86-87°C. (corr.).

Analysis.

Calcd. for cik,H19NO5S (Percent) ! C, 56.96; H, 5.68; N, 4.15; S, 9.50.

Found (percent); C, 57.11; H, 5.74; N, 4.09; S, 9.79.

Example 4.

Reaction of 5-isopropyl-1,3-cyclohexanedione with g-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-isopropyl-2-(N-g-toluenesulfonyloarbamoyl)-1,3-cyclohexanedione, m.p. 106.5107.5°C (corr.).

Analysis.

Calcd. for C^Hj^NO^S C, 58.10; H, 6.01; (percent); N, 3.99. Found (percent); c, 58.24; H, 5.71; N, 4.01. Example 5. Reaction of 5-tert.-butyl-1 with g-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-tert.-butyl-2-(N-gtoluenesulfonylcarbamoyl)-1,3-cyclohexanedione, m.p. 161.5-163°C. (corr.).

Analysis.

Calcd. for CqgHjjNOjjS (percent) s C, 59,16; H, 6.34; N, 3.83; S, 8.78.

Found (percent): C, 59.43; H, 6.27; N, 3.79; S, 8.71.

Example 6.

Reaction of equimolar amounts of spiro [5,5]undecane-2,4-dione with £-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 3-[n-(£-toluenesulfonyl)carbamoyl] spiro[5,5] undecane2,4-dione, m.p. 150.5-152°C. (corr.).

Analysis.

Calcd. for cigH23NO5S (percent) : c, 60.46; H, 6.14; N, 3.71; Found (percent): c, 60.75; H, 6.26; N, 3.69; Example 7.

Reaction of equimolar amounts of 5,5-dimethylcyclohexane-1,3-dione with £-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 2-(N-£-chlorobenzenesulfonylcarbamoyl)-5,5dimethylcyclohexane-1,3-dione, m.p. 103-105.5°C. (corr.).

Analysis.

Calcdι , for C^gH^gClNOgS (percent); c, 50.34; H, 4.51; S, 8.96. Found (percent): c, 50.12; H, 4.56; S, 9.10. 2-(N-£-Chlorobenzenesulfonylcarbamoyl)-5,5-dimethy1cyclohexane-1,3-dione sodium salt is obtained by dissolving 2-(N-£-chlorobenzenesulfonylcarbamoyl)-5,5-dimethylcyclohexane-1,3-dione and a molar equivalent of sodium methoxide in methanol and removing the solvent under reduced pressure Example 8.

Reaction of equimolar amounts of 5-isopropyl-l,3cyclohexanedione with g-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 2-(N-g-chlorobenzenesulfonylcarbamoyl)-5-isopropyl-1,3-cyclohexanedione, m.p. 100.5-101.5°C. (resolidified and melting at 183.5°C. with dec.) (corr.).

Analysis.

Calcd. , for C-^gH-^gClNOgS (percent); c, 51.68; H, 4.88; N, 3.77; S, 8.62; Cl, 9.54. Found (percent): c, 51.90; H, 5.03; N, 3.92; S, 8.87; Cl, 9.84.

Example 9.

Reaction of equimolar amounts of 5,5-dimethyl-l,3cyclohexanedione with benzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords ,5-dimethy1-2-(N-benzenesulfonylcarbamoy1)-1,3-cyclohexanedione, m.p. 101-103°C (corr.)..

Analysis.

Calcd. for C^^H^^NOj-S (percent): C, 55.71; H, 5.30; N, 4.23; S, 9.91, Found (percent): C, 55.81; H, 5.40; N, 4.37; S, 9.82.

Example 10.

Reaction of equimolar amounts of 5-(1-ethylpropyl)1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-(1-ethylpropyl)-2-(N-g-toluenesulfonylcarbamoyl)-1,3cyclohexanedione, m.p. 111.5-112.5°C. (corr.).

Analysis.

Calcd. for cigH25NO5S (percent) : C, 60.13; H, 6.64; N, 3.69; S, 8.45.

Found (percent): C, 60.10; H, 6.61; N, 3.67; S, 8.57.

Example 11.

Reaction of equimolar amounts of 5-(1-ethylpropyl)1,3-cyclohexanedione with g-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-(1-ethylpropyl)-2-(N-g-chlorobenzenesulfonylcarbamoyl)-l,3-cyclohexanedione, m.p. 121-122°C. (corr.). Analysis.

Calcd. for cigH22C1NO5S (percent): C, 54.05; H, 5.55; N, 3.50; Found (percent): c, 53.97; H, 5.58; N, 3.52; Example 12.

Reaction of equimolar amounts of 1-phenyl-1,3butanedione with £-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 1-phenyl2-(N-£-toluenesulfonyicarbamoyl)-1,3-butanedione, m.p. 113.5-116.5°C. (corr.). Analysis . Calcd. for C-^gH-^NOgS (percent): C, 60.15; H, 4.77; S, 8.92. Found (percent): C, 59.86; H, 4.81; S, 8.99. Example 13 Reaction of equimolar amounts of 2,4-pentanedione with £-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 3-(N-£-toluenesulfonylcarbamoyl)-2,4-pentanedione, m.p. 137-139.5°C. (corr.).

Analysis.

Calcd. for cj_gH^gNOgS (percent): C, 52.51; H, 5.08; S, 10.78.

Found (percent): C, 52.65; H,. 5.16; S, 10.79. - 13 Example 14.

Reaction of equimolar amounts of 5-propyl-l,3cyclohexanedione with g-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-propyl-2-(N-g-toluenesulfonylcarbamoyl)-1,3-cyclohexanedione, m.p. 132.5-133.5°C. (corr.).

Analysis.

Calcd. for C^Hg^NOgS (percent): C, 58.10; H, 6.01; N, 3.99; S, 9.12.

Found (percent); C, 58.38; H, 6.11; N, 4.06; S, 9.04.

Example 15.

Reaction of equimolar amounts of 5-isopropyl-l,3cyclohexanedione with benzene-sulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-isopropyl-2-(N-benzenesulfonylcarbamoyl)-1,3-cyclohexanedione, m.p. 112.5-114°C. (corr.).

Analysis.

Calcd, , for C^gHigNOj-S (percent) : c, 56.95; H, 5.68; N, 4.15; S, 9.50. Found (percent): c, 57.03; H, 5.78; N, 4.11; S, 9.72. Example 16. Reaction of equimolar amounts of 5-sec.-butyl-1,3- cyclohexanedione with g-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-sec.-butyl-2-(N-g-toluenesulfonylcarbamoyl)-1,3-cyclohexanedione, m.p. 92-93°C. (corr.).

Analysis.

Calcd. for cxgH23NO5s (percent): C, 59.16; H, 6.34; S, 8.77.

Found (percent): C, 59.39; H, 6.55; S, 8.95.

Example 17.

Reaction of equimolar amounts of 5-sec.-butyl-1,3cyclohexanedione with ja-chlorobenzenesulfortylisocyanate in benzene according to the procedure of Example 1 affords 5-sec.-butyl-2-(N-g-chlorobenzenesulfonylcarbamoyl)-1,3cyclohexanedione, m.p. 1O6-1O7°C. (corr.).

Analysis.

Calcd. for C1^H2OC1NO5S (percent); C, 52.92; H', 5.22; S, 8.31; Cl, 9.19.

Found (percent): ' C, 52.82; H, 5.16; S, 8.45; Cl, 9.04.

Example 18.

Reaction of equimolar amounts of 5-isobutyl-l,3cyclohexanedione with £-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-isobutyl-2-(N-£-toluenesulfonylcarbamoyl)-1,3-cyclohexanedione, m.p. 128-13O°C. (corr.).

Analysis.

Calcd. for cqgH23NO5S (percent) : C, 59.16; H, 6.34; N, 3.83; S, 8.77.

Found (percent): C, 59.16; H, 6.41; N, 3.69; S, 8.81.

Example 19.

Reaction of equimolar amounts of 5-phenyl-l,3cyclohexanedione with g-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords -phenyl-2-[N-g-toluenesulfonylcarbamoyl] -1,3-cyclohexanedione, m.p. 163.5-166°C. (corr.).

Analysis.

Calcd. for C2OH1S(NOgS (percent) : c, 62.32; H, 4.97; S, 8.32. 10 Found (percent): c, 62.15; H, 5.11; S, 8.48.

Example 20.

Reaction of equimolar amounts of l-phenyl-2,4pentanedione with g-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 1-phenyl 3-(N-D-toluenesulfonylcarbamoyl)-2,4-pentanedione, m.p. 119.5-120.5°C. (corr.).

Analysis.

Calcd. for CigH^gN05S (percent): C, 61.11; H, 5.13; N, 3.76.

Found (percent): C, 60.94; H, 5.03; N, 3.76.

Claims (33)

1. CLAIMS:1 An arylsulfonylcarbamoyl derivative having the general Formula VI 5 wherein Rg is a hydrogen or halogen atom or a lower alkyl group having from 1 to 4 carbon atoms inclusive, X is a methyl, phenyl or benzyl group, and Y is a methyl group or X and Y taken together form the group CH R 2 ch 2 wherein R^ is a lower alkyl group having from 1 to 5 carbon atoms inclusive or a phenyl group, Rg is a hydrogen atom or a straight chain alkyl group having from 1 to 3 carbon atoms inclusive or R^ and Rg taken together form the group -(CHg)g-.

2. A compound as claimed in claim 1 having the Formula I wherein R lf Rg and Rg are as defined in claim 1.

3. A compound as claimed in claim 1 having the Formula II wherein R^ is as defined in claim 1 and Rj is a methyl, 5 phenyl or benzyl group.

4. 5,5-Dimethyl-2-(N-g-toluenesulfonylcarbamoyl)1,3-cyclohexanedione.

5. 5-Methyl-2-(N-g-toluenesulfonylcarbamoyl)-1,3cyclohexanedione. 10

6. 5-Ethyl-2-(N-g-toluenesulfonylcarbamoyl)-1,3cyclohexanedione.

7. 5-Isopropyl-2-(N-g-toluenesulfonylcarbamoyl)1,3-cyclohexanedione.

8. 5-tert.-Butyl-2-(N-g-toluenesulfonylcarbamoyl)15 1,3-cyclohexanedione.

9. 3-(N-(g-Toluenesulfony1)carbamoyl]spiro [5,5]undecane-2,4-dione.

10. 2-(N-g-Chlorobenzenesuflonylcarbamoyl)-5,5dimethylcyclohexane-1,3-dione. 20

11. 2-(N-g-Chlorobenzenesulfonylcarbamoyl)-5isopropy1-1,3-cyclohexanedione.

12. 5,5-Dimethy1-2-(N-benzenesulfonylcarbamoyl)1,3-cyclohexanedione.

13. 5-(1-Ethylpropyl)-2-(N-g-toluenesulfonylcarbamoyl) 25 1,3-cyclohexanedione. 44477

14. 5-(1-Ethylpropyl)-2-(N-£-chlorobenzenesulfonylcarbamoyl)-1,3-cyclohexanedione.

15. l-Phenyl-2-(N-g-toluenesulfonylcarbamoyl)-1,3butanedione.

16. 3-(N-£-Toluenesul£onylcarbamoyl)-2,4-pentanedione.

17. 5-Propyl-2-(N-£-toluenesulfonylcarbamoyl)-1,3cyclohexanedione .

18. 5-Isopropyl-2-(N-benzenesulfonylcarbamoyl)-1,3cyclohexanedione .

19. 5-sec.-Butyl-2-(N-£-toluenesulfonylcarbamoyl)1,3-cyclohexanedione.

20. 5-seo.-Butyl-2-(N-jo-chlorobenzenesulfonylcarbamoyl)-1,3-cyclohexanedione.

21. 5-Isobutyl-2-(N-£-toluenesulfonylcarbamoyl)1,3-cyclohexanedione.

22. 5-Phenyl-2- [N~£-toluenesulfonylcarbamoyl]-l,3~ cyclohexanedi one.

23. l-Phenyl-3-(N-£-toluenesulfonylcarbamoyl)-2,4pentanedione.

24. A pharmaceutically acceptable basic salt of a compound as claimed in any one of the preceding claims.

25. A process for producing an arylsulfonylcarbamoyl derivative having the general Formula VI CNHSO R. '3 VI wherein R^, X and Y are as defined in claim 1; or a pharmaceutically acceptable basic salt thereof which process comprises acyclic-1,3-dione reacting an alicyclic-1,3-dione or having the general formula: R 4~ C \ or CH„ / 1 CH, —C z 3 II o IV are as defined in claim 1 and R^ is a benzyl group, in a suitable reactionwherein R^ and R 2 methyl, phenyl or inert solvent with a sulfonylisocyanate having the formula: wherein R^ is as defined in claim 1, and, when a pharma10 ceutically acceptable basic salt is desired, reacting the compound of Formula VI so produced with an alkaline agent.

26. A process as claimed in claim 25 wherein approximately equimolar quantities of'the reactants are dissolved or suspended in said solvent and the reaction 13 is carried out at a temperature in the range of 0 to 150°C. for from 1 to 24 hours.

27. A process as claimed in claim 25 or claim 26 wherein the reaction-inert solvent is benzene, toluene, xylene, hexane, dioxane, tetrahydrofuran or 1,1-dichloro20 ethane.

28. A process as claimed in any one of claims 25 to 27 wherein the alkaline agent is an alkali metal alkoxide, alkali metal hydroxide, alkaline earth metal - 20 41477 hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate or alkaline earth metal bicarbonate.

29. A process as claimed in claim 25 wherein the 5 compound of Formula VI is treated with substantially one chemical equivalent of sodium methoxide in methanol solution and the sodium salt is recovered by precipitation from the methanolic solution by addition of anhydrous ether or by distilling off the solvent. 10

30. A process as claimed in claim 25 substantially as hereinbefore described with reference to any one of the Examples.

31. » A method for regulating blood sugar concentration in a non-human mammal requiring such regulation which 15 comprises administering to the mammal an amount of a compound as claimed in any one of claims 1 to 24 effective to exert said blood sugar regulating effect.

32. A method as claimed in claim 31 wherein from 3 to 200 mg. of said compound per kg. of body weight of 20 said mammal is administered.

33. A method as claimed in claim 32 or claim 33 wherein said compound is orally or parenterally administered.