IL32106A - Benzoate esters of 4-pyrazolidinols and their preparation - Google Patents

Description

en3am ©a& their pm^MOttloa 8 The present invention relates to certain novel esters of Jj-pyrazolidinols and is more particularly concerned with benzoate esters of 4-pyrazolidinols, compositions containing the same as active ingredients and methods of making and using them.

The invention is particularly concerned with benzoate esters of 4-pyrazolidinols represented by the following genera structural formula: Formula I wherein; R is selected from the group consisting of lower alkyl and phenyllower alkyl, R1 is selected from the group consisting of hydrogen, nitro, lower alkyl, lower alkoxy, halogen having an atomic weight less than 80, amino, lower-alkyl amino and trifluoromethyl , R is. selected from the group consisting of hydrogen, lower alkoxy and halogen having an atomic weight less than 80, and acid addition salts thereof.

The compounds of the invention having the foregoing Formula represent new chemical compounds which have the capacity to produce physiological action and are adapted more particularly for use as local anesthetics. The local anesthetic properties of the novel benzoate esters of -pyrazolidinols of Formula I udin the method of Block, B. P. et al . , J. Pharm. Pharmcol . 16 , Suppl . 85 T-88T on the earthworm, genus Lumbricus and intra¬ dermal administration on the guinea pig, topical administration on the cornea of the rabbit and nerve block in anesthetized rabbits by the methods of Bulbring, E. and Wajda, J., J.

Pharm. and Exptl . Therap. 8>, 78-8 (19^5) and Chance, M. R. A. and Lobstein, H., J. Pharm. and Exptl. Therap. _8_2^203 (1944) .

In the above referred to procedure of Block et al, the earthworm, genus Lumbricus is placed in a solution of the compound being tested for a period of one minute, dipped in distilled water, dried lightly with absorbent paper and the tail dipped in 0.0125N hydrochloric acid. The local anesthetic action is shown by the absence of a sharp contracting response in the worm and the duration of action is measured from the application of acid until a response is noted. In the following table compounds of the invention are compared with the known local anesthetic Lidocaine( diethylaminoacet-2,6-xylide .) Table I Concentration Average Time PH of Compound of Test Solution for Response (Mins.) Solution Lidocaine 2.00% 2.0 6.69 .50 7.0 6.68 l,2-Diethyl-4- 5.00o 1.0 5-88 pyra ol idinol j5-trifluoromethyl 0.08^ 2.0 6.01 benzoate 0.04¾ 6.0 6.35 Concentration Average Time PH of Compound of Test Solution for Response (Mins.) Solution l^-Diethyl-^- 5 - 00^ 1 .0 3 . 86 pyrazolidinol 4-methylbenzoate 0.62% 1 .0 ii .80 1 , 2-Dimethy 1-4 - pyrazolidinol benzoate Moreover, the novel benzoate esters of the -pyrazolidinols of the present invention have a low order of toxicity resulting in a favorable therapeutic ratio. The acute LD50is in mice (female albino mice; Dublin Laboratory Animals, Inc. ICR Strain) weighing 20-24 grams was determined by injecting solutions of the compounds into the lateral tail vein at a constant volume of .05 ml./ΙΟ gms . of weight and at a constant rate of .05 ml . /IO seconds. A comparison of the LD50is of some of the compounds of the invention with Lidocaine is shown in Table II.

Table II Compound LD50 (intravenous) Lidocaine 45.7 mg./kg- 1 ,2-Diethyl-4-pyrazolidinol p-methoxybenzoate 20 .5 mg./kg- 1 ,2-Diethyl- -pyrazolidinol I82.4 mg . /kg . p-chlorobenzoate p-trifluoromethylbenzoate l 2-Diethyl-4-pyrazolidinol 377.Ο mg.Ag- p-fluorobenzoate When the benzoate esters were given intraperitoneally, no animals died at a maximum dose level given of 1500 mg./kg.

The local anesthetic action determined by intradermal administration on guinea pigs was carried out on female albino guinea pigs. (Lightner Enterprises) weighing 270 to 335 grams. Intradermal injections were made using concentrations of 1 , 3 , and 10 mg./kg. The injected volume of all test solutions was 0 .2 ml. A local anesthetic effect was produced with all compounds while normal saline was totally inactive. The results are given in Table II-A.

Table II-A Reduction in Responses - Concentration Minutes after Treatment Compound mq. /ml . 0 5 15 30 60 Lidocaine 1 35 15 0 3 62 19 6 0 8 70 15 0 l, 2-diethyl-4- 1 17 0 0 0 pyrazolidinol 3 33 8 0 0 4-methoxybenzoate 10 50 0 8 0 1 ,2-diethyl-1!- 1 17 8 0 0 pyrazolidinol 3 33 0 0 0 4-chlorobenzoate 10 83 25 0 0 l^-diethyl-*1)-pyrazol idinol 1 0 8 0 0 *j-trifluorometnyl 3 33 8 8 0 benzoate 10 75 42 8 0 l,2-diethyl-*{- 1 50 8 0 0 pyra'zolidinol 3 75 25 17 0 4-fluorobenzoate 10 67 58 17 0 The present invention further contemplates the use of the novel compounds in mammals when local anesthesia is desired. In topical anesthesia as in relieving pruritus preparations containing 1-2% of the esters as their salts are prepared and may be used as such in sprays, lotions and ointments. Preparations useful for infiltration, nerve block, spinal, peridural and caudal anesthesia are usually prepared as sterile aqueous solutions of the salts of the esters, the solutions containing from 0.^>%> to 5 > °f the active ingredient.

It is, accordingly, an object of the present invention to provide novel benzoate esters of 4-pyrazolidinols . Another object is to provide novel compounds which, when administered to mammals, provide local anesthetic action with minimum side effects. A still further object of the present invention is to provide methods for producing the novel benzoate esters of Jl-pyrazolidinols and methods for the utilization thereof.

Additional objects will become apparent hereinafter and still others will be apparent to one skilled in the art.

In the definition of symbols in the foregoing Formula I and where they appear elsewhere throughout this specification the terms have the following significance: The term "lower alkyl" as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive, preferably no more than six carbon atoms, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like.

The term "lower alkoxy" has the formula -O-lower alkyl.

The term "phenyllower-alkyl" refers to groups such as benzyl, phenethyl, o-methylbenzyl, phenpropyl and the like.

This invention also includes acid addition salts of the above defined bases formed with nontoxic organic and inorganic acids. Such salts are easily prepared by methods known in the art. When the compounds are to be used as intermediates for preparing other compounds or for any other non-pharmaceutical use, the toxicity or nontoxicity of the salt is immaterial; when the compounds are to be used as pharmaceuticals, they are most conveniently used in the form of nontoxic acid-addition salts. Both toxic and nontoxic salts are therefore within the purview of the invention. The acids which can be used to prepare the preferred nontoxic acid-addition salts are those which produce, when combined with the free bases, salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties n i ia d b ide effect The base is reacted with the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as ethanol or isopropanol, with isolation of the salt by concentration and coolingj or the base is reacted with an excess of the acid in aqueous . immiscible solvent, such as ethyl ether or isopropyl ether, with the desired salt separating directly. Exemplary of such organic salts are those formed with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, citraconic, itaconic hexamic, p-aminobenzoic, glutamic, stearic acid and the like. Exemplary of such inorganic salts are those formed with hydro¬ chloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids .

The novel benzoate esters of- 4-pyrazolidinols of this invention as represented by Formula I above are prepared by esterification of l,2-disubstituted-4-pyrazolidinols of Formula Formula II wherein R is as defined above.

Symmetrical disubstituted hydrazines prepared by methods described in the literature are mixed with epichlorohydrin in a mol'ar ratio of about 1:1 to about 2:1 and preferably 1.5:1 in a dry inert organic solvent, illustratively ether in a dry flask.

The flask is stoppered and allowed to stand at a temperature o o days to about twenty-four days. After the reaction period the precipitated disubstituted hydrazine hydrochloride is removed by filtration,, or the reaction mixture is treated with an excess of an aqueous alkali metal carbonate solution, the organic solvent is .separated from aqueous material, dried briefly over a drying agent and evaporated and the residual oil distilled in vacuo to give the 1 ,2-disubstituted-4-pyrazolidinols of Formula I Generally speaking, the method of preparing the compounds of Formula I is as follows: A 1,2-disubstituted-^-pyrazolidinol is reacted with an appropriately substituted benzoic acid in an inert organic solvent, illustratively benzene, containing a catalytic amount of a mineral acid or an aryl sulfonic acid and the water formed during the esterification process is removed azeotropically. After completion of the reaction as determined by the amount of water collected, the reaction mixture is washed with water, dried over an inert drying agent, the solvent removed and the residual crude ester purified by conventional procedures including distillation, crystallization, chromotagrophy and the like. Alternatively, the substituted benzoic acid is converted first to the acid halide by reaction with a thionyl halide and the substituted benzoyl halide thus formed is reacted, after suitable purification, with the l,2-disubstituted-*l-pyrazolidinol The 'reaction mixture from the latter procedure is quenched in water, an excess of a metal carbonate added, and the base insoluble ester extracted with an organic solvent and the ester isolated and purified as described hereinabove.

In the preferred method of preparing the novel esters of Formula I, a solution of the -pyrazolidinol in anhydrous pyridine is treated with a slight excess of an appropriately substituted benzoyl chloride. The initial reaction which is usually exothermic is allowed to cool to room temperature and the reaction is completed by heating the reaction mixture on a steam bath for a period of from about thirty minutes to one hour or by allowing the reaction mixture to stand at room temperature for a period of from about two days to about four days. The reaction mixture is poured into water, an excess amount of a metal carbonate is added as, for example, potassium carbonate, and the base insoluble ester extracted using an organic solvent. The organic solvent is removed after drying, using an inert drying agent, illustratively magnesium sulfate, and the residual ester purified by distillation or by conversion to an acid addition salt.

The following examples are presented to illustrate the present invention and they should not be construed as limiting it in spirit or in scope: Example 1 1 ,2-Dimethyl-l|-pyrazol idinol .

Into a dried 200 ml. Erlenmeyer flask were- placed 100 ml. of anh drous ether, 15'· 8 g. (0.263 mole) of 1,2-dimethylhydrazine and 16.2 g. (0.175 mole) of epichlorohydrin . The flask was place in the refrigerator at a temperature of H°C. for a period of 10 days. The ether solution was filtered free of precipitated salt and the ether filtrate was concentrated in vacuo on the water bath. The oily residue was distilled at 56°C . (0.1 mm.) to give of a colorless mobile oil. A picrate melted at o 175-176 c.

Analysis: Calculated for C5H12N20: 0, 1. 0; H, 10. ^l ; N,2^1.12 Found : 'c, 51.92 H,10-53 N,2^.84 Example 2 1 ,2-Diethyl-^-pyrazolidinol .

Into a dried 0 ml. Erlenmeyer flask were placed 90 ml. of anhydrous ether and ΐβ .1 g. (O.I83 mole) of 1,2-diethylhydrazine and II.3 g. (0.122 mole) of epichlorohydrin. The flask was stoppered and allowed to stand at room temperature for about one week. The ether solution was treated with an excess of aqueous potassium carbonate solution and dried over magnesium sulfate. The dried ether solution was flash evaporated and the oily residue was distilled at reduced pressure. A total of 9-3 g- (53-0^) of product collected at 53°C../0.03 nim.

Analysis: Calculated for C7H16Ns0: 0,58.^3 H,ll.l8; N,19-1÷3 Example 3 1 ,2-Dibenzyl-^-pyrazolidinol ■ Into a 500 ml. Erlenmeyer flask were placed 8.^5 g. (0.091 mole) of epichlorohydrin, 200 ml. of anhydrous ether, and 38.7 g. (O.I83 mole) of 1 ,2-dibenzylhydrazine . The glass stoppered Erlenmeyer flask was stored at room temperature for a _ period of l8 days. The precipitated white solid which separated was filtered and the ether distilled from the filtrate under reduced pressure using a water bath. The oily residue solidified to a waxy mass which melted at 8θ-8 °0. after crystallization from ligroin. The solid obtained after crystallization from benzene weighed 10.0 gms . ( ^O . Q ) and melted at 91.5-92.0°C.

Analysis: Calculated for C17H2ON£0: 0,76.08; Η,7·51; Ν,ΙΟ.1!1! Found : 0,76.42 Η,7·67; ,9·99 Example k 1 ,2-Di-n-propyl- -pyrazolidinol .

In the same manner as given in Examples 1-3* 1,2-di-n-propyl- -pyrazolidinol was prepared from 1 ,2-di-n-propylhydrazine and epichlorohydrin . The free base was a colorless oil that distilled Analysis: Calculated for C9H2oN20: C,62.75; H,11.70; N, 16.26 Found : C,63-22; Η,12.ΐ8; ,15·90 Example 1 ,2-Di-isopropyl-4-pyrazolidinol .

In the same manner as given in Examples 1-3, 1.,2-di-isopropyl- -pyrazolidinol was prepared from 1 j2-di-isopropyl-hydrazine and epichlorohydrin . The free base distilled at mm .

Analysis: Calculated for C9H2oN20: C,62.75; Η,ΙΙ.70; Ν,1β.2β ' Found : 0,63-26; Η,ΙΙ.78; N,l6.20 Example 6 1 ,2-Di- isobutyl- -pyrazolidinol .

In the same manner as given in Examples 1-3> 1,2-di-isobutyl- -pyrazolidinol was prepared from 1 ,2-di-isobutylhydrazine and epichlorohydrin. The free base distilled at 66°C./0.05 mm.

Analysis: Calculated for Cn¾4Na0: 0,65-95; H, 12.08; ,13·99 Found : C,6 -87; Η,ΙΙ.96; N, 1*1.05.

Example 7 1 ,2-Diphenethyl-4-pyrazolidinol .

In the same manner as given in Example 3, 1,2-diphenethyl- -pyrazolidinol is prepared from 1,2-diphenethylhydrazine and epichlorohydrin .

Example 8 1 ,2-Diphenpropyl-4-pyrazolidinol .

In the same manner as given in Example 3. 1 , -diphenpropyl- Example 9 1 ,2-Dimethyl-4-pyrazol idinyl Benzoate Hydrochloride.

Three g. (0.01 mole) of 1,2-dimethyl-4-pyrazolidinol was dissolved in about 30 ml. of anhydrous pyridine. To this solution was added dropwise, 1.5 g. (O.Ol mole) of benzoyl chloride. After the initial exothermic reaction subsided the solution was heated on a steam bath for about 30 minutes and then poured into a beaker containing 0 ml. of water. The solution was neutralized with 20 ml. of a 5^ sodium carbonate solution, extracted with three 50 ml. portions of ethyl acetate, and the combined organic extracts were dried and evaporated in vacuo. The residual brown oil was dissolved in absolute ether and dry hydrogen chloride gas was passed through the ether solution to yield an oil that solidified to a tan solid. The ether was evaporated to give a crude product melting at 153- 157°C . after drying. The product was crystallized from a 1:1 mixture of acetone and heptane to give a white amorphous solid that melted at 158-159.5°C. and weighed 2.2 g. (75^ yield).

Analysis: Calculated for C i2H17N202Cl : C, 56.1 ; H,6.68; Ν,10·91; 01,1 .81 Found : C,56.40; Η,β·79; Ν 10·98; ci, 13.90 Example 10 1 ,2-Dimethyl-^-pyrazolidinyl 4-Nitrobenzoate Hydrochloride .

To a flask containing 5 g. (0.05 mole) of l,2-dimethyl- -pyrazolidinol was added 5 ml. of anhydrous pyridine and to chloride. The solution was heated on a steam bath to effect solution and then heated carefully on an open flame for about five minutes. The brown solution was poured into a 5^ solution of sodium bicarbonate. The solution was extracted with ether and the ether evaporated to give a yellow solid. The yellow solid was dissolved in absolute ethanol and dry hydrogen chloride gas was passed into the solution. The solution was evaporated in vacuo and the residual oil was dissolved in n-propanol and cooled. The n-propanol was evaporated in vacuo to give a light yellow solid. Recrystallization of the solid from a 1:1 mixture of acetone- isopropanol gave 2 g. (1 ^) of o product, m.p. 215-216 C.

Analysis: Calculated for C 12H16N304Cl : C, 7.77; H,5.3^ Ν,Ι}.^; CI, 11. 5 Found : c,^7;93; H,5-51; , 13.89; 01,11.90 Using the procedure described above, the following compounds are prepared from the stated ingredients: l,2-diethyl-il-pyrazolidinyl 2-methoxy-1J-nitrobenzoate is prepared from l,2-diethyl-1i-pyrazolidinol and 2-methoxy-il- nitrobenzoyl chloride, - 1 ,2-diethyl-i1-pyrazolidinyl 2-propoxy-il-nitrobenzoate is prepared from l^-diethyl-^-pyrazolidinol and 2-propoxy-iJ-nitro- benzoyl chloride.

Example 11 1 ,2-Diethyl-4-pyrazol idinyl Benzoate Hydrochloride.

Into a 50 ml. Erlenmeyer flask were placed 12 g. (Ο.83 mole) of 1 , 2-diethyl-il-pyrazolidinol and 15 ml. of anhydrous pyridine. Benzoyl chloride (14.0 g.; 0.1 mole) was added slowly to the pyridine solution. The solution became dark and quite warm and was allowed to stand at room temperature over the week end. The mixture was poured into an aqueous solution of 5 potassium carbonate and solid potassium carbonate was added until the evolution of carbon dioxide ceased. The solution was extracted with ethyl ether and the extract was dried with anhydrous magnesium sulfate. The ether and pyridine was removed in vacuo and the red, oily residue was dissolved in anhydrous ethyl ether and dry hydrogen chloride was passed through the solution. An oil separated and slowly solidified after standing for about one week. The brown solid was recrystallized repeatedly from acetone and yielded 15·1 9- (6 iw) of product which melted at l> -l>6°C .

Analysis: Calculated for C 14¾. χ 202Cl : 0,59-04; H,7- 3; Ν,9·84; 01,12.45 Found : 0, 8-94; Ή.,Τ . >6; N, 9-66; 01,12.46 Using the procedure described above, the following compounds are prepared from the stated ingredients: li2-diethyl-4-pyrazolidinyl-2-ethoxy-4-fluorobenzoate is prepared from l,2-diethyl-4-pyrazolidinol and 2-ethoxy-4-fluoro-benzoyl chloride, li2-diethyl-il-pyrazolidinyl-2-propoxy-i-fluorobenzoate is prepared from 1 J2-diethyl-ii-pyrazolidinol and 2-propoxy-4-fluorobenzoyl chloride, 1 J 2-diethyl-il-pyrazolidinyl 2-fluorobenzoate is prepared from l, 2-diethyl-'ll-pyrazolidinol and 2-fluorobenzoyl chloride, l, 2-diethyl-^-pyrazolidinyl-3-fl orobenzoate is prepared from 1 , 2-diethyl-i)-pyrazolidinol and 3_ luorobenzoyl chloride.

Examples 12-22 Examples 12-22 were prepared by methods analagous to those described for Examples 9- 1 · The physical constants of Examples 12-22 are shown in Table III.

M. P. c H (B.P.) Calcd. Calc Example R R1 R2 Found . Foun 121 C2H5 4-F H 134-136 .72 6.6 55-63 6.5 132'5 C2H5 3-CF3 H 131-132.5 46.24 4.0 46.16 4.0 l43 C2H5 4-CH3 H 126-127 63.42 8.5 63.59 8.2 154 C2H5 4-C5H90 H 50-52 68.23 9.0 68.31 9.0 164 C2H5 2-Cl 4-Cl (126-128/.02 mm) 53.01 5.7 .1 5.6 172 ; C2H5 2-CH30 H 139-140 49.70 4. 49.74 4. 181 CeHsCIfe H H 186-188 70.49 6.1 70.37 6.2 191 CeHgCHa 4-F H 182-183 67.52 5. 67.65 5- LT\ : : 7.

M.P. C ' (B.P.) Calcd. Ca Example R R1 R2 °C Found Fo 201 C2H5 4-CH30 H 21i C2¾ 4-CF¾ H 1 -147 221 C2H5 4-ci H 164-165 Analysis of hydrochloride Analysis of picrate. 3Analysis of hydrochloride salt-semi-cyclohexane. solvate 4Analysis of free base. 5Melting point of picrate.

Example 1 ,2-Diethyl-4-pyrazolidinyl -Aminobenzoate .

Into a 1 5 ml. Erlenmeyer flask were placed 28.8 g. (0.2 mole) of l,2-diethyl-4-pyrazolidinol and about 0 ml . of anhydrous pyridine and 8 g. (0.2 mole) of -nitrobenzoyl chloride was added slowly. · The reaction mixture became warm and turned dark red. After cooling in an ice-water bath, the material was heated on the steam bath for about 15 minutes, at which time it solidified. The flask was allowed to cool to room temperature. The solid was dissolved in about 100 ml. of water and the solution saturated with potassium carbonate. The dark red oil that separated was extracted with ether, dried, and flash evaporated. The residual red oil was transferred to a pressure bottle containing a suspension of O.5 g. Pt02 in I50 ml. methanol. The bottle was shaken on the Parr apparatus in an atmosphere of hydrogen. A total of 43 pounds ( 90¾ of theory) of hydrogen was taken up in one hour. No appreciable amount of hydrogen was taken up on additional shaking. The mixture was filtered and concentrated to give a grey-green solid. The yield of the crude solid was ^7-3 g.

The compound was recrystallized from about one liter of cyclo-hexane to give 37 g. ( 69 ) of solid melting at 82-85°C.

Analysis: Calculated for C1 H21N3O2: C,63.85; Η,δ.Ο1!; ,15·9β Found : C,63.92; H.8.15 .15.88 Using the catalytic reduction procedure described above/ the following compounds are prepared from the stated ingredients 1 ^-diethyl-Jl-pyrazolidinyl 2-methoxy-il -aminobenzoate is prepared by catalytic hydrogenation of 1 ^-diethyl-)-pyrazol idinyl 2-methoxy-^-nitrobenzoate, 1 , 2-diethyl-^-pyrazolidinyl S-propoxy-^l-aminobenzoate is prepared by catalytic hydrogenation of 1 , 2-diethyl-il-pyrazoli-dinyl 2-propoxy-il-nitrobenzoate .

Example 2 1 , 2-Diethyl- -pyrazolidinyl k-( n-butylamino) -Benzoate .

Into a three-necked 00 ml. round bottom flask were placed 30 g. ( 0 . 11 mole) of 1 , 2-diethyl-^-pyrazolidinyl p-aminobenzoate_, 1J0 ml. of benzene and 31 nil. ( 0 .50 'mole) of glacial acetic acid. Powdered zinc dust ( 3 g. ; 0 - 50 mole) was added and the contents of the flask was stirred mechanically under reflux while n-butraldehyde ( 13 - 3 ml., 0 .15 mole) was added over a period of two hours. The mixture was stirred for about two hours longer and then filtered while hot through a fluted filter paper. The filtrate was treated with 20% potassium hydroxide solution until the aqueous layer was basic to litmus. The organic layer was separated, dried with anhydrous magnesium sulfate and flash evaporated. The light yellow oil that remained solidified on storing over night to a light tan solid. The solid was recrystal lized from cyclohexane to give 20 g. ( 55$) of product; m.p. 6l-63°C. A picrate was prepared and was recrystall ized from absolute alcohol; m.p. 132-133°C.

Analysis of Ester: Analysis of Picrate: Calculated for C24H32N609: 0,52.55; Η,5·88; N, 15.32 Found : 0, 2.68; H,5.73; N} 1 -33 Various modifications may be made in the present invention without departing from the spirit and scope thereof and it is to be understood that the invention is limited only by the scope of the appended claims.

Claims (1)

1. AHR-156 What is claimed is: ■ - 1 - A compound selected from the group of benzoate esters of li2-disubstituted-1l-pyrazolidinol having the formula: wherein; R is s of lower alkyl and phenyllower-alkyl , R1 is selected from the group consisting of hydrogen, nitro, lower alkyl, lower alkoxy, halogen having an atomic weight less than 80, amino, lower-alkyl amino and trifluoro-methylj R is selected from the group consistxng of hydrogen, lower alkoxy and halogen having an atomic weight less than 80, and acid addition salts thereof. - 2 - A compound according to Claim 1 which is l,2-dimethyl-4-pyrazol idinyl benzoate. • - 3 - A compound according to Claim 1 which is l,2-dimethyl-4-pyrazolidinyl-4-nitrobenzoate . AHR-156 - 4 - A compound according to Claim 1 which is 1,2-diethyl-^-pyrazolidinyl benzoate . - 5 - A compound according to Claim 1 which is 1.,2-diethyl-4-pyrazolidinyl -fluorobenzoate . - 6 - A compound according to Claim 1 which is 1j -diethyl-4-pyrazolidinyl 3_trifluoromethylbenzoate . - 7 - A compound according to Claim 1 which is 1,2-diethyl-^-pyrazolidinyl 4-methylbenzoate . - 8 - A compound according to Claim 1 which is l,2-diethyl-4-pyrazolidinyl Jj-amyloxybenzoate . - 9 - A compound according to Claim 1 which is 1 ,2-diethyl-^-pyrazolidinyl 2 , -dichlorobenzoate . - 10 - A compound according to Claim 1 which is l^-diethyl-!-pyrazolidinyl 2-methoxybenzoate . - 11 - A compound according to Claim 1 which is 1 ,2-dibenzyl-4 pyrazolidinyl benzoate . - 12 - A compound according to Claim 1 which is 1 ,2-dibenzyl-pyrazol idinyl 4-fluorobenzoate . - 13 - A compound according to Claim 1 which is 1 J2-diethyl-4 pyrazolidinyl 4-methoxybenzoate . - 14 - A compound according to Claim 1 which is 1 j2-diethyl-4 pyrazolidinyl 4-trifluoromethylbenzoate . - 15 - A compound according to Claim 1 which is lj2-diethyl-4 pyrazolidinyl 4-chlorobenzoate . - 16 - A compound according to Claim 1 which is 1 ,2-diethyl-4 pyrazolidinyl 4-aminobenzoate . - 17 - A compound according to Claim 1 which is 1 , 2-diethyl-4 razolidinyl 4-( n-butylamino) -benzoate . AHR-156 - 18 - A process for the preparation of a compound selected from the group of benzoate esters of l,2-disubstituted- -pyrazolidinols having the formula: wherein; R is selected from the group consisting of lower alkyl and phenyllower-alkyl, R1 is selected from the group consisting of hydrogen, nitro, lower alkyl, lower alkoxy, halogen having an atomic weight less than 80, amino, lower-alkyl amino and trifluoromethyl , and R is selected from the group consisting of hydrogen, lower alkoxy and halogen having an atomic weight less than 80, which comprises mixing and reacting together a 1,2-disubstituted-4-pyrazolidinol of the formula wherein R is as defined above with a compound of the formula 1 2 wherein R and R are as defined above and Y is selected from the group consisting of halogen and hydroxy. AHR-156, - 19 - A process as defined in Claim 18, wherein Y is halogen. - 20 - A process as defined in Claim 19, wherein the reactants are mixed and reacted together in anhydrous pyridine. - 21 - A process as defined in Claim 18, wherein Y is hydroxy. - 22 - A process as defined in Claim 21, wherein the reactants are mixed and reacted together in an organic solvent capable of removing azeotropically the water formed in the reaction. For the Applicants DR. fiEiNI/ojn QSHN AND PARTNERS By: