Spasmolytics: Basic esters of Substituted Malonic Acid†

Spasmolytics:

Basic Esters of Substituted Malonic Acid*,i

By ARTHUR J. McBAY,$ GLENN L. JENKINS, a n d JOHN B. DATA Certain 2-diethylaminoethyl esters of disubstituted malonic acid that resembled effective antispasmodic esters of analogous disubstituted acetic acids have been synthesized. The preparative methods used are described. Preliminary pharmacological studies indicate that all the compounds show some degree of antispasmodic activity.

methy1)phenylacetic acid; Pavatrine is a basic ester of 9-fluorenecarboxylic acid. The group,

I

-C-COO-,

(I) is a naturally occurring spasmolytic. The structure of atropine has served as a pattern in the synthetic development of potent spasmolytics which resemble this plant prototype in molecular architecture. Atropine

A

TROPINE

1

CHP-CH-CH? CHzOH NCH3 I CI H O O C L H O

I

CHZ-CH-CHZ

I I

is an ester of an aminoalcohol: namely, it is an ester of 2-(hydroxymethy1)phenylacetic acid, tropic acid, and the heterocyclic aminoalcohol, tropine. Three medicinally important synthetic spasmolytics are Trasentine (11), Syntropan (111), and Pavatrine (IV). All are esters of aminoalcohols.

)CHCOOCH~CH,N(C~H~)~

IV

Trasentine is a basic ester of diphenylacetic acid; Syntropan is a basic ester of 2-(hydroxy-

*

present in atropine, Trasentine, and

I

Received Octobcr 15 1949 from the Research Laboratories, Purdue Universit;, School of Pharmacy, Lafayette, Ind. Presented to the Scientific Section, A. PH. A,, Jacksonville meeting, April, 1949. t This work was made possible through the research fellowship established by Miles Laboratories Inc. Elkhart Ind. 1 Purdue Research Foundation Feliow, i946-194Li. Present address: Massachusetts College of Pharmacy, Boston.

Syntropan is also present in Pavatrine, except that in Pavatrine the alpha carbon is a part of the fluorene nucleus. All four of these medicinally useful spas-

I

molytics have the common group --€-COO-,

l

and thus they may be looked upon as derivatives of acetic acid. Most of the compounds which are esters of aminoalcohols prepared in the search for effective neurotropic or musculotropic spasmolytics may be classified as derivatives of the structure

I

-C-COO-

I

whether the structure be a part of a

ring or not, as illustrated in formulas (I), (11), (111), and (IV). Two excellent reviews (1, 2) covering most of work have been published. A review of the literature indicates that the physiological properties of basic esters of substituted carboxyacetic acid, malonic acid, have been studied very little. Einhorn, et al. (3), prepared bis-2-diethylaminoethyl diethylmalonate but did not report on its physiological properties. Of interest is the report of Gilman and Johnson (4) that bis-Z-diethylaminoethyl malonate shows interesting physiological properties. Revelation of these facts prompts us to make a preliminary investigation of the pharmacological properties of a few readily accessible Z-diethylaminoethyl ethyl substituted malonates and bis-2-diethylaminoethyl substituted malonates to ascertain whether these types of compounds are worthy of further investigation. Nine basic esters of substituted malonic acid have been prepared, and these compounds have been tested for spasmolytic activity by the Magnus method. The compounds reported here were prepared according to the scheme on page 139. Diethyl substituted malonates (V), prepared in the usual manner, were allowed to react with one or two equivalents of alcoholic potassium hydroxide to yield the monopotassium salt (VI) and

138

SCIENTIFIC EDITION COOK

I I

R-C-R

139

COOCzHS 2 KOH

< I -.-

COOGH, KOH

R-LR’

/

I

COOK

COOCzHb V

VII

-R-C-R’

I I

COOK VI

COOCzH6 I ( C ’ ~ H ~ ) ~ N C H , C H ~ C ~R-C-RJ

I

I

COOH

IX

I

XI

1

SOClZ

COOCHzCHzN(C2H:) 2

I

COOCzH5

I

R-C-R’ I I COOCH~CHZN(C~HS)~ Cocr XI11 X

R-C-R’

COOC~HS (CzHn)2 NCHzCHzOH -R-C-R’ (XII)

I

I COOCH~CH~N(C~H~)~ VIII

the dipotassium salt (VII), respectiyely. The monopotassium salt was converted into 2-diethylaminoethyl ethyl substituted malonate (VIII) through one of two methods: (a) by reaction of the monopotassium salt with 2-diethylaminoethyl chloride (IX), and (b) by the reaction of ethyl substituted malonyl chloride (X), prepared from ethyl hydrogen substituted malonates (XI) and thionyl chloride, with %diethylaminoethanol (XII). The dipotassium salt (VII) was allowed to react with 2-diethylaminoethyl chloride (IX) to give’bis-2-diethylaminoethyl substituted malonate (XIII). Preliminary pharmacological studies indicate that all the compounds show some spasmolytic activity against Mecholyl and barium chloride. A detailed report on the pharmacological properties of these compounds is the subject of a forthcoming paper by C. P. Headlee and L. D.

Edwards of the Pharmacology Department, School of Pharmacy, Purdue University. The authors wish to acknowledge to these investigators their appreciation for the assistance extended to them in the preliminary pharmacological studies. EXPERIMENTAL All melting points are uncorrected. Chlorine was determined by the method described by Blicke and Zienty (5) and nitrogen by a semimicro Kjeldahl method (6). Preparation of Diethyl Substituted Malonates.The diethyl malonates used in the preparation of certain 2-diethylaminoethyl esters of substituted malonic acid reported in this paper were prepared by methods described in the literature. The procedure described by Adams and Kamm (7) is designated in Table I, “Method I”; and the method described by Gyngell, Phillips, and Smith (8) is designated “Method 11.” The diethyl substituted malonates that were prepared are tabulated in Table I.

MALONATES TABLEI.-DIETHYL SUBSTITUTED COOCzHa R-C-R‘

I

COOCEH~

-

_____7---

R’

R

n-Butyl Isoamyl Benzyl Isoamyl n-Hexyl Allyl Benzyl Benzyl Benzyl

.

Hydrogen Hydrogen Hydrogen Ethyl n-Hexyl Allyl Ethyl n-Butyl Benzyl

Method Used

I I1 I1 11” IIb I Ib 11“ Id 11“

Yield

66 78 61 86

82 91 86 70 76

Prepared from diethyl isoamylmalonate. Diethyl malonate was dialkylated in one step. Prepared from diethyl benzylmalonate. d Prepared from diethyl n-butylmalonate. 0

b

C

Found, “ C . (Mm.)

130-135 126-132 175-180 135-139 150-163 125-130 172-174 190-195 210-212

(20 mm.) (15 mm.) (17 mm.) (15 mm.) ( 4 mm.) (18 mm.) (10 mm.) (15 mm.) ( 6 mm.)

Boiling Point Literature, O C . (Mm.)

130-135 102 195 150 155-158 207.5-208.5 160-170 187 235-240

( 20 mm.) ( 3 mm.) ( 22 mm.) ( 20 mm.) ( 4 mm.)

(260 mm.) ( 9 mm.) ( 15 mm.) ( 28 mm.)

Reference

7 9 10 11 12 13 14 10 15

140

JOURNAL OF THE

AMERICAN PHARMACEUTICAL ASSOCIATION

Preparation of 2-Diethylaminoethyl Chloride.To a solution of 117.0 Gm. (1.0 mole) of 2-diethylaminoethanol in 300 ml. of anhydrous benzene, there was added dropwise with stirring during two hours a solution of 155.0 Gm. (1.3 moles) of thionyl chloride in 200 ml. of anhydrous benzene while the temperature of the reaction mixture was maintained a t 0" to 5". The mixture was refluxed for six hours, the solvent and excess thionyl chloride were removed under reduced pressure, and the residue was heated a t 100" for two hours under 12-15 mm. vacuo. The crystalline mass of 2-diethylaminoethyl chloride hydrochloride, 165-171 Gm., was kept dry until the free base was needed. The crude hydrochloride was dissolved in 175 ml. of water and the solution was filtered. The filtrate was cooled t o 0' in an ice bath, and then there was added to the constantly stirred solution 200 ml. of sodium hydroxide (40%) while the temperature of the reaction mixture was maintained at 0" t o 5". The free base was extracted with 100 ml. of ether, the ethereal solution was dried over anhydrous sodium sulfate, the solvent was removed by distillation, and the residue was fractionated under reduced pressure to give 90.0 to 95.0 Gm. of a colorless liquid witha boilingpointof 47-48' (14mm.). Goughand King (16) reported a boiling point of 51-52" (16 mm.). Preparation of 2-Diethylaminoethyl Ethyl Dibenzylmalonate Hydrochloride.-To a solution of 85.0 Gm. (0.25 mole) of diethyl dibenzylmalonate in 150 ml. of absolute alcohol, there was added dropwise with stirring a solution of 16.5 Gm. (0.25 mole) of potassium hydroxide (85%) dissolved in 150 ml. of absolute alcohol. After the solution had been stirred for an additional three hours, it was allowed to stand for twenty-four hours a t room temperature. The reaction mixture was heated to boiling and filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was washed with 50 ml. of ether and then dried at 100". Sixty grams of crude potassium ethyl dibenzylmalonate was obtained. The salt was dissolved in 100 ml. of water cooled to 5", and while the solution was stirred, 25 ml. of hydrochloric acid (38%) was added in small portions. During the addition the temperature was maintained below 10". The oilylayer was removed, the aqueous layer was extracted with ether, the ethereal extract was combined with the oil, and the ethereal solution was dried with anhydrous sodium sulfate. Concentration of the ethereal solution yielded 50.0 Gm. of crude ethyl hydrogen dibenzylmalonate. The acid-ester was dissolved in 50 ml. of benzene. The solution was distilled partially until the clearness of the distillate indicated the removal of last traces of water. Thionyl chloride, 20 ml., was added, and the solution was refluxed for five hours. After removal of the low boiling fraction under reduced pressure, the residue was fractionated to give 33.0 Gm. of ethyl dibenzylmalonyl chloride with a boiling point of 224-225' (10 mm.). 2-Diethylaminoethanol, 12.4 Gm. (0.11 mole), was added to 33.0 Gm. of ethyl dibenzylmalonyl chloride dissolved in 50 ml. of anhydrous benzene. The reaction mixture was refluxed for five hours and then cooled, 50 ml. of water was added, and the mixture was made alkaline with solid sodium car-

bonate. The benzene layer was separated, the solvent was removed under reduced pressure, and the residue was fractionated to give 2i.0 Gm. of 2-diethylaminoethyl ethyl dibenzylmalonate, boiling range 210-220" (7mm.). The base was converted into the hydrochloride salt by passage of dry hydrogen chloride into an anhydrous ethereal solution of the base in the usual way. Recrystallization of the solid from ethyl acetate yielded 10.0 Gm. of pure product with a melting point of 121-122O. And-Calcd. for C2bHa4NOaCI: CI, 7.95; K. 3.13. Found: C1,8.05; N, 3.23. Preparation of 2-Diethylaminoethyl Ethyl Benzyln-butylmalonate Hydrochloride.-This product was prepared by the same procedure as described above for the dibenzylmalonate derivative. Diethyl benzyl-n-butylmalonate, 30.6 Gm. (0.1 mole), gave 26.5 Gm. of potassium ethyl benzyl-n-butylmalonate. This salt was converted into 21.0 Gm. of the corresponding acid. The acid gave 18.0 Gm. of the chloride, boiling range 167-173" (8 mm.). The chloride was converted into 15.0 Gm. of the base, boiling range 185-220" (14 mm.). The base was converted into the hydrochloride and then recrystallized from ethyl acetate t o give 6.0 Gm. of white, microcrystalline product with a melting point of 96-97". And-Calcd. for C22Hs~NOilCl: C1, 8.58; N, 3.38. Found: Q8.62; N, 3.33. Preparation of 2-Diethylaminoethyl Ethyl Benzylethylmalonate Hydrochloride.-A solution of 14.5 Gm. (0.22 mole) of potassium hydroxide (85%) in 80 ml. of absolute alcohol was added dropwise with stirring to a solution of 62.0 Gm. (0.22 mole) of diethyl benzylethylmalonate in 80 ml. of absolute alcohol. The solution w a s stirred for three hours and then allowed to stand overnight a t room temperature. The solution was liltered for the removal of a slight precipitate, 30.0 Gm. (0.22 mole) of 2-diethylaminoethyl chloride was added, and the reaction mixture was refluxed for three hours. The cold solution was filtered for the removal of the precipitated potassium chloride, and the filtrate was fractionated to give 22.0 Gm. of 2-diethylaminoethyl ethyl benzylethylmalonate, boiling range 192-214 (9 mm.). The base was converted into the hydrochloride salt by the passage of dry hydrogen chloride into an anhydrous ethereal solution of the base in the usual way. Recrystallization of the solid from ethyl acetate yielded 12.0 Gm. of a white, crystalline product with a melting point of 135-136 '. And-Calcd. for C2oH32NOaCl: Cl, 9.20; N, 3.63. Found : C1,9.25 ; N, 3.67. Preparation of 2-Diethylaminoethyl Ethyl Isoamylethylmalonate Hydrochloride.-A solution of 15.5 Gm. (0.24 mole) of potassium hydroxide (85%) in 100 ml. of absolute alcohol was added to 51.5 Gm. (0.20 mole) of diethyl isoamylethylrnalon tte in 100 ml. of absolute alcohol. The solution was stirred, allowed to stand, and then filtered as in the preparation of 2-diethylaminoethyl ethyl benzylethylmalonate hydrochloride. 2-Diethylaminoethyl chloride, 27.0 Gm. (0.20 mole), was added to the alcoholic solution, and the reaction mixture was refluxed for three hours. The alcohol was removed under reduced pressure, the residue was dissolved in ether. and the ethereal solu-

SCIENTIFIC EDITION

141

TABLE I I .-BIS-~-DIETHYLAMINOETHYL SUBSTITUTED MALONATE DIHYDROCHLORIDES COOCHzCHzN(GH5)2.HCl

I

R-C-R' I COOCHzCHzN (CaH,) 2 . H C1

R

R'

Recryst. Solvent

M. P., "C.

Ethyl n-Hexyl Ally1 Benzyl

Isoamyl n-Hexyl Ally1 n-Butyl

Alcohol-ethyl acetate Alcohol-ethyl acetate Alcohol-ethyl acetate Alcohol-benzene

155-156 160-161 157-158 157-158

tion was washed with water and then dried with anhydrous sodium sulfate. The filtered ethereal solution was treated with dry hydrogen chloride, and the precipitate was collected by filtration. The solid was dissolved in hot ethyl acetate and the solution was norited. The filtered solution was cooled, and the resultant precipitate was removed by filtration. The solid was recrystallized several times from ethyl acetate to give 12.0 Gm. of a white, microcrystalline product with a melting point of 119-120 '. AnaZ.-Calcd. for C I ~ H J ~ N O:~ CCl, I 9.72, N, 3.83. Found: C1,9.85; N, 3.82. Preparation of Bis-2-diethylaminoethyl Substituted Malonate Dihydroch1orides.-Compounds listed in Table I1 were prepared by the procedure described below for bis-2-diethylaminoethyl dibenzylmalonate dihydrochloride. To 85.0 Gm. (0.25 mole) of diethyl dibenzylmalonate, there was added a solution of 50.0 Gm. (0.75 mole) of potassium hydroxide (85%) in 100 ml. of alcohol (50%). The solution was refluxed for twenty hours on a steam bath, and the reaction mixture was then concentrated t o dryness under reduced pressure. The residue was washed with ether and then with absolute alcohol. The solid was dried at 100" for twelve hours to give 52.5 Gm. of crude dipotassium dibenzylmalonate. The dried salt was suspended in 150 ml. of absolute alcohol, and 39.5 Gm. (0.30 mole) of 2-diethylaminoethyl chloride was added. The reaction mixture was refluxed on a steam bath for three hours and then filtered. The alcohol was then removed from the filtrate by distillation under reduced pressure. The crude bis-2-diethylaminoethyl dibenzylmalonate was dissolved in ether, and the ethereal solution was washed with several 50-ml. portions of water and then dried with anhydrous sodium sulfate. The dihydrochloride was prepared by passage of dry hydrogen chloride into the dried ethereal solution of the base in the usual way. The etherinsoluble dihydrochloride was removed by filtration, the solid was digested with hot ethyl acetate, and

-

Analyses, %Chlorine Nitrogen Calcd. Found Calcd. Found

15.00 13.05 15.55 13.60

15.20 13.05 15.55 13.52

5.93 5.17 6.15 5.38

5.93 5.18

6.05 5.33

.

the product was recrystallized from alcohol-ethy acetate to give 15.0 Gm. of a white, microcrystalline solid with a melting point of 152-153 '. And-Calcd. for C29H,4N204C12: C1, 12.75; N 5.05. Found: CL12.71; N,5.05.

SUMMARY 1. Four 2-diethylaminoethyl ethyl ester hydrochlorides of dibenzylmalonic, benzyl-n-butylmalonic, benzylethylmalonic, and isoamylethyl malonic acids have been prepared. 2. Five bis-2-diethylaminoethyl ester dihy drochlorides of dibenzylmalonic, benzyl-n-butylmalonic, isoamylethylmalonic, di-n-hexylmalonic, and diallylmalonic acids have been prepared. 3. Preliminary pharmacological studies indicate that all the compounds show some spas molytic activity. REFERENCES (1) (2) (3) (4)

Raymond A. I.., THISJOURNAL 32 249(1943). Blicke F.'F. Ann. Reu. Bioche;. i3,549(1944). von Einhorn' A. et al. Ann. 359 '185(1908). Gilman, E., 'and Joh;son, B.: J . A m . Chem. Soc.,

+.

C n '""'"\r"rU,. ?2Al11(1OQ~

"")

(5) Blicke, F. F., and Zienty, F. B., ibid., 61, 776(1939). (6) "The Hengar Technique for the Kjeldahl Procedure,' Hengar Company Philadelphia Pa. (7) Adams, R:, and Kamm: R. M.. in Gilman, H.. and Blatt, A. H., "Organic Syntheses," ed. 2, John Wiley and Sons Inc. NewYork Coll. Vol. I 1941 p. 250. (!$ G;ngell, E. SI,Phillips, M. A,, h d Smith, E. L.. Ind. Chelhisf 21 531(1945). (9) khinle, H. A., Keltch, A. K., and Swanson, E. E., J . A m . Chem. SOG.52,2445('1930). (10) Dolique R: Ann. cMm. [ l o ] 15.445(1931). (11) Shonle, H. and'Mokent, A,, J . A m . Chem. Soc., 45.248(1923). (12) Armendt B. F and Adams R. i b i d . 52 1290(1930). (13) Perkin W.H. '3. Clirm. So:. 45,209i1886). (14) Dox. A. W., and Yoder, L.,'J. A m . Cham. SOC.,44, 1144(1922). (15) Dunn, M. S., Redemann, C . E.. and Lauritsen, S.. i b i d . 54 4337(1932). ( l b ) kough, G. A. C.,and King, H., J . Chcm. SOL,1928, 2437. '

k:,