US2533084A - Aminoalkyl esters of dithienyl aliphatic acids - Google Patents

Description

Patented Dec. 5, 1950 AMINOALKYL ESTERS F DITHIENYL ALIPHATIC ACIDS Frederick F.

Blicke, Washtenaw County, Mich,

assignor to Regents of the University of Michigan, Ann Arbor, 'igan Mich., a corporation of Mich- No Drawing. Application August 17, 1946, Serial No. 691,409

8 Claims.

(2-thienyl) (2-thienyl)(CH2) mCC O 0--carbon chainZ wherein m represents zero or a positive integer from 1 to 5, inclusive, n represents zero or a positive integer from 1 to 5, inclusive, the carbon chain is straight or branched and contains from 1 to 8 carbon atoms, inclusive, X is hydrogen or hydroxy, and Z is alkylamino, dialkylamino, or a piperidino ring. The term alkyl, as employed in alkylamino and dialkylamino, indicates a radical of straight or branched chain structure and preferably containing from 1 to 8 carbon atoms, inclusive. Representative alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, n-octyl and the like.

A principal object of the invention is the provision of a series of compounds having util ty as pharmaceuticals and particularly as antispasmodic agents. Members of this new group of compounds have been prepared, identified and found to have value in antispasmodic preparations for the relief of muscle spasm as determined by the method of Magnus (described in Dennis E. Jackson, Experimental Pharmacology and Materia Medica, second ed., 1939, St. Louis, C. V. Mosby 00., page 516). The compounds also appear to have local anesthetic and mydriatic effects.

The free basic esters of this group of compounds are usually oily liquids with relatively high boiling points, While the acid or quaternary ammonium salts thereof are usually crystalline solids at ordinary temperatures. The compounds included within the scope of the present invention are (a) amines of the general formula wherein m, n, the carbon chain, X and Z have the values disclosed in the formula given above; and (b) salts thereof. Instead of the simple thienyl radical, the thiophene nucleus may contain substituents.

-, ethyl chloride,

Within the meaning of the term salts are included both acid salts such as the citrate, tartrate, hydrochloride, hydrobromide, hydrosulfate, and many others, as well as the quaternary ammonium salts such as the methobromide, ethochloride and ethyl para-toluenesulfonate. The acid salts may be prepared from the free basic ester by treatment with the selected acid, while the quaternary ammonium salts are prepared by treatment of the free basic ester with the desired alkyl halide or aryl sulfonic ester. When the ester is formed by a reaction of an acid and an alkyl halide, or by the reaction of an acid halide and an alcohol, the ester usually precipitates as the hydrohalide salt.

The thienyl-substituted fatty acids employed as starting materials may be prepared by first reacting thiophene with an acid halide of an alkyl monoester of oxalic acid, e. g., ethyl oxalyl chloride, ClCO-COOC2H5, in the presence of aluminum chloride to produce an alkyl ester of alpha-thienyl glyoxylic acid, such as ethyl (alpha-thienyl) glyoxylate The keto acid is then reacted with a thiophenesubstituted Grignard reagent and the resulting complex decomposed with a suitable acidic reagent, such as HCl, NHiCl, NaHSOr, et cetera, to produce a substituted hydroxy aliphatic acid having two thienyl radicals attached to carbon atoms of the aliphatic chain. This compound may be employed without further modification in the production of the basic ester, or it may be reduced, e. g., with stannous chloride, to produce the corresponding hydroxyl-free thienyl-substituted fatty acid and thereafter treated to'prepare the basic ester.

The compounds of this invention are also obtained by a procedure which maybe as follows, using beta-diethylaminoethyl (alpha-thienyl)- methyl-beta alpha-thienyl) ethylacetate hydrochloride as an example: beta-(alpha-thienyl)- prepared from (alpha-thienyl)- magnesium bromide and beta-chloroethyl paratoluenesulfonate,'was converted to diethyl beta- (alpha-thienyl)ethylmalonate by reaction with diethyl malonate and sodium ethylate in an alcoholic medium. The monosubstituted diethyl malonate was then converted by the usual procedure into the disubstituted diethyl malonate.

(Some monoand disubstituted malonic esters are given in Table I.) The disubstituted malonic ester is then converted to the acid by treatment with alkali solution, the malonic acid is converted to the acetic acid by heating, and the acetic acid is then reacted with the selected substituted aminoalkyl halide, in this instance beta-diethylaminoethyl chloride, according to the general method of Horenstein and Pahlicke, Berichte 71, 1644 (1938), to prepare the desired ester, beta-diethylaminoethyl (alpha-thienyl) methylbeta' -(alpl1a-thienyl) ethylacetate hydrochloride. (Some substituted thienylmalonic and thienylacetic acids are listed in Table II.)

In a similar manner many other members of this new group of compounds may be prepared. As representative of these new compounds may be mentioned 2-monobutylamin0ethyl (alphathienyl) methyl (alpha-thienyl) acetate hydrochloride, 3-monomethylaminopropyl beta-(a11- pha-thienyl) ethyl (alpha thienyl) methylacetate hydrobromide, e-monoethylaminobutyl gamma- (alpha thienyl) propyl (alpha-thienyl) acetate methobromide, 3-dibiutyl-aminopropyl beta- (alpha-thienyl) ethyl gamma'-(alpha-thienyl-) propyL-acetate ethochloride, 3-monoethylamin-o- -butyl(alpha thienyl) -methyl -.(alpha thienyl) acetate ,ethyl (para-toluene)sulfonate, 2,2-di- .methyl 3 dimethylaminopropyl beta (alphathienyllethyhbeta (alpha thienyDethylacetate :hydrosul-phate, 2 dipropylamino --ethy-l(alphathienyl) methyl(alpha thienyl) acetate hydrochloride, et-cetera. Other esters will be evident from an inspection of Table III.

Hydroxyl-containing esters which are prepared according to the method herein disclosed include Z-monoethylaminoethyl di-(alpha-thienyl) hydroxyacetate hydrochloride, vZ-piperidinoethy1 alpha .thienyDmethyl (alpha thienyl) methylhydrox-yacetate hydrobromide, 3-diprcpylaminopropyl beta alpha thienyllethyl-beta (a-lpha-thienyl) ethyl-hydroxyacetate hydrochloride, 2 dibutyl amino ethyl(al-pha thienyl) methyl- (alpha thienyl) methylhydroxyacetate methobromide, 2 diethyl aminopropyl beta- (alpha-thienyl) ethyl-gamma -(alpha-thienyl) propylhydroxyacetate hydrochloride, and the like.

In the preparation of the hydrohalides of the basic-alkyl esters of the thienyl-substituted aliphatic acids, substantially equimolar proportions of a basic-alkyl halide and the thienylesubstituted acid are admixed in a suitable solvent, e. g., isopropyl alcohol, and the mixture heated until reaction has occurred. This may require heat- 'ing at reflux for from 2 to 16 hours. The crude salt may be crystallised by dissolving in a small quantity of warm ethanol, adding diethyl ether until turbidit and thereafter cooling the mixture. The hydrohalide salt separates in crystalline form and is recovered by decantation .or filtration. Other acid salts may 'be obtained in a similar manner from the free basic ester. As the 'antispasmodic activity of the esters apparently resides in the ester itself and not in the salt portion of the molecule, any acid salt may be employed without detracting materially from the efiectiveness of the compound, provided only that the anion of the acid be reasonably nontoxic. The .salt to be produced is usually chosen primarily with regard to crystallinity and solubility.

As an alternative method of salt formation, a =nn-hydroxy acid may be converted to the acid chloride, as by heating with thionyl chloride, andthe vacidchloride then reacted with'the selected basic alcohol to form the desired ester hydrochloride. The former method is preferred.

however, since higher yields of product are obtained thereby.

The free basic-alkyl esters may be obtained from the hydrohalides by treatment with aqueoussodium carbonate or other mild alkali, preferably at low temperatures, and thereafter extracting with ether or other suitable solvent. The solution may then be dried and the solvent volatilised in accordance with conventional methods.

To produce quaternar ammonium salts, the free base may be treated with alkyl halides, such as methyl bromide, ethyl chloride, propyl iodide, et cetera, or with the selected aryl sulfonic ester such as ethyl para-toluenesulfonate, under which conditions the corresponding quaternary salt, .e. g., the methobromide, ethochloride, or ethyl para-toluenesulfonate, is usually formed in high yields.

The following examples will serve to illustrate procedures whereby the production of members of this new group of compounds may be accomplished, but are in no way to be construed as limiting.

Preparation 1.(Alpha-thienyl)methyl chloride A rapid stream of hydrogen chloride was passed into a stirred mixture of 525 milliliters of concentrated hydrochloric acid, 45.0 milliliters of 10 per cent aqueous formaldehyde and 465 milliliters of thiophene at a temperature between zero and five degrees centigrade. After saturation with the gas, the material Was poured into two liters of water, the oily precipitate separated, and the aqueous layer extracted several times with ether. Extracts and the oil were combined, washed with water and dried over potassium carbonate. After removal of the ether, the product boiled at 78-82 degrees centigrade at 18 millimeters of mercury pressure. The yield was .373 grams or 47 per cent -of .the theoretical.

.The chloride should not be kept in a tightly closed container since it undergoes spontaneous decomposition, often with explosive violence. If preserved in a refrigerator, the compound remains undecomposed for .some time.

Preparation 2.(Alp'ha-thienyl) acetomtmle A mixture of 133 grams of (alpha-thienyl)- methyl chloride, 60 milliliters of acetone and 74 grams of sodium cyanide dissolved in milliliters of water was stirred and heated ina water- Prepalration 3.Ethyl (alpha-thienyl) acetate A mixture of 100 grams of (alpha-thienyl)- acetonitrile, 225 milliliters of 95 per cent alcohol-and '7 milliliters of water was saturated'with hydrogen chloride at a temperature between zero and five degrees centigrade. After 12 hours at room temperature, the mixture was heated for two hours on a steam-bath, cooled, mil iliters of water added, the oily layer separated and added to the ether extract of the aqueous layer. The solution was dried and the solvent removed. The desired product was obtained in 66 per cent yield (93 grams) and boiled at 119421 degrees centigrade at 23 millimeters of mercury pressure.

Preparation 4.-Beta-(aZpha-thienyl) ethyl chloride A solution of (alpha-thienyl) magnesium bromide (prepared from 97.8 grams of alpha-bromothiophene, 14.6 grams of magnesium and 375 milliliters of ether) was stirred and 280 grams of beta-chloroethyl para-toluenesulfonate, dissolved in 300 milliliters of ether, was added dropwise. A solid began to precipitate after about one-half of the ester had been added. The mixture was stirred and refluxed for five hours, cooled to between five and ten degrees centigrade, and 100 milliliters of concentrated hydrochloric acid diluted with 350 milliliters of water was added thereto. An amount of water sufficient to dissolve the precipitate was then added; the ether layer was washed with sodium bicarbonate solution and dried with potassium carbonate. The chloride roiled at 88-92 degrees Centigrade at 20 millimeters of mercury pressure. The yield was 62.6 grams or 71.4 per cent of the theoretical. The analysis showed the product to contain 24.06 per cent chlorine as comparedwith.

the theoretical of 24.19 for CGH'ISCI. Preparation 5 .-Diethyl aZpha-thienyl) malonate A solution prepared from 18.5 grams of sodium and 300 milliliters of alcohol was heated in an oil-bath, stirred, and the alcohol removed under reduced pressure. The cake of sodium ethylate was broken into small pieces and 650 milliliters of diethyl carbonate was added, followed by 132.4 grams of ethyl(alpha-thienyl)- acetate. The mixture .was stirred at 80-85 degrees centigrade and the alcohol was removed, as fast as formed, at 300-320 millimeters of mercury pressure. After five hours, the distillate, a mixture of alcohol and diethyl carbonate, amounted to about 200 milliliters. The material was poured into a mixture of water and ice to which 90 milliliters of concentrated hydrochloric acid had been added. The organic layer was separated, combined with the benzene extract of the aqueous layer and shaken with water. After removal of excess benzene and diethyl carbonate,

the product (117 grams) boiled at 148-151 degrees centigrade at 6 millimeters of mercury pressure.

Preparation 6.-Diethyl beta'-(alpha-thienyl)- ethylmalonate A solution of sodium ethylate (prepared from 7.8 grams of sodium and 135 milliliters of ethanol) was warmed to 50 degrees centigrade and Preparation 7.Diethyl(alpha-thienyl) methylbeta -=(aZp-ha-thienyl) -ethylmalonatc A'solution, obtained from 4.3 grams of sodium and 140 milliliters of alcohol, was warmed to 50 degrees centigrade and 37.8 grams of diethyl 'beta'-(a1pha-thienyl)ethylmalonate was added.

After removal of solvent,

nesium bromide and adding After the mixture had refluxed for a few minutes, 24.9 grams of (alpha-thienyl) methyl chloride was added dropwise at a rate such that the mixture continued to reflux. After about three hours at reflux, the product was isolated in the usual manner.

Preparation 8.--(Alpha-thienyl) methyl beta- (aZpha-thienyl)ethylrnalonic acid tion with water, it was dried over magnesium sulfate and the solvent removed to yield 25.5 grams of the desired product. The yield was 82 per cent of the theoretical.

Preparation 9.-(Alpha thienyZ)methyl-beta- (aZpha-thienyl) -ethylacetic acid Ten grams of the corresponding malonic acid was heated to 175-185 degrees centigrade for a period of about one hour and the material thereafter distilled. The yield of the desired substitr'ted acetic acid was usually of the order of '77 per cent of the theoretical.

EXAMPLE 1. 2-diethylamino-ethyl (alpha-thienyD- methyl-beta'- alpha-thienyl) ethylacetate hydrochloride (Alpha thienyl) methyl beta (alpha thienyDethylacetic acid (6.8 grams) as obtained in Preparation 9 hereinbefore, 3.5 grams of 2- diethylaminoethyl chloride and milliliters of anhydrous isopropyl alcohol were refluxed for 48 hours and the mixture then allowed to cool in a refrigerator. The ester hydrochloride precipitated from the solution and was filtered therefrom. The yield was 5.2 grams of 51 per cent of the theoretical.

Preparation 10.-.Di- (alpha-ihienyl) hydroxyacetic acid This acid was prepared by reacting 98 grams (0.6 mole) of alpha-thienyl bromide with 1&4 grams of magnesium in 300 milliliters of diethyl ether to form a solution of alpha-thienyl magthis solution portionwise, with stirring, to an ethereal solution of 31 2 grams (0.2 mole) of (alpha-thienyl) glyoxylic acid. The insoluble residue from this reaction was washed successively with anhydrous diethyl ether and saturated ammonium chloride solution, and then filtered. The residue from the filtration was washed with acetone and dispersed in dilute aqueous hydrochloric acid. The dispersion was filtered, the residue extracted with five per cent aqueous sodium bicarbonate, the alkaline solution clarified with activated carbon, acidified and filtered. The 20 grams of 'di-(alphathienyDhydroxyacetic acid so obtained melted at 93 degrees centigrade.

OTHER EXAMPLES By a condensation of the above or related hydroxy-acids with the selected substituted aminoalkyl halide, the desired hydroxyl-containing ester is produced in high yie ds. The condensation of di-(alpha-thienyl) hydroxyacetic acid and 7 2=diethy1am noethyl chlorid or e m le, is productive of, z-diethylaminoethyl -di-(alpha .thienyD-hydroxy acetate, hydrochloride, While 8 Ln aimr 1. A compound selected from the group consisting of (a) basic-alkyl esters having the the .condensation of edipropylaminobutyl chloformula rideand (alpha e thienyDethyl beta alpha e thienyl) ethylhydroxyacetic acid produces 4-di- H2)" propylaminobutyhalpha thienyl) beta (a1 pha-thienyl)ethylhydroxyacctate hydrochloride. (kmleuyn 'coofcarboncham' Z In Table I hereinafter are listed properties of X several di hyl ers of 1pha hi nyl-subst :10 wherein 'm represents an integer from '0 to 5, tuted-malonic acids Prepared inaccordance with inclusive, n represents an integer from 0 to 5 the genera] methods described hereinbefore. inclusive, the carbon chain is an alkene radical Table I .-Monoand disubstz'tutedmalomfc esters RCEKCOOCsHa): RR'C(QOOCzH.-,)z

R 11 2., P o. n I 13.1 0,.

1 cans l- ]48l5l (6r1 1m.) 1' zit-.223 (91mm) 3* oinzsom 2 .1403 (3 mm.) 3 O1'H3SCH2OH12 150-154(4.1nm.).. 3' .203-206 (4111111.)

(Alpha-'tliicnyl) methyl chloride was used ZilillOIliQgQStOlS. Each disubstituted esterof corresponding number.

-Blicke and Zienty, JJAm. Chem. Soc. 63, 2945 9 This substance was converted by hydrolysis acid; M. P. l131 degrees centigrade after recrystallisation and benzene. Calculated for 011110018: S, 14.97 per cent;

Table I I .Substituted to prepare the above disubstitutcd ester was obtained from the .monosubstituted (1941), found ll48 C. (5 mm). :into beta-(2-thionyl)ethylmalonic from a mixture of acetone Found: S, 14.90 percent.

(aZpha-thienyl) methylmalonic and (alpha-thienyl) methylacetic acids G1H3SOH:(R)C(COOH)1 oimsonamcnooon I s s Calcdi Fd. 5 Calcdi Fd.

1 0.111s 91415 26.90 26.48 2 oinasonz. 21s-219. 9. 11m, 71:72 25.12 25.64 :1: o nsscngonp 232-2336 min)... oil

Di-(alpha-thienyl) acetic acid, CmHsOzSz, as disclosed in patent application Serial No. 575,929, melts at 91-94 degrees centigrade.

Malonic acid 1 'lost carbon dioxide spontaneously to form the corresponding acetic acid. Malonic acid .2 was recrystallised from water; 3 from a mixture of benzene and acetone; the

acetic acids were recrystallised from petroleum formula ether. (2-thienyl) Other rexamples.In Table III hereinafter are H2) listed properties of other specific compounds that 5 2-tl1' 1 CH mCCO0-carbon chain-Z are preferred embodiments of the invention my) 2) l x Table III.-Hydrochlorides of esters of some substituted (aZpha-thienyl) aliphatic acids oimswnommonoooznon I Halogen, R ,m Z M.P.,G.

Caled Found cinas 1 I CHQCHQNKHHQ: 79-80 9.48 9.51 18.15 1 d0 11 1-115 9.15 9.29 0131s 1: Neon. 91-95 8.82- 8.22 .cuHts o H CH N n 90-02 19.76; 20.2 Do. 0- cn ongmcsfilo 113-115 0.53 9.35 'IXL. 'O CITQCHQCH:N(C1H 131-133 16.36 16.65 Do 0J CH2CHQCHEPI(CQH5)EQ,Mr 93-95 9.48 9.50

l alpha or 2-thienyl. 2 hydrohromide. 3 piperidino. 4 methobromlde.

All of the compounds were recrystallised from ,a mixture of absolute alcohol and ether. Various modifications may be made without departing from the spirit or scope of the present invention, and it is to be understood that I limit myselionly by the appended claims.

wherein m represents an integer from '0 to '5, inclusive, n represents an integer from 0 to 5, inclusive, the carbon chain is an alkene radical of the group consisting of straight and branched chain alkene radicals and contains from 1 to V8 .5 carbon a oms. l sive, X is selected. from the 9 group consisting of hydrogen and hydroxy radicals, and Z is selected from the group consisting of alkylamino, dialkylamino and piperidino radicals.

3. A basic-alkyl ester having the formula (2---tl1ienyl) H2) (2thieny1)(CHz) "-0- o 0 Ocarbon chainz wherein m represents an integer from 0 to 5, inclusive, 1!. represents an integer from 0 to 5, inclusive, the carbon chain is an alkene radical of the group consisting of straight and branched chain alkene radicals and contains from 1 to 8 carbon atoms, inclusive, X is selected from the group consisting of hydrogen and hydroxy radicals, and Z is selected from the group consisting of alkylamino, dialkylamino and piperidino radicals.

4. 2 diethylaminoethyl(2 thienyl) methyl (2- thienyDacetate hydrochloride.

5. 2-piperidinoethy1 di-(2-thienyl) acetate hydrochloride.

6. 2-diethylaminoethyl di-(Z-thienyl) acetate hydrochloride.

7. 2-diethylaminoethyl hydrobromide.

8. 3-diethylaminopropyl di-(Z-thienyl) acetate hydrochloride.

di- (2-thienyl) acetate FREDERICK F. BLICKE.

10 REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,079,962 Meischer et a1 May 11, 1937 2,367,702 Van Zoeren J an. 23, 1945 2,399,736 Holmes et al May '7, 1946 OTHER REFERENCES Von Seeman; Canadian Journal of Research 193 (1911), page 291.

Bernthsen v. Sudborough: Organic Chemistry, Van Nostrand, 1920-(1922 ed.), page 549.

Richter: Organic Chemistry, John Wiley, N. Y., 1938, pages 649, 650.

Gutman: Modern Drug Encyclopedia, ed. 2 (1941), pages 606 and 680 on Trasenline and Nikethamide.

Alles: J. Pharm. & Exp. Ther., Vol. '72, page 265 (1941).

Blicke et al.: J. Amer. Chem. Soc, vol. 63, page 2945 (1941).

Burtner et al.: J. Amer. Chem. $00., vol. pages 262-267 (1943).

Blicke et al.: J. Amer. Chem. Soc., vol. 66, pages 1087-1091 (1944.)

Blicke et al.: J. Amer. Chem. 300., vol. 66, pages 1645-1648 (1944).

Lands et al.: Proc. Soc. Exp. Biol. V. Med., vol. 57, page 56 (1944).

Claims (1)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) BASIC-ALKYL ESTERS HAVING THE FORMULA