US2541634A - Basic esters of substituted thienyl acetic acids - Google Patents

Basic esters of substituted thienyl acetic acids Download PDF

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US2541634A
US2541634A US125380A US12538049A US2541634A US 2541634 A US2541634 A US 2541634A US 125380 A US125380 A US 125380A US 12538049 A US12538049 A US 12538049A US 2541634 A US2541634 A US 2541634A
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Frederick F Blicke
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • This invention relates to certain basic-alky esters of substituted (alpha-thienyDacetio acids, the salts of such esters, and pharmaceutical products in which they are employed as active ingredients.
  • This application is'a continuationin-part of my prior-filed copending applications Serial 575,929, filed February 2, 1945, now abandoned, and Serial 695,811, filed September 9, 1946.
  • One of the principal objects of the present invention is the provision of a series of compounds having utility as pharmaceuticalsand particularly as antispasmodic agents.
  • Members of this new group of compounds have been prepared, identified and found to have value as antispasmodics and as the active ingredients in antispasmodic preparations for the relief of muscle spasm as determined by the method of Magnus (Archiv. fiir die gesammte Physiologie, 1905, vol. 108, pages 1-71).
  • 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 basic-alkyl esters of the present invention have the following generic formula R l (2-thienyl)(I3C O-carbon chain-Z wherein R represents a hydrocarbon radical, the carbon chain is straight or branched and contains from 2 to 8 carbon atoms, inclusive, X is hydrogen or hydroxyl radical, and Z is a primary or secondary amine radical.
  • R in the aboye formula I include such hydrocarbon radicals as alkyl radicals, for example, methyl, ethyl, isopropyl, isobutyl, isoamyl, n-hexyl and n-octyl; aryl radicals, such as phenyl, naphthyl, and para-xenyl; cycloalkyl radicals, such as cyclopentyl and cyclohexyl; cycloalkylalkyl radicals, such as cyclohexylethyl and cyclohexylmethyl; aralkyl radicals, such as phenethyl, phenylmethyl; alkaryl radicals, such as ethylphenyl; alkylcycloalkyl radicals, such as ethylcyclohexyl; alkylcycloalkylalkyl radicals, such as methylcyclohexylethyl; and al
  • the primary and secondary amine radicals represented by Z include such radicals as mono- The free basic esters of this methylamino, 'monoethylamino, monopropylamino, isopropylamino, monobutylamino, noctylamino, monocyclohexylamino, diethylamino, diisopropylamino, dibutylamino, dicyclohexylamino, diphenylamino, phenylethylamino; and the like.
  • Z can also represent a saturated nitrogen heteromonocyclic ring such as piperidyl, morpholinyl, pyrrolidyl, piperazinyl and thi azinyl.
  • the compounds included within the scope of the present invention include (a) compounds of the above general formula and (b) salts thereof.
  • salts includes acid-addition 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 paratoluenesulfonate.
  • 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.
  • ester is formed by a reaction of an acid and'an alkyl halide, or by the reaction of an acid halide and an alcohol,
  • ester usually precipitates as the hydrohalide salt.
  • aluminum chloride e. g., aluminum chloride
  • The-keto acid obtained by hydrolysis of the ester, is then reacted with a Grignard reagent containing the selected'hydrocarbon radical and the resulting complex is decomposed with a suitable, acidic reagent, such as HCl, NHiCl, NaHSO4, et cetera, to produce a substituted thienyl hydroxyacetic acid.
  • a suitable, acidic reagent such as HCl, NHiCl, NaHSO4, et cetera
  • This compound can be employed without further modificat on in the production of the hydroxy-containing basic ester, or it may be reduced, e. ,g., with stannous chloride, to produce the corresponding hydroxy-free hydrocarbon-substituted thienylacetic acid and thereafter treated to prepare the basic ester.
  • the acyl halide of the alkyl monoester of oxalic acid can first be reacted with a suitable aromaticv hydrocarbon 'such as benzene, biphenyl, naphthalene, et cetera, in the presence of, aluminum chloride .to produce ethyl oxalyl chloride,"
  • a suitable aromaticv hydrocarbon ' such as benzene, biphenyl, naphthalene, et cetera
  • a dialkyl z-thienylmalonate can be alkylated by the malonic ester syntheses with an R-halide where R is an alkyl or an arylaliphatic hydrocarbon radical. This gives a disubstituted malonic ester,
  • enyl) acetic acids prepared as intermediates include isopropyl-(alpha-thienyl) acetic acid, B. P. 163-164 C. (20 mm.), isobutyl-(alpha-thienyl acetic acid, 13. P. 128-130" C. (0.4 mm.), M. T P. 60-63 C., and isoamyl-(alpha-thienyl) acetic acid, B. P. 150-155 C. (4-5 mm.). These were prepared by reduction of the corresponding hydroxyacetic acids disclosed in Table I.
  • substantially equimolar proportions of a basic-alkyl halide and theh'ydrocarbon-substituted thienylaliphatic acid are admixed in a suitable solvent, e. g., ethanol or isopropyl alcohol, and the mixture heated until reaction has occurred. This may occur at room temperature or require heating at reflux for some time, e. g., 4 to 16 hours, more or less.
  • the crude salt can be crystallized by dissolving it in a small quantity of warm ethanol, adding diethyl ether until turbidity and thereafter cooling the mixture.
  • the salt separates in crystalline form and is recovered by decantation or filtration.
  • Other acid salts can be obtained in a similar manner from the free basic ester.
  • any acid can be employed without detracting materially from the effectiveness of the compound, provided only that the anion of the acid employed be reasonably non-toxic, and therefore the salt to be produced is usually chosen primarily with regard to crystallinity and solubility.
  • a non-hydroxy acid can be converted to the acid chloride, as by heating with thionyl chloride, and the acid chloride then reacted with the selected basic alcohol to form the desired ester hydrochloride.
  • the former method is preferred, however, since higher yieldsof product are obtained thereby.
  • any basic alcohol or basic alkyl halide which meets the requirements of the formula HO-carbon chain-Z or halogen-carbon chain-Z respectively, where carbon chain and Z have the meanings given hereinabove, can be used in the preparation of the basic esters.
  • typical halides include 2-diethylamino-l-haloethane, 2 dimethylamino-l-haloethane, 2 dipropylamino 1 haloethane, 2-dibutylamino-l-haloethane, 2 (N-piperidyD-I- halo'ethane; 2- (N-morpholinyl) -l-haloethane, 2- methylamino-l-haloethane, 2 phenylamino-lhaloethane, 3-diethylamino-l-halopropane, 3-d
  • the free basic-alkyl esters can be obtained from the hydrohalides by treatment with aqueous sodium carbonate or other mild alkali, preferably at low temperatures, and thereafter extracting with ether or other suitable solvent.
  • the solvent can then be dried and volatilized in accordance with conventional methods.
  • the free base can be warmed 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 is usually formed in high yields.
  • alkyl halides such as methyl bromide, ethyl chloride, propyl iodide, et cetera
  • aryl sulfonic ester such as ethyl para-toluenesulfonate
  • Example 1 -3-diethylaminopropyl phenyl-(alpha-thienyl) hydroxy acetate hydrochloride
  • a mixture of 3.4 grams of phenyl-(alpha-thienyDhydroxy acetic acid, 2.2 grams of 3-diethy1- aminopropyl chloride and 50 milliliters of isopropyl alcohol was refluxed for twelve hours. After milliliters of absolute alcohol had been added to the cold mixture, it was treated with activated charcoal at room temperature, filtered, and the activated charcoal treatment repeated several times. The solvents were removed from the filtrate under reduced pressure, and the residue rubbed under absolute ether. The crude ester hydrochloride (4.6 grams) was recrystallized from a mixture of absolute alcohol and absolute ether; melting point, 142-145 degrees centierade.
  • Example 2.3-diethylaminopropyl phenyl-(alpha-thienyl) acetate hydrochloride A mixture of 2.7 grams (0.0125 mole) of phenyl-(alpha-thienyl)-acetic acid, 1.7 grams (0.0125 mole) of B-diethylaminopropyl chloride and 50 milliliters of isopropyl alcohol was refluxed for twelve hours. The cold solution was mixed with milliliters of absolute alcohol, shaken with activated charcoal at ordinary temperature, filtered, the filtrate treated again with activated charcoal, and the mixture filtered. The solvents were removed under reduced pressure, and the residue rubbed under absolute ether. The crude ester hydrochloride (2.5 *grams) was recrystallized several times from benzene; melting point 87-89 degrees centigrade.
  • Example 3 -2-dz'ethylaminoethyl (para-menyh- (aZpha-thienyl) acetate hydrochloride
  • a mixture of 4.4 grams (0.015 mole) of (paraxenyl) -(alphathienyl) -acetic acid and 5.5 milliliters of pure thionyl chloride was refluxed for one and one-half hours in an oil bath.
  • the benzene and excess thionyl chloride were removed under reduced pressure.
  • Another 10 milliliters of benzene was added, removed by distillation, and this .process repeated several times.
  • Example 5.2-diethylaminoethyl phenyl- (aZpha-thienyl) acetate hydrochloride A mixture of 4.36 grams of phenyl-(alphathienyl) acetic acid, 2.75 grams of 2-diethylaminoethyl chloride and 40 milliliters of isopropyl alcohol was refluxed for 15 hours. Isopropyl alcohol was-removed under reduced pressure, the residue dissolved in absolute alcohol, decolorized with activated charcoal, filtered and alcohol removed by distillation. The residue was rubbed underv absolute ether whereupon crystallization began. The hydrochloride melted at 98-100 degrees centigrade.
  • the mixture was then distilled through a 25-centimeter Vigreaux-type column until the temperatureof the vapors reached 80 degrees centigrade.
  • the residual solution was refluxed overnight and then transferred to a beaker along with 350 milliliters of isopropyl alcohol.
  • the crystalline hydrochloride had. meanwhile separated out, and this was filtered, washed with isopropyl alcohol, ether and then dried, giving 23 grams, melting point 172-173.'5- degrees centigrade. Recrystallization.
  • a preferred embodiment; of the present invention resides in compounds of the formula R (Z-thienyD-(E-C O Ocarbon chain-Z wherein X and the carbon chain have the values previously given, and wherein R is a hydrocarbon radical of between 1 and about carbon atoms selected from the group consisting of alkyl, aryl, cycloalkyl, aralkyl and cycloalkyl alkyl; and Z is a member of the group consisting of dialkylamino and saturated nitrogen heteromonocyclic radicals, which compounds have exhibited exceptional antispasmodic activity.
  • Particularly eifective are compounds wherein R is carbocyclic (aryl or cycloalkyl). Some of the compounds also exhibit local anesthetic and mydriatic effects.
  • a compound selected from the group consisting of (a) basic-alkyl esters of the formula l (Z-thienyD-fiJ-C 0 0-carbon chain- Z wherein R represents a hydrocarbon radical having from 1 to 12 carbon atoms, the carbon chain is straight or branched and contains from 2 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 lower-alkylamino, lowerdialkylamino, cycloalkylamino, dicycloakylamino, phenyl-lower-alkylamino, piperidyl, pyrrolidyl and morpholinyl; (b) acid-addition salts and (c) quaternary ammonium salts thereof.
  • R represents a carbocyelic hydrocarbon radical having not more than 12 carbon atoms cyclopentyl.
  • the carbon chain is a normal chain and contains between 2 and 8 carbon atoms.

Description

Patented Feb. 13, 1951 BASIC ESTERS OF SUBSTITUTED ACETIC ACIDS Frederick F. Blicke, Ann Arbor, Mich., assignor to Regents of The University of Michigan, Ann Arbor, Mich., a corporation of Michigan No Drawing. Application November 3, 1949, Serial No. 125,380
8 Claims.
1 This invention relates to certain basic-alky esters of substituted (alpha-thienyDacetio acids, the salts of such esters, and pharmaceutical products in which they are employed as active ingredients. This application is'a continuationin-part of my prior-filed copending applications Serial 575,929, filed February 2, 1945, now abandoned, and Serial 695,811, filed September 9, 1946.
One of the principal objects of the present invention is the provision of a series of compounds having utility as pharmaceuticalsand particularly as antispasmodic agents. Members of this new group of compounds have been prepared, identified and found to have value as antispasmodics and as the active ingredients in antispasmodic preparations for the relief of muscle spasm as determined by the method of Magnus (Archiv. fiir die gesammte Physiologie, 1905, vol. 108, pages 1-71). 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 basic-alkyl esters of the present invention have the following generic formula R l (2-thienyl)(I3C O-carbon chain-Z wherein R represents a hydrocarbon radical, the carbon chain is straight or branched and contains from 2 to 8 carbon atoms, inclusive, X is hydrogen or hydroxyl radical, and Z is a primary or secondary amine radical.
Within the meaning of R in the aboye formula I include such hydrocarbon radicals as alkyl radicals, for example, methyl, ethyl, isopropyl, isobutyl, isoamyl, n-hexyl and n-octyl; aryl radicals, such as phenyl, naphthyl, and para-xenyl; cycloalkyl radicals, such as cyclopentyl and cyclohexyl; cycloalkylalkyl radicals, such as cyclohexylethyl and cyclohexylmethyl; aralkyl radicals, such as phenethyl, phenylmethyl; alkaryl radicals, such as ethylphenyl; alkylcycloalkyl radicals, such as ethylcyclohexyl; alkylcycloalkylalkyl radicals, such as methylcyclohexylethyl; and alkylaralkyl radicals, such as ethylphenylmethyl. Such hydrocarbon radicals preferably contain not more than twelve carbon atoms, regardless of the structure of the substituent.
The primary and secondary amine radicals represented by Z include such radicals as mono- The free basic esters of this methylamino, 'monoethylamino, monopropylamino, isopropylamino, monobutylamino, noctylamino, monocyclohexylamino, diethylamino, diisopropylamino, dibutylamino, dicyclohexylamino, diphenylamino, phenylethylamino; and the like. Z can also represent a saturated nitrogen heteromonocyclic ring such as piperidyl, morpholinyl, pyrrolidyl, piperazinyl and thi azinyl.
The compounds included within the scope of the present invention include (a) compounds of the above general formula and (b) salts thereof.
The term salts includes acid-addition 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 paratoluenesulfonate. 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 hydrocarbon substituted thienylaliphatic acids employed as starting materials can be prepared by first reacting thiophene with an alkyl oxalyl halide, e. g., C1CO=COOC2H5, in the presence of aluminum chloride to produce an a kyl ester of (alphathienyll-glyoxylic acid (SH3C4 COCOOH). The-keto acid, obtained by hydrolysis of the ester, is then reacted with a Grignard reagent containing the selected'hydrocarbon radical and the resulting complex is decomposed with a suitable, acidic reagent, such as HCl, NHiCl, NaHSO4, et cetera, to produce a substituted thienyl hydroxyacetic acid. This compound can be employed without further modificat on in the production of the hydroxy-containing basic ester, or it may be reduced, e. ,g., with stannous chloride, to produce the corresponding hydroxy-free hydrocarbon-substituted thienylacetic acid and thereafter treated to prepare the basic ester.
As an alternative procedure when the hydrocarbon substituent is aromatic, the acyl halide of the alkyl monoester of oxalic acid can first be reacted with a suitable aromaticv hydrocarbon 'such as benzene, biphenyl, naphthalene, et cetera, in the presence of, aluminum chloride .to produce ethyl oxalyl chloride,"
the corresponding aromatic substituted glyoxylic acid; the latter hydrolyzed to the free acid, and the acid then reacted with a Grignard reagent derived from a 2-thienyl halide. Decomposition of the magnesium-containing complex with acid and reduction of the hydroxy acid can be carried out as described in the preceding paragraph.
If compoundswhere X is hydrogen, that is, substituted thienylacetic acids and esters derived therefrom, are desired, it is not essential to pass through the substituted glycolic acids (X=OI-I) as intermediates. A dialkyl z-thienylmalonate can be alkylated by the malonic ester syntheses with an R-halide where R is an alkyl or an arylaliphatic hydrocarbon radical. This gives a disubstituted malonic ester,
which, upon hydrolysis and decarboxylatiou, gives a substituted thienylacetic acid,
The preparations and examples herein will serve to illustrate procedurewhereby production of members of this new group of compounds may be. accomplished, but are in no way to be construed as limiting.
Preparation 1.-Ethyl (alpha-thienyl)glyomylate A mixture of'84 grams (1 mole) of thiophene, 137 grams (1 mole) of ethyl oxalyl chloride and 1500 milliliters of tetrachloroethane was cooled to minus. 5 degrees centigrade and 147 grams (1.1 moles) of aluminum'chloride was added por tionwise thereto with stirring over a period of forty-five minutes. The mixture was stirred for three hours at room temperature and allowed to stand an additional five hours. The mixture was then treated with ice and hydrochloric acid. The organic layer was separated, washed successively with 1:1 hydrochloric acid, water, dilute sodium carbonate solution, and water. The washed layer was then dried with anhydrous sodium sulfate, and fractionally distilled. A yield of 93 grams of ethyl (alpha-thienyl)glyoxylate, boiling at 115- 200 degrees centigrade at threemillimeters of mercury pressure absolute, was obtained.
Preparation 2.(AZpha-thienyl)glyoacylic acid A mixture of 40 grams of ethyl (alpha-thienyl) glyoxylate, '75 milliliters of ethanol, 58 grams of sodium carbonate monohydrate, and. 450 milli glyoxylic acid melting at 8991 degrees centi-- rade.
Preparation 3.-Substituted hydrory acids A solution of methyl'magnesium iodide (,pre-
pared by reacting 85.2 grams (0.6 mole) of methyl iodide with 14.4 grams (0.6 mole). of magnesium in 300 milliliters of diethyl ether) was added dropwise and with stirring to 31.2 grams (0.2 mole) of (alpha-thienyDglyoxylic acid dissolved in 300 milliliters of ether and cooled with a mixture of ice and salt. An immediate vigorous reaction occurred and a precipitate separated. The
mixture was stirred for one hour at room temperature, heated to boiling under reflux for two The residue was i TABLE I M It Sulu tPer 1 K Em irical en 25 Formula Calcd Found Methyl-(alpha-thienyl) 111-113 01115038.. 18.62 18.34
hydroxyacetic acid. .Cyclohexyl-(alpa-thicnyl) 125-126 C12HmO3S 13.34 13.30
hydroxyaeetic acid. Benzyl-(alpha-thienyl) 140-142 C1aH1zO3S- 12.87 12.97
hydroxyacetic acid. Ph'enyl-(alpha-thienyl) 123 C1zH1o s .65 13.56
hydroxyacetic acid. (para-xenyD-(alpha- 129-130 0121114038-" 10.33 10.28
thignyl) hydroxyacetic aci (a1pha-naphthy1)-(alpha- 101-102 OmHuOaS 11.27 11.33
thignyD-hydroxyacetic aci Isopropyl-(alpha-thienyl) 129-132 CflHl203S 16.01 15.84
hydroxyacetic acid. Isobutyl-(alpha-thienyl) 106-111 CmH1 O S 14.96 14.79
hydroxyacetic acid. Isoamyl-(alpha-thienyl) 113-114 011111 0 8--- 14.04 13.68
hydroxyacetic acid. n-Hexyl-(alpha-thienyl) 88-90v CuHraOaS-.. 13.20 13.30
hydroxyacetic acid. Oyclopentyl-(alpha- 122 124 01111 0 8"- 14.13 13.91
thignyl) hydroxyacetic aci hours, cooled, and the ether layer decanted and discarded. The granular residue was washed with ether, decomposed with dilute sulfuric acid, extracted with ether, and the ether extract washed with an excess of aqueous twenty per cent sodium carbonate solution. The alkaline wash liquor was clarified with activated carbon, filtered, and the filtrate acidified with dilute sulfuric acid. The precipitate was separated, washed with ether, and dried. After recrystallization from benzene there was obtained 30 grams of methyl (alpha thienyDhydroxyacetic acid melting at 111-113 degrees centigrade.
By substituting cyclohexyl, benzyl, phenyl,
para-xenyl, alpha-naphthyl, phenethyl, cyclohexylethyl, isopropyl, n-hexyl or similar magnesium halides, for the methyl magnesium iodide employed in the preparation just described, the corresponding substituted (alpha-thienyDhydroxyacetic acids are obtained.
In Table I there are given the melting points, empirical formulae, and analyses of representative hydroxy acids employed in accordance with the present invention.
1 Recrystallized from benzene. 3 Recrystallized from dilute acetic acid. 3 Decomposed.
Preparation 4.Non-hydroa:y acids In the preparation of thienyl-substituted fatty acids from the hydroxy acids just described, the latter are reduced, preferably with stannous chloride. In a representative operation, 12 grams (0.051 mole) of phenyl-(alpha-thienyl)hydroxyacetic acid, 24 grams (0.106 mole) of stannous chloride dihydrate and 200 milliliters of acetic acid were stirred together. Hydrogen chloride was passed into the mixture with agitation at 15 degrees centigrade. After three hours, the mix ture was blown with air to remove acetic acid, the residue mixed with ice-water and filtered. The'residue, after washing with water and recrystallizing from fifty per cent acetic acid, weighed '7 grams and consisted of 'phenyl-(alphathienyl) acetic acid.
I In Table II there are given the melting points, empirical formulae, and analyses of representative hydrocarbon-substituted (alpha-thienyl) acetic acids employed as reactants in preparing the compounds of the invention. The compounds were purified by recrystallizing from dilute acetic acid.
enyl) acetic acids prepared as intermediates include isopropyl-(alpha-thienyl) acetic acid, B. P. 163-164 C. (20 mm.), isobutyl-(alpha-thienyl acetic acid, 13. P. 128-130" C. (0.4 mm.), M. T P. 60-63 C., and isoamyl-(alpha-thienyl) acetic acid, B. P. 150-155 C. (4-5 mm.). These were prepared by reduction of the corresponding hydroxyacetic acids disclosed in Table I.
In the preparation of the hydrohalides of the basic-alkyl esters of the hydrocarbon-substituted thienyl aliphatic acids, substantially equimolar proportions of a basic-alkyl halide and theh'ydrocarbon-substituted thienylaliphatic acid are admixed in a suitable solvent, e. g., ethanol or isopropyl alcohol, and the mixture heated until reaction has occurred. This may occur at room temperature or require heating at reflux for some time, e. g., 4 to 16 hours, more or less. The crude salt can be crystallized by dissolving it in a small quantity of warm ethanol, adding diethyl ether until turbidity and thereafter cooling the mixture. The salt separates in crystalline form and is recovered by decantation or filtration. Other acid salts can 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 can be employed without detracting materially from the effectiveness of the compound, provided only that the anion of the acid employed be reasonably non-toxic, and therefore the salt to be produced is usually chosen primarily with regard to crystallinity and solubility. I
As an alternative method of salt formation, a non-hydroxy acid can be converted to the acid chloride, as by heating with thionyl chloride, and the acid chloride then reacted with the selected basic alcohol to form the desired ester hydrochloride. The former method is preferred, however, since higher yieldsof product are obtained thereby.
Any basic alcohol or basic alkyl halide which meets the requirements of the formula HO-carbon chain-Z or halogen-carbon chain-Z respectively, where carbon chain and Z have the meanings given hereinabove, can be used in the preparation of the basic esters. In the reaction between a substituted thienylacetic acid or substituted thienylhydroxyacetic acid with a basic alkyl halide, typical halides include 2-diethylamino-l-haloethane, 2 dimethylamino-l-haloethane, 2 dipropylamino 1 haloethane, 2-dibutylamino-l-haloethane, 2 (N-piperidyD-I- halo'ethane; 2- (N-morpholinyl) -l-haloethane, 2- methylamino-l-haloethane, 2 phenylamino-lhaloethane, 3-diethylamino-l-halopropane, 3-di- 6 1 ethylamino-Z-halopropane, 4 diethylamino-lhalobutane, 4-diethylamino-2-halobutane, 5-diethylamino-l-halopentane, 6 diethylamino 1- halohexane, 7-diethylamino-l-haloheptane, and 8 diethylamino 1 halooctane. The halogen atoms can be chlorine, bromine or iodine.
The free basic-alkyl esters can be obtained from the hydrohalides by treatment with aqueous sodium carbonate or other mild alkali, preferably at low temperatures, and thereafter extracting with ether or other suitable solvent. The solvent can then be dried and volatilized in accordance with conventional methods.
To produce quaternary ammonium salts, the free base can be warmed 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 is usually formed in high yields.
Example 1.-3-diethylaminopropyl phenyl-(alpha-thienyl) hydroxy acetate hydrochloride A mixture of 3.4 grams of phenyl-(alpha-thienyDhydroxy acetic acid, 2.2 grams of 3-diethy1- aminopropyl chloride and 50 milliliters of isopropyl alcohol was refluxed for twelve hours. After milliliters of absolute alcohol had been added to the cold mixture, it was treated with activated charcoal at room temperature, filtered, and the activated charcoal treatment repeated several times. The solvents were removed from the filtrate under reduced pressure, and the residue rubbed under absolute ether. The crude ester hydrochloride (4.6 grams) was recrystallized from a mixture of absolute alcohol and absolute ether; melting point, 142-145 degrees centierade.
Example 2.3-diethylaminopropyl phenyl-(alpha-thienyl) acetate hydrochloride A mixture of 2.7 grams (0.0125 mole) of phenyl-(alpha-thienyl)-acetic acid, 1.7 grams (0.0125 mole) of B-diethylaminopropyl chloride and 50 milliliters of isopropyl alcohol was refluxed for twelve hours. The cold solution was mixed with milliliters of absolute alcohol, shaken with activated charcoal at ordinary temperature, filtered, the filtrate treated again with activated charcoal, and the mixture filtered. The solvents were removed under reduced pressure, and the residue rubbed under absolute ether. The crude ester hydrochloride (2.5 *grams) was recrystallized several times from benzene; melting point 87-89 degrees centigrade.
Example 3.--2-dz'ethylaminoethyl (para-menyh- (aZpha-thienyl) acetate hydrochloride A mixture of 4.4 grams (0.015 mole) of (paraxenyl) -(alphathienyl) -acetic acid and 5.5 milliliters of pure thionyl chloride was refluxed for one and one-half hours in an oil bath. After the addition of 10 milliliters of dry benzene to the dark brown mixture which contained the acid chloride, the benzene and excess thionyl chloride were removed under reduced pressure. Another 10 milliliters of benzene was added, removed by distillation, and this .process repeated several times. The residue was cooled and dissolved in 15 milliliters of benzene. To the solution there was added, slowly, 2.0 grams of 2-diethylaminoethanol, and the mixture was refluxed for two hours. The solvent was removed under reduced pressure. The residue, a dark red, viscous mass, was dissolved in'200 milliliters of absolute alcohol agseneaa and the .solution treated with activated charcoal several times. The solvent was removed under diminished pressure, and. the light greenish-yellow, oily ester hydrochloride was rubbed under absolute ether until it became crystalline. It was recrystallized from a mixture of absolute alcohol and absolute ether; melting point 101-103 degrees centigrade.
Example 4.2-diethylaminoethyl phenyZ-(aZpha-- thienyl) hydroxyacetate hydrochloride Example 5.2-diethylaminoethyl phenyl- (aZpha-thienyl) acetate hydrochloride A mixture of 4.36 grams of phenyl-(alphathienyl) acetic acid, 2.75 grams of 2-diethylaminoethyl chloride and 40 milliliters of isopropyl alcohol was refluxed for 15 hours. Isopropyl alcohol was-removed under reduced pressure, the residue dissolved in absolute alcohol, decolorized with activated charcoal, filtered and alcohol removed by distillation. The residue was rubbed underv absolute ether whereupon crystallization began. The hydrochloride melted at 98-100 degrees centigrade.
81 1 Example 6.-2-diethyla'mino'ethz Z' cyclopentyl- (alpha-thienyl) hydromyacetate hydrochloride An aqueous solution of 13.8 grams of 2-diethylaminoethyl chloride hydrochloride was neutralized with sodium hydroxide, and the free Z-diethylaminoethyl chloride was extracted with ether. The ether extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was added to a. solution of 13.6 grams of cyclopentyl (alpha thienyDhydroxyacetic acid in 100 milliliters of isopropyl alcohol. The mixture was then distilled through a 25-centimeter Vigreaux-type column until the temperatureof the vapors reached 80 degrees centigrade. The residual solution was refluxed overnight and then transferred to a beaker along with 350 milliliters of isopropyl alcohol. The crystalline hydrochloride had. meanwhile separated out, and this was filtered, washed with isopropyl alcohol, ether and then dried, giving 23 grams, melting point 172-173.'5- degrees centigrade. Recrystallization. from 400 'm-illiliters of isopropyl alcohol gave 20.3 grams of Z-dieth'ylamirioethyl cyclopentyl (alpha thienyl) hydroxyacetate hydrochloride, melting at 174-175 degrees centigrade; deep yellow-orange color with concentrated sulfuric acid.
In Table III are given the melting points (and in some cases, the boiling point) of some esters and salts thereof which are. representative of the present invention. They were prepared from the corresponding acids and alcohols by the method described in. the preceding examples. The intermediate acidsv are all disclosed in Tables I and II- TABLE III.
C-OO'O R1 3 I X R R1 M. P. C.
1 H CgHa CH2CH2N(C2H5)z-HC1 99-101. 2 H CHzCH2N(CgH51-z HEP..- 115-117. 3 H OH CH N (c2115); OH3Br 65-66. 4 H -CHgCHg (02H 197-199 (0.2 5 OH -CH2CH2N(C2H5)z H01. 3. 0H CH2CH2N(C2H5)2 CHaBI 141-142. 7 H CHzCH2CH2N (C211 H Cl. 87-89. 8 H CH2CH' CH2N(C;' 162-165 (0.01 111111 1 9 OH -CHzCH2CHzN(C2 51z 1101"-" 142-14 10 H CH2C 2CH2N(C4H912'CHZB1' 131-133 11 OH "'C'H2CH2OH2N (C411 0 6-158 12 H --CH2CHzN (1800311110 H 99-100 13 H CHQCH2N(1SOC3H7 2 174-176 (0.05 mm 1 14 OH -CH2CH2N (iSOC3H7)2-H 01 156-157. 15 H -CB2CH2N (CH3)3-HC1 113-115. 16 H CH: CHgN (0113): i 150-160 (0.01.- mm.) 17 OH CH2CH2N(CH3)2'HC1 1 159-161. 18 OH CHzCHgN(OHa)z-CH3BF 189.5-191. 19 H -CH CH2N (C 4 9 180-183 (0.01 mm.). 20 OH CH2CH2N (C4H9)2 H01 119-120. 21 H CH2C (CH3)2CH N(CH3)2 HG 126-128. 22 OH -CHzC (CH312CH2N(CH3)1 142-144. 23 H CH (CH3)CH;N(C H 12 162-165 (0.01 mm.). 24 OH CH (CH3)OH2N (C2H5)2-- l 142. 25 H CH2CH2NHC 3 132.5-134 26 OH CH2CH2NHCH3 HBI 139-140. 27 H CH CH NH (OUHK) HG]. 164-105. 28 OH CB2CH2NH(CBH5 HCL 164-165. 29 H CH2CH2N (C2135) (C0115 100-162. 30 OH CH2CH2N (C'zHEX aHs) H01. 172-178. 31 H CH2CH2N(C H )g -HC1 H 184-185. 32 OH -CHgCH2N (G ll p-H01 175-170. 33 H CH2CF12NH (CaHu) HBL" 151-152. 34 OH --CHzCHgNH (C H HBl' 194-195. 35 H CH2 CH2NC Hm C 3131. 153-155. 36 OH -CHzCHzNC5H o H01 177-178 ((160 37 OH -CH2CHzN((-2H H01 203 ((160.) 38 H -CH2CH2CH2N(C4H91 CHaBI 162-164. 39 H CH2CH2CH2N(C2H512 HCI--. 151-153. 40 H CHzCH2N C Hm 169-172. 41 OH CHzCH2NC H o -HC1 127-129 (1190.). 42 OH D-CaBsCgEL See footnotes on following page.
CHzOH N(CzH;.)g-HO1 -1 178-180 (dec.).
7 '1" 1 r X R R1 M. P., C.
43 H D-CBHECQH CH2CH2N(C2 5)2-HCI 101-103. 44 H PCGHSOQHJ --CH2CH2NC5H10 H01... 163-165. 45 OH -CH2OH2NC5H10 H01 189-191 (dec.). 46 H OH2OH2NC4H8O HOl 165-166. 47 OH -OH2CH2NO4HO H01. 225 (doc 48 H CH2OH2CH2N(C2H5)2 CHaB 134-136. 49 OH -OH2CH2N(C2H 148-151 50 OH CH2OH2N(OHa)2-HCl 187-189 51 OH -CHzCHgNEOH3)2-O2H5CL 186-188 52 H CH2CH2N C2H5)2-H(Jl 137-140. 53 OH CH2CH CH;4N (CzH5)2-HC1; 152-154. 54 OH -CHzCHzN( CzH5)2-HC1 above 200. 55 OH CH2OH2N (CZH5)Z HBr. 184-185. 56 OH -CH2CH2N (021102 4 005 118-123 57 OH CH2CH2N (C2H5)z-HNO3- 79-82. 58 OH CH2 2 2H5)2-C4Ha0u 1325-133 59 OH CH2CH2N(C2H5)2-C4HuOu 140-141. 60 OH CHzCH-2N (0211512 CHaBr 174-176. 61 OH CH2CH2NC5H1o 1 186-188 (100.). 62 OH CH2CH2N(C2H5)2 H01 174-175. 63 OH GH2CH2N(C2H5)2 H01 119-121. 64 H -OH2C 2N(O2 135-1365 (0.7 mm.). 65 OH (011502013: CH2OH2N (O2H5)2 HO 159-161. 66 H (OHmOH OH -OH2GH2N(C2H5)2 H01- 116-118. 67 OH (CH3)2CHC-H2. OH2OHzN(C2H5)2-HCI 105-108. 68 H (CH3)2OHCH2CH2 OH2 2N(C2 5)2 160 (0.05 111111.), 69 OH (CHahCHOHgCHz -CH2CH2N(C2H.,)2-HCL- 120-123. 70 OH CHAOHZMCHZ CH2CH2N 2 92- IDS-109.5.
1 boiling point, C. B morpholinyl.
Z cyclohexyl. 7 bitartrate.
3 piperidyl. a dextro-ester dextro-bitartrate.
4 alpha-naphthyl. 9 levo-ester dextro-bitartrate.
5 para-xenyl.
A preferred embodiment; of the present invention resides in compounds of the formula R (Z-thienyD-(E-C O Ocarbon chain-Z wherein X and the carbon chain have the values previously given, and wherein R is a hydrocarbon radical of between 1 and about carbon atoms selected from the group consisting of alkyl, aryl, cycloalkyl, aralkyl and cycloalkyl alkyl; and Z is a member of the group consisting of dialkylamino and saturated nitrogen heteromonocyclic radicals, which compounds have exhibited exceptional antispasmodic activity. Particularly eifective are compounds wherein R is carbocyclic (aryl or cycloalkyl). Some of the compounds also exhibit local anesthetic and mydriatic effects.
It is to be understood that many variations can be made without departing from the spirit and scope of the invention, and that I am to be limited only by the appended claims.
I claim:
1. A compound selected from the group consisting of (a) basic-alkyl esters of the formula l (Z-thienyD-fiJ-C 0 0-carbon chain- Z wherein R represents a hydrocarbon radical having from 1 to 12 carbon atoms, the carbon chain is straight or branched and contains from 2 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 lower-alkylamino, lowerdialkylamino, cycloalkylamino, dicycloakylamino, phenyl-lower-alkylamino, piperidyl, pyrrolidyl and morpholinyl; (b) acid-addition salts and (c) quaternary ammonium salts thereof.
2. A basic ester having the formula R (2-thiei1yl)1-C o O-carbon chain-N 0.11,),
in which R represents a carbocyelic hydrocarbon radical having not more than 12 carbon atoms cyclopentyl.
and the carbon chain is a normal chain and contains between 2 and 8 carbon atoms.
3. A basic ester having the formula R (2-thlenyD-l-0 O O-carbon chain- Z H in which R represents a carbocyclichydrocarbon radical, having not more than 12 carbon atoms, the carbon chain is a normal chain and Z is an N-piperidyl radical.
4. An acid-addition salt of 2-(N-piperidyl) ethyl alpha phenyl alpha(2-thienyl) hydroxyacetate having the formula I a cH.oH2
S COOCH2CH2N\ OHz AH CH2CH2 5. An acid-addition salt of 2-diethylaminoethyl alpha cyclohexyl alpha(2thienyl) hydroxyacetate having the formula 6. An acid-addition salt of 2-diethylaminoethyl alpha cyclopentyl-alpha(Z-thienyl) hydroxyacetate having the formula alpha, phenyl alphaCZ thiei'ii fiacetiite ha'fl'iig' REFERENcEspITEfi the formula v The following references are of record hi the file of this patent: 5 UNITED STATES PATENTS? Nt'ifigper- Name Date M 2,265,184 Miescher etal; Bee. 9, 194i 2,379,381 Shelton et a1; June-'26; 1-945 8. An acid-addition salt of 2-dietfij15rh1noethyl m alpha phenyl alpha(2-thienyl)hydroxyajcetat having the formula,
FREDERICK F. BmcfiE; 2o

Claims (1)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) BASIC-ALKYL ESTERS OF THE FORMULA
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2615894A (en) * 1951-03-10 1952-10-28 Sterling Drug Inc N-heterylalkyl-isobutyl-(2-thienyl) acetonitriles and preparation thereof
US2655511A (en) * 1950-11-18 1953-10-13 Upjohn Co 1-pyrrolidyl esters
US2662887A (en) * 1951-07-21 1953-12-15 Warner Hudnut Inc Substituted esters of cyclic alcohols
US2684370A (en) * 1951-07-21 1954-07-20 Warner Hudnut Inc Certain aminoalkyl-2-thienyl-cycloalkenyl thiolacetates
US2684369A (en) * 1951-07-21 1954-07-20 Warner Hudnut Inc Certain thienyl, cycloalkenyl acetamides
US2684368A (en) * 1951-07-21 1954-07-20 Warner Hudnut Inc Basic esters of substituted thienyl acetic acids
US2685589A (en) * 1952-02-19 1954-08-03 Wm S Merrell Co Therapeutic composition
US2686186A (en) * 1951-07-21 1954-08-10 Warner Hudnut Inc Aminopropyl-2-thienyl-cycloalkenyl acetate
US2987517A (en) * 1954-04-20 1961-06-06 Cilag Chemie Alpha aryl-3-methyl-pentanoic acid-nu-lower alkyl heterocyclic esters
US2993054A (en) * 1954-03-22 1961-07-18 Upjohn Co Alpha-five carbon cyclic hydrocarbon mandelic acid esters of beta-pyrrolidino-ethanol
US4005095A (en) * 1974-05-30 1977-01-25 Innothera Substituted thienyl-acetic acid esters

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2265184A (en) * 1938-08-05 1941-12-09 Ciba Pharm Prod Inc Basic esters and process of preparing same
US2379381A (en) * 1941-04-09 1945-06-26 Wm S Merrell Co Composition of matter

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2265184A (en) * 1938-08-05 1941-12-09 Ciba Pharm Prod Inc Basic esters and process of preparing same
US2379381A (en) * 1941-04-09 1945-06-26 Wm S Merrell Co Composition of matter

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2655511A (en) * 1950-11-18 1953-10-13 Upjohn Co 1-pyrrolidyl esters
US2615894A (en) * 1951-03-10 1952-10-28 Sterling Drug Inc N-heterylalkyl-isobutyl-(2-thienyl) acetonitriles and preparation thereof
US2662887A (en) * 1951-07-21 1953-12-15 Warner Hudnut Inc Substituted esters of cyclic alcohols
US2684370A (en) * 1951-07-21 1954-07-20 Warner Hudnut Inc Certain aminoalkyl-2-thienyl-cycloalkenyl thiolacetates
US2684369A (en) * 1951-07-21 1954-07-20 Warner Hudnut Inc Certain thienyl, cycloalkenyl acetamides
US2684368A (en) * 1951-07-21 1954-07-20 Warner Hudnut Inc Basic esters of substituted thienyl acetic acids
US2686186A (en) * 1951-07-21 1954-08-10 Warner Hudnut Inc Aminopropyl-2-thienyl-cycloalkenyl acetate
US2685589A (en) * 1952-02-19 1954-08-03 Wm S Merrell Co Therapeutic composition
US2993054A (en) * 1954-03-22 1961-07-18 Upjohn Co Alpha-five carbon cyclic hydrocarbon mandelic acid esters of beta-pyrrolidino-ethanol
US2987517A (en) * 1954-04-20 1961-06-06 Cilag Chemie Alpha aryl-3-methyl-pentanoic acid-nu-lower alkyl heterocyclic esters
US4005095A (en) * 1974-05-30 1977-01-25 Innothera Substituted thienyl-acetic acid esters

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