US3511832A - 3-thiotropanyl esters of certain substituted - 2 - aminophenylacrylate compounds - Google Patents

Description

United States Patent US. Cl. 260240 Claims ABSTRACT OF THE DISCLOSURE Substituted 3-tropanyl-2aminophenylacrylate esters having gastrointestinal spasmolytic activity, the substituent on the 3 carbon atom of the 2-phenylacrylic acid derivatives being hydrogen, phenyl, furyl, thienyl and pyridyl. Method of preparation comprises reacting the properly substituted nitrophenylacetic acid with paraformaldehyde or an aromatic aldehyde, treating the formed acid with tropine or thiotropine and converting the resulting ester to the final amino derivative by hydrogenating with Raney nickel.

This application is a division of our application Ser. No. 679,656, filed Nov. 1, 1967, now Pat. No. 3,458,507 granted July 29, 1969.

This invention relates to novel substituted 3-tropanyl- Z-aminophenylacrylate esters which have useful pharmacodynamic activity. More specifically, the compounds of this invention possess gastrointestinal spasmolytic activity as demonstrated in standard animal pharmacological test procedures. For example, in the modified Janssen test for the inhibition of fecal pellet count, spasmolytic activity was observed as doses of 3.2 mg./kg. and 51.2 mg./ kg. in mice.

These novel compound are particularly advantageous because they produce the spasrnolytic activity without the concomitant mydriatic and antisalivary side effects which are common to known anticholinergic-antispasmodic drugs. Prior to the present invention, there has been a great need for compounds which produce spasmolytic activity without the usual anticholinergic side etfects such as for example, dry mouth, blurred vision and urinary retention which are common to known anticholinergicantispasmodic drugs. The need of safe and effective compounds free of the above-noted side effects and having spasmolytic activity has been great.

3-tropanyl esters of atropic and thiotropic acid are known in the literature as set forth in US. Pat. No. 3,308,129. The novelty of the compounds of the present invention resides, however, in the presence of a basic amino group on the phenyl moiety of the 0: carbon atom. These novel compounds have a greater therapeutic index than the above-noted prior art compounds. In brief, the ratio of the minimum lethal dose to the effective spasmolytic dose is greater, thereby resulting in a much safer compound. Further, 3-tropanyl-2-p-aminophenyl-3-phenylacrylate, a representative compound of thi invention was compared to a closely related congener such as 3- tropanyl-2-p-chlorophenyl-3-phenylacry1ate. The following results in mice were obtained.

MLD Spasrno- Thera- (toxie lytic dose peutic dose) (ED index 3-tropanyl-2-p-aminophenyl-3- phenylaorylate 512 5. 7 3-tr0panyl-2-p-chlorophenyl-3- phenylacrylate 15. 7 12 It can be seen that the aminophenylacrylate derivative of this invention has a much greater margin of safety than the known chlorophenyl congener.

The novel substituted amino tropanyl esters of this invention are represented by the following general formula:

when X represents oxygen or sulfur;

R and R represent hydrogen or a lower alkyl group having from 1 to 4 carbon atoms;

R represents hydrogen, phenyl, furyl, thienyl or pyridyl.

Advantageous compounds of this invention are represented by the above structural formula when R and R represent hydrogen or a lower alkyl and R represents phenyl.

The preferred and most advantageous compound of this invention is represented by the following structural formula:

FORMULA 2 The substituted 3-tropany1-Z-aminophenylacrylates are prepared according to the following synthetic procedure:

S0 C1 tropine or thlotropine salt nlkl N02 Alternatively, 3-tropanyl 2 p-nitrophenylacrylate can be prepared by the method outlined in Schwenker, Archivder Pharmazie, 298, 826 (1965).

The invention also includes nontoxic pharmaceutically acceptable addition salts of the above-defined bases former with organic and inorganic acids. Such salts are easily prepared by methods known to the art, The base is reacted with either the stoichiometric amount of organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palrnitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids as well as with the 8-halotheo phyllines, for example, 8-chlorotheophylline and 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. These salts may also be prepared by the classical method of double decomposition of appropriate salts which is well known to the art.

Further, exemplary of salts are nontoxic quaternary ammonium salts of the above-defined bases formed with pharmacologically acceptable lower alkyl or aralkyl esters of, for example, sulfuric, hydrohalic and aromatic sulfonic acids. These salts are prepared by treating a solution of the base in a suitable solvent, such as chloroform, acetone, benzene, toluene or ether with an excess of an organic ester of sulfuric, hydrohalic or aromatic sulfonic acid. This reaction is carried out most advantageously at a temperature in the range of from about 25 C. to about 115 C. Exemplary of such reactive esters are lower alkyl halides of a maximum of 8 canbon atoms such as methyl chloride, methyl bromide, methyl iodide, ethyl chloride, propyl bromide, butyl chloride, isobutyl chloride, ethylene bromohydrin, ethylene chlorohydrin, allyl bromide, methallyl bromide, crotyl bromide, benzyl chloride, benzyl bromide, naphthylmethyl chloride, penethyl bromide, dimethyl sulfate, diethyl sulfate, methyl benzene sulfate and ethyl toluene sulfonate.

The novel compounds of this invention may be admin istered orally or parenterally in conventional dosage unit forms such as tablets, capsules, injectables or the like, by incorporating the appropriate dose of a compound of Formula 1 with carriers according to accepted pharmaceutical practices. The substituted amino tropanyl esters of Formula 1 will be present in an amount to produce gastrointestinal spasmolytic activity. Preferably the dosage unit forms will contain the compounds of Formula 1 in an amount of from about 2.0 mg. to about 100 mg, advantageously from about mg. to about 50 mg. Advantageously equal daily doses are administered one to four times daily to provide a daily dosage regimen.

The following examples are not limiting but are illustrative of this invention and the procedures for their preparation, Other variations of this invention will be obvious to those skilled in this art.

Example 1 To a mixture containing 31.8 g. of p-nitrophenylacetic acid, ml. of benzaldehyde and 16.2 ml. of triethylamine is stirred with cooling 44 ml. of acetic anhydride. The mixture is stirred for approximately /2 hour and heated in an oil bath at 70 C. The temperature is raised to 100 C. over a /2 hour period and heating continued for approximately five hours. The solution is cooled and made acidic with concentrated hydrochloric acid. The crude acid is filtered dried and recrystallized from alcohol to yield 2-p-nitrophenyl-3-phenylacrylic acid.

A suspension of 13.0 g. of 2-p-nitrophenyl-3-phenylacrylic acid, 20 ml, of dry benzene and 10 ml. of thionyl chloride is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess thionyl chloride and benzene is removed by asperator. The solution is further Washed with three separate portions of dry benzene. To the resulting oil is added 9.1 g. of tropine hydrobromide and the mixture is then chilled. To this mixture is added 20 ml. of dry pyridine and the solution is stirred for about /2 hour at room temperature and then at 60 C. to 70 C. for one hour.

The mixture solidifies ruring this process and 10 ml. of dry pyridine is added. Then ml. of Water is added and the solution is warmed and treated with charcoal. The solution is made basic and the free base is extracted with ether and dried. The pyridine is removed by treatment with several portions of benzene. The benzene is distilled oft" to yield 3-tropanyl 2 p-nitrophenyl-3- phenylacrylate.

An ethereal solution of the free base is treated with hydrogen chloride to yield the hydrochloride salt A solution of 14 g. of 3-tropanyl 2 p-nitrophenyl-3- phenylacrylate hydrochloride in 250 ml. of methanol is hydrogenated over Raney nickel. The reaction mixture is warmed and filtered. The precipitate formed on cooling is recrystallized from methanol to yield 3-tropanyl-2-paminophenyl-3-phenylacrylate hydrochloride as a yellow solid having a melting point of 265 C. to 266 C.

Example 2 Similarly following the procedure outlined in Example 1, 25.5 g. of m-nitrophenylacetic acid was employed as the starting material to yield 3 tropanyl-Z-m-aminophenyl-3-phenylacrylate having a melting point of 230 C-231 C.

Example 3 To a mixture under nitrogen containing 500 ml. of anhydrous ether, 27.6 g. of magnesium turnings and 11 drops of ethyl bromide is added 15 ml. of isopropyl chloride. The mixture is warmed until the reaction proceeds and 87 ml. more of isopropyl chloride is added and the mixture refluxed moderately for approximately one hour. A solution of 90.6 g, of p-nitrophenylacetic acid in 500 ml. of dry benzene is then added and the mixture further refluxed for approximately two hours. 50.0 g. of paraformaldehyde is then distilled into the mixture with the aid of a stream of dry nitrogen. The thick solution is stirred for about an hour after the formaldehyde distillation is completed and the mixture then poured into ice and 200 ml. of concentrated sulfuric acid, stirred and cooled to about 5 C. The crude solid is then filtered, recrystallized from water and dried at 40 C. in vacuo. The solid is then purified by treating with benzene, dissolving in hot water and extracting once again with benzene until aqueous layer is colorless. The aqueous solution is cooled and precipitate filtered to yield Z-p-nitrophenylacrylic acid.

21.1 g. of Z-p-nitrophenylacrylic acid and 50 ml. of acetyl chloride is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess acetyl chloride distilled oil" under reduced pressure. 100 ml. of thionyl chloride is added to the residual oil and the mixture refluxed for about an hour. The excess thionyl chloride is distilled off, 3 separate portions of benzene added and also distilled off. 20.0 g. of tropine hydrobromide in 35 ml. of dry pyridine is then added and heated for one hour. The mixture is cooled to about 10 C., water is added and the solid filtered and then recrystallized from water. The impure salt is dissolved in water and made basic with 1 N sodium hydroxide and extracted with ether. The ether solution is washed with water and dried over anhydrous magnesium sulfate to yield 3-tropanyl-2-p-nitrophenylacrylate.

An ethereal solution of the free base is treated with hydrogen chloride to yield the hydrochloride salt.

A solution of g. of 3-tropanyl-2-p-nitrophenylacrylate hydrochloride in 150 ml. of methanol is hydrogenated over Raney nickel. The reaction mixture is warmed and filtered. The precepitate which results on cooling is recrystallized from ethanol to yield 3-tropanyl- Z-p-aminophenylacrylate hydrochloride.

Example 4 A mixture containing 7.7 g. of 3-tropanyl-2-p-nitrophenylacrylate hydrochloride (as prepared in Example 3), 4.72 g. of isobutyraldehyde and 0.436 g. of sodium acetate in 100 ml. of methanol is hydrogenated over Raney nickel. The resulting free base is distilled to give 3-tropanyl-2-p-isobutylaminophenylacrylate having a boiling point of about 200 C. at 0.03 mm.

Example 5 A mixture containing 10.0 g. of 3-tropanyl-2-p-nitrophenyl-3-phenylacrylate hydrochloride (as prepared in Example 1), 6.1 g. of acetaldehyde and 0.55 g. of sodium acetate in 250 ml. of methanol is hydrogenated over Raney nickel. The resulting free base is distilled to yield 3-t.ropanyl-2-p-ethylaminophenyl-3-phenylacrylate.

Example 6 To a mixture containing 30.0 g. of m-nitrophenylacetic acid, 14.5 ml. of Z-furfural and 24.4 ml. of triethylamine is added 66.4 ml. of acetic anhydride. The mixture is heated on an oil bath at 100 C. for about one hour, cooled to room temperature and taken up in acetone. The solution is heated with activated carbon, filtered and the acetone evaporated. The mixture is then acidified with concentrated hydrochloric acid, cooled and filtered. The crude acid is recrystallized twice from alcohol to yield 2-m-nitrophenyl-3-(2-furyl)acrylic acid.

A suspension of 14.5 g. of 2-m-nitrophenyl-3-(2- furyl)acrylic acid, 10.0 ml. of thionyl chloride and ml. of dry benzene is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess thionyl chloride and benzene is removed. The solution is further washed with three portions of dry benzene. To the resulting oil is added 11.5 g. of tropine hydrobromide and the mixture is then chilled. To this mixture is added ml. of dry pyridine and the solution is stirred for about /2 hour at room temperature and then at 60 C. to 70 C. for one hour. The mixture solidifies during this process and 25 ml. of dry pyridine is added. Then 100 ml. of water is added and the solution warmed and treated with charcoal. The solution is made basic and the free base is extracted with ether and dried. The pyridine is removed by treatment with several portions of benzene. The benzene is distilled oil? to yield 3 -tropanyl-2-m-nitrophenyl-3- Z-furyl) acrylate.

An acetone solution of the free base is reacted with succinic acid to yield the succinate salt.

A solution of 10 g. of 3-tropanyl-2-m-nitrophenyl-3- (2-furyl)acrylate succinate in 200 m1. of methanol is hydrogenated over Raney nickel. The reaction mixture is warmed and then filtered. The precipitate formed on cooling is recrystallized from ethanol to yield 3-tropanyl-2- m-aminophenyl-3- (Z-furyl) acrylate maleate.

Example 7 To a mixture containing 60.0 g. of p-nitrophenylacetic acid, 32.1 ml. of thiophenealdehyde and 48.2 ml. of triethylamine is added 120 ml. of acetic anhydride. The mixture is heated at 150 C. for about /2 hour and cooled to room temperature. The liquid is acidified with concentrated hydrochloric acid and the precipitated crude acid is extracted with 300 ml. of methylene chloride. The methylene chloride solution is washed with about 500 ml. of water and then extracted several times with 2% sodium hydroxide and the basic solution cooled in 6 ice. The solution is acidified with glacial acidic acid, cooled to 5 C., and the acid filtered and dried. The acid is recrystallized from alcohol to yield 2-p-nitrophenyl- 3-(2-thienyl)acrylic acid.

A suspension of 27.2 g. of 2-p-nitrophenyl-3-(2- thienyl)acrylic acid, 10.0 ml. of thionyl chloride and 15 ml. of dry benzene is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess thionyl chloride and benzene is removed. The solution is further washed with three portions of dry benzene. To the resulting oil is added 9.95 g. of tropine hydrobromide and the mixture is then cooled. To this mixture is added 15 ml. of dry pyridine and the solution is stirred for about /2 hour at room temperature and then at 60 C. to 70 C. for one hour. The mixture solidifies during this process and 30 ml. of dry pyridine is added. Then ml. of water is added and the solution warmed and treated with charcoal. The solution is made basic and the free base is extracted with ether and dried.

The pyridine is removed by treatment with several portions of benzene. The benzene is distilled off to yield 3-tropanyl-2-p-nitrophenyl-3- (2-thienyl) acrylate.

An acetone solution of the free base is reacted with ethyl bromide to yield the ethobromide quaternary salt.

A solution of 5 g. of 3-tropanyl-2-pnitrophenyl-3- (2-thienyl)acrylate ethobromide in 100 ml. of methanol is hydrogenated over Raney nickel. The reaction mixture is warmed to dissolve the formed solid and the solution is filtered to yield 3-tropanyl-2-p-aminophenyl-3-(2- thienyl)acrylate ethobromide.

Example 8 To a mixture containing 30.0 g. of m-nitrophenylacetic acid, 18.5 g. of 4-pyridylcarboxaldehyde, 24.4 ml. of triethylamine is added 66.4 ml. of acetic anhydride. The mixture is stirred for approximately one hour at room temperature. The solution is cooled and made acetic with concentrated hydrochloric acid. The crude acid is filtered, dried and recrystallized from alcohol to yield 2-m-nitrophenyl-3-(4-pyridyl) acrylic acid.

A suspension of 15.0 g. of 2-nitrophenyl-3-(4-pyridyl) acrylic acid, 20 ml. of thionyl chloride and 40 ml. of dry benzene is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess thionyl chloride and benzene is removed. The solution is further washed with three separate portions of dry benzene. To the resulting oil is added 10.0 g. of tropine hydrobromide and the mixture is then chilled. To this mixture is added 25 ml. of dry pyridine and the solution is stirred for about /2 hour at room temperature and then at 60 C. to 70 C. for one hour. The mixture solidifies during this process and 30 ml. of dry pyridine is added. Then-100 ml. of Water is added and the solution warmed and treated with charcoal. The solution is made basic and the free base is extracted with ether and dried. The pyridine is removed by treatment with several portions of benzene. The benzene is distilled oif to yield 2-tropanyl-2-m-nitrophenyl-3-(4-pyridyl)acrylate.

Reacting the free base with bismethylene-salicylic acid in ethyl acetate solution results in the bismethylenesalicylate salt.

A solution of 20.0 g. of the resulting salt is hydrogenated over Raney nickel to yield 3-tropanyl-2-m-aminophenyl-3-(4-pyridyl)acrylate bismethylene salicylate.

Example 9 A suspension of 26.0 g. of 2-m-nitrophenyl-3-phenylacrylic acid, as prepared in Example 2, 40 ml. of dry benzene and 20 ml. of thionyl chloride is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess thionyl chloride and benzene is removed by asperator. The solution is further washed with three separate portions of dry benzene. To the resulting oil is added 18.2 g. of thiotropine hydrobromide and the mixture is then chilled. To this mixture is added 40 ml. of dry pyridine and the solution is stirred for about /2 hour at room temperature and then at 60 C. to 70 C. for one hour. The mixture solidifies during this process and 20 ml. of dry pyridine is added. Then 200 ml. of water is added and the solution warmed and treated with charcoal. The solution is made basic and the free base is extracted with ether and dried. The pyridine is removed by treatment with several portions of-benzene. The benzene is distilled ofl? to yield 3-thiotropanyl-Z-m-nitrophenyl-3-phenylacrylate.

Reacting an ethereal solution of the free base with hydrogen chloride yields the hydrochloride salt.

A solution of 10.5 g. of 3'-thiotropanyl-2-m-nitrophenyl-3-phenylacrylate hydrochloride in 200 ml. of methanol is hydrogenated over Raney nickel. The solution is filtered and upon cooling the product is precipitated. The precipitate is recrystallized from methanol to yield 3-thiotropanyI-Z-m-aminophenyl-3-phenyla-crylate hydrochloride.

What is claimed is:

1. A chemical compound of the formula 8 or a pharmaceutically acceptable acid addition salt thereof, in which:

R and R are respectively hydrogen or a lower alkyl group containing'from 1 to 4 carbon atoms; and R is hydrogen, phenyl, Z-furyl, Z-thienyl or 2- and 4-pyridyl. 2. A chemical compound in accordance with claim 1 in which R is phenyl.

3. A chemical compound in accordance with claim 2 in which R and R are both hydrogen.

4. A chemical compound in accordance with claim 1 in which R R and R are hydrogen.

5. A chemical compound in accordance with claim 1 in which R and R are hydrogen and R is isohutyl.

References Cited UNITED STATES PATENTS 3,308,129 3/ 1967 Caldwell et al. 260-292 HENRY R. JILES, Primary Examiner A. L. ROTMAN, Assistant Examiner Us. 01. X.R.