US3275658A - Tertiary-aminoalkoxy-substituted 3, 4-diphenylcoumarins - Google Patents

Description

United States Patent Ofiice 3,275,658 Patented Sept. 27, 1966 3,275,658 TERTIARY-AMINOALKOXY-SUBSTITUTED 3,4-DIPHENYLCOUMARINS Daniel Lednicer, Portage Township, Kalamazoo County, Mich., assignor to The Upjohn Company, Kalamazoo,

Mich, a corporation of Delaware No Drawing. Filed May 23, 1963, Ser. No. 282,563 9 Claims. (Cl. 260343.2)

This invention relates to novel coumarin derivatives and is more particularly concerned with tertiary-aminoalkoxy-substituted 3,4-diphenylcoumarins and derivatives thereof including the acid addition salts and quaternary ammonium salts thereof and with processes for their preparation.

The novel compounds of the invention are selected from the class consisting of:

(a) Compounds having the formula:

wherein R R and R are each selected from the class consisting of loWer-alkyl, lower-alkenyl, trifluoromethyl, loWer-alkoxy, lower-alkenyloxy, lower-alkylenedioxy, hydroxy, halogen, lower-alkylmercapto, and

wherein A is an alkylene group containing from 2 to 6 carbon atoms, inclusive, R and R are selected from the class consisting of lower-alkyl and lower-alkyl linked together to form, with the attached nitrogen atom, a 5 to 7 ring atom saturated heterocyclic radical, and x, y, and z are each integers from O to 4, inclusive, provided that at least one of the groups R R and R represents (b) The acid addition salts of the above compounds with pharmacologically acceptable acids; and

(c) The quaternary ammonium salts of the compounds of the above formula wherein the anion of the quaternary salt is that of a pharmacologically acceptable acid.

The term lower-alkyl means an alkyl group containing from 1 to 8 carbon atoms, inclusive, such as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, and isomeric forms thereof. The term lower-alkenyl means an alkenyl group containing from 2 to 8 carbon atoms, inclusive, such as vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, and isomeric forms thereof. The term IoWer-alkoxy means an alkoxy group containing from 1 to 8 carbon atoms, inclusive, such as methoxy, e-thoxy, propoxy, butoxy, amyloxy, hexyloxy, heptyloxy, octyloxy, and isomeric forms thereof. The term lower-alkenyloxy means an alkenyloxy group containing from 2 to 8 carbon atoms, inclusive, such as vinyloxy, allyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, and isomeric forms thereof. The term halogen is inclusive of fluorine, chlorine, bromine, and iodine. The term loWer-alkylmercapto means an alkylmercapto group containing from 1 to 8 carbon atoms, inclusive, such as methylmercapto, ethylmercapto, propylmercapto, butylmercapto, amylmercapto, hexylmercapto, heptylmercapto, octylmercapto, and isomeric forms thereof. The term lower-alkylenedioxy means an alkylenedioxy group containing from 1 to 8 carbon atoms such as metl1- ylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy, pentylenedioxy, hexylenedioxy, heptylenedioxy, octylenedioxy, and isomeric forms thereof. The term alkylene group from 2 to 6 carbon atoms, inclusive, means ethylene, propylene, butylene, pentylene, hexylene, and isomeric forms thereof. The term loWer-alkyl linked together to form, with the attached nitrogen atom, a 5 to 7 ring atom saturated heterocyclic radical is inclusive of pyrrolidino, lower-alkylpyrrolidino such as Z-methylpyrrolidino, 2,2-dimethylpyrrolidino, 3-inethylpyrrolidino, and the like, piperazino, lower-alkylpiperazino such as Z-methylpiperazino, 4-methylpiperazino, 2,4-dimethylpiperazino, and the like, piperidino, lower-alkylpiperidino such as Z-methylpiperidino, S-methylpiperidino, 4,4-dimethylpiperidino, and the like, morpholino, hexamethylenimino, homopiperazino, homomorpholino, and the like.

The acid addition salts of the invention comprise the salts of the compounds having the Formula I with pharmacologically acceptable acids such as sulfuric, hydrochloric, nitric, phosphoric, lactic, benzoic, methanesulfonic, p-toluenesulfonic, salicylic, acetic, propionic, maleic, malic, tartaric, citric, cyclohexylsulfamic, succinic, nicotinic, ascorbic acids, and the like.

The quaternary ammonium salts of the invention are the salts obtained by reacting the compounds having the Formula I with quaternating agents, for example, loweralkyl halides, lower-alkenyl halides, di(lower-alkyl) sulfates, aralkyl halides, lower-alkyl arylsulfonates, and the like. The terms lower-alkyl and lower-alkenyl have the meaning hereinbefore defined. The term aralkyl means an aralkyl group containing from 7 to 13 carbon atoms, inclusive, such as benzyl, phenethyl, phenylpropyl, benzhydryl, and the like. The term lower-alkyl arylsulfonates means the esters formed from lower-alkyl alcohols and arysulfonic acids such as benzenesulfonic, toluenesulfonic, xylenesulfonic, and like acids. Examples of quaternary salts of the compounds of Formula I are the methobromide, methiodide, ethobromide, propyl chloride, butyl bromide, octyl bromide, methyl methosulfate, ethyl ethosulfate, allyl chloride, allyl bromide, benzyl bromide, benzhydryl chloride, methyl p-toluenesulfonate, ethyl p-toluenesulfonate, and the like.

The novel compounds of the invention, including the free bases of Formula I, the acid addition salts thereof, and the quaternary ammonium salts thereof, possess pharmacological activity. Illustratively, the compounds of the invention are useful as antifertility agents, antiestrogenic agents, gonadotrophin-inhibiting agents, and as agents for the lowering of lipid and cholesterol blood levels in mammals, including man and animals of economic value. In addition, the compounds of the invention possess activity as anti-inflammatory agents which makes them useful, for example, in human therapy when administered topically for the alleviation of inflammation and burns, and also in the treatment of atopic dermatitis and contact dermatitis. In addition, the compounds of the invention possess activity as central nervous system stimulants.

Illustratively, the compounds 3-(p-rnethoxyphenyD-4 [p (Z-diethylaminoethoxy)phenyl]coumarin, 3-(p-methoxyphenyl) 4 phenyl 7-(Z-diethylaminoethoxy)coumarin, and 3,4-diphenyl-7-(Z-diethylaminoethoxy)coumarin, have been found to possess anti-inflammatory activity of the order of that shown by hydrocortisone, when tested in the granuloma pouch assay in rats using the procedure described by Robert et al., Aeta Endocrinologica 25, 105, 1957. Further, the compound 3,4-diphenyl-7-(Z-diethylaminoethoxy) coumarin when tested by the method de- 3 scribed by Duncan et al., Proc. Soc. Exp. Biol. Med. 112, 439-442, 1963, exhibited oral antifertility activity in rats.

For purposes of administration to mammals, the novel compounds of the invention can be combined with solid or liquid pharmaceutical carriers and formulated in the form of tablets, powder packets, capsules, and like solid dosage forms, using starch and like excipients, or dissolved or suspended in suitable solvents or vehicles, for oral or parenteral administration.

In addition to their pharmacological activity, the compounds of the invention are also useful as intermediates. For example, the compounds of the Formula I can be reacted with fiuosilicic acid to form the fluosilicate salts which in diulte aqueous solution are effective moth-proofing agents as more fully disclosed in US. Patents 2,075,359 and 1,915,334.

The compounds of the invention having the Formula I can be prepared readily, first by reacting the appropriately substituted o-hydroxybenzophenone having the Formula II with an alkali metal salt of the appropriately substituted phenylacetic acid (III) to obtain a coumarin having the Formula IV, and then etherifying the latter as described below.

The first reaction is shown schematically below:

[R8]: [Rbh l 'i (13H?- OR 002M (II) (III) l vly I [Rslz [Rah \O/ In the above formulae R R and R are each selected from the class consisting of lower-alkyl, lower-alkenyl, trifiu-oromethyl, lower-alkoxy, lower-alkenyloxy, loweralkylenedioxy, halogen, lower-alkylmercapto, hydroxy, and acyloxy, wherein the acyl radical is that of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, provided that at least one of the groups R R and R represents hydroxy or acyloxy, R is selected from the class consisting of hydrogen and acyl as hereinbefore defined, M is an alkali metal, preferably sodium or potassium, and x, y, and z are as hereinbefore defined.

The term hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, means saturated and unsaturated aliphatic acids and aromatic acids of the stated carbon atom content such as acetic, propionic, butyric, isobutyric, t-butylacetic, Valerie, isovaleric, caproic, caprylic, decanoic, dodecanoic, acrylic, crotonic, hexynoic, heptynoic, octynoic, cyclobutanecarboxylic, cyclopentanecarboxylic, cyclopentenecarboxylic, cyclohexanecarboxyltic, dimethylcyclohexanecarboxylic, benzoic, toluic, naphthoic, ethylbenzoic, phenylacetic, naphthaleneacetic, phenylvaleric, cinnamic, phenylpropiolic, phenylpropionic, p-butoxyphenylpropionic acids, and the like.

The above reaction is carried out according to the conditions employed in the Kostaneki-Robinson reaction; see, for example, Heterocyclic Compounds, by R. C. Elderfield, vol. II, pp. 176, 234 (New York, 1951). In general, the reactants (II) and (III) are heated together in the presence of a lower aliphatic acid anhydride such as acetic anhydride, propionic anhydride, butyric anhydride, and the like, to produce the courmarin (IV). The reaction is conveniently carried out at the reflux temperature of the mixture but lower temperatures can be employed if desired. In most instances, the reactants (II) and (III) are preferably employed in approximately stoichiometric proportions where optimum yields of the desired coumarin are required, but other proportions of the reactants can be employed if desired. The reaction normally requires several hours to proceed to completion but the exact time of reaction required varies according to the nature and reactivity of the individual reactants. The desired coumarin (IV) is isolated from the reaction mixture by conventional procedures, for example, by pouring the reaction mixture into water. The coumarin separates as a solid, in which case it is isolated by filtration, or as an oil, in which case it is isolated by solvent extraction. The coumarin so obtained can be purified, if desired, by conventional procedures such as by recrystallization, chromatography, and the like.

When one or both of the reactants (II) and (III) contain one or more free hydroxy groups as substituents, said groups will be acylated during the above condensation and will be present in the coumarin (IV) as the corresponding acyloxy groups. The corresponding coumarin (IV) in which the free hydroxy group or groups have been regenerated can be obtained by hydrolysis of the acyloxy group or groups. Said hydrolysis is advantageously carried out by acid hydrolysis, for example, using aqueous or aqueous-alcoholic mineral acid, or by alkaline hydrolysis, for example, using aqueous or aqueous-alcoholic alkali metal hydroxide or carbonate such as sodium hydroxide, potassium hydroxide, potassium carbonate, and the like, or using alcoholic alkali metal alkoxide solution such as ethanolic sodium ethoxide and the like.

The compounds of the invention having the Formula I are obtained from the corresponding coumarin (IV) in which at least one of the groups R R and R represents free hydroxy by etherification of the latter compounds, using the appropriate tertiary-aminoalkyl halide. The etherification is preferably conducted by reacting the free hydroxy coumarin with the appropriate tertiary-aminoalkyl halide NA-Hal R4 wherein R R and A have the significance hereinbefore defined and Hal represents halogen, in solution in an inert organic solvent such as a lower-alkanol, for example, methanol, ethanol, isopropyl alcohol, and the like, in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium eth-oxide, and the like.

The reaction is advantageously carried out at elevated temperatures, preferably at or near the reflux temperature of the reaction mixture. Advantageously, the tertiaryaminoalkyl halide is employed in slight excess of the stoichiometric proportion with respect to the free hydroxy compound. The desired compound (I) is isolated from the reaction mixture by conventional procedures, for example, by evaporation under reduced pressure followed by treatment of the residue with water and solvent extraction of the water-insoluble material. The compound (I) so isolated is purified by conventional procedures such as recrystallization, chromatography, and like procedures.

The benzophenones of the Formula II which are employed as starting material in the above-described process are for the most part known. They can be prepared by reacting the appropriately substituted phenol wherein R and x have the significance hereinbefore described, with the appropriately substituted benzoyl chloride wherein R and have the significance above defined, under the conditions normally employed in the Friedel- Crafts reaction; see, for example, Berliner, Organic Reactions, vol. V, p. 229 (John Wiley and Sons, Inc., New York, 1949).

Similarly, the phenylacetic acids, .from which the starting stalts (III) are derived, are for the most part known. In general, the phenylacetic acids can be prepared by reduction of the correspondingly substituted benzoic acids, either as the free acid or simple alkyl esters thereof, with lithium aluminum hydride according to the procedure described by Nystrom and Brown, J, Am. Chem. Soc. 69, 2548, 1947. The be-nzyl alcohols so obtained are then converted to the corresponding benzyl halides using procedures known in the art, for example, that described by Gilmaniand Kirby, J. Am. Chem. Soc. 51, 475, 1929. The benzyl halides so obtained are then reacted with an alkali metal cyanide such as sodium cyanide, to form the corresponding phenylacetonitrile under conditions well-known in the art for the conversion of ar-alkyl halides to the corresponding nitriles, and the phenylacetonitrile so obtained is hydrolyzed, for example, using aqueous mineral acid or aqueous alkali to yield the desired phenylacetic acid.

The tertiary-aminoalkyl halides /NA-Ha1 R5 wherein R R A and Hal are as hereinbefore defined, which are employed in the reaction described above, can be prepared by halogenation of the corresponding tertiaryaminoalkanols, which latter in turn can be made by interaction of the requisite secondary amine with the appropriate haloalkanol, Hal--AO-H, wherein Hal and A have the significance hereinbefore defined, in

accordance with known methods. The condensation between the secondary amine NH R5 and the haloalkanol HalA-OH can be carried out, for example, using the procedure described by Molfett, J. Org. Chem. 14, 862, 1949. Alternatively, the desired tertiaryaminoalkanols can be prepared by heating the secondary amine NH R5 with the appropriate haloalkanoic acid ester, lfollowed by reduction of thus-produced aminoalkanoic acid ester with lithium aluminum hydride according to the method described by Motfett, supra.

The coumarins (IV) which are employed in the preparation of the compounds of the invention (1) can be prepared by an alternative route as follows:

OMe

In the above formulae R R R x, y, and z have the significance hereinbefore defined.

The above series of reactions is carried out under the conditions described by Biiu-Hoi et al., J. Org. Chem. 19, 1548, 1954, for the preparation of 7-hydroxy-3,4-diphenyl-, 3-phenyl-4-(p-hydroxyphenyl)- and 3,4-di-(p-hydroxyphenyl)coumarin from the appropriately substituted 0- methoxybenzophenone and phenyl-acetonitrile. The preparation of the phenyl-acetonitrile starting materials has already been described above together with that of the ohydroxybenzophenones corresponding to the o-methoxybenzophenones employed in the above reaction. The 0- methoxybenzophenones are obtained from the corresponding o-hydroxybenzophenones by methods Well known in the ant tor the methylation of phenols, for example, by reaction with methyl iodide in the presence of a base such as sodium hydroxide, potassium hydroxide, and the like.

The acid addition salts of the compounds of the invention having the Formula I can be prepared by methods well-known in the art. For example, the acid addition salts of the invention can be prepared by reacting a free base having the Formula I with a pharmacologically acceptable acid, as hereinbefore defined, in the presence of an inert solvent such as methanol, ethanol, and the like.

The quaternary ammonium salts of the invention can be prepared by reacting -a free base of the Formula I With a quaternating agent, for example, an. alkyl halide such as methyl iodide, ethyl chloride, isopropyl bromide, and the like, an alkenyl halide such as allyl chloride, allyl bromide, and the like, a di-alkyl sulfate such as dimethyl sulfate, diethyl sulfate, and the like, an aralkyl halide such as benzhydryl chloride, phenethyl bromide, and the like, or an alkyl arylsulfonate such as methyl p-toluenesulfonate, and the like. Preferably the reaction is effected by heating the reactants together in the presence of an inert solvent such as acetonitrile, acetone, methanol. ethanol, and the like. Generally speaking, the desired quaternary salt separates from solution upon cooling the reaction mixture and can be isolated by filtration. Purification of the quaternary salt can be elfected by conventional methods, for example, by recrystallization. The anion of the quaternary ammonium salt obtained as described above can be exchanged for any other desired anion, e.g., the anions of the various acids enumerated previously, by conventional procedures. 'For example, any of the quaternary ammonium salts of the invention can be converted to the corresponding quaternary ammonium hydroxide, illustratively, by treatment with silver oxide, and the quaternary ammonium hydroxide so obtained is reacted with the appropriate acid to obtain the desired quaternary ammonium salt.

The lfollowing examples illustrate the best method contemplated by the inventor for carrying out his invention, but are not to be construed as limiting the scope thereof.

Example J.3,4-diphenyl-7-(Z-diethylaminoethoxy) coumarin and the hydrochloride thereof (A) 7-acet0xy-3,-4-diphenyleozmzarin.--A mixture of 5.89 g. of sodium phenylacetate, 7.90 g. of 2,4-dihydroxybenzophenonle, and 60 ml. of acetic anhydride was heated under reflux for 30 hr. The cooled solution was poured into water and the mixture was stirred for 1 hour. The resulting mixture was extracted with methylene chloride and the extract was washed with water, dried over anhydrous sodium sulfate, and evaporatedto dryness. The oily solid residue was recrystallized twice from a mixture of benzene and ethanol. There was thus obtained 3.19 g. of 7-acetoxy-3,4-diphenylcoumarin in the form of a crystalline solid having a melting point of 222 to 225 C.

(B) 3,4 diphenyl 7 hydrxycoumarin.A total of 7.55 g. of 7-acetoxy-3,4 diphenylcoumarin was added slowly with stirring to 75 ml. of ice-cold concentrated sulfuric acid. As soon as the solution became homogenous it was poured carefully into ice-water. The solid which sepanted was isolated by filtration and recrystallized twice from ethanol. There was thus obtain 5.95 g. of 3,4-diphenyl- 7-hydroxycoumarin in the form of a crystalline solid having a melting point of 287 to 289 C.

(C) 3,4 diphenyl-7-(2-diethylamin0eth0xy)coumarin and the hydrochloride thereof.-A solution of 2.69 g. of sodium methoxide in methanol (4.64 meg./ g.) was added to a stirred suspension of 3.91 g. of 3,4-diphenyl-7-hydroxy-coumarin in 100 ml. of ethanol. When all the suspended solids had dissolved 3.36 of a 1:1 solution of 2-diethylaminoethyl chloride in ethanol was added and the resulting mixture was heated under reflux for 20 hours. The mixture so obtained was evaporated to dryness under reduced pressure and the residue was treated with a mixture of water, ether, and methylene chloride. The organic layer was separated, washed with dilute aqueous potassium hydroxide solution and then with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was evaporated to dryness. The residue was recrystallized twice from ligroin. There was thus obtained 3.46 g. of 3,4-diphenyl-7-(Z-diethylaminoet-hoxy)courmarin in the form of a crystalline solid having a melting point of 95 to 97 C.

Analysis.-Calcd. for C27H27NO3I C, 78.42; H, 6.58; N, 3.39. Found: C, 78.03; H, 6.64; N, 3.82.

A solution of 1 g. of 3,4-diphenyl-7-(2-diethylaminoethoxy)coumarin (obtained as described above) in 25 ml. of absolute ethanol is saturated with gaseous hydrogen chloride. The resulting solution is evaporated to dryness under reduced pressure. There is thus obtained the hydrochloride of 3,4 diphenyl-7-(2 diethylaminoethoxy) coumarin in the form of a crystalline solid.

Example 2. 3-(p-meth0xyphenyl)-4-[p(diethylamin0- ethyl)-phenyl]coumarin and the hydrochloride thereof (A) 3 (p-methoxypehnyl)-4-(p-acet0xyphenyl)coumarin.A mixture of 9.95 g. of 2,4'-diacetoxybenzophenone and the alcohol-free sodium salt prepared from 5.56 g. of p-methoxyphenylacetic acid and 7.20 g. of 25 rnethanolic sodium methoxide, was heated under reflux with 50 ml. of acetic anhydride for 40 hrs. The resulting mixture was cooled and poured into water. The aqueous mixture was stirred for 2 hours before decanting the supernatant liquid and extracting the residual gum with methylene chloride. The methylene chloride extract was washed successively with water and saturated aqueous sodium bicarbonate solution, and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was evaporated to dryness. The residue was recrystallized once from methanol and twice from aqueous acetic acid. There was thus obtained 1.85 g. of 3-(pmethoxyphenyl) 4 (p-acetoxyphenyl)coumarin in the form of a crystalline solid having a melting point of 197 to 199 C.

Analysis.Calcd. for C H O C, 74.60; H, 4.70'. Found: C, 74.37; H, 4.87.

(B) 3 (p methoxyphenyl)-4-(p-hydroxyphenyl)coumarin.-A mixture of 15.87 g. of 3-(p-methoxyphenyl)-4- (p-acetoxyphenyl)coumarin, 2.0 g. of potassium hydroxide, and 200 ml. of water was shaken mechanically for 16 hours. At the end of this time the mixture was filtered and the filtrate was acidified by the addition of hydrochloric acid. The solid which separated was isolated by filtration, washed with water, and recrystallized from aqueous acetic acid. There was thus obtained 11.6 g. of 3-(p-methoxyphenyl)-4-(p-hydroxyphenyl)coumarin in the form of a crystalline solid having a melting point of 232 to 235 C. An analytical sample having a melting point of 235 to 237 C. was obtained by further recrystallization from the same solvent.

Analysis.Calcd. for C H O C, 76.73; H, 4.68. Found: C, 76.99; H, 4.67.

(C) 3 (p methoxyphenyl) 4 [p-(Z-dz'ethylaminoethoxy)phenyl]-c0umarin and the hydrochloride thereof.To a suspension of 6.88 g. of 3-(p-methoxyphenyl)- 4-(p-hydroxyphenyl)coumarin in ml. of ethanol there was added 4.32 g. of 25% w./w. sodium methoxide in methanol. The resulting mixture was stirred for 1 hr. before being treated with a solution of 6.0 g. of Z-diethylaminoethyl chloride in 200 ml. of ethanol. The mixture so obtained was heated under reflux for 20 hrs. before being cooled and evaporated to dryness under reduced pressure. The residue was treated with a mixture of water, ether, and methylene chloride. The organic layer was separated, washed with dilute aqueous potassium hydroxide solution and then with saturated sodium chloride solution, and dried over hydrous sodium sulfate. The dried solution was filtered and the filtrate was evaporated to dryness. The residue was recrystallized twice from methanol. There was thus otbained 6.52 g. of 3-(p-methoxyphenyl)- 4 [p (Z-diethylaminoethoxy)phenyl]coumarin in the form of a crystalline solid having a melting point of 131.5 to 133 C.

Analysis.-Calcd. for C H NO C, 75.82; H, 6.59. Found: C, 75.55; H, 6.46.

The above free base is converted to its hydrochloride using the procedure described in Example 1, part C.

Example 3.3-phenyl-4-[p-(Z-diethylaminothoxy) phenyl] coumarin and the hydrochloride thereo;

(A) 3-phenyl-4-(p-acetoxyphenyl)coumarin.-A mixture of 31.8 g. of sodium phenylacetate, 44.3 g. of 2,4'-dihydroxybenzophenone, and 350 ml. of acetic anhydride was heated under reflux for 40 hrs. The reaction product was cooled and poured into water. The aqueous suspension was stirred for 2 hrs. and the aqueous layer was then removed by decantation. The residual gum was triturated with ether and the ether-insoluble material was isolated by filtration and recrystallized from aqueous acetic acid. There was thus obtained 7.08 g. of 3-phenyl-4- (p-acetoxyphenyl)coumarin in the form of a crystalline solid having a melting point of 231 to 243 C.

Analysis.-Calcd. for C H O C, 77.51; H, 4.53. Found: C, 77.40; H, 4.75.

(B) 3-phenyl-4-(p-hydroxyphenyl)coumarin. Using the procedure described in Example 2, part B, but replacing 3 (p-methoxyphenyl)-4-(p-acetoxyphenyl)coumarin by 11.94 g. 3-phenyl-4-(p-acetoxyphenyl)coumarin, there was obtained 9.63 g. of 3-phenyl-4-(p-hydroxyphenyl) coumarin in the form of a crystalline solid having a melting point of 291.5 to 295 C.

(C) 3 phenyl- 4 [p-(Z-diethylaminoethOxy)phenyl] coumarin and the hydrochloride thereof-Using the procedure described in Example 2, part C, but replacing 3-(p-methoxyphenyl)-4-(p hydroxyphenyhcoumarin by 3-phenyl-4-(p-hydroxyphenyl) coumarin, there was obtained 3-phenyl-4- [p-(2-diethylan1inoethoxy)phenyl] coumarin in the form of a crystalline solid having a melting point of 82.5 to 86 C.

Analysis.Calcd. for CQ7H27NO3Z C, 78.42; H, 6.58; N, 3.39. Found: C, 78.45; H, 6.50; N, 3.37.

The free base so obtained is converted to its hydrochloride using the procedure described in Example 1, part C Example 4.-3-(p-methoxyphenyl)-4-phenyl-7-diethylaminoethoxy)-coumarin and the hydrochloride thereof (A) 7 acetoxy 3 (p-methoxyphenyl)-4-phenylcoumarirt-A mixture of 8.30 g. of sodium p-rnethoxyphenylacetate, 8.90 g. of 2,4-dihydroxybenzophenone, and 85 ml. of acetic anhydride was heated under reflux for 40 hr. The reaction product was cooled and poured into water. The aqueous mixture was stirred for 2 hr. before removing the aqueous layer by decantation. The residual gum was extracted with methylene chloride and the methylene chloride extract was dried over anhydrous sodium sulfate. The dried extract was filtered and the filtrate was evaporated to dryness. The residue was recrystallized from ethanol. There was thus obtained 3.37 g. of 7-acetoxy-3- (p-methoxyphenyl)-4-phenylcoumarin in the form of a crystalline solid having a melting point of 175.5 to 177.5 C.

Analysis.-Calcd. for C H O C, 74.60; H, 4.70. Found: C, 74.05; H, 4.53.

(B) 3-(p-methoxyphenyl)-4 phenyl-7-hydr0xycoamarin.-A mixture of 13.2 g. of 7-acetoxy-3-(p-methoxyphenyl)-4-phenylcoumarin and 2.0 g. of potassium hydroxide in 220 ml. of 90% ethanol was shaken mechanically for 18 hours. The heterogenous mixture was acidified by the addition of hydrochloric acid and then filtered. The solid so isolated was recrystallized from aqueous acid. There was thus obtained 9.96 g. of 3-(p-methoxyphenyl)-4-phenyl-7-hydroxycoumarin in the form of a crystalline solid having a melting point of 254 to 256 C.

Analysis.-Calcd. for C H O C, 76.73; H, 4.68. Found: C, 76.73; H, 4.69.

(C) 3 (p-methoxyp henyl)- 4 phenyl-7-(2-diethylaminoethoxy)coumarin and the hydrochloride thereof. Using the procedure described in Example 1, part C, but replacing 3,4-diphenyl-7-hydroxycoumarin by 3-(pmethoxyphenyl)-4-phenyl-7-hydroxycoumarin, there was obtained 3- (p -methoxyphenyl) -4-phenyl-7- Z-diethylaminoethoxy)coumarin in the form of a crystalline solid having a melting point of 95 to 97 C.

Analysis.-Calcd. for C H NO C, 75.82; H, 6.59; N, 3.16. Found: C, 76.20; H, 6.66; N, 3.06.

The free base so obtained is converted to its hydrochloride using the procedure described in Example 1, part C.

Example 5.3,4-diphenyl-7-(S-diethylaminopropoxy) coumarin and the hydrochloride thereof Using the procedure described in Example 1, part C, but replacing Z-diethylaminoethyl chloride by 3-dimethylaminopropyl chloride, there is obtained 3,4-diphenyl-7-(3- diethylaminopr-opoxy)coumarin and the hydrochloride thereof.

Example 6.3,4-diphenyl-7-(Z-diethylaminopropoxy) cottmarin and the hydrochloride thereof Using the procedure described in Example 1, part C, but replacing Z-diethylarninoethyl chloride by Z-diethylaminopropyl chloride, there is obtained 3,4-diphenyl-7- (Z-diethylaminopropoxy)coumarin and the hydrochloride thereof.

l@ Example 7.-3,4-diphenyl-7-(2-dibutylaminoethoxy) CULlITlLlIiIL and the hydrochloride thereof Using the procedure described in Example 1, part C, but replaciny 2-diethylaminoethyl chloride by 2-dibutylaminoethyl chloride, there is obtained 3,4-diphenyl-7- (Z-dibutylaminoethoxy)coumarin and the hydrochloride thereof.

Example 8 .3,4-di pheny I17 2-N -eth yl-N -ethylam inoethoxy)coumarin and the hydrochloride thereof Using the procedure described in Example 1, part C, but replacing Z-diethylaminoethyl chloride by Z-N-methyl- N-ethylaminoethyl chloride, there is obtained 3,4-diphenyl- 7-(Z-N-methyl-N-ethylaminoethoxy)coumarin and the hydrochloride thereof.

Example 9.-3,4-diphenyl-7-(3-diethylaminobutoxy) coumarin and the hydrochloride thereof Using the procedure of Example 1, part C, but replacing 2-diethylaminoethyl chloride by 3-diethylaminobutyl chloride, there is obtained 3,4-diphenyl-7-(3-diethylaminobutoxy)coumarin and the hydrochloride thereof Example 10.3,4-diphenyl-7-(Z-pyrrolidinoethoxy) coumarin and the hydrochloride thereof Using the procedure described in Example 1, part C, but replacing 2-diethylaminoethyl chloride by Z-pyrrolidinoethyl chloride, there is obtained 3,4-diphenyl-7-(2-pyrrolidinoethoxy)cournarin and the hydrochloride thereof.

Example 11.3,4-diphenyl-7-[2-(2,2-dimethylpyrrolidino)ethoxy]coumarin and the hydrochloride thereof Using the procedure described in Example 1, part C, but replacing Z-diethylaminoethyl chloride by 2-(2,2-dimethylpyrrolidino)ethyl chloride, there is obtained 3,4- diphenyl- 7 [2-(2,2-dimethylpyrrolidino)ethoxy1coumarin and the hydrochloride thereof.

Example 12.3,4-diphenyl-7(2-piperidinoethoxy) coumarin and the hydrochloride thereof Using the procedure described in Example 1, part C, but replacing Z-diethylaminoethyl chloride by Z-piperidinoethyl chloride, there is obtained 3,4-diphenyl-7-(2-piperidinoe-thoxy)coumarin and the hydrochloride thereof.

Example 13.--3,4-diphenyl-7-(2-mo1pholinoethoxy) coumarin and the hydrochloride thereof Using the procedure described in Example 1, part C, but replacing Z-diethylaminoethyl chloride by 2-morpholinoethyl chloride, there is obtained 3,4-diphenyl-7-(2-morpholinoet hoxy)coumarin land the hydrochloride thereof.

Example 14.3,4-diphenyl-7- [2-(1 methyl 4 piperazino)ethoxy]coumarin and the hydrochloride thereof Example 15.-3,4-diphenyl-7-(Z-hexamethyleniminoethoxy)coamarin and the hydrochloride thereof Using the procedure described in Example 1, part C, but replacing Z-diethylaminoethyl chloride by 2-hexamethyleniminoethyl chloride, there is obtained 3,4-diphenyl-7- (Z-hexamethyleniminoethoxy)coumarin and the hydro chloride thereof.

Example 16.3,4-diphenyl-7-(2-homopiperazinoethoxy) coumarin and the hydrochloride thereof Using the procedure described in Example 1, part C, but replacing Z-diethylaminoethyl chloride by 2-homopiperazinoethyl chloride, there is obtained 3,4-diphenyl- 7-(2-homopiperazinoethoxy)coumarin and the hydrochloride thereof.

Example 17.3,4-diphenyl-7-(homomorpholinoethoxy) coumarin and the hydrochloride thereof Using the procedure described in Example 1, part C, but replacing Z-diethylaminoethyl chloride by 2-homomorpholinoethyl chloride, there is obtained 3,4-diphenyl-7-(homom-orpholinoethoxy)coumarin and the hydrochloride thereof.

Example 18.3-(m-trifluoromethylphenyl) -4- [p-(2-diethylaminoethoxy)phenyl] coumarin and the hydrochloride thereof Using the procedure described in Example 2, parts A, B, and C, but replacing p-methoxyphenylacetic acid used in part A by m-trifiuoromethylphenylacetic acid (Corse et al., I. Am. Chem. Soc. 70, 2837, 1948), there are obtained 3- (m-trifluoromethylphenyl) -4- [p- Z-diethyl aminoethoxy)phenyl]coumarin and the hydrochloride thereof.

Example J9.--3-(p-methylmercaptophenyl) 4-[p-(2-diethylaminoethoxy)phenyl]coumarin and the hydrochloride thereof Using the procedure described in Example 2, parts A,

B, and C, but replacing p-methoxyphenylacetic acid used in part A by p-methylmercaptophenylacetic acid (Corse et 'al., supra), there are obtained 3-(p-methylmercaptophenyl) 4-[p-(Z-diethylaminoethoxy) phenyl1coumarin and the hydrochloride thereof.

Example 20.-3-(3-allyl 4-methoxyphenyl)-4-[p-(2-diethylaminoethoxy) phenyl] coumarin and the hydrochloride thereof Using the procedure described in Example 2, parts A, B, and C, but replacing p-methoxyphenylacetic acid used in part A by 3-allyl-4-methoxyphenylaceltic acid (Van der Zanden et al., Rec. trav. chim. 71, 879, 1952), there are obtained 3-(3-a1lyl 4-methoxyphenyl)-4-[p'(2-diethylaminoethoxy)phenyl]coumarin and the hydrochloride thereof.

Example 21.3-(2,4-dichl0rophenyl) 4-[p-(2-diethylaminoethoxy)phenyl]coamarin and the hydrochloride thereof Using the procedure described in Example 2, parts A,

B, and C, but replacing p-methoxyphenylacetic acid used in part A by 2,4-dichlorophenylacetic acid, there are obtained 3-(2,4-dichlorophenyl) 4-[p-(2-diethylaminoethoxy)phenyl]coumarin and the hydrochloride thereof.

Example 22.-3-(p-allyloxyphenyl) 4 [p-(2-diethylamirzoethoxy)phenyl]coumarin and the hydrochloride thereof Using the procedure described in Example 2, parts A,

B, and C, but replacing p-methoxyphenylacetic acid used in part A by p-allyloxyphenylacetic acid (Corse et a1.,

supra), there are obtained 3-(p-allyloxyphenyl)-4[p-(2- diethylaminoethoxy)phenyl] coumarin and the hydrochloride thereof.

Example 23.3(p-butylphenyl) 4-[p-(2-diethylaminoethoxy)phenyl]coumarin and the hydrochloride theref Using the procedure described in Example 2, parts A,

B, and C, but replacing p-methoxyphenylacetic acid used in part A by p-butylphenylacetic acid (Anderson et al., J.

Am. Pharm. Assoc., Sci. Ed. 41, 643, 1952), there are obtained 3-(p butylphenyl) 4-[p-(Z-diethylaminoethoxy) phenyl1coumarin and the hydrochloride thereof.

Example 24.3-(3,4-methylenedi0xyphenyl)-4-[p-(2-diethylaminoethoxy)phenyl]coumarin and the hydrochloride thereof Using the procedure described in Example 2, parts A,

B, and C, but replacing p-meth-oxyphenylacetic acid used in part A by 3,4-methylenedioxyphenylacetic acid (Shepard et al., J. Org. Chem. 17, 568, 1952), there are obtained 3-(3,4-methylenedioxyphenyl) 4-[p-(Z-diethylaminoethoxy)phenyl]coumarin and the hydrochloride thereof.

Example 25.3-(p-methoxyphenyl) 4-phenyl-5-diethylaminoethoxy-8-bromoc0umarin and the hydrochloride thereof Using the procedure described in Example 2, parts A, B, and C, but replacing 2,4-diacetoxybenzophenone used in part A by 3-bromo-2,6-dihydroxybenzophenone (Setalvad et al., J. Ind. Chem. Soc. 31, 600, 1954), there are obtained 3-(p-methoxyphenyl)-4-phenyl-S-diethylaminoethoxy-8-brornocoumarin and the hydrochloride thereof.

Example 26.3- (p-methoxyphenyl) 4- (p-chlorophenyl) 7-diethylaminoethoxycoumarin and the hydrochloride thereof Using the procedure described in Example 2, parts A, B, and C, but replacing 2,4-diacetoxybenzophenone used in part A by 4'-ch1oro-2,4-dihydroxybenzophenone (Van Allan et al., J. Org. Chem. 19, 1243, 1954), there are obtained 3- (p-methoxyphenyl -4- (p-chlorophenyl -7-diethylaminoethoxycoumarin and the hydrochloride thereof.

Example 27.3-(p-methoxyphenyl)-4-phenyl-6-hexyl-7- diethylaminoethoxycoumarin and the hydrochloride thereof Using the procedure described in Example 2, parts A, B, and C, but replacing 2,4-diacetoxybenzophenone used in part A by 5-hexyl 2,4-dihydroxybenzophenone (Van Allan et al., supra), there are obtained 3-(p-rnethoxyphenyl)-4-phenyl 6 hexyl 7 diethylaminoethoxycoumarin and the hydrochloride thereof.

Example 28.3-(p-methoxyphenyl)-4-(3,4-m'ethylenedioxyphenyl) -7-diethylaminoethoxycoumarin and the hydrochloride thereof Using the procedure described in Example 2, parts A, B, and C, but replacing 2,4'-diacetoxybenzophenone used in part A by 2,4-dihydroxy-3,4'-methylenedioxybenzophenone (Houben et al., I. Prakt. Chem. 123, 38, 1929), there are obtained 3-(p-methoxypheny1)-4-(3,4-methylenedioxyphenyl)-7-diethylaminoethoxycoumarin and the hydrochloride thereof.

Example 29.3-(p 2 diethylaminoethoxyphenyl)-4- phenyl-6-chI0ro-8-allylcoumarin and the hydrochloride thereof Using the procedure described in Example 2, parts A, B, and C, but replacing 2,4'-diacetoxybenzophenone and p-methoxyphenylacetic acid used in part A by 2-hydroxy- 3-allyl-5-chlorobenzophenone (US. Patent 2,904,529) and p-acetoxyphenylacetic acid, respectively, there are obtained 3-(p-2-diethyla1ninoethoxyphenyl) 4-phenyl 6- chloro-8-allylcoumarin and the hydrochloride thereof.

Example 31.3,4-di (p-2-diethylaminoethoxyphenyl) coumarin and the dihydrochloride thereof Using the procedure described in Example 1, part C, but replacing 3,4-diphenyl-7-hydroxycoumarin by 3,4-di- (p-hydroxyphenyl)coumarin (Bii u-Hoi et al., supra) and employing double the quantity of 2-diethylaminoethyl chloride, there are obtained 3,4-di-(p-Z-diethylaminoethoxyphenyl) coumarin and the dihydrochloride thereof.

Example 32.3,4-diphenyl-7-(2-diethylaminoethoxy) coumarin methiodide A solution of 1 g. of 3,4-diphenyl-7-(2-diethylaminoethoxy)c-oumarin (Example 1, part C) in 12 ml. of aceto nitrile is cooled in ice. To the cooled solution is added 1.5 ml. of methyl iodide and the mixture is allowed to stand overnight before being poured into 100 ml. of ether. The solid which separates is isolated by filtration and recrystallized from a mixture of acetonitrile and ether. There is thus obtained 3,4-diphenyl-7-(Z-diethylaminoethoxy)coumarin methiodide in the form of a crystalline solid.

Similarly, using the above procedure, but replacing methyl iodide by ethyl bromide, propyl bromide, allyl bromide, and benzyl bromide, there are obtained the ethobromide, propyl bromide, allyl bromide, and benzyl bromide, respectively, of 3,4 diphenyl 7-(2-diethylaminoethoxy)coumarin.

Similarly, using the procedure described in Example 32, but replacing 3,4-diphenyl-7-(Z-diethylaminoethoxy)coumarin by any of the free bases prepared as described in Examples 2 through 31, there are obtained the corresponding methiodides and like quaternary ammonium salts.

Example 33.-3,4-diphenyl-7-(Z-dZethyIaminoethoxy) coumarin methochlo ride A solution of 1 g. of 3,4-diphenyl-7-(Z-diethylaminoethoxy)coumarin methiodide (Example 32) in dimethylformamide is .shaken with a slight excess of silver oxide until the precipitation of silver iodide is complete. The resulting mixture is filtered and the filtrate containing the corresponding quaternary ammonium hydroxide is neutralized by the addition of aqueous hydrochloric acid. The resulting mixture is evaporated to dryness to obtain 3,4 diphenyl-7-(2 diethylaminoethoxy)coumarin methochloride.

Similarly, using the above procedure, but replacing hydrochloric acid by other acids such as sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, methanesulfonic acid, and the like, there are obtained the corresponding quaternary ammonium salts.

In like manner, using the above procedure, the anion of any of the quaternary ammonium salts of the invention can be exchanged by any other desired anion by forming the corresponding quaternary ammonium hydroxide and reacting the latter with the appropriate acid.

Example 34.-3,4-diphenyl-7-(Z-diethylaminoethoxy) coumarin hydrobro mide To a solution of l g. of 3,4-diphenyl-7-(Z-diethylaminoethoxy)coumarin (Example 1, part C) in 100* ml. of other is added dropwise with stirring a slight excess of a 0.1 N ethereal solution of hydrogen bromide. The solid which separates is isolated by filtration, washed with ether, and dried. There is thus obtained 3,4-diphenyl-7-(2-diethylaminoet hoxy) coumarin hydrobromide.

In like manner, employing any of the free bases of Examples 1 to 31 and the appropriate acid, there are obtained the corresponding acid addition salts. Illustratively, using procedures analogous to that described above, the free bases of Examples 1 to 31 are converted to their acid addition salts with sulfuric, nitric, phosphoric, lactic, benzoic, :methanesulfonic, p-toluenesulfonic, salicylic, acetic, propionic, malic, tartaric, citric, cyclohexylsulfamic, succinic, nicotinic, and ascorbic acids.

I claim:

1. A compound selected from the class consisting of (a) a compound having the formula:

14 wherein R R and R are each selected from. the class consisting of lower-alkyl, lower-alkenyl, trifluoromethyl, loWer-alkoxy, loWer-alkenyloxy, loweralkylenedioxy, hydroxy, halogen, lower-alkylmercapwherein A is an alkylene group containing from 2 to 6 canbon atoms, inclusive, R and R are selected from the class consisting of loWer-alkyl and loweralkyl linked together to form, with the attached nitrogen atom, a 5 to 7 ring atom saturated heterocyclic radical, and x, y, and z are each integers from 0 to 4, inclusive, provided that at least one of the groups R R and R represents (b) an acid addition salt of the compound of the above formula with a pharmacologically acceptable acid; and

(c) a quaternary ammonium salt of the compound of the above formula wherein the anion of the quaternary salt is that of a pharmacologically acceptable acid.

2. 3,4diphenyl-7- (Z-diethylaminoethoxy) coumarin.

3. A compound selected from the class consisting of 3,4-diphenyl-7-(2 diethylarninoethoxy)coumarin and a pharmacologically acceptable acid addition salt thereof.

4. 3 (p-methoxyphenyl)-4-[p-Z-diethylarninoethoxy) phenyllcoumarin.

5. A compound selected from the class consisting of 3 (p-methoxyphenyl) -4- [p-Ldiethylaminoethoxy phenyl] coumarin and a pharmacologically acceptable acid addition salt thereof.

6. 3 phenyl-4-[p-(2-diethylamin0ethoxy)phenyl]coumarin.

7. A compound selected from the class consisting of 3 phenyl-4-[p-(2-diethylaminoethoxy)phenyl]coumarin and a pharmacologically acceptable acid addition salt thereof.

8. 3 -(p-methoxyphenyl)-4-phenyl-7-(Z-diethylaminoethoxy) coumarin.

9. A compound selected from the class consisting of 3- (p-methoxyphenyl -4-phenyl-7- (2-diethylaminoethoxy) coumarin and a pharmacologically acceptable acid addition salt thereof.

References Cited by the Examiner UNITED STATES PATENTS 1,934,361 11/1963 Levinson 260---343.2

FOREIGN PATENTS 3/1961 Germany.

OTHER REFERENCES WALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

J. A. PATTEN, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 275,658 September 27 1966 Daniel Lednicer It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 7, line 34, for "meg./g." read meq./g. line 37, for "3036 of" read 3036 g. of column 8, line 40, for "over hydrous" read over anhydrous line 65, for "243 C." read 234 C, column 9, lines 41 and 42, for "aqueous acid" read aqueous acetic acid column 14, lines 36 and 39, for "-4[p2-", each occurrence, read 4-[p-(2- Signed and sealed this 29th day of August 1967.

( L) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents

Claims (1)

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF (A) A COMPOUND HAVING THE FORMULA: