US2967182A - Novel substituted tetrahydropyridines - Google Patents

Description

United States Patent NOVEL SUBSTITUTED rErRAnYnRorYnmmEs Albert Pohland, Indianapolis, Ind, asslgnor to Eli Lilly alggi Company,'lndianapolis, Ind a co 'lm' flon of ans No Drawing. Filed Aug. 16, 1951, Se!- No. man 6 Claims. 01. 260-295) This invention relates to novel substituted tetrahydropyridines. More particularly it relates to oxygenated phenethyl-substituted tetrahydropyridines.

The compounds provided by this invention are represented by the following formula:

wherein R, R and R are chosen from the group consisting of hydrogen, hydroxy, and lower alkoxy and lower alkylcarbacyloxy radicals in which the alkyl groups have from 1 to 3 carbon atoms, and not more than two of R, R and R are hydrogen. Thus when R, R and R, represent lower alkoxy groups they can be illustratively methoxy and ethoxy and when they represent lower alkylcarbacyloxy radicals in which the alkyl groups have from 1 to 3 carbon atoms, they canvbe, illustratively, acetoxy, propionoxy and butyroxy radicals. Also included in this invention are the pharmaceutically-acceptable acid addition salts of compounds coming within the scope of the above formula.

Illustrative compounds provided by this invention include 1 homoveratryl 4 phenyl 1,2,3,6 tetrahydropyridine hydrochloride, 1 homopiperonyl 4 --phenyl- 1,2,},6 tetrahydropyridine hydrochloride, 1 homovanillyl"- 4 phenyl l,2,3,6 tetrahydropyridine hydr'obrm mide, 1 (4 acetoxyphenethyl) 4 phenyl 1,2,31,6- tetrahydropyridine sulfate, 1 (4 acetoxy 3 methoxyphenethyl) 1,2,3,6 tetrahydropyridine maleate, 1-(3- ethoxyphenethyl) 4 phenyl l, 2, 3, 6 tetrahydrok pyridine succinate, and 1 (3,5-dihydroxyphenethyl) 4 phenyl-1,2,3,6-tetrahydropyridine hydrochloride. It will be apparent to those skilled in the art that certain substituting groups, for example, lower alkyl radicals, can be present in positions in the molecule other than those specified above, as for example, in the a-position of the tetrahydropyridine ring.

The novel compounds provided by this invention are characterized by a physiological action of marked central depressant activity of selected character; that is, the compounds have a pronounced activity on the central nervous system in their abilityto depress transmission of nerve impulses across synapses mediated by endogenous sympathetic agents. The above physiological action makes them useful in treating mammals to provide neurosedation and to reduce hypertension. Additionally the compounds show anti-pyretic, anti-inflammatory and antiemetic activity. v

For administration to humans and animals, the tetrahydropyridines of this invention can be compounded into the various pharmaceutical forms commonly employed in the art, such as tablets, capsules, solutions and elixlrs.

.The novel tetrahydropyridine compounds are generally employed in the form of a pharmaceutically acceptable acid addition salt since the salt forms are preferred by "2,967,182 Patented Jan. s, 1961 reason of increased solubility and stability, decreased volatility, greater adaptability to compounding, etc. Pharmaceutically acceptable. acids useful in forming salts with the above compounds are those acids which do not markedly increase the toxicity of the salt,over

that of the free base. Among the pharmaceutically acceptable acids which can be employed for this purpose are inorganic acids such ashydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as maleic, benzoic, succinic and citric acids. The! acid addition salts of the free bases of this invention are in general white crystalline solids melting above 100' C. The free bases from which they are derived are high boiling viscous oils or low melting crystalline solids having a typical amine odor.

The compounds of this invention can readily be prepared by alkylating 4-phenyl-1,2,3,6-tetrahydropyridine with a phenethyl halide which is appropriately substituted. For example, the reaction of 4-phenyl-1,2,3,6-tetrahydropyridine with homoveratryl chloride yields the hydrochloride salt of l-homoveratryl-4-phenyl-l,2,3,6-tetrahydropyridine. Those compounds in which R, R or R, represent hydroxy or alkylcarbacyloxy radicals can also be The hydroxy-substituted tetrahydropyridine so produced. can, if desired, be acylated by conventional methods toyield a tetrahydropyridine substituted with one or more= alkylcarbacyloxy groups.

This invention is further illustrated by the following;

specific examples.

EXAMPLE 1 Preparation of 1-homoveratryl-4-phenyI-1,2,3,6-tetrahydropyridine A reaction mixture containing 16 g. of 4-phenyl-l,2,3,6'

tetrahydropyridine, 24.6 g. of homoveratryl bromide, 200 ml. of ethanol and 25.2 g. of sodium bicarbonate was heated with stirring at refluxing temperature for about three hours. The solvents were then removed from thereaction mixture by evaporation in vacuo. About 200 ml. of water and about 20 ml. of 5 N sodium hydroxide were added to the residue which contained l-homoveratryl-4-phenyl-l,2,3,6-tetrahydropyridine formed in the above reaction. The alkaline, aqueous mixture was extracted with two 100 ml. portions of chloroform, and one 100 ml. portion of ether. 1 homoveratryl 4 -phenyll,2,3,6-tetrahydropyridine, being insoluble in the alkaline solution, was extracted into the organic solvent layers which were separated in each instance. The separated layers were combined and dried and the solvents were removed therefrom by evaporation in vacuo. The white residue, comprising 1-homoveratryl-4-phenyl-1,2,3,6-tetrahydropyridine melted at about l10-11l C. after being recrystallized from an ethyl acetate-hexane solvent mixture. l-homoveratryl-4-phenyl-l,2,3,6-tetrahydropyridine hydrochloride was prepared by passing gaseous hydrogen chloride into an acetone solution of the free base. After two recrystallizations from ethanol it melted with decomposition at about 242-243 C.

A'nalysis.Calculated for Cg1Hg5NO3'HCl: C, 70.08; i H, 7.22. Found: C, 70.03; H, 7.28.

, EXAMPLE 2 Preparation of I-(3,4-dihydroxyphnethyl) -4-phenyl- 1,2,3,6-tetrahydropyridine A mixture containing 10 g. of l-homoveratryl-4-phenyll,2,3,6-tetrahydropyridine and 200 ml. of glacial acetic acid saturated with gaseous hydrogen bromide was heated at about C. for about four hours. The solvents were i acamaa ethyl)-4-phenyl-l,2,3,6-tetrahydropyridine hydrobromide precipitated and was isolated by filtration. The filter cake was recrystallized from a mixture of methanol and ethyl acetate, 1-(3,4-dihydroxyphenethyl)-4-phenyl'-1,2,3 ,6-tetrahydropyridine hydrobromide thus prepared melted at about 257-258 C.

Analysis.Calculated: C, 60.64; H, 5.89; N, 3.72; Br, 21.24. Found: C, 60.48; H, 6.01; N, 3.54; Br, 21.70.

EXAMPLE 3 Preparation of 1-(3,4-diacetoxyphenethyl) -4-phenyl- 1 ,2,3,6-tetrahydrpyridine About 2.5 g. of 1-(3,4-dihydroxyphenethyl)-4-phenyl- 1,2,3,6-tetrahydropyridine hydrobromide were mixed with 60 ml. of acetic anhydride and the mixture was refluxed for about 1 hour. The excess acetic anhydride was removed by evaporation in vacuo. The solid residue comprised 1 (3,4-diacetoxyphenethyl)-4-phenyl-l,2,3,6-tetrahydropyridine hydrobromide. This compound melted at about 214-215" C. after recrystallization from a methanol-acetone solvent mixture.

Analysis.Calculated: C, 60.00; H, 5.69; Br, 17.38. Found: C, 60.20; H, 5.90; Br, 17.42.

EXAMPLE 4 Preparation of 1-(3,4-dipr0pi0noxyphenethyl) -4-phenyl- 1,2,3,6-tetrahydropyridine EXAMPLE 5 Preparation of 1-(3,4-dibutyroxyphenethyl) -4-phenyl- 1 ,2,3,6-tetrahydropyridine A reaction mixture was prepared containing 1 g. of 1-( 3,4-dihydroxyphenethyl) -4-phenyl-1,2,3,6 tetrahydropyridine, 3 ml. of n-butyryl chloride, ml. of pyridine and 10 ml. of benzene. The free 1-(3,4-dihydroxyphenethyl 4 phenyl-1,2,3,6-tetrahydropyridine base was prepared from the hydrobromide salt by dissolving the salt in water, making the water solution alkaline with ammonium hydroxide and extracting the thus formed free base into benzene. The benzene was evaporated from the extraction mixture in vacuo, leaving the free base as a residue. The reaction mixture prepared as above was allowed to remain at ambient room temperature for about 16 hours after which time the volatile constituents were removed by evaporation in vacuo. The residue containing 1-(3,4-dibutyroxyphenethyl)-phenyl-4-1,2,3,6-tetrahydropyridine hydrochloride was dissolved in water. The water layer was washed with about 50 ml. of ether and the ether wash was discarded. The water layer was made alkaline with 10 percent concentrated ammonium hydroxide thus forming 1-(3,4-dibutyroxyphenethyl)-4-phenyl- 1,2,3,6-tetrahydropyridine free base. The free base, being insoluble in the alkaline layer, was extracted therefrom by three successive 50 ml. portions of ether. The ether extracts were combined, were washed once with water and were dried. The drying agent was removed by filtrasodium hydroxide and 14 ml. of water.

tion and the filtrate was saturated with gaseous hydrogen chloride to form 1(3,4-dibutyroxyphenethyl)-4-phenyll,2,3,6-tetrahydropyridine hydrochloride. The ether was removed from the mixture byevaporation in vacuo and the residue was crystallized from an acetone-ethyl acetate solvent mixture. 1-(3,4-dibutyroxyphenethyl)-4-phenyl- 1,2,3,6-tetrahydropyridine hydrochloride thus prepared melted at about 192 C. after being twice recrystallized from a methanol-ethyl acetate solvent mixture.

Analysis.--Calculated: C, 67.80; H, 7.26; Cl, 7.51. Found: C, 68.97; H, 7.44; Cl, 7.35.

EXAMPLE 6 Preparation of 1-h0movanillyl-4-phenyl-1,2,3,6-tetrahydropyridine 11.0 g. of 4-benzyloxy-3-methoxyphenyl acetic acid and 20 ml. of thionyl chloride were mixed and the mixture was warmed at about 40 C. for about one hour, thus forming 4-benzyloxy-3-methoxyphenylacetyl chloride. The excess thionyl chloride was removed in vacuo. The substituted phenylacetyl chloride remaining as a residue was dissolved in about 30 ml. of benzene. To this solution was added a solution containing 3.3 g. of 4- phenyl-4-hydroxy piperidine in 30 ml. of pyridine. The mixturewas heated at about C. for about one hour and was then allowed to stand at ambient room temperature for about 16 hours. The solvents were removed by evaporation in vacuo. The residue comprising N-(4- benzyloxy-3-methoxyphenylacetyl)-4-phenyl-4 hydroxypiperidine dissolved in ether. The ether layer was washed successively with 5 percent hydrochloric acid, 5 percent sodium bicarbonate and water. The washed ether layer was dried over magnesium sulfate and the drying agent was removed by filtration. The filtrate was added to a suspension of 3.8 g. of lithium aluminum hydride in 100 ml. of ether. After the addition had been completed, the reaction mixture was heated at about 35 C. for one hour. Next, the reaction mixture was decomposed by successive addition of 4 ml. of water, 3 ml. of 20 percent The resulting mixture was filtered and the filtrate which contained l-(4- benzyloxy 3 methoxyphenethyl)-4-phenyl-4-hydroxypiperidine formed in the above reaction was evaporated to dryness. The residue comprising l-(4-benzyloxy-3- methoxyphenethyl)-4-phenyl-4-hydroxy piperidine was dissolved in about 220 ml. of 6 N hydrochloric acid, and the resulting solution was heated at refluxing temperature for six hours in order to debenzylate and dehydrate the compound, thus forming 1-homovanillyl-4-phenyl- 1,2,3,6-tetrahydropyridine as the hydrochloride salt. The reaction mixture was then evaporated to dryness. The resulting residue was crystallized from an ethyl acetatemethanol mixture yielding l-homovanillyl-4-phenyll,2,3,6-tetrahydropyridine hydrochloride melting at about 203-204 C.

1-homovanillyl4-phenyl-1,2,3,6 tetrahydropyridine prepared as above can be acetylated by the procedure of Example 3 to yield 1-(4-acetoxy-3-methoxyphenethyl)- 4-phenyl-1,2,3,6-tetrahydropyridine melting at about 231- 232 C.

EXAMPLE 7 Preparation of J (4 methoxyphenethyl) 4 phenyl- 1,2,3,6-tetrahydropyridine Following the procedure of Example 1, 4-methoxyphenethyl bromide and 4-phenyl-1,2,3,6-tetrahydropyridine were reacted together in ethanol solvent in the presence of sodium bicarbonate, thus forming 1-(4- methoxyphenethyl)-4-phenyl-1,2,3,6 tetrahydropyridine. This compound was isolated as the hydrochloride salt which after being twice recrystallized from a methanolethyl acetate solvent mixture melted at about 2l6217 C.

1 (4-hydroxyphenethyl)-4-phenyl-1,2,3,6-tetrahydropyridine and 1-(4-acetoxyphenethyl)-4-phenyl-l,2,3,6- tetrahydropyridine can be prepared from 1-(4-methoxy 5 v phenethyl)-4-pheny1+1,2,3,6-tetrahydropyridine by following the procedures of Examples 2 and 3 respectively.

I claim:

addition salts thereof, said substituted tetrahydropyridine being represented by the following formula:

wherein R, R; and R, are chosen trom the group consisting of hydrogen, hydroxy, and lower alkoxy and alkyl- 15 2,748,140

carbacyloxy radicals in which the alkyl groups have from *1 to 3 carbon atoms, and from zero to. two of R, R and dine.

3. 1-(3,4-dihydroxyphenethyl)-4-pheny1-1,2,3,6 tetrahydropyridine. 4. l-(3,4-diacetoxyphenethyl)-4-phenyl-1,2,3,6 tetrahydropyridine.

5. 1-(3,4-dipropionoxyphenethyD-4-pheny1 1,2,3,6- tetrahydropyridine.

6. l-homovanillyl-4-phenyl-l,2,3,6-tetrahydropyridine.

References Cited in the file of this patent UNITED STATES PATENTS Schmidle et a1 May 29, 1956 2,784,192 Schmidle et a1. Mar. 5, 1957

Claims (1)

1. A COMPOUND OF THE CLASS CONSISTING OF A SUBSITUTED TETRAHYDROPYRIDINE AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, SAID SUBSTITUTED TETRAHYDROPYRIDINE BEING REPRESENTED BY THE FOLLOWING FORMULA