US2967182A - Novel substituted tetrahydropyridines - Google Patents

Novel substituted tetrahydropyridines Download PDF

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Publication number
US2967182A
US2967182A US678542A US67854257A US2967182A US 2967182 A US2967182 A US 2967182A US 678542 A US678542 A US 678542A US 67854257 A US67854257 A US 67854257A US 2967182 A US2967182 A US 2967182A
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United States
Prior art keywords
tetrahydropyridine
phenyl
mixture
homoveratryl
residue
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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US678542A
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English (en)
Inventor
Pohland Albert
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Eli Lilly and Co
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Eli Lilly and Co
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Priority to US678542A priority Critical patent/US2967182A/en
Priority to CH6297658A priority patent/CH371115A/de
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Publication of US2967182A publication Critical patent/US2967182A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4

Definitions

  • This invention relates to novel substituted tetrahydropyridines. More particularly it relates to oxygenated phenethyl-substituted tetrahydropyridines.
  • 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.
  • 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.
  • pharmaceutically-acceptable acid addition salts of compounds coming within the scope of the above formula are also included in this invention.
  • 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.
  • 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.
  • 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.
  • 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
  • the free base is that of the free base.
  • 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.
  • a phenethyl halide which is appropriately substituted.
  • 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.
  • 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.
  • 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.
  • 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.
  • R, R; and R are chosen trom the group consisting of hydrogen, hydroxy, and lower alkoxy and alkyl- 15 2,748,140

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
US678542A 1957-08-16 1957-08-16 Novel substituted tetrahydropyridines Expired - Lifetime US2967182A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US678542A US2967182A (en) 1957-08-16 1957-08-16 Novel substituted tetrahydropyridines
CH6297658A CH371115A (de) 1957-08-16 1958-08-15 Verfahren zur Herstellung von substituierten Tetrahydropyridinen

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US678542A US2967182A (en) 1957-08-16 1957-08-16 Novel substituted tetrahydropyridines

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3072648A (en) * 1963-01-08 X-phenyl-s
US3073837A (en) * 1960-02-25 1963-01-15 Smith Kline French Lab Process for the preparation of 1, 2, 5, 6-tetrahydro-1-phenethyl-2-(p-methoxybenzyl)-3, 4-dimethylpyridine and intermediate
US3125488A (en) * 1964-03-17 Method of inducing analgesia by
US3223710A (en) * 1959-12-01 1965-12-14 Ici Ltd 2-beta-methoxyethylpyridine and its preparation
US3238217A (en) * 1961-09-07 1966-03-01 Geschickter Fund Med Res Azaspiranes
US3277098A (en) * 1960-10-07 1966-10-04 Bayer Ag Di-urethanes and processes for their production
US4228288A (en) * 1978-11-29 1980-10-14 Eli Lilly And Company Certain substituted 3,4,5,6-tetrahydropyridinium salt intermediates
US4645771A (en) * 1978-04-12 1987-02-24 Imperial Chemical Industries Plc Tetrahydropyridine derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2748140A (en) * 1954-10-07 1956-05-29 Rohm & Haas 3-hydroxymethyl-4-phenyltetrahydro-pyridines and their esters
US2784192A (en) * 1954-06-24 1957-03-05 Rohm & Haas Preparation of 4-hydroxypiperidines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2784192A (en) * 1954-06-24 1957-03-05 Rohm & Haas Preparation of 4-hydroxypiperidines
US2748140A (en) * 1954-10-07 1956-05-29 Rohm & Haas 3-hydroxymethyl-4-phenyltetrahydro-pyridines and their esters

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3072648A (en) * 1963-01-08 X-phenyl-s
US3125488A (en) * 1964-03-17 Method of inducing analgesia by
US3223710A (en) * 1959-12-01 1965-12-14 Ici Ltd 2-beta-methoxyethylpyridine and its preparation
US3073837A (en) * 1960-02-25 1963-01-15 Smith Kline French Lab Process for the preparation of 1, 2, 5, 6-tetrahydro-1-phenethyl-2-(p-methoxybenzyl)-3, 4-dimethylpyridine and intermediate
US3277098A (en) * 1960-10-07 1966-10-04 Bayer Ag Di-urethanes and processes for their production
US3238217A (en) * 1961-09-07 1966-03-01 Geschickter Fund Med Res Azaspiranes
US4645771A (en) * 1978-04-12 1987-02-24 Imperial Chemical Industries Plc Tetrahydropyridine derivatives
US4228288A (en) * 1978-11-29 1980-10-14 Eli Lilly And Company Certain substituted 3,4,5,6-tetrahydropyridinium salt intermediates

Also Published As

Publication number Publication date
CH371115A (de) 1963-08-15

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