US3399206A - Substituted tetrahydropyridine derivatives - Google Patents

Substituted tetrahydropyridine derivatives Download PDF

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Publication number
US3399206A
US3399206A US671563A US67156367A US3399206A US 3399206 A US3399206 A US 3399206A US 671563 A US671563 A US 671563A US 67156367 A US67156367 A US 67156367A US 3399206 A US3399206 A US 3399206A
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United States
Prior art keywords
acid
compounds
formula
methyl
general formula
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Expired - Lifetime
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US671563A
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English (en)
Inventor
Kuhnis Hans Herbert
Ryf Hugo
Denss Rolf
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Novartis Corp
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Geigy Chemical Corp
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    • 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
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • 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

Definitions

  • the present invention relates to compounds which may be characterized by the following Formula I Rz-CH-OH Hz? 2O wherein:
  • R represents alkyl with at most 4 carbon atoms or allyl
  • R represents alkyl with at most 4 carbon atoms or phenyl and their salts with inorganic and organic acids, all of which have valuable pharmacological properties.
  • the instantly claimed compounds are particularly excellent antitussive agents; moreover, they have mild analgetic activity. There is no addiction liability either on administration as antitussives or as analgetics.
  • Compounds of Formula I wherein R is methyl and R is alkyl of from 1 to 3 carbon atoms are preferred as they are particularly good nonaddicting antitussives.
  • the presently claimed compounds have no parasympatholytic properties, rather they have a parasympathomimetic action. At the same time, they have a relatively low toxicity and are suitable, therefore, for the relief and removal of tussive irritation and also of pain of various origin.
  • the compounds of Formula I and their salts with inorganic and organic acids may be administered orally, rectally and parenterally.
  • the daily dosages of the free bases or of nontoxic salts thereof vary between 1 and 500 mg. for adult patients.
  • Suitable dosage units such as drages (sugar coated tablets), tablets, suppositories or ampoules, preferably contain 1-200 mg. of an active substance according to the invention or of a non-toxic salt thereof.
  • non-toxic salts of the bases usable according to the invention are meant salts with those acids the anions of which are pharmacologically acceptable in the usual dosages, i.e. those which have no toxic effects. It is also of advantage if the salts to be used crystallize Well and 3,399,206 Patented Aug. 27, 1968 are not or are only slightly hygroscopic.
  • non-toxic salts instead of the free bases, for example, the salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, B-hydroxyethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicyclic acid, phenyl acetic acid, mandelic acid and embonic acid can be used as active substances.
  • the present invention relates to novel compositions containing a compound of the above-mentioned formula for producing analgesic and antitussive effects in warm-blooded animals, especially mammals, when administered in therapeutic doses.
  • R stands for alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl or allyl; R stands for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, tert. butyl or phenyl.
  • the production of compounds of general Formula I and their salts with inorganic and organic acids is characterized by partially reducing in that a compound of the general Formula II Rr-CO ill wherein R and R have the same meanings as defined above, and, if desired, converting the resulting compound Formula I to a salt with an inorganic or organic acid.
  • the partial reduction is most simply performed by using reducing agents which do not attack, or at least do not seriously attack double bonds, e.g.
  • the reduction temperature should be held between about 0 and the boiling temperature of the reaction medium used, but not be higher than, about
  • the partial reduction can also be performed with catalytically activated hydrogen in organic or aqueous/organic medium.
  • a suitable catalyst is, e.g.
  • the above-mentioned compounds of general Formula II can be produced from compounds of the general Formula III Rz-CO wherein Z represents a hydrogen atom or a low alkanoyl radical and R and R have the meanings given in Formula I, by splitting off Z-OH.
  • Agents which split off water and are of the inorganic acid halide type such as chloride, or'organic acid anhydrides and halides such as acetanhydride, phthalic acid anhydride, acetyl chloride and acetyl bromide or other substances which, in themselves, have an acylating action'such as phenyl isocyanate can be used for this cleavage.
  • inorganic bases such as sodium hydroxide and organic bases such as piperidine, piperazine and, in anhydrous medium or in the presence of solvents, also alkali metal alcoholates, and on the other, basic ion exchangers, preferably those having quaternary ammonium groups such as Amberlite IRA 400 (0H or also more weakly basic ones such as Amberlite IR 4B, which can be used in batches or, optionally, in a continuous process.
  • water, an aqueous or an anhydrous low alkanol or another polar solvent can be used as reaction medium.
  • acid condensing agents are ammonium salts such as ammonium acetate, alone or combined with glacial acetic acid and, optionally an inert solvent, e.g. benzene, as well as acid ion exchangers, e.g. Amberlite IR 120 (H form) in water or an aqueous low alkanol as reaction medium.
  • ammonium salts such as ammonium acetate, alone or combined with glacial acetic acid and, optionally an inert solvent, e.g. benzene, as well as acid ion exchangers, e.g. Amberlite IR 120 (H form) in water or an aqueous low alkanol as reaction medium.
  • condensation is preferably performed at room temperature to moderately raised temperature.
  • water is generally split oii after the hydroxy compound has been formed, whereby the corresponding compound containing a cyclic double bond, i.e., a starting material falling under Formula II, is formed directly as main product.
  • This is a sometimes advantageous modification of the above described process of producing compounds of Formula 11 via compounds of Formula IH.
  • carrying out the process in two separate stages, namely, first by the actual aldol condensation and, secondly, the splitting off of water is not always a less economical method of obtaining compounds of Formula II starting from compounds of the Formulae 1V and V, as it may lead to higher yields of pure starting material of the Formula II.
  • An acyl radical Z e.g. an acetyl or propionyl radical, can easily be introduced by reacting compounds of the general Formula III containing a hydrogen atom as Z with the corresponding anhydride at room temperature or slightly raised temperature.
  • the compounds of general Formula I are produced by that a pyridinium compound of the general Formula VI Rr-CO 1 wherein X represents the hydroxyl ion, a monovalent anion or the normal equivalent of an anion, and R and R have the meanings given in Formula I, is partially reduced, i.e. until three times the molar amount of hydrogen has been taken up, and if desired, the compound obtained of general Formula I is converted into a salt with an inorganic or organic acid. Partial reduction is performed, for instance, with alkali metal borohydride, e.g. sodium or potassium borohydride, which can be used in the theoretical amount or in excess, in an aqueous or aqueous-organic medium e.g. aqueous-methanolic medium, at room temperature or moderately raised temperature.
  • alkali metal borohydride e.g. sodium or potassium borohydride
  • the starting materials of the general Formula VI are obtained, e.g. from ketones of the general Formula VII wherein R has the meaning given in Formula I, in a known manner, e.g. by quaternization with a reactive ester of a hydroxy compound of the general Formula VIII R OH (VIII) wherein R has the meaning given in Formula I.
  • This quaternization e.g. with the corresponding halides or p-toluene sulphonic acid esters, can be performed in suitable organic solvents such as methanol, ethanol, ethyl acetate, dioxan, acetone or tetrahydrofuran.
  • ketones of generalFormula VII 1-(4'-pyridyl)- 2-prop'anone is known and other such ketones can be produced in an analogous way.
  • salts are the salts with. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, p-hydroxyethane sulphonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid.
  • Example 1 17 g. of 1-(1-methyl-1,2,3,64tetrahydro-4'-pyridyl)- 2-butanone are dissolved in 170 ml. of methanol and, at 10 while stirring, a solution of 3.9 g. of sodium borohydride in 40 ml. of water and 4 'ml. of sodium hydroxide solution is slowly added. The mixture is then stirred at room temperature for another 2 hours and then evaporated in vacuo. Concentrated sodium hydroxide solution is added to the residue until the reaction is alkaline and it is then extracted with chloroform. The chloroform solution is dried, filtered, evaporated and the residue is distilled.
  • citrate M.P. 84-86 citrate M.P. 84-86.
  • Example 2 1.5 g. of lithium aluminum hydride are dissolved in 25 ml. of abs. ether and the solution is refluxed for minutes. Then, at 10' While cooling, a solution of 4.8 g. of 1-(1'-methyl-l',2,3',6-tetrahydro-4-pyridy1l) 2 propanone in 15 ml. of abs. ether is slowly added dropwise within 15 minutes. The reaction mixture is stirred for another 3 hours at room temperature, then cooled at 10, 7 ml. of 70% methanol are added, a little Water is added and the whole is filtered. The filtrate is concentrated, the residue is dissolved in methylene chloride, the solution is dried and concentrated and the residue is distilled. The a,l-dirnethyl-l,2,3,6-tetrahydro-4-pyridine ethanol boils at 7577/ 0.01 torr, the citrate melts at 107-110".
  • Example 3 2.46 g. of 4-pyridyl acetone and 14.2 g. of methyl iodide in 30 ml. of methanol are refluxed for 3 hours. The solution is then evaporated in a rotary evaporator and the crude 4-pyridyl acetone metho-iodide which remains is worked up immediately.
  • R represents alkyl of at most 4 carbon atoms or allyl
  • R represents alkyl of at most 4 carbon atoms or phenyl, and a therapeutically acceptable acid addition salt thereof 2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US671563A 1965-01-15 1967-09-29 Substituted tetrahydropyridine derivatives Expired - Lifetime US3399206A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH60665A CH448086A (de) 1965-01-15 1965-01-15 Verfahren zur Herstellung von neuen Derivaten des 1,2,3,6-Tetrahydro-pyridins

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US671563A Expired - Lifetime US3399206A (en) 1965-01-15 1967-09-29 Substituted tetrahydropyridine derivatives
US671571A Expired - Lifetime US3505343A (en) 1965-01-15 1967-09-29 1-lower alkyl-4-(2'-hydroxylower alkyl)-4-piperidinols and lower alkyl acid esters thereof

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BE (2) BE675148A (en))
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ES (3) ES321807A1 (en))
FR (2) FR1463648A (en))
GB (2) GB1117041A (en))
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4467095A (en) * 1969-02-10 1984-08-21 Fmc Corporation Anticholinergic compounds
US4585865A (en) * 1969-02-10 1986-04-29 Fmc Corporation Azabicyclic methanols

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5350758A (en) * 1992-07-08 1994-09-27 Merrell Dow Pharmaceuticals Inc. Piperidyl sulfonamides and sulfoxamides as inhibitors of cholesterol biosynthesis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1414820A (fr) * 1963-07-19 1965-10-22 Geigy Ag J R Nouveaux dérivés de la 1, 2, 3, 6-tétrahydro-pyridine et leur préparation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL124853C (en)) * 1963-07-19

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1414820A (fr) * 1963-07-19 1965-10-22 Geigy Ag J R Nouveaux dérivés de la 1, 2, 3, 6-tétrahydro-pyridine et leur préparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4467095A (en) * 1969-02-10 1984-08-21 Fmc Corporation Anticholinergic compounds
US4585865A (en) * 1969-02-10 1986-04-29 Fmc Corporation Azabicyclic methanols

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IL24973A (en) 1969-09-25
US3505343A (en) 1970-04-07
BE675147A (en)) 1966-07-14
ES321807A1 (es) 1966-06-16
GB1117041A (en) 1968-06-12
ES321808A1 (es) 1966-06-16
AT257607B (de) 1967-10-10
AT257608B (de) 1967-10-10
FR1463649A (fr) 1966-12-23
FR1463648A (fr) 1966-12-23
NL6600524A (en)) 1966-07-18
NL6600525A (en)) 1966-07-18
BE675148A (en)) 1966-07-14
GB1102357A (en) 1968-02-07
ES321806A1 (es) 1967-01-16
CH448086A (de) 1967-12-15
IL24974A (en) 1969-04-30
DK116129B (da) 1969-12-15

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