US3795677A - Aryl 4-piperidyl ketone derivatives - Google Patents

Aryl 4-piperidyl ketone derivatives Download PDF

Info

Publication number
US3795677A
US3795677A US00197116A US3795677DA US3795677A US 3795677 A US3795677 A US 3795677A US 00197116 A US00197116 A US 00197116A US 3795677D A US3795677D A US 3795677DA US 3795677 A US3795677 A US 3795677A
Authority
US
United States
Prior art keywords
piperidyl
ketone
phenyl
piperidyl ketone
aryl
Prior art date
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
Application number
US00197116A
Other languages
English (en)
Inventor
A Carr
D Meyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richardson Vicks Inc
Original Assignee
Richardson Merrell Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Richardson Merrell Inc filed Critical Richardson Merrell Inc
Application granted granted Critical
Publication of US3795677A publication Critical patent/US3795677A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

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
    • C07D211/06—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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

Definitions

  • n is a positive whole integer of from 1 to 3;
  • R represents phenyl, a straight or branched alkyl chain of from 1 to 4 carbon atoms attached to the phenyl ring at the ortho, meta, or para positions, or a difunctional 1,4-butadienylene moiety which together with the phenyl ring forms a naphthyl ring with the proviso that when -R represents a difunctional 1,4-butadienylene moiety, n is equal to 1; or pharmaceutically acceptable acid salts thereof, are useful as analgesic and as anticoagulant agents.
  • This invention relates to novel aryl 4-piperidyl ketone derivatives which are useful as analgesic and anticoagulant agents.
  • n is a positive whole integer of from 1 to 3;
  • R represents phenyl, a straight or branched alkyl chain of from 1 to 4 carbon atoms attached to the phenyl ring at, the ortho, meta, or para positions, or a difunctional 1,4-butadienylene moiety which together with the phenyl ring forms a naphthyl ring with the proviso that when R represents a difunctional 1,4-butadienylene moiety,
  • n is United States Patent 3,795,677 Patented Mar. 5, 1974 "Lee equal to 1; or pharmaceutically acceptable acid addition salts thereof.
  • substituents which 'R may represent in Formula I there may be mentioned phenyl, a straight or branched alkyl chain of from 1 to 4 carbon atoms wherein al'kyl may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tertiary butyl attached to the phenyl ring at the ortho, meta or para position, or -R may represent a difunctional 1,4-butadienylene moiety which together with the phenyl ring forms an alpha or a beta naphthyl ring.
  • the compounds of this invention may be substituted phenyl-4- piperidyl ketone derivatives as represented by the following Formula II, alpha naphthyl 4-piperidyl ketone derivatives as represented by the following Formula III, or beta naphthyl 4-piperidyl ketone derivatives as represented by the following Formula IV.
  • R represents phenyl or a straight or branched lower alkyl chain of from 1 to 4 carbon atoms and may be attached at the ortho, meta, or para positions of the phenyl ring, and m is a positive whole integer of from 1 to 3.
  • R is phenyl or a straight or branched lower alkyl chain of from 1 to 4 carbon atoms attached to the phenyl ring at the ortho, meta, or para positions.
  • Pharmaceutically acceptable acid addition salts of the base compounds of this invention are those of any suit able inorganic or organic acids.
  • Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric, phosphoric acids, and the like.
  • Suitable organic acids are, for example, carboxylic acids, such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, and dihydroxymaleic, benzoic, phenylacetic, 4- aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic acid, and the like.
  • the compounds of this invention are useful as analgesic agents and anticoagulants and can be used in the form of pharmaceutical preparations suitable for oral or parenteral administration.
  • the quantity of compound in the unit dosage can vary over a wide range to provide from about 0.5 mg./kg. to about 50 mg./'kg. of body weight of the patient per dose to achieve the desired effect.
  • the desired effect can be obtained by the consumption of from 5 to 300 mg. of the active ingredient taken 1 to 4 times daily.
  • the compounds of this invention can be administered to warm blooded animals and particularly mammals.
  • novel compounds, together with conventional pharmaceutical carriers can be employed in unit dosage forms such as solids, for example, tablets or capsules, or liquid solutions, suspensions, or elixirs for oral administration, or liquid solutions, suspensions, emulsions, and the like for parenteral use.
  • the quantity of active ingredient in each dosage will generally differ depending on the type of unit dosage, the type of animal, and its weight. Thus, each dosage can contain from about 5 mg. to over 300 mg. of active ingredients in a significant quantity of pharmaceutical carrier.
  • the utility of the compounds of this invention is illustrated by the following.
  • the compound of Example 5 demonstrated in vitro a 100% inhibition of adenosine diphosphate induced platelet aggregation in human platelet rich plasma when 100 ,ug. of compound was added to each milliter of plasma.
  • the compound of Example 4 when tested in mice in the standard hot plate test [N. B. Eddy and D. Leimbach, J. Pharm. Exp. Therap. 107, 385 (1953)] blocked reaction to the heat stimulus. This compound produced in ED of 33.5 mg./kg. in mice when administered orally.
  • the compounds of this invention may be administered alone or may be used in combination with other analgesics such as acetylsalicylic acid or p-ethoxyacetanilide with or without a stimulant such as wfieille to achieve the desired analgesic efiects.
  • analgesics such as acetylsalicylic acid or p-ethoxyacetanilide with or without a stimulant such as wfieille to achieve the desired analgesic efiects.
  • the ratio of the amount of compound to other analgesics may vary from about 1:1 to 1:10, preferably about 1:5.
  • a stimulant such as caffeine is used in combination with a compound of this invention and other analgesics the amount of stimulant used is about one-half as much as the amount of compound.
  • the compounds of this invention may be prepared by the Friedel-Crafts acylation of an appropriate aromatic compound as illustrated by the following:
  • the above reaction may be carried out in a variety of solvents, such as, nitrobenzene, chlorinated hyrocarbons, such as, chloroform, tetrachloroethane, and the like, or an excess of the aromatic reactant, that is, Compound 1, and under catalysis of a variety of Lewis acids, such as, aluminum chloride, boron trifiuoride, hydrofluoric acid, stannic chloride, and the like.
  • Lewis acids such as, aluminum chloride, boron trifiuoride, hydrofluoric acid, stannic chloride, and the like.
  • the amount of Lewis acid employed in the reaction varies from one to eight times, and is preferably three to four times more than the amount of acid chloride, Compound 2, employed on a molar basis.
  • a preferred procedure is to combine the reactants, using an excess of the aromatic reactant as the solvent, in an ice bath and slowly adding an excess of aluminum chloride with stirring during which time the reaction temperature is maintained below 35 C. After the addition is complete the temperature of the reaction is elevated to from 25 to 0., preferably 50 to 70 C. for from 10 minutes to six hours, preferably 10 to 30 minutes.
  • the reaction mixture is decomposed with water and ice then made strongly alkaline by treating with a 50% solution of sodium hydroxide with cooling.
  • the reaction mixture is then extracted with a suitable solvent such as toluene, chloroform, chlorobenzene and the like.
  • the organic extract is dried, filltered and concentrated to give a base of Formula I, which may be converted to an acid salt by generally known procedures.
  • the compounds of this invention may also be prepared by the oxidation of the corresponding a-(substituted)aryl-4-piperidine1nethanol derivatives with the appropriate chloride of oxidizing agents such as chromic acid, sodium dichromate, manganese dioxide, lead tetraacetate, and the like, with an appropriate solvent, such as, acetic acid, sulfuric acid, pyridine, and the like.
  • the temperature of the reaction may vary from 0 to C., and it is preferred that the reaction be carried out at room temperature.
  • the reaction time may vary from 10 minutes to one day depending upon the reaction conditions. Preferably the reaction time varies from one-half to one hour.
  • the (it-(substituted)aryl-4-piperidinemethanol derivatives are obtained by catalytic reduction of the corresponding (substituted)aryl pyridine ketone or the corresponding a-(substituted)aryl 4 pyridinemethanol derivative.
  • the (substituted)aryl pyridine ketones are prepared by the reaction of an appropriately substituted aryl Grignard reagent and isonicotinonitrile followed by hydrolysis of the resulting imine complex.
  • the u-(substituted)aryl-4-pyridinemethanol derivatives are obtained by the reaction of an appropriately substituted Grignard reagent and pyridine-4-carboxaldehyde, subsequently decomposing the resulting complex with a saturated ammonium chloride solution.
  • the following specific examples illustrate the invention.
  • EXAMPLE 1 p-Tert-butylphenyl 4-piperidyl ketone hydrochloride (A) To 450 ml. of thionyl chloride was added slowly and with stirring 129 g. (1.0 mole) of isonipecotic acid. The mixture was heated to 45 C. for minutes then the excess thionyl chloride was removed under vacuum at 50 C. The resulting oil was poured into ether, and a precipitate formed which was collected, washed with ether and vacuum dried to give 168 g. of isonipecotic acid chloride hydrochloride.
  • EXAMPLE 2 2-naphthyl 4piperidyl ketone hydrochloride To a slurry of 99 g. of naphthalene (0.75 mole and 96 g. of isonipecotic acid chloride hydrochloride (0.5 mole) in tetrachloroethane was added over a period of ten minutes 200 g. (1.5 moles) of aluminum chloride. The reaction mixture was allowed to stand at room temperature for 10 minutes, then decomposed by pouring it over ice water, made basic with a 50% NaOH solution, and extracted with diethyl ether. The other layer was dried over magnesium sulfate, filtered, and treated with ethereal HCl.
  • EXAMPLE 4 p-Isopropylphenyl 4-piperidyl ketone hydrochloride To a stirred mixture of 900 ml. (3.22 moles) of cumene and 368 g. (2.0 moles) of isonipecotic acid chloride hydrochloride was added with stirring on an ice bath 800 g. (6.0 moles) of aluminum chloride. The reaction mixture was heated to 50 C. for 10 minutes, cooled decomposed by pouring into ice-water and made basic with a 50% NaOH solution. The mixture was cooled and extracted into toluene. The toluene solution was dried over magnesium sulfate, filtered, and treated with ethereal HCl. The resulting precipitate was recrystallized from methanol-butanone to give the desired product, M.P. 245.5-246" C.
  • EXAMPLE 6 4-piperidyl p-tolyl ketone hydrochloride To a chilled and stirred mixture of 96.5 g. (0.4 mole) of a-(p-tolyl)-4-piperidinemethanol hydrochloride, 600 ml. of acetic acid, 40 ml. of 25% (v./v.) sulfuric acid and 72 ml. of water was added with stirring 26.5 g. (0.27 mole) of chromium trioxide in 30 ml. of acetic acid over a period of 1 /2 hours, during which time an additional 20 ml. of water was added. The mixture was stirred for half an hour at less than 9 C.
  • EXAMPLE 7 4-piperidyl p-tolyl ketone hydrochloride To a stirred mixture of 147 g. (0.8 mole) of isonipecotic acid chloride hydrochloride and 300 m1. of dry toluene was added 320 g. (2.4 moles) of aluminum chloride while stirring in an ice bath. The reaction mixture was then warmed to 65 C. for 10 minutes, cooled and decomposed by pouring into an ice/water mixture. A solution of 800 ml. of 50% NaOH was added maintaining the temperature below 35 C. This material was extracted into toluene, dried over anhydrous magnesium sulfate, filtered through celite and treated with ethereal HCl. The resulting precipitate was washed with ether and recrystallized from methanol-butanone to give the desired product, M.P. 274-277 C. (dec.).
  • EXAMPLE 9 As an example of a tablet formulation of an active compound of this invention the following may be mentioned:
  • the granulation obtained upon mixing lactose with the active compound and part of the starch and granulated with starch paste is dried, screened and mixed with the magnesium stearate. The mixture is compressed into tablets weighing 253 mg. each.
  • EXAMPLE 10 (a) Mesityl 4-piperidyl ketone hydrochloride 50.0 (b) Acetylsalicylic acid 250.0 (c) Starch 40.0 (d) Lactose 120.0 (e) Magnesium stearate 5.0
  • the granulation obtained upon mixing lactose with mesityl 4-piperidyl ketone hydrochloride and part of the starch is granulated with starch paste, dried, screened and mixed with the acetylsalicylic acid and magnesium stearate. The mixture is compressed into tablets weighing 465.0 mg.
  • a 4-piperidyl ketone compound selected from the group consisting of p-biphenylyl 4-piperidyl ketone, a-naphthyl-4-piperidyl ketone or fi-naphthyl-4-piperidyl ketone or a pharmaceutically acceptabe acid addition salt thereof.
  • a compound of claim 1 which is 4-biphenylyl-4- piperidyl ketone or a pharmaceutically acceptable acid ad dition salt thereof.
  • a compound of claim 1 which is 5 naphthyl 4- piperidyl ketone or a pharmaceutically acceptable acid addition salt thereof.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US00197116A 1971-11-09 1971-11-09 Aryl 4-piperidyl ketone derivatives Expired - Lifetime US3795677A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US19711671A 1971-11-09 1971-11-09

Publications (1)

Publication Number Publication Date
US3795677A true US3795677A (en) 1974-03-05

Family

ID=22728114

Family Applications (1)

Application Number Title Priority Date Filing Date
US00197116A Expired - Lifetime US3795677A (en) 1971-11-09 1971-11-09 Aryl 4-piperidyl ketone derivatives

Country Status (12)

Country Link
US (1) US3795677A (enrdf_load_stackoverflow)
JP (1) JPS4854076A (enrdf_load_stackoverflow)
AU (1) AU473130B2 (enrdf_load_stackoverflow)
BE (1) BE791088A (enrdf_load_stackoverflow)
CA (1) CA978190A (enrdf_load_stackoverflow)
CH (1) CH576960A5 (enrdf_load_stackoverflow)
DE (1) DE2253377A1 (enrdf_load_stackoverflow)
FR (1) FR2159323B1 (enrdf_load_stackoverflow)
GB (1) GB1341955A (enrdf_load_stackoverflow)
IL (1) IL40634A (enrdf_load_stackoverflow)
NL (1) NL7214654A (enrdf_load_stackoverflow)
SE (1) SE380017B (enrdf_load_stackoverflow)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3980657A (en) * 1973-02-19 1976-09-14 Ciba-Geigy Corporation Oxoalkylpyridines
US4024264A (en) * 1974-08-15 1977-05-17 Ab Ferrosan Diphenylbutylpiperidines
US4076822A (en) * 1973-02-19 1978-02-28 Ciba-Geigy Corporation Certain pyridyl methanones and pharmaceutical compositions containing same
US4246268A (en) * 1979-02-09 1981-01-20 Richardson-Merrell Inc. Neuroleptic-4-(naphthylmethyl)piperidine derivatives
US4443462A (en) * 1979-08-06 1984-04-17 Merrell Dow Pharmaceuticals Inc. Antipsychotic 4-(naphthalenyloxy)piperidine derivatives
US4665076A (en) * 1984-03-09 1987-05-12 Rhone-Poulenc Sante Pharmacologically active piperidine derivatives and their use
US4711899A (en) * 1985-05-14 1987-12-08 Synthelabo 2-(4-benzoyl-1-piperidyl)-1-phenylalkanol derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3576810A (en) * 1968-06-20 1971-04-27 Robins Co Inc A H 1-substituted-3-(-4)-aroylpiperidines

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3980657A (en) * 1973-02-19 1976-09-14 Ciba-Geigy Corporation Oxoalkylpyridines
US4076822A (en) * 1973-02-19 1978-02-28 Ciba-Geigy Corporation Certain pyridyl methanones and pharmaceutical compositions containing same
US4112099A (en) * 1973-02-19 1978-09-05 Ciba-Geigy Corporation Cyclo aliphatic-phenylene-carbonyl-pyridines
US4024264A (en) * 1974-08-15 1977-05-17 Ab Ferrosan Diphenylbutylpiperidines
US4246268A (en) * 1979-02-09 1981-01-20 Richardson-Merrell Inc. Neuroleptic-4-(naphthylmethyl)piperidine derivatives
DK152669B (da) * 1979-02-09 1988-04-11 Richardson Merrell Inc Analogifremgangsmaade til fremstilling af 4-(naphthyl-methyl)-piperidin-derivater eller farmaceutisk acceptable syreadditionssalte deraf samt forbindelser til anvendelse som udgangsmaterialer ved fremgangsmaaden
US4443462A (en) * 1979-08-06 1984-04-17 Merrell Dow Pharmaceuticals Inc. Antipsychotic 4-(naphthalenyloxy)piperidine derivatives
US4665076A (en) * 1984-03-09 1987-05-12 Rhone-Poulenc Sante Pharmacologically active piperidine derivatives and their use
US4711899A (en) * 1985-05-14 1987-12-08 Synthelabo 2-(4-benzoyl-1-piperidyl)-1-phenylalkanol derivatives

Also Published As

Publication number Publication date
SE380017B (enrdf_load_stackoverflow) 1975-10-27
DE2253377A1 (de) 1973-05-17
FR2159323B1 (enrdf_load_stackoverflow) 1976-03-05
IL40634A0 (en) 1972-12-29
IL40634A (en) 1975-03-13
CA978190A (en) 1975-11-18
JPS4854076A (enrdf_load_stackoverflow) 1973-07-30
NL7214654A (enrdf_load_stackoverflow) 1973-05-11
AU473130B2 (en) 1976-06-17
CH576960A5 (enrdf_load_stackoverflow) 1976-06-30
GB1341955A (en) 1973-12-25
FR2159323A1 (enrdf_load_stackoverflow) 1973-06-22
AU4792972A (en) 1974-04-26
BE791088A (fr) 1973-03-01

Similar Documents

Publication Publication Date Title
GB2084573A (en) Improvements in or relating to 3-aryl-5-isothiazole derivatives
US3795677A (en) Aryl 4-piperidyl ketone derivatives
US3852455A (en) 4-{8 4({60 hydroxybenzyl)piperidino{9 -4-fluorobutyrophenone derivatives as tranquilizers
US4308207A (en) Morphanthridine derivatives
US3708482A (en) 4-morpholinoethoxy-benzophenones
Smith Jr et al. α-Aminophenacylpyridines and Quinolines1
JPS5982367A (ja) ６−置換キノリン−５，８−キノン類
US3981877A (en) Piperidylidene derivatives of carboxy-5H-dibenzo[a,d]cycloheptene
US3888983A (en) Derivatives of thiazolino-pyrimidin-6-ones, in inducing analgesia
US3851059A (en) Method for the stimulation of appetite in patients
US3775430A (en) Octalone carboxylic acids and their derivatives
US3810905A (en) Pyrazolo(3,4-b)pyridine-5-carboxamides
US3929812A (en) Derivatives of 1H-triazolo {8 4,5-c{9 pyridine-7-carboxylic acids and esters
US4022779A (en) Amino derivatives of pyrido(3,4-b)pyrazine carboxylic acids and esters
US3960872A (en) 1 Alkyl-4-(10:oxo or hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine compounds
US3823151A (en) 4,5,6,7-tetrahydrothieno(2,3-d)pyridines
US4077955A (en) Amino derivatives of 1,2,3,4-tetrahydro-2-oxopyrido[2,2-b]-pyrazine carboxylic acids and esters
US4032640A (en) 4H-Benzo[4,5]cyclohepta[1,2-b]thiophenes
US3917833A (en) Amino-substituted benzocycloheptenones for inducing sleep
US3780064A (en) Thiolpulvinic acid derivatives
US3673177A (en) Substituted 4-(anilinomethylene)-3-galanthamaninones
US3835144A (en) Amino derivatives of (4,3-c pyrazolopyridine cabroxylic acids and esters
US3968115A (en) 1-Alkyl-4-(10 and/or 11)-bromo-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ylidene piperidine compounds
US3988342A (en) Piperidylidene derivatives of cyano-5H-dibenzo[a,d]cycloheptene
US3458578A (en) Aminodibenzocycloalkenones