US3410859A - 2-aryl-1, 3-di(4-pyridyl)-2-propanols - Google Patents

2-aryl-1, 3-di(4-pyridyl)-2-propanols Download PDF

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US3410859A
US3410859A US649477A US64947767A US3410859A US 3410859 A US3410859 A US 3410859A US 649477 A US649477 A US 649477A US 64947767 A US64947767 A US 64947767A US 3410859 A US3410859 A US 3410859A
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pyridyl
hours
propanol
phenyl
reaction mixture
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Brust Bernard
Hills Troy
Fryer Lan
Sternbach Leo Henryk
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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Priority to US465774A priority patent/US3420836A/en
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Priority to CH809766A priority patent/CH464918A/de
Priority to FR65142A priority patent/FR5586M/fr
Priority to BR180358/66A priority patent/BR6680358D0/pt
Priority to BE682682D priority patent/BE682682A/xx
Priority to FR66035A priority patent/FR1503565A/fr
Priority to NL6608581A priority patent/NL6608581A/xx
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Priority to US649453A priority patent/US3398156A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • C07D211/10—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/02—Lithium compounds

Definitions

  • Novel pharmacologically active 2 aryl-1,3-di(4-pyridyl)-2propanols are prepared inter alia by the reaction of a picolyl metal compound and a benzoyl halide or a benzoic acid ester.
  • This invention relates, in general, to novel compounds and to processes for producing same. More particularly, the invention relates to pharmacologically active pyridyl compounds and to processes for their manufacture.
  • the invention includes salts of the Formula 1 compounds with medicinally acceptable acids such as hydrochloric acid, sulfuric acid, nitric acid, p-toluene sulfonic acid, etc.
  • the compounds of Formula I as well as the acid addition salts thereof relieve or diminish tremors which are brought about in animals by Tremorine, i.e., 1,4 di-pyrrolidino Z-butyne, with a minimum of peripheral anti-cholinergic side elfects. Additionally, they reduce hypothermia produced by Tremorine.
  • Tremorine i.e., 1,4 di-pyrrolidino Z-butyne
  • the compounds are indicated for use in the study of the treatment of tremors which are characteristic of Parkinsons disease.
  • the compounds of this invention when administered orally to animals such as mice relieve Tremorine-induced tremors in single dose amounts ranging between about 7 and about mg./kg.
  • the compound 2-phenyl-1,3-di(4-pyridyl)-2-propan0l which has an LD of 2.8 grams/kg. orally in. mice exhibits activity in the anti-Tremorine test when administered at a single oral dose of 7.1 m-g./kg.
  • the anti-Tremorine test employed in determining anti Pankinson activity was carried out as follows:
  • mice of both sexes weighing 17 to 22 grams were employed per dose level.
  • the test compounds were administered orally and one-half hour later 20 ting/kg.
  • Tremorine was administered intraperitoneally.
  • the Tremorine-treated mice were observed for 30 minutes. Animals not exhibiting tremors within this time were considered protected.
  • the ED is calculated by the method of Miller and Tainter (Proc. Soc. Exptl. Biol. Med, volume 57, page 261, 1944).
  • the compounds of this invention have also demonstrated high potency and long duration of action in reducing hypothermia induced by Tremorine in mice.
  • the efiectiveness of the compounds of this invention against Tremorine-induced hypothermia in mice was determined by administering Tremorine intraperitoneally to mice at a level of 5 mg/ kg. Rectal temperatures were taken before treatment and after treatment. Test compounds were ad ministered orally and the Tremorine was adminstered 15, 45, 105, 165, 225 and 285 minutes later. The temperatures were then taken 15 minutes following administration of the Tremorine. Six mice were used for Tremorine control effects during the tests and 16 mice were used for each.- compound at each test interval.
  • Activity was determined by calculation of the percent protection by drawing activity lines on graph paper using the method of least squares. The results for illustrative compounds of this invention are given below. For comparison the activity of the known anti-Parkinson agent a-cyclohexyl-a-phenyl-lpiperidine propanol when tested by the same method is also given.
  • the compounds of this invention alter the activity of the liver microsimal drug metabolizing enzymes. For example, they inhibit the following enzymatic oxidative reactions: hexabarbital to ketohexobarbital, acetanilid to p-hydroxyacetanilid, amphetamine to phenylacetone, dilantin to its p-hydroxy derivatives, etc.
  • the compounds of this invention stimulate the activity of the liver microsomal drug metabolizing enzymes. Because of their activity, these compounds provide a valuable tool for the study of the drug metabolizing enzyme systems associated with the liver microsomes and are useful in the study and treatment of diseases caused by metabolic failures of such enzyme systems, for example, in the treatment of phenylketonuria.
  • reaction mixture was prepared using 2 ml. of the enzyme fraction obtained as described in the preceding paragraph, a substrate of 0.5 ml. of sodium hexobarbital, 1.0 ml. of a solution containing 2 moles of triphosphopyridine nucleotide and 20 ,umoles of glucose- 6-phosphate disodium salt, 40 moles of nicotinamide hydrochloride and 20 moles magnesium chloride, 0.5 ml. of a compound of Formula I and the mixture was adjusted to a final volume of 5.0 ml. with 0.1 molar sodium dihydrogen phosphate buffer, pH 7.4.
  • the ingredients, except the substrate, i.e., sodium hexobarbital, and the inhibitor, i.e., a compound of Formula I, were preincubated for a period of about fifteen minutes at a temperature of about 37 C. under a mixture of 95 percent oxygen5 percent carbon dioxide, After the addition of the substrate and inhibitor, the mixture was incubated for a period of about fifteen minutes under the same conditions.
  • the reaction was terminated by placing 3 ml. of the incubation tube containing ml. of hexane (washed with 0.5 volume of 0.1 molar sodium dihydrogen phosphate buffer, pH 5.5), 1.5 grams of sodium chloride and 1.0 ml. of 0.1 molar sodium dihydrogen phosphate buffer (washed with 2 volumes of heptane), pH 5.5.
  • the zero time tube was prepared as follows: One ml. of a solution containing 2 moles of triphosphopyridine nucleotide, 20 moles of glucose-6-phosphate disodium salt and 20 moles of magnesium chloride were incubated for a period of fifteen minutes with 2 ml. of enzyme and 1.5 ml. of 0.1 molar sodium dihydrogen phosphate buffer, pH 7.4. An aliquot of 2.7 ml. of the incubation mixture and 0.3 ml. of substrate was added to a centrifuge tube containing the heptane extraction mixture described heretofore. The blank tube was prepared in the same way as the zero time tube except that 2.0 ml. of buffer was used. The blank tube was preincubated for a period of about fifteen minutes and incubated for a period of about fifteen minutes.
  • the hexobarbital was extracted by vigorously shaking the reaction mixture containing the heptane, sodium chloride and buffer for a period of about forty-five minutes in an International Bottle shaker, following which it was centrifuged at 1,000 times gravity for a period of about twenty minutes at a temperature of about 20 C.
  • the supernatant (heptane) was removed with a 10 ml. pipette, with a suction bulb attached, and it was placed in another 50 ml. ground glass stoppered centrifuge tube containing 5.0 ml. of 0.1 molar sodium dihydrogen phosphate buffer (washed with 2 volumes of heptane) of pH 5.5.
  • the tubes were shaken by hand for a period of about fifteen seconds and then allowed to stand until the phases separated. Fifteen ml. of the resulting supernatant was placed in a 50 ml. ground glass stoppered centrifuge tube and 4 ml. of 0.8 molar sodium monohydrogen phosphate, pH 11 (adjusted with 5.0 molar sodium hydroxide), was added and the tubes were shaken for a period of about three minutes on the International Bottle shaker. After centrifuging the tubes for a period of about three minutes at 1,000 times gravity, the buffer phase was removed with a 5 ml. pipette and transferred to a silica cuvette. The absorbency of the solution at 245 nm was read in a Beckman D.U. spectrophotometer against a blank containing the pH buffer. A standard solution of sodium hexobarbital (20 g./ml.) was used. The absorbance of this solution was about 0.590.
  • mice A group of five mice were injected with 2-phenyl-1,3- di(4-pyridyl)-2-propanol (100 mg./kg., i.p.) for ten successive days.
  • Five control mice were given saline each day.
  • Twenty-four hours after the last injection the mice were given DL-phenylalanine-3-C (4,4LC/IDOUS6, i.p.).
  • Four hours later were sacrificed and their livers were extirpated.
  • An alcoholic liver extract was prepared and an aliquot of this material was placed on paper and chromatographed in a system which clearly separates phenylalanine from tyrosine.
  • mice treated with 2-phenyl-1,3-di(4- pyridyl)-2-propanol synthesized 2.2 and 2.8 times more tyrosine than the control.
  • rats were injected with 2-phenyl-1,3-di(4-pyridyl)-2-propanol (100 mg./kg./day, i.p.) for four days.
  • the treated and control rats were sacrificed and their livers were extirpated.
  • a supernatant fraction was obtained by centrifuging the liver homogenate at 9000 g.
  • the enzyme fraction from the control and treated rats was incubated in a medium containing a TPNH generating system, oxygen and radioactive phenylalaine. After 1 hour of incubation the radioactive phenylalanine and tyrosine were isolated by paper chromatography and counted. The synthesis of tyrosine from phenylalanine was stimulated percent and 58 percent, respectively, in two separate experiments. This effect has been confirmed clinically as shown by clinical results in the examples appended hereto.
  • the symbol M represents an alkali metal such as sodium, potassium or lithium and is reacted with a compound having the formula C O-Hal in which the symbol X represents a hydrogen atom, a halogen atom, a lower alkyl group, i.e., an alkyl group having from 1 to 6 carbon atoms, a lower alkoxy group or a lower alkyl mercapto group; and in which Hal represents a halogen atom.
  • benzoyl chloride a halogen-substituted benzoyl chloride, such as 3-fiuorobenzoyl chloride, 4-fluorobenzoyl chloride, 4-chlorobenzoyl chloride, etc., or a lower alkyl-substituted benzoyl chloride, such as p-toluoyl chloride, etc., an alkoxy, for example, methoxy, substituted benzoyl chloride or a lower alkyl-, for example, methyl, mercapto-substituted benzoyl chloride.
  • Halides, other than chlorides can be used, if desired.
  • an alkyl ester of benzoic acid such as, methyl benzoate, ethyl benzoate, etc.
  • an alkyl ester of an alkyl substituted benzoic acid such as, .a methyl ester of toluic acid, an ethyl ester of toluic acid
  • an alkyl ester of a halogen substituted benzoic acid such as, methyl chlorobenzoate, ethyl cholobenzoate, methyl fiuorobenzoate, ethyl fluorobenzoate, etc.
  • benzyl benzoate a benzyl ester of an alkyl-substituted benzoic acid, such as, a benzyl ester of toluic acid
  • a benzyl ester of a halogenated benzoic acid such as, benzyl chlorobenzoate, benzyl fluorobenzoate
  • methoxy substituted benzoic acid an alkyl ester of an alkyl-, e.g. methyl, mercapto substituted benzoic acid; a benzyl ester of a methoxy substituted benzoic acid; or a benzyl ester of a methyl mercapto benzoic acid.
  • a compound ofFormula II is reacted with phenyl benzoate, or with a lower alkyl-substituted phenyl benzoate, a halogen-substituted phenyl benzoate, an alkoxy substituted, e.g., methoxy substituted, phenyl benzoate or an alkyl, e.g., methyl, mercapto phenyl benzoate.
  • phenyl methyl-benzoate phenyl ethyl-benzoate, phenyl propyl-benzoate, phenyl chloro-benzoate, phenyl bromo-benzoate,
  • a 4-picolyl magnesium bromide is reacted with phenyl benzoate or with a phenyl ester of an alkylsubstituted-, halogen-substituted-, alkoxy-substituted or alkyl mercapto-substituted benzoic acid of the type named in the preceding paragraph.
  • an organic solvent solution of the 4-picolyl metal compound, of 4-pic0lyl magnesium bromide is first prepared.
  • any organic solvent in which the 4-picolyl compound is soluble, and which is inert under the reaction conditions employed, can be used in preparing this solution.
  • Solvents which are suitable for use in the practice of this invention include, for example, benzene, diethyl ether, toluene, 4-picoline, tetrahydrofuran and the like. Mixtures of these solvents can be used, if desired.
  • the organic solvent solution of the 4-picoly1 metal compound which is described in the preceding paragraph, is thereafter, cooled by some appropriate means to a temperature below room temperature. In the preferred embodiment of the invention, this solution is cooled to a temperature of about 0 C. or lower. Preferably, the solution of the 4-picolyl metal compound is cooled to a temperature within the range of from about 10 C. to 60 C. thereafter, the Formula IIE reactant, or the unsubstituted or substituted phenyl benzoate reactant, dissolved in a suitable solvent, is added to the cooled solution of the 4-picolyl compound.
  • solvents include, for example, ethyl ether, n-butyl ether, dioxane, tetrahydrofuran, etc., either alone or in admixture with some other organic solvent which is inert under the reaction conditions employed.
  • the reaction mixture should be maintained at a relatively low temperature.
  • the reaction mixture should be maintained at a temperature below about 0 C., preferably at a temperature within the range of from about l0 C. to 60 C.
  • the reaction mixture is stirred, while continuously cooled, until the reaction has been completed.
  • the reaction can be brought to completion by stirring the reaction mixture first for a period of about one hour at a low temperature, for example, at a temperature within the range of from about -10 C. to 60 C. and, thereafter, for an additional period of about one hour at room temperature.
  • reaction mixture is Worked up, by appropriate and suitable means, to isolate the pyridyl compound thus produced.
  • the crude product in turn, can be purified by conventional means. Methods of working up the reaction mixture to isolate the reaction product therefrom, as well as methods for purifying those products, will be readily apparent to persons skilled in the art. Examples for specific procedures and techniques which are useful in accomplishing this will be found in the examples which follow hereinafter.
  • the compounds of this invention are useful, inter alia, in the study and treatment of diseases caused by metabolic failures of enzyme systems.
  • the manner in which they are used for such purpose will be readily apparent to persons skilled in the art.
  • the compounds can be formulated, with conventional inert adjuvants, into dosage forms suitable for oral or parenteral administration.
  • dosage forms include tablets and capsules as well as solutions and suspensions. Specific examples showing the embodiment of the present compounds in particular dosage forms will be found in the examples which follow hereinafter.
  • the frequency of administration is variable, depending upon the needs and requirements of the patient.
  • Example 1 An ether-benzene solution of 1.89 liters containing 3.5 moles of phenyl lithium was added, over a 3 /2 hour period, to a stirring solution of 326 grams of 4-picoline (3.5 moles) in 800 ml. of tetrahydrofuran. This addition was carried out in an atmosphere of dry nitrogen. When the addition of the phenyl lithium solution to the 4-picoline solution was completed, the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was then cooled to a temperature of about 20 C. There was thus produced picolyl lithium.
  • the reaction mixture was then diluted with 1 liter of water, stirred vigorously and transferred to a separatory funnel.
  • the reaction mixture was acidified using 800 ml. of 6 N hydrochloric acid.
  • the acid layer was separated from the organic phase and the latter was extracted two times, using 200 ml. of 3 N hydrochloric acid each time.
  • the acid extracts were combined, washed first three times using 500 ml. of toluene each time, and, subsequently, one time using 500 ml. of ether.
  • kg. of ice was added to the acid extracts which were then made alkaline using ammonium hydroxide.
  • the acid extracts were maintained at a temperature of about 10 C.
  • Example 2 To a stirring solution of 0.5 mole of 4-picolyl lithium cooled to a temperature within the range of from 30 C. to '50 C., there was added 0.2 mole of p-toluoyl chloride dissolved in about 100 ml. of tetrahydrofuran. Addition of the p-toluoyl chloride to the 4-picolyl lithium was accomplished under an atmosphere of dry nitrogen in a dropwise fashion over a period of about sixty minutes.
  • reaction mixture was allowed to stir overnight, following which it was diluted by the addition of ml. of water.
  • the reaction mixture was extracted three times using 150 ml. of 6 N hydrochloric acid each time.
  • the acid extracts were collected, combined and washed three times using 150 ml. of ether each time.
  • the desired product was liberated by stirring the reaction mixture with a mixture of 500 grams of ice and 300 ml. of ammonium hydroxide. During this step of the process, ice was added, as needed, to maintain the temperature at about 0 C.
  • the precipitate which formed in this step was recovered by filtration in the form of a brown semi-solid.
  • the precipitate was partitioned between 300 ml. methylene chloride and 300 ml. of water.
  • the undissolved product was recovered by filtration yielding 1,3-di(4-pyridyl)-2-(ptoly)-2-propanol.
  • 1,3 di(4 pyridyl) 2-(p-tolyl)-2-propanol as colorless plates, melting point at 100 C. to C., resolidifying and melting again at 160 C. to 161 C.
  • Example 3 2-(3-fluorophenyl)-1,3-di(4-pyridyl)- 2-propanol was prepared by the process described in the preceeding example using 3-fluorobenzoyl chloride in place of p-toluoyl chloride.
  • Example 4 2-(4-fluorophenyl)-l,3-di(4pyridyl)- 2-propanol was prepared by the process described in Example 2 using 4-fluorobenzoyl chloride in place of ptoluoyl chloride.
  • the precipitate which was obtained by treating the acid extracts with concentrated ammonium hydroxide, was recovered by filtration and stirred vigorously with 40 ml. of methylene chloride and 400 ml. of water. Filtration of this mixture yielded 2-(4-fluorophenyl)-1,3- di(4-pyridyl)-2-propanol in the form of colorless crystals. Recrystallization of this product, from an acetone-water mixture, yielded the compound in the form of colorless plates, melting first at 122 to 125 C., resolidifying and melting again at 155.5 to 157 C.
  • Example 5 In this example, a solution of 35.0 grams (0.2 mole) of p-chlorobenzoyl chloride in 25 ml. of anhydrous tetrahydrofuran was added, slowly, over a period of about twenty minutes to a stirring 0.5 molar solution of 4-picolyl lithium. During this addition, the reaction mixture was maintained at a temperature of about 20 C. When this addition was completed, the reaction mixture was stirred at a temperature of about 20 C. for a period of about thirty minutes, following which it was stirred at room temperature for an additional sixty-minute period. Thereafter, 800 ml. of water was added to the reaction mixture, following which the mixture was made acid using 3 N hydrochloric acid.
  • the acid layers were combined, washed three times using 300 ml. of ether each time, made alkaline with 10 N sodium hydroxide solution and diluted to a volume of 4.0 liters using ice water. On standing, a precipitate formed. After standing for a period of about 18 hours, the precipitate was recovered by filtration, washed with 500 ml. of water and subsequently partitioned between 200 ml. of water and 50 ml. of methylene dichloride. The suspension, thus formed, was stirred for about 30 minutes and then filtered.
  • the precipitate was recrystallized from aqueous acetone to yield 2-(4-chlorophenyl) 1,3 di(4-pyridyl)-2-propanol as pale yellow prisms, melting first at 87 to 102 C., resolidifying and melting again at 181 to 183 C.
  • Example 6 In this example, 24 grams (0.11 mole) of m.-bromobenzoyl chloride in 125 ml. of anhydrous terahydrofuran was added, in dropwise fashion over a period of about 75 minutes, to a stirring 0.5 molar solution of 4-picoly1 lithium. The reaction mixture was maintained at a temperature of about 40 C. during such addition and for a period of sixty minutes after the addition had been completed. Thereafter, the reaction mixture was stirred at room temperature for a period of about 60 minutes. Subsequently, 800 ml. of water was added to the reaction mixture following which the mixture was made acid using 3 N hydrochloric acid. The layers, thus formed, were separated and the organic phase was extracted twice using 200 ml.
  • Example 7 there was added to a stirring solution of 0.5 mole of 4-picolyl lithium, under dry nitrogen, and cooled to a temperature of -30 to 50 C., 34.12 grams (0.2 mole) of p-methoxy benzoyl chloride dissolved in 50 ml. of tetrahydrofuran. Addition of the methoxy benzoyl chloride solution was accomplished, in a dropwise fashion, over a period of about one hour. Thereafter, the reaction mixture was stirred at room temperature for a period of about 17 hours, following which the reaction mixture was diluted with 50 ml. of water. The reaction mixture was extracted three times using 150 ml. portions of 6 N hydrochloric acid each time.
  • Example 8 In this example, a solution of 116.4 grams (1.25 mole) of 4-picoline in 290 ml. of tetrahydrofuran was first prepared. To this solution, there was added, over a period of about 3 /2 hours at a temperature of about 30 C., 2.28 moles of phenyl lithium in a benzene-ether solution. The mixture was stirred for a period of about 15 minutes, following which it was cooled to a temperature of -20 C. To this cooled mixture, there was added 116 grams of 3,4,5-trimeth0xy benzoyl chloride dissolved in 260 ml. oftetrahydrofuran.
  • the precipitate which formed during the neutralization step was removed by filtration and partitioned between 600 ml. of methylene chloride and 600 ml. of water.
  • the insoluble product was obtained by filtration and it was washed first with 200 ml. of cold water and subsequently two additional times using 200 ml. portions of methylene chloride each time.
  • the product, thus obtained namely, 1,3 di(4 pyridyl) 2 (3,4,5-trimethoxyphenyl)-2- propanol, melted at a temperature of 151 to 154 C. On recrystallization from ethanol, the compound melted at a temperature of 168 to 170 C.
  • Example 9 In this example, 0.2 mole of p-methyl mercapto benzoyl chloride, dissolved in 150 ml. of tetrahydrofuran, was added dropwise, over a period of about sixty minutes at a temperature within the range of from about -30 to 50 C. under dry nitrogen, to a solution containing 0.5 mole of 4-picolyl lithium. The reaction mixture was allowed to stir overnight, following which the reaction mixture was diluted with ml. of water. The reaction mixture was thereafter extracted three times using ml. of 6 N hydrochloric acid each time. The acid extracts were combined and washed three times using 150 ml. of ether each time. Subsequently, the reaction mixture was treated with 500 grams of ice and 300 ml.
  • Example 10 In this example, a solution of 39.6 grams (0.2 mole) of phenyl benzoate in 100 ml. of anhydrous tetrahydrofuran was slowly added to 0.5 molar solution of 4-picolyl lithium. During this addition, temperature of the reaction mixture rose to a temperature of about 40 C. The reaction mixture was stirred for a period of about one hour, following which it was treated with 800 ml. of water. The aqueous phase was made acidic by the addition of 350 ml. of 3 N hydrochloric acid. Subsequently,
  • the mixture was shaken and the layers comprising the two-phase system were separated.
  • the organic phase was extracted two times using 200 ml. of 3 N hydrochloric acid each time.
  • the acid layers were then combined, washed three times using 5 00 ml. of ether each time, made alkaline with N sodium hydroxide solution and diluted to a volume of about 4 liters with ice water.
  • the mixture was allowed to stand at room temperature for a period of about 18 hours, during which time a precipitate formed.
  • the precipitate was recovered by filtration and washed with 500 ml. of water.
  • the product was purified by partitioning between 200 ml. of water and 50 ml. of methylene chloride. Filtration and subsequent recrystallization of the product from aqueous acetone yielded 2-phenyl- 1,3-di(4-pyridyl)2-propanol melting at 164 to 166 C.
  • Example 11 In this example, included herein to demonstrate an alternate procedure for making 2-phenyl-1,3-di(4-pyridyl)- 2-propanol, 4-picolyl magnesium bromide starting material was prepared by the dropwise addition of 64.9 grams (0.7 mole) of 4-picoline to a refluxing solution of ethyl magnesium bromide in 350 ml. of tetrahydrofuran. The ethyl magnesium bromide which was used, was prepared from 17 grams (0.7 mole) of magnesium and 76.3 grams (0.7 mole) of ethyl bromide.
  • the 4-picolyl magnesium bromide solution produced as described in the preceding paragraph, was cooled to a temperature of about 6 C. Thereafter, a solution of 63.7 grams (0.3 mole) of benzyl benzoate in 60 mlv of tetrahydrofuran was added, with the temperature of the reaction mixture, during such addition, being maintained within the range of about -4 C. to -6 C. When the addition of the benzyl benzoate solution was completed, the reaction mixture was allowed to reach room temperature, following which it was stirred at such temperature for a period of about 18 hours. The Grignard complex was decomposed by the addition of 375 ml. of 2 N hydrochloric acid and the tetrahydrofuran was removed un der reduced pressure.
  • the solution was thereafter made strongly acidic using hydrochloric acid. Thereafter, the acid solution was extracted four times, using 200 ml. of ether each time. The aqueous phase was then made alkaline using sodium hydroxide solution. The alkaline aqueous phase was filtered and the filtrate was extracted four times using 200 ml. of methylene chloride each time. The organic layers were then combined, washed two times using 50 ml. of water each time and finally dried over anhydrous sodium sulfate.
  • Example 12 In this example, 20 grams of 2-phenyl-1,3-di(4-pyridyl)-2-propanol, produced as described in Example 1, was dissolved in 3000 cc. of ethyl acetate and saturated with dry hydrogen chloride. The resulting precipitate was filtered and the filter cake dried, in vacuo, at 60 C. over concentrated sulfuric acid. The crude cake was then digested for thirty minutes with 1000 cc. of refluxing ethyl acetate.
  • Example 13 In this example, 0.2 mole of m-toluic acid chloride dissolved in 150 ml. of tetrahydrofuran was added in a dropwise fashion over a period of about sixty minutes to a stirred solution of 0.5 mole of 4-picolyl lithium. This addition was carried out under an atmosphere of dry nitrogen. with the 4-picolyl lithium solution being maintained at a temperature of from about C. to C. on a bath of dry ice-acetone. After about three hours, the reaction mixture was treated with 100 m]. of water, following which it was extracted three times using 150 ml. portions of 6 N hydrochloric acid each time. The acid extract was then washed three times, using 150 ml. portions of ether each time. Thereafter, the product was liberated by stirring into a mixture of 500 grams of ice and 300 ml. of concentrated ammonium hydroxide. Ice was added to the mixture to maintain the temperature thereof at about 0 C.
  • Example 14 In this example, 0.2 mole of m-toluic acid chloride dissolved in 150 ml. of tetrahydrofuran was added, in a dropwise fashion over a period of about sixty minutes, to a stirred solution of 0.5 mole of 4-picolyl lithium. This addition was carried out under an atmosphere of dry nitrogen, with the 4-picolyl lithium solution being cooled to a temperature of 30 C. to 50 C. in a bath of dry ice-acetone. After about three hours, the reaction mixture was treated with ml. of water, following which it was extracted three times, using ml. portions of 6 N hydrochloric acid each time. Thereafter, the acid extracts were combined and washed three times using 150 ml. portions of ether each time. The product was then liberated by stirring the reaction mixture into a mixture of 500 grams of ice and 300 ml. of. concentrated ammonium hydroxide. lce was added, as needed, to maintain the temperature at about 0 C.
  • Example 15 In this example, 0.2 mole of p-isopropylbenzoic acid chloride dissolved in 150 ml. of tetrahydrofuran was added in a dropwise fashion over a period of about sixty minutes to a stirred solution of 0.5 mole of 4-picolyl lithium. This addition was carried out under an atmosphere of dry nitrogen with the 4-picolyl lithium solution being cooled to a temperature of from about 30 C. to 50 C. On a bath of dry ice-acetone. After about three hours, the reaction mixture was treated with 100 ml. of water, following which it was extracted three times, using 150 ml. portions of 6 N hydrochloric acid each time. The acid extract was then washed three times, using 150 ml. portions of ether each time. Thereafter, the product was liberated by stirring into a mixture of 500 grams of ice and 300 ml. of concentrated ammonium hydroxide. Ice was added to the mixture, as needed, to maintain the temperature thereof at about 0 C.
  • Example 16 In this example, 0.2 mole of 2-fluorobenzoyl chloride dissolved in 150 ml. of tetrahydrofuran was added, in a dropwise fashion over a period of about sixty minutes, to a stirring solution of 0.5 mole of 4-picolyl lithium. This addition was carried out under an atmosphere of 3 dry nitrogen, with the 4-picolyl lithium solution being cooled to a temperature within the range of from about -30 C. to 50 C. in a bath of dry ice-acetone. The reaction mixture was allowed to stir overnight, following which it was hydrolyzed by the addition of 100 m1. of water. Thereafter, the reaction mixture was extracted three times, using 150 ml. portions of 6 N hydrochloric acid each time.
  • the acid extracts were combined and washed three times, using 150 ml. portions of ether each time.
  • the product was liberated by stirirng the washed acid extracts into a mixture of 500 grams of ice and 300 ml. of ammonium hydroxide. The mixture was filtered to obtain a gum-like, orange solid. Vigorous stirring of this product with 400 ml. of water and 100 ml. of methylene chloride, followed by filtration yielded 2(2-fiuorophenyl)-1,3-di(4-pyridyl)-2-propanol melting at 157 C. to 160 C. This compound, after recrystallization three times from an acetone-water mixture, was obtained in the form of colorless needles melting at 159 C. to 161 C.
  • Example 17 This example is included herein to demonstrate the preparation of dosage forms of a compound representative of the compounds of this invention.
  • Example 18 The activity of an exemplary compound of this invention has also been converted clinically as follows:
  • n 1 and X is methoxy and is in para-position, i.e., the compound 2-(4-methoxyphenyl)-1,3-di(4 pyridy1)-2-propanol.
  • n 3 and X is methoxy and is in para and meta-positions, i.e., the compound 1,3-di(4-pyri'dyl)-2-(3,4,5-trimethoxyphenyl -2-propanol.

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US465753A US3420841A (en) 1964-07-07 1965-06-21 1,3-di-(4-pyridyl)propane derivatives
US465774A US3420836A (en) 1964-07-07 1965-06-21 1,3-di-(4-piperidyl)propane derivatives
NL6508725A NL6508725A (enrdf_load_html_response) 1964-07-07 1965-07-07
CH809766A CH464918A (de) 1965-06-21 1966-06-03 Verfahren zur Herstellung von 2-Isopropyl-1,3-di-(4-piperidyl)-propan
FR65142A FR5586M (enrdf_load_html_response) 1965-06-21 1966-06-11
BR180358/66A BR6680358D0 (pt) 1965-06-21 1966-06-14 Processo para a preparacao de derivados de propana
BE682682D BE682682A (enrdf_load_html_response) 1965-06-21 1966-06-17
FR66035A FR1503565A (fr) 1965-06-21 1966-06-18 Procédé pour la préparation de 2-isopropyl-1, 3-di-(4-pipéridyl)-propane et de ses sels
NL6608581A NL6608581A (enrdf_load_html_response) 1965-06-21 1966-06-21
US649453A US3398156A (en) 1965-06-21 1967-06-28 2-aliphatic-1, 3-di (4-pyridyl)-2-propanols
US649477A US3410859A (en) 1965-06-21 1967-06-28 2-aryl-1, 3-di(4-pyridyl)-2-propanols
US649470A US3371096A (en) 1965-06-21 1967-06-28 4-pyridylmethyl ketones and 4-pyridylmethyl carbinols

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