US3719712A - 2-phenylethynyl-benzyl-amines - Google Patents

2-phenylethynyl-benzyl-amines Download PDF

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Publication number
US3719712A
US3719712A US00861987A US3719712DA US3719712A US 3719712 A US3719712 A US 3719712A US 00861987 A US00861987 A US 00861987A US 3719712D A US3719712D A US 3719712DA US 3719712 A US3719712 A US 3719712A
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phenylethynyl
acid
benzylamine
compound
amines
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US00861987A
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D Remy
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings

Definitions

  • ABSTRACT This application discloses methods of preparing styrylaralkylamines and phenylethynylaralkyl-amines by the lithium aluminum hydride reduction of the corresponding cyanostilbenes and phenylethynylbenzonitriles.
  • the produced alkylamines are converted to the corresponding N-alkyl and N,N-dialkyl derivatives thereof.
  • the amines and their alkylated derivatives are useful as antiarrhythmics.
  • This invention relates to unsaturated derivatives of aralkylamine compounds. More specifically, it relates to substituted and unsubstituted derivatives of styrylaralkylamines, phenylethynylaralkylamines and the corresponding N-substituted derivatives such as the N-alkyl and N,N -dialkyl derivatives thereof.
  • This invention also relates to the novel processes and the novel intermediates utilized in the production of new aralkylamines, to pharmaceutical formulations of the new aralkylamines and to methods of treating or preventing cardiac arrhythmias using the novel compounds and/or pharmaceutical formulations thereof, described hereinafter.
  • the new compounds of my invention are arylalkenylaralkylamines, arylalkynylaralkylamines, and the correspondingheterocyclic alkenyl (or alkynyl) aralkylamines represented by the following structural formula X l R2 UK smurf in which m is an integer varying from 1 to 4 inclusive; R and R, are either similar or dissimilar and are either hydrogen, alkyl (preferably of from one to six carbon atoms), branched chain alkyl, alkenyl, alkynyl (each preferably containing one to six carbon atoms), and can be joined together or alternatively may be linked through an atom of carbon, nitrogen, oxygen, or sulfur to, one of the methylene substituents bridging the aromatic ring and the amine radical to form a heterocyclic ring of from five to six atoms such as l-piperidyl, l-pyrrolidinyl, l-morpholinyl, 4-thiomorpholin
  • a preferred group of such compounds includes derivatives in which one or more of the hydrogens of the benzene rings is replaced by substituents selected from the group consisting of hydrogen, an alkyl group having up to six carbon atoms, an alkenyl group having up to six carbon atoms, a perfluoroalkyl group having up to four carbon atoms, a phenyl or a substituted phenyl radical, amino, an alkylamino group having up to four carbon atoms, a dialkylamino group having up to four carbon atoms (halogen, particularly fluorine or chlorine), hydroxyl, an alkoxyl group having up to four carbon atoms, a perfluoroallroxyl group having up to four carbon atoms, mercapto, an alkylmercapto group having up to four carbon atoms, a perfluoroalkylmercapto group having up to four carbon atoms. More than one of these substituents may be on each ring. These substituents are identified
  • R and R are either hydrogen, alkyl (preferably of from one to six carbon atoms), alkenyl, alkynyl (each preferably of from one to six carbon atoms), and can be joined together through an atom of carbon, nitrogen, oxygen or sulfur to form a heterocyclic ring of from five to six atoms (such as lpiperidyl, l-pyrrolidinyl, 4-morpholinyl, 4- thiomorpholinyl or 1-loweralkyl-4-piperazinyl).
  • the dotted line in the formula represents either an additional carbon to carbon single bond or two hydrogens attached to the adjacent carbons.
  • Illustrative of the compounds included within the scope of the invention are 2-(phenylethynyl)- benzylamine, 2-(4-methoxyphenylethynyl)- benzylamine, 2-(4-tolylethynyl)-benzylamine, 2-(4- fluorophenyl-ethynyl)-benzylamine, trans-2-styrylbenzylamine, trans-2-(4-methoxystryl)-benzylamine, the corresponding N-alkyl and the N,N-dialkyl derivatives thereof.
  • the compounds represented above in either their free base or salt form, possess useful pharma-cological properties. In particular, they have been found to possess antiarrhythmic activity. It has been found that the administration of compounds of the present invention, depicted in the above formula, results in the prevention of arrhythmia in animals under conditions which ordinarily cause the development of arrhythmia in the animal percent of the time.
  • salts formed by the reaction of an equivalent amount of the amine compound of the above formula and an acid which is pharmacologically acceptable in the intended doses are salts formed by the reaction of an equivalent amount of the amine compound of the above formula and an acid which is pharmacologically acceptable in the intended doses.
  • Salts of the above compound which are useful are salts of the amine with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, acetic acid, propionic acid, lactic acid, gluconic acid, maleic acid, succinic acid, tartaric acid, and the like. Salts of these acids with the amine base are useful as the active component of the compositions in the method of this invention.
  • the daily doses are based on the total body weight of the test animal and vary between about 1.00 and 100.00 mg./kg. for mature animals.
  • a unit dose based on four-times-a-day administration is between 2.5 mg. and 250 mg. for a kg. dog, and a total daily dose for a 10 kg. dog would vary between about 10 mg. and l,000 mg.
  • proportional dosages are employed, based on the weight of the animal.
  • Suitable dosage units provided for the administration of the compositions used in the method of the invention are tablets, capsules (which may be suitably formulated for either immediate or sustained release), syrups, elixirs, parenteral solutions, and the like. These dosage forms preferably contain per unit one or more multiples of the desired dosage unit in combination with the pharmaceutically acceptable diluent or carrier required for preparing the dosage unit.
  • alkoxy preferably of from one to five carbon atoms
  • perfluoroalkyl e.g., trifluoromethyl
  • alkylmercapto preferably of from one to six carbon atoms
  • n is an integer selected from the group consisting of l to 4 inclusive;
  • i 1 Alk is alkyl (preferably lower alkyl of from one to six carbon atoms).
  • X and X are selected from the group consisting of hydrogen, halogen (chlorine or fluorine), alkyl III contacting the nitrile compound l in the structural for mulas illustrating the process of my invention in the presence of a suitable inert organic solvent, such as tetrahydrofuran, ether or other solvents conventionally employed with lithium aluminum hydride.
  • a suitable inert organic solvent such as tetrahydrofuran, ether or other solvents conventionally employed with lithium aluminum hydride.
  • the N,N-dimethylamine (III), wherein R, and R each represent methyl, is readily prepared by the treatment of the primary amine compound (II) with formaldehyde and formic acid in accordance with the known Eschweiler-Clarke modification of the Leuckart Reaction. Recovery of the N,N-dimethylamine is accomplished in conventional manner.
  • the N-methylbengylamine represented by (V) wherein Alk is methyl may be prepared by either reduction of the corresponding Ne(phenylethenyl or phenylethynylbenzyl)formamide (IV) or by monodealkylation of the corresponding N,N-dimethylamine (III) wherein R and R represent methyl.
  • Reduction of the formamidoderivative (IV) is effected utilizing lithium aluminum hydride under the conditions set forth above for carrying out the reduction of the corresponding benzonitrile (I).
  • dealkylation of the N,N-dimethylamine (III) can be effected in known manner such as by treatment with cyanogen bromide followed by hydrolysis of the intermediate cyanamide or by treatment with a haloformate followed by hydrolysis of the resulting urethane intermediate. In each instance; the desired compound can be recovered employing conventional techniques.
  • responding tertiary amines (III), the N,N-dilower-alkyl derivatives, are prepared from the secondary amines by repeating the process employed in the preparation of the secondary amines.
  • the amides of the secondary amines are prepared and reduced with lithium aluminum hydride to produce the corresponding tertiary amines as, for example, the corresponding N,N-diethyl, N-ethyl-N-methyl, N,N-dipropyl, N,N-dibutyl and the N ,N-diamyl derivatives of substituted and unsubstituted phenyl-ethenyl or phenylethynyl benzylamine.
  • the primary amine (II) is condensed with an am-dihalo compound such as tetramethylene bromide, pentamethylene bromide, fl,fi'-dichlorodiethyl ether, 3,13- dichlorodiethyl sulfide, or an N-alkyl-B,/3'- dichlorodiethyl amine.
  • an am-dihalo compound such as tetramethylene bromide, pentamethylene bromide, fl,fi'-dichlorodiethyl ether, 3,13- dichlorodiethyl sulfide, or an N-alkyl-B,/3'- dichlorodiethyl amine.
  • a benzyl halide of Iformula (VI) hereinabove is convertedby reaction with ammonia or an amine to form the corresponding primary, secondary or tertiary amine (IIIA) as indicated below wherein Hal, R R X, and X have the significance previously indicated.
  • the starting compounds of the process of my invention that is the aralkenylbenzonitrile and the aralkynylbenzonitriles containing X and X substituents in the aromatic rings, are either known compounds or may be prepared from the corresponding halo substituted compounds by replacement of the halogen with cyanide through reaction with cuprous cyanide in pyridine.
  • Other similarly substituted compounds may be prepared in accordance with the following flow sheet:
  • the intermediates used in the preparation of the starting material wherein Y is bromo can be converted to the corresponding compound wherein y is cyano by treatment with cuprous cyanide.
  • Compounds B and C can exist in two isomeric forms, the cis and trans isomers. These isomers have different physical characteristics and therefore are readily separable by conventional means as by crystallization.
  • the product formed is 2-(phenylethynyl)-benzonitrile, b.p. l27-129C.(0.1mm.).
  • EXAMPLE 3 2-(4-Methoxyphenylethynyl)-benzylamine A. Trans-2-cyano-4'-methoxystilbene dibromide A mixture of o-cyanobenzaldehyde and 4-methoxyphenylacetic acid in approximately equimolar proportions is refluxed in a mixture of acetic anhydride and triethyl amine for 1.5 hours. The reaction mixture is diluted with water and the formed tra ns a -(4-methoxyphenyl)-2 cyano-cinnamic acid is precipitated and filtered from the diluted reaction mixture.
  • the trans a-(4-methoxyphenyl)-2 cyano-cinnamic acid is added portion-wise over a period of 10 minutes to redistilled quinoline containing a catalytic amount of copper-chromium oxide catalyst at a temperature of 225-230C. in the proportion of approximately 1 g. of acid of to 2.5 ml. of quinoline.
  • carbon dioxide evolution ceases the reaction mixture is cooled, decanted from the catalyst, distilled under reduced pressure and the distillate poured into dilute aqueous hydrochloric and the fimedcis 2 cyano V-methoxystilbene recovered by extraction into methylene chloride.
  • the methylene chloride extract of product is washed to remove acid and after removal of the solvent by evaporation under reduced pressure the product is further purified by distillation.
  • the dibromide of the trans-2-cyano-4-methoxy stilbene is prepared by treatment with an equimolar amount of bromine in carbon tetrachloride and crystallizes readily from the reaction mixture.
  • EXAMPLE 4 2-(p-Tolylethynyl)-benzylamine hydrochloride The procedure of Example 3 is repeated using as the starting material p-tolylacetic acid and o-bromobenzaldehyde to produce trans-2-bromo-4-methylstilbene
  • EXAMPLE 5 Z-(p-Fluorophenylethynyl)-benzylamine hydrochloride The procedure of Example 3 is repeated using as starting materials approximately equimolar portions of p-fluorophenylacetic acid and o-cyanobenzaldehyde to produce 2-(p-fluorophenylethynyl)-benzylamine hydrochloride, m.p. l72-l7 4C.
  • EXAMPLE 7 Trans-2-(4'-methoxystyryl)-benzylamine hydrochloride The procedure of Example 6 is repeated utilizing as the starting material the intermediate trans-2-cyano4'- methoxystilbene prepared in accordance with the procedures of Example 3A herein-above to produce trans-2-(4-methoxystyryl)-benzyl-amine WE'lhiiriT' l.
  • a compound represented by the formula wherein X and X' are selected from the group consisting of hydrogen, chlorine, fluorine, loweralkyl and loweralkoxy; and R, and R are hydrogen or loweralkyl.
  • a compound in accordance with claim 1 consisting of 2-(phenylethynyl)-benzylamine.
  • a compound in accordance with claim 1 consisting of 2-(4-methoxyphenylethynyl)-benzylamine.
  • a compound in accordance with claim 1 consisting of 2-(4-tolylethynyl)-benzylamine.
  • a compound in accordance with claim 1 consisting of 2-(4-fluorophenylethynyl)-benzylamine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
US00861987A 1969-09-29 1969-09-29 2-phenylethynyl-benzyl-amines Expired - Lifetime US3719712A (en)

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JP (1) JPS5010584B1 (enrdf_load_stackoverflow)
CH (1) CH554830A (enrdf_load_stackoverflow)
DE (1) DE2047658C3 (enrdf_load_stackoverflow)
FR (1) FR2070096B1 (enrdf_load_stackoverflow)
GB (1) GB1281289A (enrdf_load_stackoverflow)
NL (1) NL167412C (enrdf_load_stackoverflow)
SE (1) SE372256B (enrdf_load_stackoverflow)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3882130A (en) * 1969-09-29 1975-05-06 Merck & Co Inc 4-Phenylethynyl benzylamines
US3903165A (en) * 1974-08-19 1975-09-02 Merck & Co Inc Ethynylaryl amines and processes for their preparation
US4017543A (en) * 1973-12-19 1977-04-12 Merck & Co., Inc. α,α-Dialkyl-4-phenethyl-benzylamines and the salts thereof
US4042584A (en) * 1974-08-19 1977-08-16 Merck & Co., Inc. Ethynylaryl phenyl cyclopropyl thiazines and morpholines
US4661635A (en) * 1983-11-21 1987-04-28 Mcneilab, Inc. Aralykyl (arylethynyl)aralkyl amines and their use as vasodilators and antihypertensives
US4725602A (en) * 1984-02-06 1988-02-16 Mcneilab, Inc. Acetylene amines and their use as vasodilators and antihypertensives
US4742084A (en) * 1983-11-21 1988-05-03 Mcneilab, Inc. Aralykyl (arylethynyl)aralkyl amines and their use as vasodilators and antihypertensives
US4772755A (en) * 1987-03-19 1988-09-20 Mcneilab, Inc. 1,2-1,4 addition reaction sequence leading to disubstituted acelylenes
US4898889A (en) * 1983-11-21 1990-02-06 Mcneilab, Inc. Methods for the treatment of hypertension
US4960798A (en) * 1983-11-21 1990-10-02 Mcneilab, Inc. Methods for the treatment of angina

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO135027C (enrdf_load_stackoverflow) * 1971-01-15 1977-01-26 Merck & Co Inc
JPS5339683U (enrdf_load_stackoverflow) * 1976-09-10 1978-04-06
JPS54109688U (enrdf_load_stackoverflow) * 1978-01-19 1979-08-02
CA1292747C (en) * 1983-11-21 1991-12-03 John Robert Carson Aralykyl (arylethynyl) aralkyl amines and their use as vasodilators and antihypertensives
CA1242718A (en) * 1983-11-21 1988-10-04 John R. Carson Acetylene derivatives and methods for the treatment of hypertension and angina
CA1300632C (en) * 1984-02-06 1992-05-12 John Robert Carson Acetylene amines and their use as vasodilators and antihypertensives
ZA874448B (en) * 1986-06-20 1989-02-22 Mcneilab Inc Cis & trans stilbenes and their composition for the treatment of hypertension
JPH01112837U (enrdf_load_stackoverflow) * 1988-01-25 1989-07-28

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3882130A (en) * 1969-09-29 1975-05-06 Merck & Co Inc 4-Phenylethynyl benzylamines
US4017543A (en) * 1973-12-19 1977-04-12 Merck & Co., Inc. α,α-Dialkyl-4-phenethyl-benzylamines and the salts thereof
US3903165A (en) * 1974-08-19 1975-09-02 Merck & Co Inc Ethynylaryl amines and processes for their preparation
US4042584A (en) * 1974-08-19 1977-08-16 Merck & Co., Inc. Ethynylaryl phenyl cyclopropyl thiazines and morpholines
US4661635A (en) * 1983-11-21 1987-04-28 Mcneilab, Inc. Aralykyl (arylethynyl)aralkyl amines and their use as vasodilators and antihypertensives
US4742084A (en) * 1983-11-21 1988-05-03 Mcneilab, Inc. Aralykyl (arylethynyl)aralkyl amines and their use as vasodilators and antihypertensives
US4898889A (en) * 1983-11-21 1990-02-06 Mcneilab, Inc. Methods for the treatment of hypertension
US4960798A (en) * 1983-11-21 1990-10-02 Mcneilab, Inc. Methods for the treatment of angina
US4725602A (en) * 1984-02-06 1988-02-16 Mcneilab, Inc. Acetylene amines and their use as vasodilators and antihypertensives
US4772755A (en) * 1987-03-19 1988-09-20 Mcneilab, Inc. 1,2-1,4 addition reaction sequence leading to disubstituted acelylenes

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NL167412B (nl) 1981-07-16
CH554830A (de) 1974-10-15
DE2047658C3 (de) 1980-11-13
SE372256B (enrdf_load_stackoverflow) 1974-12-16
GB1281289A (en) 1972-07-12
JPS5010584B1 (enrdf_load_stackoverflow) 1975-04-22
DE2047658B2 (de) 1980-03-20
DE2047658A1 (enrdf_load_stackoverflow) 1971-04-08
FR2070096A1 (enrdf_load_stackoverflow) 1971-09-10
FR2070096B1 (enrdf_load_stackoverflow) 1974-02-22
NL7013565A (enrdf_load_stackoverflow) 1971-03-31
NL167412C (nl) 1981-12-16

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