Classifications

• • 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
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
  • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

Definitions

• trimethylene, tetramethylene or butadien-1,3)-ylene-(1,4) e.g., 3,4-dimethyl acetophenone, S-acetylindane, 2-acetyl naphthalene and Z-acetyl 5,6,7,8 tetrahydronaphthalene.
• the products are useful as antitussive and analgesic agents.
• This invention relates, in general, to novel compounds and to a process for the production thereof. More particularly, the invention relates to tetrahydroisoquinoline compounds which have valuable phanmacological activity and to a method for producing same.
• novel compounds of this invention are tetrahydroisoquinoline compounds which have the general for- R R 4 I in which the symbol R represents hydrogen or a lower alkyl group; in which R represents a lower alkyl group; in which R represents .a lower alkyl group or, alternatively, in which R and R taken together, represent a methylene group; in which R represents a lower alkyl group; in which R represents a lower alkyl group or, alternatively, in which R and R taken together, represent a trimethylene, tetramethylene or butadien-(1,3)- ylene-(1,4) group; and in which A represents a carbonyl or hydroxymethylene group, and medicinally acceptable acid addition salts of the Formula I compounds.
• the compounds of Formula I, and the acid addition salts thereof have analgesic and antitussive activity and, hence, they are useful as analgesic agents and antitussive agents.
• lower alkyl denotes a straight chain or branched chain alkyl group containing from 1 to 8 carbon atoms.
• the term lower alkyl embraces methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and isobutyl radicals.
• R represents hydrogen or a methyl group
• R and R each represent a methyl group or in 3,450,704 Patented June 17, 1969 which R, and R taken together, represent a methylene group
• R and R each represents a methyl group or in which R, and R taken together represent a trimethylene, tetramethylene or butadien-(1,3)ylene- (1,4) group.
• the compounds of Formula I, and the medicinally acceptable acid addition salts thereof are readily prepared.
• the preparative method involves reacting an amine having the formula Ii -O l R II in which the symbol R represents hydrogen or a lower alkyl group; in which R represents a lower alkyl group; in which R represents lower alkyl group; or, in the alternative, in which, taken together, R and R represent a methylene group, or an acid addition salt of such amine, with formaldehyde and a ketone having the formula R4 III in which R represents a lower alkyl group; and in which R represents a lower alkyl group; or, in the alternative, in which R and R taken together, represent a trimethylene, tetramethylene or butadien (1,3) ylene-(1,4)- group, by means of a Mannich reaction.
• the carbonyl compound which is produced can be reduced either catalytically or by treatment with an alkali-metal borohydride or an alkali-metal aluminum hydride.
• the amine of Formula II is provided in the form of the free base
• the product, which is produced when it is reacted with formaldehyde and the ketone is obtained as the free base.
• an acid addition salt of the amine is used as the starting material
• the product is obtained as the salt.
• the reduction product will be obtained as the free base or salt depending upon whetherthe reaction product which is reduced is in the form of the free base or the salt.
• the reaction product and the reduction product in the form of the free base can be converted into a salt or the salt converted into the free base by conventional procedures.
• the amines of Formula II which are used as the starting material in the practice of this invention, and the acid addition salts of such amines, are known compounds. They can be obtained, for example, by reducing the corresponding 3,4-dihydroisoquinolines and, if desired, con verting the reduction product into an acid addition salt.
• the aforesaid 3,4-dihydroisoquinolines can be produced from the appropriate nuclear-substituted a-phenethyl amines by N-acylation and subsequent ring closures of the N-acylamine by means of the Bischler-Napieralski reaction.
• An interesting class of materials are the amines of Formula II, either in the form of the free base or an acid addition salt thereof, in which R represents hydrogen or a methyl group and in which R and R each represent a methyl group or, when taken together, R and R represent a methylene group.
• ketones of Formula III which are used in producing the products of this invention are also known compounds. They can be obtained, for example, by reacting a 3,4-di(lower alkyl)-benzene, indane, naphthalene or 5,6,7,8-tetrahydronaphthalene with acetyl chloride by means of a Friedel-Craft reaction.
• ketone starting materials are 3,4-dimethyl acetophenone, S-acetyl indane, 2-acetyl naphthalene and 2- acetyl-5,6,7,8-tetrahydronaphthalene.
• the Mannich reaction involving the amine of Formula II, either in the form of the free base or an acid addition salt, formaldehyde and the ketone of Formula III is carried out conveniently by heating the reactants in an inert organic solvent. Generally, the reactants will be heated for a period of from about three to about sixty hours.
• the inert organic solvent one can employ, for example, a lower alkanol, such as, ethanol.
• an acid addition salt of Formula II amine particularly, a hydrohalide salt, such as, the hydrochloride, is employed.
• a hydrohalide salt such as, the hydrochloride
• the catalytic reduction of those compounds of Formula I in which the symbol A represents a carbonyl group, or an acid addition salt thereof, is carried out conveniently in an inert organic solvent, such as a lower alkanol, for example, methanol, using hydrogen in the presence of a palladium or platinum catalyst.
• a palladium or platinum catalyst As the catalyst, there can be used, for example, palladium-on-carbon or platinum oxide.
• the reduction is carried out generally at room temperature and atmospheric pressure.
• the carbonyl compound of Formula I i.e., the compound of Formula I in which the symbol A represents a carbonyl group, or an acid addition salt thereof, can be reduced by treatment with an alkali metal aluminum hydride or an alkali metal borohydride in an inert organic solvent.
• an anhydrous ether such as diethyl ether or tetrahydrofuran
• the inert organic solvent is employed as the inert organic solvent.
• a lower alkanol such as, methanol, ethanol, etc., or dioxan, or an aqueous solution thereof, is used as the solvent. In either event, the reduction is effected at a temperature of about 20 C. or lower.
• the reduction is carried out using an alkali metal aluminum hydride, lithium aluminum hydride is preferably employed.
• sodium borohydride is preferably used.
• Those compounds of Formula I in which the symbol A represents a carbonyl group and R represents a methyl group have an asymmetric carbon atoms and, hence, occur in the form of a stereoisomeric racemate.
• Those compounds of Formula I, in which the symbol A represents a hydroxymethylene group and R is a lower alkyl group have two asymmetric carbon atoms and, hence occur in the form of two stereoisomeric racemates.
• Such racemates can, if desired, be separated into their optical isomers by conventional procedures. One such procedure involves the fractional crystallization of their salts.
• medicinally acceptable acid addition salts connotes salts of the base with medicinally acceptable acids.
• Such acids may be inorganic or organic in nature and they include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, maleic acid, citric acid, oxalic acid, toluenesulfonic acid, etc.
• the compounds can be used as medicaments in the form of pharmaceutical compositions suitable for enteral or parenteral administration.
• the compounds of Formula I, including the medicinally acceptable acid addition salts thereof can be provided as, and administered orally in the form of, tablets, pills, powders, capsules and granules.
• the compounds can be provided as, and administered orally in the form of, emulsions, solutions, suspensions, etc. for oral administration.
• the compounds of the invention can be provided as, and administered parenterally in the form of, sterile aqueous suspensions, solutions or emulsions. Conventional procedures are utilized in producing the aforementioned dosage forms.
• the commonly used pharmaceutical adjuvants and/or excipients can be employed in preparing the various dosage forms. Such adjuvants and excipients include, for example, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, water, etc.
• the compounds of Formula I can be present in such preparations as the sole active ingredient thereof or they can be present therein in admixture with other therapeutically valuable substances.
• the quantity of active medicament which is present in any of the above-described dosage forms is variable. It is preferred however, to provide capsules or tablets containing from about 5 mg. to about mg. of the Formula I base or an equivalent amount of a medicinally acceptable acid addition salt thereof. For parenteral administration, it is preferred to provide a solution containing from about 5 mg./ml. to about 11 mg./ml. of the Formula I base, or an equivalent quantity of a salt thereof.
• the frequency with which any such dosage form will be administered to a patient will vary, depending upon the quantity of active medicament present therein and the needs and requirements of the patient, as diagnosed by the prescribing physician. Under ordinary circumstances, however, up to about 8 mg/kg. of the compound can be administered daily in several dosages. It is to be understood, however, that the dosages set forth therein are exemplary only and that they do not, to any extent, limit the scope or practice of this invention.
• EXAMPLE 1 (a) In this example, a mixture of 22.2 grams (0.15 mol) of 3,4-dimethyl acetophenone, 36.6 grams (0.15 mol) of 1-methyl-6,7-dimethoxy l,2,3,4-tetrahydroisoquinoline hydrochloride and 6.75 grams of paraformaldehyde was added to a solution of 1 ml. of concentrated hydrochloric acid in 75 ml. of ethanol. This mixture was heated at its reflux temperature for a period of about twenty-four hours. At the end of that period of time the reaction mixture was cooled to a temperature of about C. The cream colored mass which was obtained was filtered and recrystallized from ethanol.
• This product was recrystallized from an ethanol-ether mixture to yield l-methyl 2 [3 (3,4 dimethylphenyl)-3-hydroxypropyl] 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline hydrochloride in the form of white crystals melting at a temperature of about 99 C.
• EXAMPLE 2 In this example, a mixture was prepared using 7.4 grams (0.05 mol) of 3,4dimethyl acetophenone, 11.51 grams (0.05 mol) of 6.7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and 1.8 grams of paraformaldehyde in 25 ml. of ethanol. This mixture was heated at its reflux temperature for a period of about three hours. Thereafter, the mixture was cooled to a temperature of 0 C. whereupon there was deposited a solid product which wa recovered by filtration.
• the reaction mixture was then stirred for a period of about two and one-half hours, following which 200 ml. of water was added thereto.
• the reaction mixture was then extracted three times with ether.
• the ether extracts were combined, washed with water and dried over anhydrous sodium sulfate.
• the dried solution was filtered and the solvent was removed by evaporation.
• a colorless oil remained as the residue.
• This oil was dissolved in ethanol and ethanolic hydrogen chloride added thereto. Thereafter, the ethanol and ether were removed by evaporation and the oily residue which remained was dissolved in chloroform.
• the chloroform solution shaken for several minutes with an excess of an aqueous solution of potassium iodide. A two phase system developed.
• reaction mixture was filtered to remove the catalyst and the filtrate was concentrated to a volume of about 30 ml. and cooled. Ether was added to the concentrate to cause the precipitation of a white solid product.
• the product was recrystallized from an ethanol-ether mixture to yield 1 methyl-2-[3-[5,6,7,8-tetrahydronaphthyl-(2) ]-3- hydroxypropyl] 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline hydrochloride in the form of white crystals melting at a temperature of 108 C. to 110 C.
• EXAMPLE 5 In this example, a mixture of 25.5 grams (0.15 mol) of 2-acetyl naphthalene, 36.6 grams (0.15 mol) of l-methyl 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline hydrochloride and 6.75 grams of paraformaldehyde in a solution of 0.5 ml. of concentrated hydrochloric acid in 100 ml. of ethanol was first prepared. This mixture was heated at its reflux temperature for a period of about sixty hours. At the end of that period of time, the reaction mixture was cooled to a temperature of 0 C. whereupon there was deposited a solid product which was recovered by filtration.
• the reaction mixture thus obtained, was stirred at room temperature for a period of about three hours, following which it was diluted with about 200 ml. of water and extracted two times with ether. The ether extracts were combined, washed with water and dried over anhydrous sodium sulfate. The dried solution was then filtered and evaporated under reduced pressure. A residual pale, yellow-colored, free flowing oil was obtained.
• This oil was treated with a methanolic solution of oxalic acid to yield 1 methyl 2 [3 [naphthyl (2)] 3 hydroxypropyl]- 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline oxalate, which after recrystallization from an ethanol-ether mixture, was obtained in the form of white crystals having a melting point at a temperature of 103 C.
• EXAMPLE 6 In this example, a mixture of 6.0 grams (0.04 mol) of 3,4-dimethylacetophenone, 8.6 grams (0.04 mol) of 6,7- dimethylenedioxy 1,2,3,4 tetrahydroisoquinoline hydrochloride and 1.8 grams of paraformaldehyde in 25 ml. of ethanol was heated at its reflux temperature for a period of about two hundred and fifty-two minutes. At the end of that period of time, the reaction product was cooled to a temperature of 0 C.
• R is a member selected from the group consisting of hydrogen and methyl; R represents a methyl group; R represents a methyl group and, together with R a methylene group; R represents a methyl group; R represents a methyl group and, together with R a member selected from the 9 group consisting of trimethylene, tetramethylene and butadien- 1,3 )-ylene- (1,4).
• A is a carbonyl group; R is methyl; R is methyl; R is methyl; R is methyl and R is methyl.
• A is a hydroxymethylene group; R is methyl; R is methyl; R is methyl; R is methyl and R is methyl.

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Cited By (2)

Citations (2)

• 1965
  • 1965-07-19 GB GB30549/65A patent/GB1079520A/en not_active Expired
• 1966
  • 1966-06-24 CH CH919866A patent/CH464922A/de unknown
  • 1966-06-27 IL IL26040A patent/IL26040A/en unknown
  • 1966-06-28 DE DE19661695147 patent/DE1695147A1/de active Pending
  • 1966-07-07 US US563396A patent/US3450704A/en not_active Expired - Lifetime
  • 1966-07-13 BR BR181255/66A patent/BR6681255D0/pt unknown
  • 1966-07-15 BE BE684185D patent/BE684185A/xx unknown
  • 1966-07-16 ES ES0329218A patent/ES329218A1/es not_active Expired
  • 1966-07-18 NL NL6610093A patent/NL6610093A/xx unknown
  • 1966-07-19 FR FR69810A patent/FR5796M/fr not_active Expired
  • 1966-07-19 DK DK373466AA patent/DK117704B/da unknown

Patent Citations (2)

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