IL26040A - Tetrahydroisoquinoline derivatives and process for the manufacture thereof - Google Patents

Description

fiimi |Π3 ΤΪΙΠΙ"Ί m PATENT ATTORNEYS ■ D'DIBS ' 3111J * DR. REINHOLD COHN | Π D t H il 1 · · Ί 'Π DR. MICHAEL COHN | Π 3 l ll . ' D 'Π ISRAEL SHACHTER B.Sc. .Ώ.3 -I B D OI Ι Κ Ί -ϋ ' 24806 PATENTS AND DESIGNS ORDINANCE SPECIFICATION Tetrahydroisoquinoline derivatives and procese for the maa faeture thereof I (we) F. Hoffmann-La Roche * Co, Aktiengesellschaft, a Swiss corporation, of renzaeherstraaee 124» Bas¾e, Switzerland do hereby declare the nature of this invention and in what manner the same is to be performed, to be particularly described and ascertained in and by the following statement :- The present invention is concerned with novel tetrahydroieoquAnoline derivatives and a process for the manufacture thereof.

The novel tetrahydrolsoquinoline derivatives provided by the invention are compounds of the general formula (I) wherein R represents hydrogen or a lower alkyl group, R1 and R2 each represent a lower alkyl group or together represent the methylene group, ^ ^ and R4 each represent a lower alkyl group or together represent a trimethylene, tetramethylene or butadien-(l,3)-ylene-(l,4) group and A represents a earbonyl or hydroxy-methylene group, and acid addition salts thereof.

The term "lower alkyl" is used in this specification to mean straight-chain and branched-chain alkyl groups containing a low number of carbon atoms, particularly 1 to carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec.butyl and isobutyl).

An interesting class of derivatives provided by the invention comprises those compounds of formula I in 1 which R represents a methyl group, R and R2 each represent a methyl group or together represent the methylene group and R and R each represent the methyl group or together represent a trimethylene , tetramethylene or butadien-(l,3)-ylene-(l,4) group, and their acid addition salts. The most interesting derivatives are l-methyl-2-[3-(3,4-dimethyl-phenyl)-3-oxo-propyl]-6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride; l-methyl-2-[3-(3, -dimethyl-phenyl)-3-oxo-propyl ]-6,7-methylenedioxy-1,2, ,4-tetrahydro-isoquinoline hydrochloride; l-methyl-2-^-[indanyl-(5) ]-3-oxo-propyl7-6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride ; 2-[3-(3,4-dimethyl-phenyl )-3-oxo-propyl ]-6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride ; l-methyl-2- "3-[5,6,7,8-tetrahydro-naphthyl-(2)]-3-0x0-propyl7-6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride; 6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride; 2-[3-(3,4-dimethyl-phenyl)-3-oxo-propyl]-6,7-me-thylenedioxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride ; l-methyl-2-[3-(3,4-dimethyl-phenyl )-3-hydroxy-propyl]-6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride; l-methyl-2-[3-(3,4-dimethyl-phenyl)-3-hydroxy-propyl]-6,7-methylenedioxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride; l-methyl-2-^"-[indanyl-(5) ]-3-hydroxy-propyl7-6,7-dimethoxy-isoquinoline hydro- chloride or hydroiodide? l-methyl-2-^3"-[5,6,7,8-tetra-hydro-naphthyl- (2) ]-3-hydroxy-propyl7-6,7-dimethoxy-1,2,3* —tetrahydro-isoquinoline hydrochloride; l~methyl~ 2- "-[naphthyl-(2) ]-3-hydroxy-propyl7-6,7-dimethoxy-1*2,3, -tetrahydro-isoquinoline oxalate and 2-[3-(3* ~ dimethyl-phenyl )-3-hydroxy-propyl ]-6,7-meth lenedioxy- 1*2,3* -tetrahydro-isoquinoline hydrochloride and the respective free bases.

According to the process provided by the invention, the novel derivatives aforesaid are manufac-ured by reacting an amine of the formula (II) 1 wherein R, R and R2 have the significance given above, or an acid addition salt thereof, with formaldehyde and a ketone of the formula (III) wherein R^ and R have the significance given above, by means of a MANNICH reaction and, if desired, reducing the carbonyl group of the resultant reaction product in a known manner, e.g. catalytically or by treatment with an alkali-metal aluminum hydride or an alkali-metal borohydride to the hydroxymethylene group and, if desired, converting the reaction or reduction product, into the free base or an acid addition salt.

The amine starting materials of formula II and their acid addition salts are known and can be obtained, for example, by reducing the corresponding 3^-dih dro-isoquinolines and, where required, converting the product into an acid addition salt. The 3,4-dihydro-isoqui-nolines aforesaid can, in turn, be obtained from the appropriate nuclear-substituted a-phenethyl amines by N-acylation and subsequent ring-closure of the resulting N-acyl-amines by means of the BISCHLER-NAPIERALSKI reaction. The most interesting amine starting materials are those in which R represents the methyl group and "*" 2 and R each represent the methyl group or together represent the methylene group, and their acid addition salts.

The ketones of formula III are also known and can be obtained, for example, by reacting a 3*4-di(lower alkyl)-benzene, indane, naphthalene or 5*6,7,3-tetrahydro-naphthalene with acetyl chloride by means of a PRUEDEL-CRAPTS reaction. The most interesting ketone starting materials are 3* -dimethyl-acetophenone s 5-acetyl-indane: 2-acetyl-naphthalene and 2-acetyl-5,6,7,8-tetrahydro-naphthalene .

The MANNICH reaction of the amine of formula I or an acid addition salt thereof, formaldehyde and the ketone of formula III can conveniently be carried out by heating the reactants in an inert organic solvent (e.g. a lower alkanol, such as ethanol) for a period of from about 3 to about 60 hours. It is preferred to use an acid addition salt, especially a hydrohalide salt such as the hydrochloride, of the amine in the reaction. In the latter case it may be advisable to include in the reaction mixture a small amount of the acid corresponding to the acid addition salt employed.

The catalytic reduction of the reaction product (that is to say, of a compound of formula I in which A represents a carbonyl group or an acid addition salt thereof) can suitably be carried out in a lower alkanol, e.g. methanol, using hydrogen in the presence of a palla dium or platinum catalyst, e.g. palladium-on-carbon or platinum oxide at room temperature and atmospheric pressure. The reduction of the reaction product by treat ment with an alkali-metal aluminum hydride or alkali-metal borohydride can conveniently be carried out in an inert organic solvent, e.g. an anhydrous ether such as diethyl ether or tetrahydrofuran in the case of the alkali-metal aluminum hydrides or a lower alkano such as methanol or ethanol or dioxan or an aqueous solution thereof in the case of the alkali-metal boro-hydrides, at a temperature of about 20 °C or below. Lithium aluminum hydride is the preferred alkali-metal aluminum hydride and sodium borohydride is the preferred alkali-metal borohydride.

It will be appreciated that those compounds of formula I, in which A represents a carbonyl group and R represents a lower alkyl group, contain an asymmetric carbon atom and occur in the form of a stereoisomeric racemate. It will further be appreciated that those compounds of formula I in which A represents a hydroxy-methylene group and R represents a lower alley group contain two asymmetric carbon atoms and occur in the form of two stereoisomeric racemates. The racemates can, if desired, be separated into their optical isomers in accordance with methods known per se, for example, by fractional crystallization of their salts.

The acid addition salts provided by the invention are those with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphor acid and with organic acids such as acetic acid, tartaric acid, aleic acid, citric acid oxalic acid and toluenesulphonic acid.

The novel tetrahydro-isoquinoline derivatives provided by the present invention have analgesic and antitussive properties.

The compounds of formula I and their pharmaceutically acceptable acid addition salts may thus be used as medicaments, for the relief of pain and cough, in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier. The pharmaceutical preparations may be made up for enteral, e.g. oral, or parenteral administration.

Solid preparations for oral administration include tablets, pills, powders, capsules and granules, the carrier being inorganic, e.g. talc, or organic, e.g. lactose or starch. Additives such as magnesium stearate (a lubricant) may also be present. Liquid preparations for oral administration include emulsions, solutions and suspensions, and diluents which are commonly used in pharmacy, e.g. water and petroleum jelly, may be incorporated in such preparations. The liquid pre-parations may take the form of sterile aqueous or nonaqueous solutions, suspensions or emulsions.

Polyoxyethyleneglycols and vegetable oils are useful suspending media. Emulsifying agents, dispersing agents and other adjuvants may also be present. The pharmaceutical preparations may be submitted to the usual pharmaceutical operations and other therapeutically valuable materials may also be present therein.

The following Examples illustrate the process provided by the invention.

Example 1 A mixture of 22.2 g (0.15 mol) of 3 ,4-dimethyl-aeetophenone, 36.6 g (0.15 mol) of l-methyl-6,7-di-methoxy-l<2,3, -tetrahydro-isoquinoline hydrochloride and 6.75 g of paraformaldehyde t in a solution of 1 ml of concentrated hydrochloric acid in 75 ml of ethanol, was heated under reflux for 24 hours. On cooling to 0 *C there was deposited a cream coloured mass which was filtered off and recrystallized from ethanol to yield 38.2 g of l-methyl-2-L3-(3 , -dimethyl-phenyl) -3-oxo-propyl]-6,7-dlmethoxy-l,2,3 ,4-tetrahydro-isoquinoline hydrochloride in the form of white prisms of melting point 182-183 °C.

Example 2 In a manner analogous to that described in Example 1, l-methyl-2-[3-(3 ,4-dimethyl-phenyl) -3-oxo-propyl] -6 ,7-methylenedioxy-l ,2 ,3 ,4-tetrahydro-iso-quinoline hydrochloride (pale yellow prisms of melting point 13 °C from ethanol) was prepared from ^s -d±-methyl-acetophenone and l-methyl-6,7-methylenedioxy- 1»2,3,4-tetrahydro-isoquinoline hydrochloride .

Example 0.02 mol of l-methyl-2-[3-(3,4-dimethyl-phenyl) 3-oxo-propyl]-6,7-dimethoxy-l,2,3,4-tetrahydro-iso-quinoline (prepared from 8.5 g (0.02 mol) of the hydrochloride obtained according to Example l, in 100 ml of dry ether were added dropwise at room temperature to a stirred suspension of 1.15 g (0.03 mol) of lithium aluminum hydride in 50 ml of dry ether. On completion of the addition, the mixture was heated under reflux for 4 hours and then cooled in ice-water. The excess lithium aluminum hydride was decomposed by careful addition of ethyl acetate. The mixture was acidified with dilute sulfuric acid and the phases were separated. The aqueous phase was made alkaline with dilute sodium hydroxide solution and extracted twice with ether. The combined ether extracts were washed with water and dried over sodium sulfate. The dried solution was filtered and the solvent was evaporated under reduced pressure. The residual oil was taken up in ethanol and ethanolic hydrogen chloride and, after cooling, dry ether was added. The white solid thus formed was recrystallized from ethanol&her to give 0.8 g of l-methyl-2-[3-(3,4-dimethyl-phenyl)- -hydroxy-propyl ]-6,7-dimethoxy~ 1*2,3,4-tetrahydro-isoquinoline hydrochloride in the form of white crystals of melting point 99 °C.

Example 4 In a manner analogous to that described in Example 3, l-methyl-2-[3-(3,4-dimethyl-phenyl)-3-hydroxy-propyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride (white crystalline powder of melting point 165 °C from isopropanol/ether) was prepared from l-methyl-2-[3-(3,4-dimethyl-phenyl)-3-oxo-propyl]-6,7-raethylenedioxy-l,2,3,4-tetrah3rdro-isoqui-noline hydrochloride (obtained according to Example 2).

Example 5 A mixture of 7Λ g (0.05 mol) of 3,4-dimethyl-acetophenone, 11.51 g (0.05 mol) of 6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride and 1.8 g of paraformaldehyde in 25 ml of ethanol was heated under reflux for 3 hours. On cooling to 0 °C there was deposited a solid which was filtered off and recrystallized from iso--propanol/ethanol/water to yield 10.1 g of 2~[3-(3,4-dimethyl-phenyl)-3-oxo-propyl"J-6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride of melting point 225 °C.

Example 6 A mixture of 32.0 g (0.2 mol) of 5-acetyl-indane, 48 ,8 g (0.5 mol) of l-methyl-6 ,7-dimethoxy- *2 ,3 >4-tetrahydro~isoquinoline hydrochloride and 9 g of paraformaldehyde in a solution of 0.5 mol of concentrated hydrochloric acid in 100 ml of ethanol, was heated under reflux for 16 hours. On cooling to 0 °C there was deposited a solid which was filtered off and re-crystallized from ethanol to yield 43.4 g of 1-methyl- [indanyl-( ) ] -3-oxo-propyl7-6 , 7-dimethoxy-l, 2 ,3 ,4-tetrahydro-isoquinoline hydrochloride of melting point 189-191 °c.

Example 7 12. j(0.03 mol) of l-methyl-2-2j- [indanyl- (5 ) ] ~ 3-oxo-propyl7-6, 7-dimethoxy-l, 2 ,3 , -tetrahydro-iso-quinoline hydrochloride (obtained according to Example 6 ) were dissolved at room temperature in a mixture of 5 ml of methanol and 25 ml of 2-N sodium hydroxide solution. A solution of 1.2 g (0.03 mol) of sodium borohydride in a mixture of 45 ml of methanol and 6< ml of 2-N sodium hydroxide solution was added dropwise over 0.5 hour.

The reaction mixture was stirred at room temperature for a further 2.5 hours, 200 ml of water were added and the mixture was extracted three times with ether. The combined ether extracts were washed once with water and dried over anhydrous sodium sulfate. The dried solution was filtered and the solvent was removed by evaporation. The residual colourless oil was dissolved in ethanol and ethanolic hydrogen chloride was added; a crystalline hydrochloride could be obtained neither by cooling the solution nor by dilution with ether. The oily hydrochloride obtained after evaporation of the ethanol and ether was dissolved in chloroform and the solution shaken for several minutes with excess of an aqueous solution of potassium iodide. The chloroform layer was separated, washed once with brine and dried over anhydrous sodium sulfate. The dried solution was filtered and the solvent evaporated under reduced pressure. The residual yellow gum was dissolved in isopropanol and the solution was cooled. On the addition of ether, 3.4 g of ]-3-hydroxy-propyl7-6,7-dimethoxy-l,2,3,4-tetrahydro-iso-quinoline hydroiodide was obtained as a pale yellow, hygroscopic, crystalline solid of melting point 95-98 °c.

Example 8 (5) ]-3-oxo-propyl7-6*7-dimethoxy-l,2,3, -tetra ydro-isoquinoline hydrochloride (obtained according to Example 6 ) were dissolved in 100 ml of ethanol. 0.15 g of platinum oxide was added and the mixture was hydrogenated at room temperature and atmospheric pressure. The theoretical amount of hydrogen was taken up in 8 hours. The mixture was filtered, the filtrate was evaporated to about 30 ml and, after the addition of dry ether, a white crystalline precipitate separated out. Recrystallization of this precipitate from ethanol/ ether gave 1.9 g of l-methyl-2-<5'-[indanyl- ( 5 ) ] -3~ hydroxy-propyl7-6,7-dimethoxy-l, 2 ,3 , -tetrahyd o-isoquinoline hydrochloride as white microcrystals of melting point 108-110 °C (with decomposition) .

Example 9 A mixture of 17A g (0.1 mol) of 2-acetyl-5,6 ,7,8-tetrahydro-naphthalene, 24.4 g ( 0.1 mol) of l-methyl-6 , 7-dimethoxy-l , 2 ,3 , -tetrahydro-isoquinoline hydrochloride and 4.5 g of paraformaldehyde, in a solution of 0.5 ml of concentrated hydrochloric acid in 50 ml of ethanol, was heated under reflux for 48 hours. On cooling to 0 °C there was deposited a solid which was filtered off and recrystallized from ethanol to yield 18.9 g of 1-methyl-2-^- C 5 ,6^7 ,8-tetrahyd o-naphthyl--( 2 ) ] -3-oxo-propyl7~6 ,7 ·~ι. dimethoxy-1 , ,3 , -tetrahyd c~ isoqulnoline hydrochloride of melting point 171-172 °G.

Example 10 0.15 g of platinum oxide (ADAMS catalyst) were added to a suspension of .3 g (0.01 mol) of 1-methyl-2-^5-[ ,6,7 -tetrahydro-naphthyl- (2) ]-3-oxo-propyl/-6,7-diroethoxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride (obtained according to Example 9) in 100 ml of ethanol under nitrogen. The mixture was hydrogenated at room temperature and atmospheric pressure. After 4 hours the theoretical quantity of hydrogen (270 ml) had been absorbed and the product which formed had dissolved in the ethanol. The catalyst was removed by filtration and the solution was concentrated to a volume of about 30 ml and cooled. Ether was added and the precipitated white solid was recrystallized from ethanol/ether to yield 2.5 of l-methyl-2-^-[5,6,7,8-tetrahydro-naphthyl-(2)]-3-hydroxy-prop l -6,7-dimethoxy-1,2,3, -1etrah d o-iso« quinoline hydrochloride in the form of white crystals of melting point 108°-110 °C.

Example 11 A mixture of 25.5 g (0.15 mol) of 2-acetyl-naphthalene, 36.6 g (0.15 mol) of l-methyl-6,7-di-metho2:y-l,2,3i -tetrahydro-isoquinoline hydrochloride and 6.75 g of paraformaldehyde , in a solution of 0.5 ml of concentrated hydrochloric acid in 100 ml of ethanol, was heated under reflux for 60 hours. On cooling to 0 °C there was deposited a solid which was filtered off and recrystallized from ethanol/ether to yield l6.9 g of ]-3-oxo-propyl7-6,7-dimethoxy- 1,2,3, -tetrahydro-isoquinoline hydrochloride of melting point 187 °C.

Example 12 A solution of 0.6 g (0.015 mol) of sodium borohydride in 10 ml of methanol containing 3 ml of dilute sodium hydroxide solution was added dropwise over a period of 0.5 hour to a stirred solution of 6.4 g (0.015 mol) of l-methyl-2~^-[naphthyl-(2)]-3-oxo-propyl7-6,7-dimethoxy-l,2,3, -tetrahydro-isoquinoline hydrochloride (obtained according to Example 11) in 30 ml of methanol and 15 ml of 2-N sodium hydroxide solution. The reaction mixture was stirred at room temperature for a further 3 hours, diluted with about 200 ml of water and extracted twice with ether. The combined ethereal extracts were washed with water and dried over anhydrous sodium sulfate. The dried solution was filtered and evaporated under reduced pressure. The residual pale yellow oil of low viscosity would not form a crystalline hydrochloride when treated with ethanolio hydrogen chloride, but gave a crystalline oxalate on treatment with a methanollc solution of oxalic acid. 3.0 g of l-methyl-2- "-[naphthyl-(2) ]-3-hydroxy-propy]J7-6,7-dimethoxy-l,2,3,4-tetrahydro-iso-quinoline oxalate in the form of white crystals of melting point 103 °C were obtained after recrystalliz-ation from ethanol/ether .

Example 13 A mixture of 6,0 g (0.04 mol) of 3,4-dimethyl-acetophenone, 8.6 g (0.04 mol) of 6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride and 1.8 g of paraformaldehyde in 25 ml of ethanol was heated under reflux for 4.2 hours. On cooling to 0 °C there was deposited a solid which was recrystallized from ethanol to yield 7.1 g of 2-[3-(3,4-dimethyl-phenyl)-3-oxo-propyl]-6,7-methylenedioxy-l,2,3 ,4-tetrahydrolsoquinoline hydrochloride of melting point 212 °C.

Example 1 0.3 g of 5 palladium-on-charcoal catalyst were added to a solution of 3.74 g (0.01 mol) of 2- [3- (314-dimethyl-phenyl ) -3-oxo-propyl] -6 ,7-methylene-dioxy-1,2 ,3 , -tetrahydro-isoquinoline hydrochloride (obtained according to Example 13 ) in 100 ml of methanol and the mixture was hydrogenated at room temperature and atmospheric pressure. After 16 hours the theoretical quantity of hydrogen had been absorbed. The catalyst was removed by filtration through diatomaceous earth which was then washed with methanol. The combined filtrate and washings were evaporated to a volume of about 25 ml. Ether was added to the cooled solution and the white solid which formed was recrystallized from methanol/ether to yield 2.0 g of 2-[3- (3 , -dimethyl-phenyl) -3-hydroxy-propyl] -6 ,7-methylenedioxy-1 ,2,3 ,4-tetrahydro-isoquinoline hydrochloride of melting point 199 °c.

Example 15 g of l-methyl-2-^-B.ndanyl- (5 ) ]-3-oxo-propyl7-6 ,7-dimethoxy-l ,2,3 * 4-tetrahydro-isoquinoline hydrochloride (obtained according to Example 6), 102 g of starch, 30 g of hydrated silica and 3 g of magnesium stearate were thoroughly mixed and the mass obtained was pressed into tablets each weighing 150 mg.

Example 16 3 g of l-methyl-2-[3-(3,4-dimethyl-phenyl)-3-oxo-propyl]-6,7-dimethoxy-l,2,31 -tetrahydro-lso-quinoline hydrochloride (obtained according to Example 44 g of lactose, 48 g of corn starch and 5 g of talc were thoroughly mixed and the mass obtained was pressed into tablets each weighing 100 mg.

Claims (1)

1. HOW particularly described and ascertained tne nature of our said invention and in what manner the same is to be we declare that what we claim derivatives of the general formula wherein fi is hydrogen or a lower and 2 are each a lower group or together represent 3 4 the methylene and are each a lower alkyl group or together represent a methylene or group and A a carbonyl or and acid addition salts Tetrahydroisoquinoline derivatives of the 1 2 formula X in Claim wherein is R and R are each methyl or together represent the methylene 4 group and and are each methyl or together represent a tetramethylene or and acid addition salts quinoline and acid addition salts 1 and aeid addition salts and acid addition salts th isoquinoline and acid addition salts and acid addition salts and acid addition salts h isoquinoline and aeid addition salts isoquinoline and acid addition salts and acid addition salts isoquinoline and acid addition salts uinoline and acid and acid addition salts The hydrochlorides of the bases set forth in any one of Claims and hydroiodide A process for the manufacture of isoquinoline derivatives of the general formula I in Claim and of acid addition salts which comprises reacting an amine of the formula wherein R and R have the same meaning as in Claim or an acid addition salt with formaldehyde and a ketone of the wherein R and have the same meaning as in Claim by means of a reaction if reducing the group of the ing reaction product to the hydroxymethylene group if converting the reaction or reduction product into the free base or an A process as claimed Claim wherein the carbonyl group of the resulting produot is reduced either catalytically or by treatment with an aluminum hydride or A process as claimed in Claim or wherein an amine of formula in which is methyl and and are each methyl or together represent the methylene or an acid addition salt thereof used as the amine starting A process as claimed in Claim 20 or wherein a hydrohalide salt of an amine of formula II is used as starting A process as claimed in Claim wherein a hydrochloride salt is used as starting A process as claimed in any one of Claims to wherein or is used the ketone starting material of formula III in Claim A process as claimed in any one of Claims to wherein the catalytic reduction of the reaction product is carried out using hydrogen in the presence of a palladium or platinum A process as claimed in any one of Claims to wherein the reduction of the reaction product is carried out using lithium aluminum hydride or sodium A process for the of the derivatives of I in 1 and of acid salts substantially as described with re to 1 to derivatives of the general foratula I in Claim t and acid addition salts whenever prepared by the process claimed in any one of Claims to 27 or by an obvious chemical equivalent derivatives of the 1 2 foratula I in 1 wherein is and a are group or together represent the 3 4 group and and are each methyl or together represent a tetramethylene or and acid addition salts whenever prepared by the process as claimed in any one of Claims 21 to 27 or by an obvious chemical equivalent 1 and acid addition salts whenever prepared by the process claimed in any one of Claims t o 24 or by an obvious chemical equivalent 3 1 and acid addition salts whenever prepared by the process claimed in any one of Claims 19 to 24 or by an obvious chemical equivalent 32 h acid addition salts whenever prepared by the process claimed in any one of Claims 19 to 24 r by an obvious chemical equivalent and acid addition salts whenever prepared by the process claimed in any one Claims 19 to 24 or by an obvious chemical equivalent 3 and addition salts whenever prepared by the process claimed in any one cf Claims 19 to 24 or by an obvious chemical equivalent and acid addition salts whenever prepared by the process claimed in any one of Claims 19 to 24 or by an obvious chemical equivalent and addition salts whenever prepared by the process claimed in any one of Claims 19 to 24 or by an obvious chemical equivalent 3 and acid addition salts whenever prepared by the process claimed in any one of Claims isoquinoline and addition salts whenever prepared by the process claimed in any one of 19 to 27 or by an obvious chemical equivalent and acid addition salts whenever prepared by the process claimed in any one of Glaims 19 to 27 or by an obvious chemical equivalent isoquinoline and addition salts whenever prepared by the prooees claimed in any one of Claims 19 to 27 or by an obvious chemical equivalent and acid addition salts whenever prepared by the process claimed in any one of Claims 19 to 27 or by an obvious chemical equivalent and acid addition salts whenever prepared by the process claimed in any one of Claims 19 to 27 or by an obvious chemical equivalent hydrochlorides of the bases set forth in any one of Claims 30 to whenever prepared by the process claimed any one of Claims 19 to 24 or by an obvious chemical equivalent hydrochlorides the bases set forth in any one of Claims 37 to 40 and whenever prepared by the process elaimed in any one of Claims to 27 or by an obvious equivalent The of the base set forth in Claim prepared by the process elaimed in any one of Claims to 27 by an obvious equivalent The oxalate of the base set forth in Claim whenever prepared by the process elaimed in any one of Claims to 27 or by an obvious ehemical equivalent Compositions aaalgesic and antitussive containing a derivative of the general formula X in Claim or a pharmaceutically acceptable acid addition in combination with at least pharmaceutically acceptable Bated this 26th day For the Applicants insufficientOCRQuality