NO147752B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 11 (EQ) - (2-ACYLETHYL) -2,6-METANO-3-BENZAZOCINES - Google Patents

Description

The present invention relates to the production of new 11(eq)-(2-acylethyl)-2,6-methano-3-benzazocines, which can be used as analgesic agents and analgesic antagonists.

US Patent No. 3,932,422 describes the use of certain 3-acyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo(g)-quinolines as intermediates for the preparation of 1 ,2,3,4,5,6-hexahydro-11(eq)-(2-acylethyl)-2,6-methano-3-benzazocines. Even under the most favorable reaction conditions, however, by means of the above-mentioned method, significant quantities of 2-substituted-1, 2", 3, 4, 4a, 5, 10, 10a-octahydro-3, 5-ethenobenzo will be produced as a by-product. (g) quinolines, so that the yield of the main product, namely the aforementioned 2,6-methano-3-benzazocines, is significantly reduced.

In Norwegian explanatory document no. 146326, valuable intermediate products are described with the formula:

which can be designated as lower-alkyl 1-R^-3-R5CO-4aa-R2-5a-R4~ 6-R2„-7-R2-8-R2,~9-R2„, -1,2,3,4, 4a,5,10,10a-octahydro-2,5-methanobenzo(g)quinoline-3-carboxylates and which can be used in a new method (cf. Norwegian explanatory document no. 147106) for the production of 3-R.^-e (eq) -R4~7-R2„-8-R2-9-R2 ,-10-R2„, - 11(ax)-R^-ll(eq)-CH2CH2COR^-2,6-methano-3- benzazocines with the following formula:

and where, in both formulas I and II,

R^ is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, cycloalkyl with 3-7 ring carbon atoms, cycloalkyl-lower alkyl containing 3-7 ring carbon atoms with 1-7 carbon atoms in the alkyl part, 2- or 3 -furylmethyl, where the latter 2- or 3-phenylmethyl groups further on the unsubstituted ring carbon atoms can be substituted with 1-3 methyl groups, phenyl-lower-alkyl or phenyl-lower-alkyl substituted on the phenyl ring with 1-2 groups from the group consisting of halogen ( this includes bromine, chlorine and fluorine), lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkyl mercapto, trifluoromethyl, amino, lower alkanoyl amino or a single methylenedioxy group attached to the adjacent carbon atoms;

R2, R2' ' R2" °^ R2'" is ^ver hydrogen, or three of them are hydrogen and the fourth is halogen (this includes bromine, chlorine or fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower- alkoxy, lower alkylmercapto, trifluoromethyl, nitro, amino, lower alkanoylamino, lower alkoxycarbonylamino or phenyl, or two of the adjacent such groups may together form methylenedioxy;

R 3 is hydrogen or lower alkyl;

R^ is hydrogen, lower-alkyl, lower-alkyl-lower-alkyl, hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkyl-sulfinyl-lower-alkyl, phenylthio-lower-alkyl, phenyl-sulfinyl -lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R^ and R^ together form divalent lower-alkylene, ~(CH2^n-' where n is 3 or 4;

R5 is lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkyl-lower-alkyl, lower-alkoxy, cycloalkyl with 3.7 ring carbon atoms, cycloalkyl-lower-alkyl containing 3-7 ring carbon atoms with 1-7 carbon atoms in the alkyl part,

2- or 3-furyl, 2- or 3-furyl-(CH_2 ) m, where m is from 2 to 4, or where such 2- or 3-furyl or 2- or 3- furyl-(CH2)m~ groups may be substituted on the unsubstituted ring carbon atoms with 1-3 methyl groups, phenyl, phenyl-(CH2)m or phenyl or phenyl-(CH2) substituted on the phenyl ring with 1-2 groups taken from the group consisting of halogen

(herein includes bromine, chlorine and fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoyl-amino, or a single methylenedioxy group attached to the adjacent carbon atoms; and Alk is lower alkyl.

The above-mentioned US patent describes a method

for the preparation of compounds of formula II which includes heating a l-R^-3-R^,-CO^aa-R^-Sa-R^-G-R2„-7-R2-8-R2, 9-R2„, -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo(g)quinoline of formula Ia with formic acid in an inert organic solvent or with a benzyl-di- lower alkyl ammonium formate or a tri-lower alkyl ammonium formate. The products of formula II can be prepared by ring-opening the starting material of formula I by breaking the bond indicated by the letter (b). This process also produces, by breaking the bond indicated by (a) followed by cyclization of the R^,CO-carbonyl group to the nitrogen atom, significant amounts of l-R^-2-R^ , ^aa-R^ -Sa-R^-6-R2„-7-R2,-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo-(g)quinolines of formula III whereby lowering the yield of the main product of formula IIa. The two transformations are indicated by the following reaction kernel:

where R^, R2, ^2'' R2"' R3 °^ R4 ^are the same meaning as stated above and R5 is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl.

According to the present invention, compounds are prepared with the above-mentioned formula II, where R 1 is lower alkyl; R 2 , R 2 , and R 2 , are each hydrogen; R 2 is hydroxy;

R 3 is hydrogen or lower alkyl; R 1 is lower alkyl; and

R 1 is lower-alkylthio-lower-alkyl, lower-alkyl-lower-alkyl, lower-alkoxy, (C3-C1-) cycloalkyl or (C3-C5)-cycloalkyl-lower-alkyl.

In the latter context, the terms lower-alkyl and lower-alkoxy mean groups containing 1-4 carbon atoms. Furthermore, examples of cycloalkyl groups with 3-5 ring carbon atoms are cyclopropyl, cyclobutyl, cyclopentyl and 2-methylcyclobutyl.

The last above-mentioned compounds of formula II

which is produced according to the present invention, is obtained by cleaving with aqueous hydrobromic acid or with sodium propyl sulphide a corresponding compound of formula II where one of R2, R2, , R2„ and R-jn is alkoxy, the other radicals having the above meaning .

Compounds with particularly beneficial effects

is achieved by preparing compounds where R^ is 2-cyclopropylethyl, 2-cyclobutylethyl or 2-cyclopentylethyl and R^, R^ and R^ are each methyl.

When aqueous hydrobromic acid is used to produce the cleavage, the reaction can be carried out by boiling a solution of the ether under reflux in aqueous hydrobromic acid and the compound is isolated either directly from the reaction mixture in the form of the hydrobromide salt or from a neutral solution in the form of the free base.

When sodium propyl sulphide is used to cleave the ether, the reaction is carried out by refluxing a solution of the ether in an inert organic solvent, e.g. dimethylformamide (DMF), with a molar excess of sodium propyl sulphide, which can be prepared by adding propanethiol to sodium hydride.

The compounds produced according to the present invention can exist in stereochemical isomeric forms, i.e. optical isomers and geometric isomers. If desired, isolation or preparation of certain particular stereochemical forms can be achieved by applying known principles.

In the nomenclature used for compounds of formula II, "ax" means axial and "eq" equatorial, and the configuration is given with reference to the hydroaromatic ring. So-

thus 6(eq), 11(ax) compounds of formula II are in the cis configuration, while 6(eq), 11(eq) compounds are in the trans configuration.

In the nomenclature used for compounds of formulas I, Ia and III, the configurations are again indicated with reference to the hydroaromatic ring, and the designation "3" indicates the cis configuration with respect to the indicated 2,5-methano bridge in compounds with formula I, or the 3,5-etheno bridge in compounds of formula III. Accordingly, the designation "a" will indicate the trans configuration with respect to the same groups.

The structure of compounds produced according to the present invention was determined by means of the synthesis route, elemental analysis and by infrared and nuclear magnetic resonance spectra. The direction of the reactions and the homogeneity of the products were routinely examined using thin-layer chromatography.

Compounds with the general formula II where R^ e.g. is lower-alkyl, phenyl or phenyl-lower-alkyl,

described in the above-mentioned US Patent No. 3,932,422, are known to be active as narcotic antagonists and narcotic analgesics, both of which activities have been found in compounds of the same general class, which compounds are homologous with respect to R^ -lower-alkyl- or

-phenyl lower alkyl group. It has been found that entire "families" of compounds prepared according to the present invention have a surprising degree of specificity of activity, depending on the importance of the R 1 group. Thus, compounds in which R^

is 2-cycloalkylethyl (Examples 1-3 and 17 below), lower-alkylthio-lower-alkyl (Examples 7 and 10 below),

lower-alkoxy-lower-alkyl (Example 8 below)

or certain specific lower alkyl groups such as pentyl (Example 4 below) or 3-methylbutyl (Example 5 below), have generally been found to have narcotic antagonist properties, while compounds where are lower alkoxy (Example 9 below), cycloalkyl (Example 5 below examples 11-13) or cycloalkylmethyl (examples 14 and 15 below) have generally been found to have properties as morphine-like narcotic analgesics.

The following examples illustrate the invention. Melting points are uncorrected unless otherwise stated.

Example 1

A solution of 0.013 mol of 3,6(eq),11(ax)-trimethyl-8-methoxy,11(eq)-(3-oxo-5-cyclopropylpentyl)-1,2,3,4,5,6- To hexahydro-2,6-methano-3-benzazocine in 65 mL DMF was added a solution of 0.065 mol sodium propyl sulfide prepared by adding 5.9 mL propanethiol to 2.7 g (0.065 mol) of a 50% mineral oil dispersion of sodium hydride. The mixture was stirred and refluxed for 4 hours, then cooled and poured into a solution of 65 g of ammonium chloride in 325 ml of water. The mixture was extracted three times with diethyl ether and the combined ether layers were extracted with 150 ml of 0.1N methanesulfonic acid. The acidic extracts were made basic by adding an excess of ammonium hydroxide, and the mixture was again extracted with diethyl ether. The combined ether extracts were washed once with water, once with sodium chloride solution, then dried, filtered and evaporated to dryness to give 4.3 g of a glass which was crystallized from ethyl acetate/hexane to give 1, 1 g 3,6(eq),-11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-5-cyclopropyl-pentyl)-1,2,3,4,5,6- hexahydro-2,6-methano-3-benzazocines, melting point 128-130°C.

Part of the free base was converted to the hydrochloride salt and a salt was obtained which melted at 271-273°C (crystallized from ethanol).

Example 2

A solution of 12.7 g (0.032 mol) of 3,6(eq), 11(ax)-trimethyl-8-methoxy-11(eq)-(3-oxo-5-cyclopentyl-pentyl)-1,2 . add sodium hydroxide. The mixture was extracted with diethyl ether, and the combined ether extracts were washed 2 times with water, 1 time with sodium chloride solution, then dried and filtered and evaporated to dryness in vacuo to give 12.0 g of a syrup which was dissolved in ethanol and treated with a molar excess of sulfuric acid. The product 1 form of the sulfate salt was obtained by diluting the mixture with diethyl ether, and the salt was crystallized with ethanol, whereby 4.8 g of 3,6(eq),11(ax)-trimethyl-8-hydroxy-11(eq) was obtained -(3-oxo-5-cyclopentylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine sulfate, melting point 230-2 35°C.

Example 3

By using the same procedure as described in example IA in Norwegian interpretation document no. 146. 326 was obtained ethyl-7-methoxy-1,4aa,5a-trimethyl-3-(3-cyclobutyl-1-oxopropyl)-1/2,3,4,4a,5,10,10a-octahydro-2,5 -methanobenzo(g)quinoline-3-carboxylate (12.4 g, 26%, mp 121-123°C from hexane) by reacting 36.0 g (0.105 mol) of ethyl 7-methoxy-1,4aa,5a- trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo(g)-quinoline-3-carboxylate with 0.115 mol lithium diisopropylamide and reacting the resulting salt with 7.7 g (0.052 mol) of cyclobutanepropionyl chloride.

A solution of 12.4 g (0.027 mol) of this product was boiled with 50 ml of trimethylammonium formate for 20 minutes using the procedure of Example 4. The product was isolated as the methanesulfonate which was crystallized from acetone/diethyl ether to give 8 .3 g 3,6(eq),11(ax)-trimethyl-8-methoxy-11(eq)-(3-oxo-5-cyclobutylpentyl)-1,2,3,4,5,6-hexahydro- 2,6-methane-3-benzazocine methanesulfonate, melting point 153-155°C.

The latter compound (5.5 g, 0.012 mol) was cleaved with 35 ml of 48% hydrobromic acid, and the product was isolated in the form of the hydrochloride salt, and 3.9 g of 3,6(eq),11(ax)-trimethyl- 8-hydroxy-11(eq)-(3-oxo-5-cyclobutylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine hydrochloride, m.p. 271-275°C.

Using the same method as described in example 2, the following compounds of formula II were prepared, and R 2 is in each case hydroxy.

Example 4

3,6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-octyl)-1,2,3,4,5,6-hexahydro-2,6-methano -3-benzazocine hydrochloride (20.1 g), mp 252-255°C (from isopropanol) prepared by cleaving 32.0 g (0.07 mol) 3,6(eq),11(ax)-trimethyl -8-methoxy-11(eq)-(3-oxooctyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine with 320 ml of 48% hydrobromic acid. The methanesulfonate has a melting point of 178-179°C (from methanol)

and the 2-naphthalene sulfonate has a melting point of 195-198°C

(from methanol)diethyl ether).

Example 5

3,6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-t-methylheptyl)-1,2,3,4,5,6-hexahydro-2,6 -methano-3-benzazocine hydrochloride (3.6 g), m.p. 260-263°C (from isopropanol), prepared by cleaving 4.0 g (0.0097 mol) 3.6(eq),11(ax )-trimethyl-8-methoxy-11(eq)-(3-oxo-6-methylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine with 40 ml 48 % hydrobromic acid. The methanesulfonate has a melting point of 189-191°C (from acetone). Example 6

3,6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-butyl)-1,2,3,4,5,6-hexahydro-2,6-methano -3-benzazocine (1.3 g), m.p. 170-173°C (from ethanol) is prepared by cleaving 5.8 g (0.0018 mol) of 3,6(eq),11(ax)-trimethyl-8 -methoxy-11(eq)-(3-oxobutyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine with 58 ml of 48% hydrobromic acid. The methanesulfonate has a melting point of 265-269°C (from ethanol/diethyl ether).

Example 7

Ethyl 1,4aa,5a-trimethyl-7-methoxy-3-(4-methylthio-butyryl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]- quinoline-3-carboxylate, m.p. 116-118°C (23.1 g from hexane)

was prepared by reacting 34.3 g (0.1 mol) of ethyl 1,4aa,5a-trimethyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5- methanobenzo[g]quinoline-3-carboxylate with 0.11 mol lithium-

diisopropylamide in 600 mL of a solution of THF followed by reaction of the resulting lithium salt with 15.2 g (0.1

mol) 4-methylthiobutyryl chloride.

A solution of 23.1 g (0.05 mol) of the preceding product in 150 ml of trimethylammonium formate (TMAF) was heated under reflux for 20 minutes and this gave 22.7 g of the methyl ether isolated as the methanesulfonate, m.p. 139-142°C (from acetone), and 10.3 g (0.0026 mol) of this compound was cleaved by refluxing with 45 ml of 48% hydrobromic acid to give 2.85 g of 3,6(eq),11(ax )-trimethyl-8-hydroxy-11(eq)-(3-oxo-6-methylthiohexyl)-1,2,3,4,5,6-hexahydro-2,6-methane-3-benzazocinetane sulfonate, m.p. 169-172°C (from acetone).

Example 8

Ethyl 1,4aa,5a-trimethyl-7-methoxy-3-(4-methoxybutyryl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3 -carboxylate, m.p. 91-95°C (43.3 g, from hexane) was prepared by reacting 58.3 g (0.17 mol) ethyl 1,4act,5a-trimethyl-7-methoxy-1,2,3,4, 4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylate with 0.20 mol lithium diisopropylamide in 600 mL THF followed by reaction of the resulting lithium salt with 28.0 g (0.21 mol) 4-methoxybutyryl chloride.

A solution of 21.0 g (0.047 mol) of the product obtained in 120 ml of TMAF was heated under reflux for 15 minutes and this gave 15.0 g of a methyl ether which was isolated as the methanesulfonate, m.p. 144-147°C (from acetone/diethyl ether) and 11.6 g (0.0247 rnOl) of this compound was cleaved by refluxing in a solution of 0.124 mol sodium propyl sulphide in 300 ml DMF and this gave 1.9 g 3.6 (eq),11(ax)-trimethyl - 8-hydroxy-11(eq)-(3-oxo-6-methoxyhexyl)-1,2,3, 4,5,6-hexahydro-2,6-methano- 3-benzazocine methanesulfonate,

m.p. 211-214°C (from acetone).

Example 9

Diethyl 1,4aa,5a-trimethyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3,3-dicarboxylate, m.p. . 81-85°C (28 g, from pentane) was prepared by reacting 68.5 g (0.20 mol) ethyl 1,4aa,5a-trimethyl-7-methoxy-1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo[t]-quinoline-3-carboxylate with 0.22 mol of lithium diisopropylamide in 600 ml of THF followed by reaction of the resulting lithium salt with 21.6 g (0.20 mol) of ethyl chloroformate .

A solution of 10 g (0.24 mol) of the preceding product in 40 ml of TMAF was heated under reflux for 3

hours and this gave 7.5 g of the methyl ether (in the form of an oil),

and 10.5 g (0.30 mol) of this compound was cleaved by refluxing with 75 ml of 48% aqueous hydrobromic acid and this gave 6.2 g of ethyl 3-[3,6(eq),11(ax)-trimethyl- 8-hydroxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-11(eq)-yl]propionate hydrochloride, m.p. 258-261°C (from ethanol).

Example 10

Ethyl 1, 4aot, 5a-trimethyl-7-methoxy-3-(4-propylthio-butyryl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]- quinoline-3-carboxyl is produced by reacting ethyl 1,4aa,5a-trimethyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline- 3-carboxylate with a molar equivalent amount of lithium diisopropylamide in THF followed by reaction of the resulting lithium salt with a molar equivalent amount of 4-propylthiobutyryl chloride.

A solution of the preceding product in TMAF was heated under reflux and this gave the methyl ether which was cleaved by refluxing in a solution of sodium propyl sulphide in DMF to give 3,6 (eq),11(ax)-trimethyl-8-hydroxy-11( eq)-(3-oxo-6-propylthiohexyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine sulfate, m.p. 198-202°C

(from ethanol/diethyl ether).

Example 11

Ethyl 1, 4aa, 5<x-trimethyl-7-methoxy-3-cyclobutanecarbonyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate (22 g as an oil) was prepared by reacting 20.0 g (0.058 mol) of ethyl 1,4a,a,5a-trimethyl-7-methoxy-1,2,3,4,4a,5,10,10a -octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate with a small molar excess of lithium diisopropylamide in THF followed by reaction of the resulting lithium salt with a molar equivalent amount of cyclobutanecarbonyl chloride.

A solution of 22 g (0.052 mol) of the preceding product in 110 ml of TMAF was heated under reflux for 15 minutes and this gave 5.3 g of the methyl ether isolated as the hydrochloride salt, m.p. 111.0-113.5°C (from ethanol), and 0.50 g (0.0014 mol) of this compound was cleaved by refluxing in a solution of 0.0054 mol lithium methyl sulfide in 7 mL DMF to give 1.4 g 3,6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-3-cyclobutylpropyl)-1,2,3,4,5,6-hexahydro -2,6-methane-3-benzazocine hydrochloride, m.p. 272-276°C (from ethanol/diethyl ether).

Example 12

Ethyl 1,4aa,5a-trimethyl-7-methoxy-3-cyclopentane-carbonyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3- carboxylate (57.8 g as a straw-colored syrup) was prepared by reacting 60.0 g (0.175 mol) of ethyl 1,4aa,5a-trimethyl-7-methoxy-1,2,3,4a,5,10,10a -octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate with a molar equivalent amount of lithium diisopropylamide in THF followed by reaction of the resulting lithium salt with 24.8 g (0.187 mol) of cyclopentanecarbonyl chloride.

A solution of 57.8 g (0.132 mol) of the preceding product in a solution of 40.0 ml of formic acid in 578 ml of mesitylene was heated under reflux for approx. 16 hours and this gave 43.7 g of the methyl ether isolated in the form of the methanesulfonate salt, m.p. 85.0-88°C (from ethanol/diethyl ether), and 6.8 g (0.019 mol) of the free base of the latter compound was cleaved by refluxing with 34 ml of 48% aqueous hydrobromic acid to give 1.8 g of 3, 6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-3-cyclopentylpropyl)-1,2,3,4,5,6-hexahydro-2,6-methano -3-benzazocine, m.p. 142-148°C (from hexane).

Example 13

Ethyl 1,4aa,5a-trimethyl-7-methoxy-3-cyclohexane-carbonyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3- carboxylate (10.3 g as an orange oil) was prepared by reacting 30.0 g (0.087 mol) of ethyl 1,4aa,5a-trimethyl-7-methoxy-1,2,3,4,4a,5,10 ,10α-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate with a molar equivalent amount of lithium diisopropylamide in THF followed by reaction of the resulting lithium salt with a molar equivalent amount of cyclohexanecarbonyl chloride.

A solution of 29 g (0.064 mol) of the preceding product in 145 ml of TMAF was heated under reflux for 15 minutes and this gave 17.8 g of the methyl ether isolated as the oxalate salt, m.p. 189-195°C (from ethanol/diethyl ether) and 8.0 g (0.023 mol) of the free base of the latter compound was cleaved by refluxing for 2 hours with 40 ml of 48% hydrobromic acid to give 3.4 g of 3.6 (eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-3-cyclohexylpropyl)-1,2,3,4,5,6-hexahydro-2,6-methano- 3-benzazocine methanesulfonate, m.p. 212-217°C (from ethanol)diethyl ether).

Example 14

Ethyl 1,4aa,5a-trimethyl-7-methoxy-3-(1-oxo-2-cyclobutylethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo [g] quinoline-3-carboxylate (20 g as an oil) was prepared by reacting 17.1 g (0.05 mol) of ethyl 1,4aa,5a-trimethyl-7-methoxy-1,2,3,4 ,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate with 0.055 mol lithium diisopropylamide in 150 ml THF followed by reaction of the resulting lithium salt with 6.6 g (0.05 mol) •cyclobutylacetyl chloride.

A solution of 20 g (0.045 mol) of the preceding product in 70 ml of TMAF was heated under reflux for 20 minutes and this gave 5.2 g of the methyl ether isolated as the methsulfonate salt, m.p. 166-168°C (from acetone/diethyl ether), and 2.4 g (0.0065 mol) of the free base of the latter compound was cleaved by refluxing for 40 min in 48% aqueous hydrobromic acid to give 1.6 g of 3, 6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-4-cyclobutylbutyl)-1,2,3,4,5,6-hexahydro-2,6-methano -3-benzazocine hydrochloride, m.p. 278-281°C (from isopropanol/methanol/diethyl ether).

Example 15

Ethyl 1,4aa,5a-trimethyl-7-methoxy-3-(1-oxo-2-cyclopentylethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g ]-quinoline-3-carboxylate (70.9 g as an oil) was prepared by reacting 60.0 g (0.17 mol) of ethyl 1,4aa,5a-trimethyl-7-methoxy-1,2,3, 4,4a,5 /10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylate with a molar equivalent of lithium diisopropylamide in THF followed by reaction of the resulting lithium salt with a molar equivalent of cyclopentylacetyl chloride.

A solution of 70.9 g (0.156 mol) of the preceding product in 47.1 ml of formic acid and 709 ml of mesitylene was heated under reflux and this gave 37.3 g of the methyl ether isolated as the hydrochloride salt, m.p. 239-241°C (from ethanol/diethyl ether), and 8.9 g (0.021 mol) of the latter compound was cleaved by refluxing for 2 hours in 44.5 ml of 48% aqueous hydrobromic acid to give 6.4 g of 3.6 (eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-4-cyclopentylbutyl)-1,2,3,4,5,6-hexahydro-2,6-methano- 3-benzazocine sulfate, m.p. 192-196°C

(from ethanol/diethyl ether).

Example 16

Ethyl 1, 4aa, 5tx-trimethyl-7-methoxy-3-(1-oxo-2-cyclohexylethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo [g] quinoline-3-carboxylate (62.9 g as a yellow syrup) was prepared by reacting 50.0 g (0.145 mol) of ethyl 1,4aa,5a-trimethyl-7-methoxy-1,2,3, 4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate with a molar equivalent amount of lithium diisopropylamide in THF followed by reaction of the resulting lithium salt with a molar equivalent amount of cyclohexylacetyl chloride.

A solution of 62.9 g (0.13 mol) of the preceding product in 189 ml of TMAF was heated under reflux for 1

hour and this gave 23.0 g of the methyl ether, and 8.0 g (0.020 mol) of this compound was cleaved by refluxing for 1 hour in 40 ml of 48% aqueous hydrobromic acid to 2.6 3.6(eq),11( ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-4-cyclohexylbutyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 133-135°C (from ethanol).

Example 17

Ethyl 1,5a-dimethyl-7-methoxy-3-(1-oxo-3-cyclopentyl-propyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g ]-quinoline-3-carboxylate (38.9 g as a syrup) was prepared by reacting 30.2 g (0.092 mol) of ethyl 1,5a-dimethyl-7-methoxy-1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylate with a molar equivalent amount of lithium diisopropylamide in THF followed by reaction of the resulting lithium salt with 18.8 g (0.117 mol) of 3-cyclopentylpropionyl chloride .

A solution of 38.9 g (0.086 mol) of the preceding product in 195 ml of TMAF was heated under reflux for 40 minutes and this gave 21.0 g of the methyl ether isolated as the oxalate salt, m.p. 166-168°C (from acetone/diethyl ether), and 8.0 g (0.021 mol) of the free base of the latter compound was cleaved by refluxing for 2 hours in a solution of 40 ml of 48% aqueous hydrobromic acid and 10 ml glacial acetic acid which gave 6.0 g of 3,6(eq)-dimethyl-8-hydroxy-11(eq)-(3-oxo-5-cyclopentylpentyl)-1,2,3,4,5,6-hexahydro-2 ,6-methano-3-benzazocine, m.p. 114-116°C (from acetonitrile).

Claims (2)

1. Analogy method for the preparation of therapeutically active compounds with the formula: where is lower alkyl; R 2 , R 1 and R 2 are each hydrogen; R 2 is hydroxy; R 1 is hydrogen or lower alkyl; R 1 is lower alkyl; and R^ is lower-alkylthio-lower-alkyl, lower-alkyl-lower-alkyl, lower-alkyl, (C^-C^)cycloalkyl or (C-^-C,-)-cycloalkyl-lower-alkyl, characterized by cleaving with aqueous hydrobromic acid or with sodium propyl sulphide a corresponding compound of formula II where one of R 2 , R 2 , R 2 , and R 2 , is alkoxy, the other radicals having the meaning indicated above. 2. Analogous method according to claim 1, for the preparation of a compound of formula II, where the R2~ groups have the meaning indicated above, R^ is 2-cyclopropylethyl, 2-cyclobutylethyl or 2-cyclopentylethyl, and R-^, R^ and R ^ each is methyl, characterized by cleaving a corresponding compound of formula II where one of the R-^ groups is methoxy.