NO762292L - - Google Patents

Description

The present invention relates to new compounds of formula I and their suitable pharmaceutical salts, methods for their preparation, pharmaceutical compositions containing them and methods for using them as analgesia in mammals.

where is hydrogen, C1-C8 alkyl, -CH2Y where Y is C2-C8 alkenyl or C2-C8 alkynyl; where more 1 or 2, X is Cl, Br,.F,'CF3,. OCH 3 , CH 3 , isopropyl, -NH 2 or -N(CH 3 ) 2 , a = 9, 1 or 2;

or cycloalkylmethyl of the formula

provided that when R3 is -F, R4 must be -H.

Detailed description

Representative R^ groups are methyl, ethyl, propyl, butyl, hexyl, allyl (-CH2.CH=CH2) , 2-butenyl, 3-butenyl, 4-heptenyl, 3,3-dimethylallyl [-CH2CH=C(CH3 ) 2], propargyl (-CH2C=CH), phenylpropargyl, heptynyl, benzyl, phenethyl, 4-phenyl-n-butyl[-CH2(CH2)3CgH5J , cyclopropylmethyl

[-CH2CH<tCH?)?] , cyclobutylmethyl-[-CH-CfK (CH2)3] , cyclohexyl-

methyl [-CH2CH<(CH2)5], furylmethyl

2-furylethyl 2-thienylethyl o p-methylphenethyl p-fluorophenethyl, p-methoxyphenethyl p-chlorophenethyl p-aminophenethyl

, p-dimethylaminophenethyl

and cinnamyl (-CH2CH=CHC6H5).

Representative Ar groups are 3-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-acetoxyphenyl, 2,3-dihydroxy-phenyl, 3,4-dimethoxyphenyl, 3,4-diacetoxyphenyl, 3-hydroxy-4-methoxyphenyl, 2 -methoxy-3-acetoxyphenyl, 3-fluorophenyl and 4-fluorophenyl.

The 4α-aryl-cis-decahydroisoquinolines of formula I include various stereochemical isomers derived from

the substitution at the 6-position, and from optical asymmetry of it

entire structure. When monovalent R 2 substituents at the 6-position

is different (e.g. when R is 2

requires room view-

nings the existence of axial and equatorial isomers. In the molecule as a whole, spatial considerations will establish the existence of d and 1 optical isomers. These are normally present as racemic mixtures which can be resolved by known methods

(Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, 1962, p. 31).

Pharmaceutically suitable acid addition salts of these compounds include those prepared with physiologically acceptable acids known in the art, such salts include hydrochloride, sulfate, phosphate, nitrate, citrate, maleate and the like.

Preferred connections

The preferred analgesic compounds because of their high degree of activity are those in which R₂ is H and R₂ is m₂OH or m-OCH₃.

Preferred for the same reason are those compounds in which R-^

is a substituted phenethyl group.

The most preferred are the following two compounds: . 4a-m-hydroxyphenyl-N-phenethyl-cis-decahydroisoquinoline, 4a-m-hydroxyphenyl-N-(p-tolyl-3-ethyl-cis-decahydroisoquinoline).

Syntheses

The multi-step process according to the invention starts with 2-cyano-3-aryl-3-carbalkoxymethylcyclohexenes which can be obtained according to the methods which. is described by Boekelheide and Schilling (loe. eit.) with respect to 2-cyano-3-phenyl-3-carbethoxymethylcyclohexene (see Example 1, part A). Reaction of st 2-cyano-3-aryl-3-carbalkoxymethylcyclohexene with hydrogen chloride in a lower alkanol such as ethanol gives a 4a-aryl-1,3-diketo-1,2,3,4,4a,5,6,7 -octahydroisoquinoline (see Example 1, part B). These 1,3-diketo-octahydroisoquinolines exhibit a 4

structural order of condensed rings that require the formation of

trans-decahydroisoquinoline structures when the 8,8α-double bond is converted to a single bond (see Example 1, Part D, Example 6, Part A). A key step according to the invention is the novel isomerization of a 1,3-diketo-trans-decahydroisoquinoline to the cis-isomer in the presence of a relatively strong base (Example 1, Part E, Example 4., Part A).

The choice of the specific preparation steps that follow the immediate formation of a 1,3-diketo-1,2,3,4,4a,5,-6,7-octahydroisoquinoline depends on the specific 4a-aryl- cis-decahydroisoquinoline derivative pm is desired. The reaction sequence includes at least three steps, A, B and C which are . illustrated below.. Compounds having no unsaturated carbon-to-carbon bonds in R 1 (R la in the process steps) are prepared by steps A, B-1 and C. Compounds with saturated or unsaturated carbon-to-carbon bonds. in R1 is produced at steps A, B-2 and C.

R la In reaction path B-1 is the same as R 1 with the exception that it does not include unsaturated groups such as alkenyl or alkynyl. These groups seem to undergo reduction to alkyl, simultaneously, with the reduction of the 8,8a-bond, when going from compound 3 to compound 4. It is thus possible to obtain compounds of formula II where R"*" has alkenyl or alkynyl bonds, reaction pathway B-2 is followed. In this reaction pathway, the 8,8a bond is reduced. in compound 2 first and the resulting trans-product (6) is then reacted with R1Er/ R<1>! all mesylates to form the cis-product 5 in which R1 has alkenyl or alkynyl groups. Reaction pathway B-2 includes the option of isolation of N-unsubstituted cis-imide followed by normal N-alkylation with either a saturated or unsaturated R"*" group. In the preceding formulas 1 to 8 inclusive, the groups R1 have the previously indicated meanings. R<5>'s

wherein R 7 is hydrogen, F or methoxy, R 8 is H or methoxyl, provided that when R<7> is F, R<8> is H.

In step A, a reactant R^OH is used which is also the reaction medium, usually in excess, but to ensure maximum yield it must be used in an amount of at least 1 mol per moles of cyanoester. Likewise, the HCl reactant can be used in excess, but to ensure maximum yield it must be present in an amount of at least 1 mol per moles of cyanoester. The reaction is carried out in liquid phase under anhydrous conditions. The reaction temperature must be in the range from 50 to 120° C. The reaction pressure is not critical, usually atmospheric pressure is used for expedient reasons, but it must be in accordance with the achievement of the stated reaction temperature.

In step B-l for conversion of 2 to 3, or in step . B-2 for conversion of 2 to 6, any reactive alkylating agent can be used, such as hydrocarbyl iodide, bromide, mesylate,

tosylate, azide and the like. Alkyl iodides, bromides, mesylates,

Tosylates and azides are included and the hydrocarbyl group corresponds to R"*" in the general formula I. Any base capable of withdrawing a proton from the imide is satisfactory. Examples are alkali metal hydrides (sodium hydride or potassium hydride) in aprotic media (dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide); alkoxides in aprotic or alcoholic

ke solvents such as e.g. sodium ethoxide in ethanol and potassium t-butoxide in ethanol. Mesylates (Ms = mesyl group = Jnetanesulfonyl group) are described in Fieser and Fieser,

Advanced Organic Chemistry, 1961, pp. 292, 293 and 319. Hydrocarbyl bromides, iodides or mesylates are readily available as indicated in the following table (Table I).

In the reaction paths B-1 and B-2, a relatively

siterk base with or without an inert solvent. Representative strong bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal alkoxides in which the alkoxide group contains 1-4 carbon atoms, such as sodium methoxy, potassium methoxy, lithium prop-

oxide and the like. An inert solvent can be used if desired, including lower alkanols, e.g. methanol,

ethanol, t-butanol and the like. The reaction temperature can vary from room temperature to the reflux temperature of the reaction mixture.

Preparation of a 2-cyano-3-phenyl-3-carbalkoxy-methylcyclohexene The Boekelheide and Schiliing procedure involves preliminary steps starting with cyclohexane as follows: a. Cyclohexanone 2-chlorocyclohexanone (Horning, Qrganic Syntheses y Coll. Vol. III, 1955, p.188).

b. 2^chlorocyclohexanone 2-phenylcyclohexanone [Newman et al. J., Am. Chem., Soc. 66, 1551

(1944) J . c. 2-phenylcyclohexanone 2-phenyl-2-carbethoxycyclohexanone, Newman et al, Chem. Soc. 69, 942 (1947)] d. 2-phenyl-2-carbethoxycyclohexanone -*■. 2-cyano-3-phenyl-3-carbethoxycyclohexene.

End products corresponding to formula I contain certain groups R 2 which do not appear to be compatible with the chemistry of the process steps. R5 groups which are stable at the various process steps are used in the process and at the end of the synthesis these are converted into R 2 groups. The preliminary steps stated above are helpful in the preparation of different equivalents defined by different values for Ar and R in general formula 1 by starting with suitable substituted cyclohexanones in step (a) and with suitable substituted arylmagnesium bromides as intermediates in step (b). Thus, 4-methylcyclohexanone and 4-methoxycyclohexanone, which are commercially available, can be used as main starting materials to prepare compounds of formula I in which R 2 is respectively

The compounds of formula I in which R 2 (R in the process description) serve as intermediates for formula I in which R had other values. The subsequent table (table II) shows further R 2 values and known methods for obtaining them. Likewise, the use of suitable substituted phenyl bromides in the preparation of the arylmagnesium bromide Grignard reactant for step (b) will lead to corresponding Ar groups (Ar"*" in the process description) in products of formula I. The following table (Table III) shows relevant Ar ^-groups .with substituent R 7 and R 8 groups as defined above.

Compounds in which Ar"*" has methoxyl substituents

(as in Table III) serve as intermediates for compounds of formula I in which Ar has hydroxyl or acetoxyl substituents2 using methods for converting R 5 groups to R groups as shown in Table II. This seems necessary as certain substituents such as OH must be introduced at the end of the synthesis. Thus Ar"<*>"contains a methoxyl,

or "masked hydroxyl", which is then converted to OH.

Process steps A, B-1 and C are illustrated by examples 1 - 3. and process steps A, B-2 and C are illustrated by examples 4 - 7 etc. In the following examples, all amounts are on a weight basis and the temperatures are given in °C about nothing else is specified. Nmr spectra were at 60 H and the resonance position is described as eps or in ppm from tetramethylsilane (tms). Example 1 N-methyl-4a-phenyl-cis-decahydroisoquinoline A. 2-cario-3-phenyl-3-carbethoxymethylcyclohexene 90 g (0.346 mol) 2-carbethoxymethyl-2-phenylcyclohexene hexanone (Boekelheide et al., 200 ml of hydrogen cyanide and 12 drops of a saturated aqueous solution of potassium cyanide were stirred at 0° C overnight. 15 drops of concentrated sulfuric acid were then added and excess hydrogen cyanide evaporated. The impure cyanohydrin was taken up in ether and washed with cold 10% sulfuric acid solution, then dried with Na 2 SO 4 and evaporated. The residual oil was dissolved in 500 ml of pyridine and 100 ml of phosphorus oxychloride was added. The reaction mixture was stirred under a nitrogen atmosphere at reflux for 5 hours and then allowed to stand at 25°C overnight. It was then carefully poured into a mixture of 2 liters of ice water and 400 ml of concentrated hydrochloric acid and extracted with ether. The ether extract was washed with dilute hydrochloric acid, water and brine and then dried (Na 2 SO 4 ) and evaporated. The residual oil was distilled to give 45 g of pale yellow liquid, bp 135°C (0.20 mm), identified as 2-cyano-3-phenyl-3-carbethoxymethylcyclohexene. NMR (CDCl 3 )(<2>): triplet at 64, 71, 78 eps, 3H (-OCH 2 CH 3 ); methylene envelope from 70 - 150 eps, approx. 6H; singlet at 178 eps, 2H (-C-CH2-CO2-)} quartet at 234 , 242, 249 , 256', 2H (-OCH2CH3); triplet at 406, 410, 414, 1H (H><=;>—< ); . singlet at 436 eps, 5H (aromatic H). IR. (neat): 4.50 y (C=N); 5.5 and 5.85 y (lactone impurity); 5.75 y (-CO2-). B. 4a-f enyl-1, 3-diketol-l, 2, 3f4, 4a, 5, 6 , 7- octahydroisoquino. lin 50 g of the product from part A dissolved in a minimal amount of absolute ethanol was added to 2.5 liters of absolute ethanol which had previously been saturated with anhydrous hydrogen chloride. The solution was boiled under reflux in a nitrogen atmosphere for 48 minutes. It was then cooled and concentrated to approx. 300 ml on a rotary evaporator. On cooling, a white crystalline solid precipitated which was filtered, washed with cold ethanol and dried to yield 25 g (56%) of 4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline, m.p. 241 - 243°C. (2)

Peaks indicated in eps from tetramethylsilane (TMS)..

Analysis: Calculated for C15H15N02: C 74.65, H 6.26, N 5.81

Found: C 74.67, H 6.25, N 5.65.

C. N-methyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline

7.20 g (29.9 mmol) of the product from part B in 50 ml of dry dimethylformamide was added to 1.58 g of a 55.5% suspension of sodium hydride in mineral oil (36.5 mmol NaH) while the reaction mixture was kept at 70°C under a nitrogen atmosphere. When the evolution of hydrogen subsided (about 1 hour), the reaction mixture was cooled to 25° C. and a solution of 8.52 g (60 mmol)

methyl iodide in 20 ml of dimethylformamide was added dropwise. The mixture was then heated to 90 - 100° C. for 2 hours, after which it was cooled, poured into ice water and extracted with ether. The ether was evaporated and the residue recrystallized from ethanol to give 6.56 g (86%) of N-methyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline produced.

Analysis: Calculated for C16H1702N: C 75.27, H 6.71, N 5.49

Found: C 75.22, H 6.71, N 5.71

Using the same procedure but using cyclohexylmethyl bromide instead of methyl iodide, N-cyclohexylmethyl-4a-phenyl-J,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline was prepared. By correspondingly using cyclopropyl methyl bromide and cyclobutyl methyl bromide instead of methyl iodide, N-cyclopropylmethyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline and N-cyclobutylmethyl-4a -phenyl-1,3-diketo-1,3,3,4,4a,5,6,7-octahydroisoquinoline was prepared.

D. N- methyl- 4a- phenyl- 1, 3- diketo- trans- decahydroisoquinblin

A mixture of 2.0 g (7.85 mmol) of the product from Part C, 175 mL of absolute ethanol, and 300 mg of 5% palladium-on-carbon was shaken under a hydrogen pressure of 2.81 kg/cm 2 for 24 hours. The catalyst was removed by filtration and the solution evaporated from the filtrate. Recrystallization of the residue from ethanol gave 1.8 g (90%) of N-methyl-4α-phenyl-1,3-diketo-trans-decahydro-isoquinoline, m.p. 151 - 153° C.

Analysis: Calculated for C16H18N02: C.74 .66 , H 7.44, N 5.44

Found: C 74 ,74 ,. H 7.66, W 5.33,

Analogously, the reduction of the N-hydrocarbyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinolines described in Part C gave N-cyclohexylmethyl-4a -phenyl-1,3-diketo-trans-decahydroisoquinoline, N-cyclopropyImethy1-4a-phenyl-1/.3-diketo-trans-decahydroisoquinoline and N-cyclobutylmethyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline.

E. N- methyl- 4a- phenyl- 1, 3- diketo- cis- decahydroisoquinoline

2.0 g of N-methyl-4α-phenyl-1,3-diketo-trans-decahydroisoquinoline in 100 ml of methanol was treated with 400 mg of sodium methoxide and the mixture was refluxed for 30 minutes. It was allowed to stand overnight at 25° C. and was then poured into 1N hydrochloric acid and extracted with ether. The ether extracts were washed respectively with water and brine and then dried (MgSO 4 ) and the ether was evaporated to yield 1.9 g of an oil. NMR (CDCl 3 ): methylene envelope from 70 to 140 eps (8H)^ singlet at 177 eps (3H); multiplet at 145 to 205 eps (3H); singlet at.434 eps (5H).

An experiment in a small scale (40 mg of compound 1,

1 ml methanol and 10 mg sodium methoxyd) carried out in an nmr tube where spectra were taken at fixed intervals, clearly showed the gradual disappearance of the N-methyl resonance of the starting compound part 1 and appearance of a new N-methyl resonance due to the cis-compound. The aromatic proton resonance pattern also underwent a change in the transition from trans to cis conformation. Accordingly, the above oil was believed to be N-methyl-4α-phenyl-1,-3-diketo-cis-decahydroisoquinoline. F. N-methyl-4a-phenyl-cis-decahydroisoquinoline

1.9 g of N-methyl-4α-phenyl-1,3-diketo-cis-decahydroisoquinoline in 75 ml of anhydrous tetrahydrofuran was treated with 2.0 g of lithium aluminum hydride and refluxed overnight. The reaction was stopped by the successive addition of 2.0 ml of water, 2.0 ml of 15% sodium hydroxide bg finally 6.0 ml of water. The inorganic salts were filtered and washed well with ether.

The combined filtrates were evaporated to yield 1.6 g of an oil which was evaporated, b.p. 125°C (0.05 mm), nQ 20 1.5514 and identified as N-methyl-4a-phe■nyl-cis-decahydroisoquinblin.

Analysis: Calculated for C_6H23N: C 83.77' H 10.10, N .6.11.

Found: C 83.74, H 10.11, N 6.07

83.41 10.11

Example 2

N-methyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline

A. 2- cyano- 3- carbethoxymethyl- 3-( m- methoxyphenyl)- cyclohexene

A mixture of 25 g (86.3 mmol) of 2-carbethoxymethyl-2-(m-methoxyphenyl)-cyclqhexanone, Langlois et al., Tetrahedron 27, 5641 (1971>), 100 ml of hydrogen cyanide and 4 drops of a saturated aqueous potassium cyanide solution was stirred at 0° C. under nitrogen for 24 hours. After this time 5 drops of concentrated sulfuric acid were added and excess hydrogen cyanide was evaporated. The residual oil was taken up in ether and washed with 10% aqueous sulfuric acid and then with brine, dried (MgSO4 ) and the ether evaporated. The impure cyanohydrin thus obtained was taken up in 175 ml of pyridine, 35 ml of phosphorus oxychloride was added and the solution was stirred at reflux under nitrogen for 3 hours. It was then cooled and poured into a flask of 500 ml of ice water and 100 ml of concentrated hydrochloric acid and the resulting blariding was extracted with ether. After washing the ether extract with brine, drying and concentrating, 2 2 g of impure product was obtained. This was distilled by short path distillation to a yield of 16 g with boiling point 166° C (0.5 mm). The infrared spectrum for this material indicated that it was 2-cyano-3-carbethoxymethyl-3-(m-methoxyphenyl)-cyclohexene with a small amount of impurity, probably a lactone, with bands at 5.50 u and 5.85 y . This material was considered to be of sufficient purity to be used in the subsequent step.

Analysis: Calculated for<C>18<H>2103N: C 72.20, H 7.07, N 4.68

Found: C 72.22, H 7.13, N 4.10

B. 4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octa-hydrbisoquinoline

16 g (53.5 mmol) of the product from part A dissolved in absolute ethanol was added to 1.5 liters of absolute ethanol which had previously been saturated with anhydrous hydrogen chloride. The solution was refluxed under nitrogen for 48 hours and then allowed to stand at 25° C. for 24 hours. It was concentrated on a rotary evaporator to 500 mL, cooled in ice and the resulting crystalline precipitate was filtered to yield 8.0 g (55%) of 4α-(m-methoxyphenyl)-1,3-diketo-1,2 ,3,4,4a,5,6,7-octahydroisoquinoline, m.p. 230 - 232° C. Analysis: Calculated for C16H17N03: C 70.83, H 6.31, N 5.16 Found: C 70.97, H 6.33, N 5.59 C. N-methyl-4a -(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7- octahydroisoquinoline

4.07 g (15 mmol) of the product from part B in 50 ml of dry dimethylformamide was added to a mixture of 790 mg of a . 55% suspension of sodium hydride (18.1 mmol NaH) in mineral oil in 25 ml of dimethylformamide while the temperature of the reaction mixture was maintained at 60 - 70° C. under a nitrogen atmosphere. After the addition was complete, the reaction mixture was heated to 90°C for 2 hours, after which time the evolution of hydrogen had subsided. The reaction mixture was then cooled to 30° C., after which a solution of 4.25 g (30 mmol) of methyl iodide in 10 ml of dimethylformamide was added dropwise. The mixture was heated to 90 - 100° C. for 2 hours, then cooled and poured into ice water and extracted with ether. The ether extracts were washed with water, dried (MgSO 4 ) and evaporated. The residue was recrystallized from ethanol to give crystalline N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (3.8 g, 89%), sm. p.

139 - 141° C.

Analysis: Calculated for C17HlgN03: C 71.54, H 6.71, N 4.91

Found: C 71.58, H 6.93, N 4.94 D. N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline,

o

3.2 g (11.21 mmol) of the product from part C, 100 ml glacial acetic acid, 50 ml dioxane and 700 mg 5% palladium-on-carbon were shaken under a hydrogen pressure of 2.81 kg/cm 2 for 24 hours . The catalyst was then filtered off and washed well with dioxane, and the combined filtrate was concentrated to a clear oil in a yield of 3.2 g (99.4%). The product was pure N-methyl-4a-. (m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline as determined by thin layer chromatography (20% ether-benzene on silica gel plates) and by its nmr spectrum. NMR (CDCl3 l: complex multiplet at 50 - 150 eps from TMS (9H, -CH9- and -C1-H); quartet at 148, 163, 173, 189 eps (2H, -CH2-CO-), singlet at 180 eps (3H, NCH3), singlet at .220 eps (3H, OCH3), multiplet at 397 - 420 eps (4H, Ar-H).

E.. N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline

A solution of 4.6 g (1.6 mmol) of N-methyl-4a-(m-methoxyphenyl)-1,3-dikato-trans-decahydroisoquinoline and 1.84 g (3.4 mmol). sodium methoxide in 150 ml of methanol was stirred at room temperature under nitrogen for 20 hours. The reaction mixture was poured into 150 ml of ice water and extracted with ether, and the combined extracts were washed with 3N hydrochloric acid and saturated sodium bicarbonate, dried (Na 2 SO 4 ) and evaporated. The impure product was a white viscous oil (3.8 g). Thin layer chromatography on silica gel, eluting with 10% ether/benzene showed a major spot (Rf 0.31) and a minor component (R_- 0.07). The major component, N-methyl-4α-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline, was clearly separated by preparative thick layer chromatography and isolated as a: f pure oil.

NMR: 7.2 (q, J = 8, 1H, Ar-H), 7.0 - 6.65 (m's, 3H, Ar-H), 3.76 (s, 3H, -OCH3), 3, 0 (s, 3H, NCH3), 3.15 - 2.95 (m, 2H, -CH2CO-), 3.4 - 3.2 (br, m, 1H, -CH-) 2.2 - 1, 4. (m's, 8H,

-CH2-).

F. N-methyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinblin

A solution of 3.8 g (1.3 mmol) of N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline in 50 ml of dry tetrahydrofuran was added dropwise to a stirred suspension of 3.8 g lithlumaluminium hydride. in 25 ml of tetrahydrofuran under a nitrogen atmosphere. When the addition was complete, the reaction mixture was refluxed overnight, then cooled and excess hydride destroyed by dropwise addition of 3.8 mL of water, 3.8 mL of 3N sodium hydroxide, and 11.4 mL of water. The resulting white salt was filtered off and washed with ether. The organic solution was dried (Na 2 SO 4 ) and evaporated to give 2.5 g of an opaque oil. This was evaporatively distilled at 50°C at 0.3 micron Hg. The product was isolated as a colorless viscous oil identified as N-methyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline, yield 2.38 g.

HRMS: Calculated MW for C^H^NO: 259. 19.35 Measured: 259.1936 NMR: 7.27 (t, J = 8, 1H, Ar-H), 7.18 - 6.95 (m's, 2H, Ar- H), 6.73 (d x t, J = 7.5, 2, IR, Ar-H), 3.78 (s,.3H, -OCH3), 2.6 - 2.3 (sh, m, 4H, - CH2-), 2.23 (s, 3H, -NCH3), 2.0 - 1.2

(m, 11H, -CH2, -CH-).

Example 3

N-allyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline

A. 4a-(m- methoxyphenyl)- 1, 3- diketo- trans- decahydroisoquinoline

A solution of 6.0 g of 4a-(m-methoxyphenyl)-1,-3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline in 250 ml of glacial acetic acid was treated with 1 g of 5 % palladium-on-carbon and the mixture was hydrogenated under a hydrogen pressure of 2.81 kg/cm 2 for 24 hours in a Parr shaker. The catalyst was then filtered off and the filtrate evaporated. The residue 4a-(m-methoxyphenyl).-1,3-diketo-trans-decahydroisoquinoline was recrystallized from ethanol and had a melting point of 189 - 190°C.

Analysis: Calculated for' C16H19N03: C 70'31'H 7'01'N 5/12

Found: C 70.60, H 7.01, N 5.05

70.46 7.02 5.13

B. N-allyl-4a-(m-methoxyphenyl)-cis-1,3-diketodecahydroisokirioline

4/5 g (16/5 mmol) of the product from Part A in 70 ml of dry dimethylformamide was added dropwise to 880 mg of a 55% suspension of sodium hydride in mineral oil in 30 ml of dimethylformamide at 70-80° C. The mixture was heated to 70° C and stirred for 1 hour. It was then cooled to 35° C. after which 2.02 g (16.7 mmol) of allyl bromide in 30 ml of dimethylformamide was added dropwise. After heating the reaction mixture at 90 - 110° C. for 2 hours and standing at 25° C. overnight, it was poured into ice-cold 1% hydrochloric acid and extracted with ether.

The organic extracts were washed with water, brine and then dried (magnesium sulfate). Evaporation of the ether gave 5.6 g of impure product which was chromatographed on 200 g of "Florisil" and eluted with 5% acetone-hexane to yield 4.0 g of N-allyl-4a-(m-methoxyphenyl)-cis- Evaporatively distilled 1,3-diketodecahydroisoquinoline (oil), m.p. 160°C (0.05mm).

Analysis: Calculated for C19H23C>3N: C 72.81, H 7.40, N 4.47

Found: C 72.62, H 7.50, N 4.48

72.46 7.37

Treatment of a sample of the allyl derivative prepared as above with sodium methoxide in methanol (both at room temperature and reflux temperature) or with potassium t-butoxide in THF left the sample completely unchanged, confirming that the cis derivative had been formed first. This was also confirmed by spectral analysis. NMR: 7.2 (q, J=8, 1H, Ar-H), 7.05 - 6.75 (m, 3H, Ar-H), 5.9 - 5.3 (m, 1H, -CH =),'

5.1 - 4.5 (m, 2H, =CH_), 4.4 - 4.15 (m, 2H, n-CH2~), 3.75 (s,

3H, -OCH3)/3.4 - 2.6 (m's, 3H, -CH2CO and -CHCO), 2.1 - 1.4 (m, 8H, -CH2-).

C. N-allyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline

4.0 g (12.8 mmol) of the product from Part B in 75 mL sodium-dried tetrahydrofuran was treated with 4.0 g (105

mmol.) of lithium aluminum hydride under nitrogen, and the mixture was stirred and refluxed for 24 hours. It was allowed to cool and was then treated respectively with 4.0 ml of water, 4.0 ml of 15% aqueous sodium hydroxide and finally with 12.0 ml

water. The precipitated inorganic salts were filtered off and washed well with ether. The combined filtrates were dried over anhydrous potassium carbonate and after evaporation of the ether gave 3.27 g of N-allyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline (oil) which was evaporatively distilled, b.p. 150°C (0.05mm).

NMR (CDCI3): complex multiplet at 70 to 190 eps from TMS (methylene H, 17H), singlet at 234 eps (3H, OCH3), multiplets at 300 - 350 eps (vinyl H) and multiplets at 405 to 460 eps (aromatic H).

IR: 6.10-y (C-C), 6.25, 6.35 u (Ar).

Example 4 N-phenethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline

A. N-phenethyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline

10.0 g (37 mmol) of 4α-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 250 mL of anhydrous dimethylformamide was added with stirring to a suspension of 2.8 g (55.5 mmol) of 50 % sodium hydride in mineral oil (washed with pentane) in 125 ml of anhydrous dimethylformamide heated to 50° C. under nitrogen. The mixture was heated to 90° C. for 2 hours, then cooled to 40° C. during which time a solution of 14.0 g (74 mmol) phenethyl bromide in 20 ml anhydrous dimethylformamide was added and the reaction mixture was heated at 90° C. over the night. The cooled solution was poured into ice water and extracted with ether. Evaporation of the ether gave an oil which was purified by column chromatography (Silicar CC-7, elution with acetone-benzene). The major fraction was identified as N-phenethyl-4α-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline.

NMR (CDCl 3 ): 7.2 - 7.0 (m, -6H), 6.95 - 6.6 (m, 3H), 4.0 -

3.7 (m, 2H), 3.75 (s, 3H), 3.2 - 2.8 (m, 3H), 2.8 - 2.35 (m, 2H), 2.0 - 1.3 (m, 8H).

B. N-phenethyl-(m-methoxyphenyl)-cis-decahydroisoquinoline

5.0 (13.3 mmol) of the product from Part A in 200 mL sodium-dried tetrahydrofuran was added to a stirred suspension of 5.0. g of lithium aluminum hydride in 80 ml of tetrahydrofuran under a nitrogen atmosphere, and the mixture was stirred under reflux for 20 hours. It was cooled and treated respectively with 5.0 ml water, 5.0 ml•3N sodium hydroxide and 15.0 ml water. The inorganic salts were filtered and washed with ether. The combined filtrates were evaporated and the residue, N-phenethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline (oil), was evaporated, m.p. 70°C (0.002mm). NMR (CDCl 3 ): 7.21 (s, 5H), 7.3 - 6.88 (m, 3H), 6.8 - 6.55 (m, 1H), 3.79 (s, 3H), 2 .9 - 2.3 (m, 8H), 2.1 - 1.1 (m, 11H). Analysis: Calculated for C24H31NO: C 82.47, H 8.94, N 4.01 Found: C 82.21, H 9.06, N 3.96 82.25 9.04 3.98 Example 5 N-phenethyl - 4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline

1.49 g (4.28 mmol) of N-phenethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline was mixed with 3.0 g (25.9 mmol) of pyridine hydrochloride and stirred under nitrogen for 1 hour while heated to 190° C. After cooling, the solid mixture was dissolved in chloroform and the chloroform solution was washed with water, dried (Na 2 SO 4 ) and evaporated. The residue was evaporated, b.p. 95°C (0.0002 mm) which gave a glass (m.p. 70-80°C) which was identified as N-phenethyl-4α-(rn-hydroxyphenyl)-cis-decahydroisoquinoline hydrochloride salt.

NMR (CDCl3)' 7'17 (s'5H)' 7'3"6'6 ("i' 4H> '3' 1 2'5 <m'

9H), 2.3 - 1.2 (m, 10H).

Example 6

N-methyl-4a(p-fluorophenyl)-cis-decahydroisbquinoline

A. 2-(p-fluorophenyl)-cyclohexanone

The Grignard reagent prepared by adding 210 g of p-fluorobromobenzene in .800 ml of anhydrous ether to 29.1 g of magnesium shavings in 50 ml of ether was added with cooling to keep the temperature of the reaction below 15°C, to a solution of 158.4 g of 2-chlorocyclohexanone in 800 ml of anhydrous benzene. The reaction mixture was stirred at 25°C for 18 hours and the ether was distilled off and the resulting benzene solution boiled under reflux for 24 hours. It was then poured into a mixture of 1 liter of water and 200 ml of hydrochloric acid and extracted with ether. After evaporation of the ether, the residue was distilled to give 117 g (51%), m.p. 15° C (0.2 mm). The material solidified

on standing and was recrystallized from hexari, and had a melting point of 56 - 59° C.

Analysis: Calculated for C12H13FO: C 74.98, H 6.82

Found: C 74.24, H 6.83

B. 2-(p-Fluorophenyl)-2-carbethoxymethylcyclohexanone

117 g of the product from Part A in 120 ml of anhydrous tetrahydrofuran was added to sodium amide (from 14.7 g of sodium) in 2000 ml of liquid ammonia. The reaction mixture was stirred for 90 minutes, after which 68 ml of ct-bromomethyl acetate was added in

during 4 5 minutes. The reaction mixture was stirred for 3 hours, after which the ammonia was allowed to slowly evaporate. 100 ml of methanol and 1000 ml of water were added to the residue. Extraction with ether gave the product which after distillation gave 115.4 g (68%), b.p. 134°C (0.25mm).

Analysis: Calculated for C16H1SF03: C 69.05, H 6.88

Found: C 68.97, H 6.95

C. 2-cyano-3-(p-fluorophenyl)-3-carbethoxymethylcyclohexanone

50 g of the product from part B was reacted on the same

manner as described in example 1, part A, with 200 g of hydrogen cyanide and 12 drops of saturated aqueous potassium cyanide. Reaction of the product of this reaction with phosphorus oxychloride in pyridine (as described in Example 1, part A) gave 2-cyano-3-(p-fluorophenyl)-3-carbethoxycyclohexene. Yield 33 g, k.p. 160° C )0.35 mm). D. 4a-(p-fluorophenyl)-1,3-diketo-1,2,3,4,4a,5,6,7,.

octahydroisoquinoline

75 g of the product from part C was added to 500 ml of anhydrous ethanol saturated with anhydrous hydrogen chloride and the mixture boiled under reflux for 48 hours. The solution was then concentrated, cooled and the white precipitate was collected. Yield was 32 g, m.p. 201 - 203° C.

Analysis: Calculated for C15H14FN02:. C 69.49, H 5.44, N 5.40

Found: C 69 , 30, H 5.27, N 5.0.2

E.. N-methyl-4a-(p-fluorophenyl)-1,3-diketo-1,2,3,4,4a,

5, 6, 7- octahydroisoquinoline

20 g of the product from part D in 150 ml of anhydrous dimethylformamide was added to 3.35 g of a 55% suspension of sodium hydride in mineral oil in 100 ml of dimethylformamide in the same manner as described in Example 1, part C. The alkylation with 11, 5 g of methyl iodide and work-up (described in example 1, part C) gave 12 g of N-methyl-4a-(p-fluorophenyl)-1,3-diketo-1,2,3,4-4a,5,6,7-octahydroisoquinoline with melting point 124 - 128° C. F. N- methyl-4α-(p-fluorophenyl)-1,3-diketo-trans-decahydro isoquinoline \ _ '.' 12 g of the product from part E in 150 ml of ethanol and 50 ml of glacial acetic acid was hydrogenated over 3 g of 5% palladium-on-carbon with a hydrogen pressure of 2.81 kg/cm 2 as described in example 1, part D>as after column chromatography on 350 g of Silicon CC-7 and elution with benzene gave 9 g of med. melting point 141 - 14 3° C. Analysis: Calculated for Cl6<H>18<F><N>o2: C 69.80, H 6.59, N 5.09 Found: C 69.81, H 6.54 , N 5.08 G. N-methyl-4a-(p-fluorophenyl)-1,3-diketo- cisdecahydroisoquinoline 2 g of the product from Example F, 100 ml of methanol and .400 mg of sodium methoxide were stirred at 25° C. for 4.8 hours after immediate heating at reflux temperature. The mixture was then poured into dilute hydrochloric acid and extracted with ether to give 2 g of a clear oil.

NMR(CDC1-}) methylenes appeared as a broad singlet centered at, 100 eps (8H) , singlet at 181 eps (ISHCH3, 3H), multiplet plus quartet at 177,183, 186, 190 eps (CH_CO and CHCO, 3H) , multiplet at 410 to 450. eps (ArH, 4H) .

H. N-methyl-4a-(p-fluorophenyl)-cis-decahydroisoquinoline

2 g of the product from part G, 75 ml of anhydrous tetrahydrofuran and 2 g of lithium aluminum hydride were refluxed. . cooling for 24 hours. The reaction mixture was worked up as described in example 1, part F, forming 1.35 g of product with a boiling point of 110° C. (0.15 mm).

Analysis: Calculated for C16H2_FN: C 77.69 , H 8.97, N 5.66

Found: C 77 , 55, H 9 .10, N 5.63

By following the above general procedure, N-phenethyl-4a-(m-fluorophenyl)-cis-decahydroisoquinoline can be obtained.

Example 7

Salts of N-phenethyl-4a-m-methoxyphenyl-cis-decahydroisoquinoline

When N-phenethyl-4a-m-methoxyphenyl-cis-decahydroisoquinoline is added to 0.1 to 3N hydrochloric acid, a white solid is obtained which can be recrystallized from ethanol. This hydrochloride had a melting point of 220 - 222° C (decomposition).

When N-phenethyl-4a-m-methoxyphenyl-cis-decahydroisoquinoline is mixed with a slight molar excess of maleic acid in

hot acetonitrile, the crystalline maleate salt is formed on cooling, with a melting point of 167 - 168° C.

Example 8

Dectro- N- methyl- 4a- phenyl- cis- decahydroisoquinoline

A. levo- and dextro-2-^carboxymethyl-2-phenylcyclohexanone- .

α-phenethylamine salt

1. 40 g (0.154 mol) of 2-carboxymethyl-2-phenylcyclohexanone (Boekelheide et al) obtained by alkali hydrolysis of 2-carbethoxymethyl-2-phenylcyclohexanone was dissolved in 140 ml of hot ethanol and treated with 27 g of (+)-α-phenethylamine . The mixture was allowed to slowly crystallize and gave 21.8 g of the 1-salt. Sm.p. 130 - 132°C, [α] -94. Another recrystallization from ethanol • gave the material with m.p. 137 - 139°C, [α]D142°. Further recrystallizations did not change the optical rotation. 2. The mother liquors were taken up in 6N hydrochloric acid and the free acid was extracted with ether. This material was dissolved in ethanol, treated with (-)α-phenethylamine and allowed to slowly crystallize. The white crystalline d-salt had m.p.

136 - 137.5° C, [a]25° + 141° C.

B. ' levo- and dextro-2-carboxymethyl-2-phenylcyclohexanone

1. A solution of the product from part A-I (14.0 g) in 250 ml of cold 6N hydrochloric acid was extracted with ether and treated as above to give 9.6 g of 1-keto acid, m.p. 94-95°C, [α]D -194 (c 1.04, CHCl 3 ). 2. A solution of 15.9 g of the product from part A-2 in 250 ml of cold 6N hydrochloric acid was extracted with ether. The ether extracts were dried with anhydrous magnesium sulfate, filtered and the ether evaporated to give 10.0 g of d-keto acid, m.p. 94-95°C, [α]<25>°+ 193° (c 1.03, CHCl 3 ). C. levo- and dextro- 2- carbethoxymethyl- 2- phenylcyclohexanone

1. A solution of 28 g of the product from part B-l i

700 ml of ethanol containing 3 ml of concentrated sulfuric acid was boiled under reflux in a soxhlet extractor apparatus with a sleeve filled with 3A molecular sieve. After refluxing for 24 hours, excess potassium carbonate was added. The mixture was filtered and the solution evaporated. The residue was distilled to give 1-ketoester, a clear oil, m.p.

125° C (0.1 mm), [α]<25>° -207° (c 1.5, CHCl 3 ).

2. A solution of 40 g of the product from part B-s in 1000 ml of ethanol containing 8 ml of concentrated sulfuric acid was treated as above and after distillation gave the d-keto ester as a clear oil, b.p. 125°C (0.1 mm), [a]25 + 234°C (c 1.00, CHC13). D. Levo- and dextro* °-2-cyano-3-phenyl-3-carbethoxymethylcyclo hexene 1. 36 g (0.138 mol) of the product from part C-l, 200 ml of hydrogen cyartide and 12 drops of a saturated aqueous solution of potassium cyanide was stirred at 0°C overnight. Concentrated sulfuric acid was added and excess hydrogen cyanide evaporated. The residue was taken up in ether, washed successively with 0.1N sulfuric acid and brine, dried (Na 2 SO 4 ) and evaporated. The residual oil was dissolved in 250 ml of pyridine and 50 ml of phosphorus oxychloride was added. The reaction mixture was stirred under nitrogen and reflux for 5 hours and then allowed to stand overnight at 25° C. It was then poured into a mixture of 1 liter of ice water and 200 ml of concentrated hydrochloric acid, and the resulting mixture was extracted with ether. The ether extract was washed with dilute hydrochloric acid, water and brine and then dried (Na 2 SO 4 ) and evaporated. The residual oil was distilled to give 28 g of the 1-cyanoester, b.p. 130° C. (0.1 mm.), 2. 35 g (0.134 mol) of the product from part C-2 was treated as above to give 25 g of the d-cyano ester, b.p. 130°C (0.1mm). E. dextro- and levo-4a-phenyl-1,3-diketo-1,2,3,4a,5,6,7- octahydroisoquine. \ 1. 28 g of the product from part D-l, dissolved in 50 ml absolute ethanol previously saturated with anhydrous hydrogen chloride was added to 600 ml of absolute ethanol. The solution was boiled under reflux under nitrogen for 48 hours. It was then cooled and concentrated. A white crystalline solid precipitate which was filtered was then recrystallized at 25° from ethanol to give 12.0 g of the unsaturated d-imide, [ct]D + 219 (c 1.00, CHCl 3 ). 2. 17 g of the product from part D-2 in 40 ml of absolute ethanol was added to 400 ml of absolute ethanol previously saturated with anhydrous hydrogen chloride, and then treated as above to give 8.9 g of the unsaturated 1 -imide, m.p. 169 - 170° C, [aj" ..-208 (c 1.20, CHCl3). In this example, the sign of rotation changed in the ring-closing reactions. • F. dextro- and levo-N-jnethyl-4a-f. enyl-1,3-diketo-1,2,3,4,4a,5,6,7- octahydroisoquinoline 1. 7.2 g (29.9 mmol) of the product from part E-.l in 50 ml of dry dimethylf ormamide was added to 1.58 g of a 55.5%t-dg suspension of sodium hydride in mineral oil (36.5 mmol) NaH) in 50 mL of dimethylformamide, while the reaction mixture was maintained at 70° C. under nitrogen. The mixture was stirred and heated at 70° C. for 1 hour after the addition was complete, then cooled and 8.5 g of methyl iodide in 20 ml of dimethylformamide was added dropwise. The mixture was heated at 90° C. for 30 minutes and then allowed to stand overnight at 25 ° C. It was poured into water and extracted with ether. The ether extracts were dried (Na 2 SO 4 ) and evaporated and the residue recrystallized from ethanol to give 6.17 g of the unsaturated d-N-methylimide, mp 156 - 158 °C, [α]<25>+ 245° (c 1.25, CHCl 3 ). 2. 8.94 g (37.1 mmol) of the product from part E-2 in 60 ml dimethylformamide was added to 1.96 g of a 55.5% suspension of sodium hydride in mineral oil in 50 ml of dimethylformamide as stated above, and which after recrystallization in ethanol gave 6.0 g of the unsaturated 1-N-methylimide, m.p. 149 - 153° C [aj 25° 258°.

G. dextro- and levo-N-methyl-4a-phenyl-1,3-diketo-trans-decah<y>droisoquinoli<n>

1. A mixture of 6.1 g (23.9 mmol) of the product from Part F-1, 100 ml of glacial acetic acid and 2 g of 5% palladium-on-carbon was shaken under a hydrogen pressure of 2.81 kg/cm for 24 hours. The catalyst was removed by filtration and the solvent evaporated. Recrystallization of the residue from ethanol gave 3.7 g of the trans-saturated d-N-methylimide, m.p. 189 - 191 C, [<x]-D + 81°. 2. 6.0 g (23.5 mmol) of the product from part F-2 was treated as above to give 4.0 g of the trans-saturated 1-N-methylimide, m.p. 159 - .160°, [ct]D"72° (c, 1.02, CHC13). H. dextro- N- methyl- 4a- phenyl- 1, 3- diketo- cis- decahydroisoquinoline

A mixture of 2 g of the product from G-I, 100 ml of methanol and 500 mg of sodium methoxide was boiled under reflux for 1 hour and then allowed to stand at 25° C. for 18 hours. The reaction mixture was worked up as described in Example 1, part E, forming an oil which was used without further purification.

I. d-N-methy1-4a-phenyl-cis-decahydroisoquinoline

2 g of the crude product from part H, 100 ml of anhydrous tetrahydrofuran and 2 g of lithium aluminum hydride were refluxed for 24 hours. The reaction was stopped by the successive addition of 2 ml of water, 2 ml of 15% sodium hydroxide and 6 ml of water. . The inorganic salts were filtered off and the filtrate concentrated. The residue was evaporatively distilled to give a clear oil, b.p. 100° C (0.07 mm), [a]_g5+ 368°. The picrate derivative was readily formed and had a melting point of 144 - 147°C.

Dosage forms and application

The analgesic agents of the invention may be administered to relieve pain in any manner such as. .provides contact between the active agent and the agent's site of action in the body of the mammal. They may be administered in any suitable conventional manner for use in conjunction with pharmaceutical agents, either as individual therapeutic agents or in combination with therapeutic agents. They may be administered alone, but are generally administered with pharmaceutical carriers selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The administered dose will of course vary depending on known factors such as the pharmacocynamic characteristics of the particular agent, and its mode of action and route of administration, age, health and weight of the recipient, the nature and degree of symptoms, the type of concomitant treatment, the frequency of treatment - the ling and the desired effect. Generally, a daily dose of active ingredient can be approx. 0.01 - 100 mg per kg body weight. Usually 0.1 - 50, and preferably 1 - 25 mg per kg per day given in divided doses 2 to 4 times per day or in the form of a dose that is released slowly, effectively to achieve the desired results.

Dosage forms (compositions) suitable for. internal administration contains from 25 mg to 75 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will usually be present in an amount of 0.5 - .95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions, it can also be administered parenterally in sterile liquid dosage forms, or rectally in the form of suppositories.

Gelatin capsules contain the active ingredient and

- powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to prepare compressed

pills. Both tablets and capsules can be manufactured as products with extended release of active ingredient to provide a continuous release of medication over a period of several hours. Compressed tablets can be sugar-coated or film-coated to mask any unfavorable taste and protect the tablet from the atmosphere, or coated for selective dissolution in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain dyes or flavors to increase patient compliance.

In general, water, a suitable oil, physiological saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, buffer substances. Antioxidants such as sodium bisulphite, sodium sulphite or ascorbic acid either alone or in combination are suitable stabilizers. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride. methyl or propyl paraben and chlorobutanol.

Suppositories contain the active ingredient in a suitable oil-active or water-soluble base. The oil-active class includes cocoa butter and fats with similar properties.

the sparingly soluble class includes polyethylene glycols.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E.W. Martin, a standard reference in this field.

Suitable pharmaceutical dosage forms for administering the compounds according to the invention can be illustrated as follows:

Capsules

A large number of unit capsules were prepared by filling standard two-part hard gelatin capsules each with 50 mg powdered active ingredient, 110 mg lactose, 32 mg talc and 8 mg magnesium stearate.

Capsules

A mixture of active ingredient in soybean oil was prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 50 mg of the active ingredient. The capsules were washed in petroleum ether and dried.

Pills

A large number of tablets were prepared by conventional technique so that the dosage unit is 50 mg of active ingredient, 7 mg of ethyl cellulose, 0.2 mg of colloidal silicon dioxide, 7 mg of magnesium stearate, 11 mg of microcrystalline cellulose, 11 mg of corn starch and 98.8 mg of lactose. Appropriate coatings can be applied to increase palatability or slow absorption.

Injectable

A parenteral composition suitable for administration

by injection was prepared by stirring 1.5% by weight of active ingredient in 10% by volume of propylene glycol and water. The solution was sterilized by filtration.

Suspension

An aqueous suspension was prepared for oral administration such that each 5 ml contained 10 mg of finely divided active ingredient, 500 mg of acacia, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, USP, 5 mg of sodium saccharin and 0.025 ml of vanilla tincture.

Injectable

A parenteral composition suitable for administration

by injection was prepared by dissolving 1% by weight of active ingredient in sodium chloride injection solution USP XV and the pH of the solution was regulated to between 6 and 7. The solution was sterilized by filtration.

A standard procedure for determining and comparing the analgesic activity of compounds in this series for which there is good correlation with efficacy in man is the standard phenylquinone twist test. modified from Siegmund et. at., Proe. Soc. Exp. Biol. With. 95_, 7 29 (1957). A test compound suspended in 1% methylcellulose was given orally to the fasted (17 - 21 hours) [white female mice, 5 - 20 animals per double blind test. Aqueous (0.01% phenyl-p-benzoquinone) phenylquinone was injected intraperitoneally at 23 or 30 minutes later using 0.25 ml per mouse. Beginning at the 30th or 37th minute after oral administration of the test compound, the mouse was observed for 10 minutes for a characteristic stretching or writhing syndrome indicative of pain induced by phenylquinone. The effective analgesic dose for 50% of the mouse (ED 50 ) was calculated by the average movement method of Weil, Biometrics 8, 249 (1952). The following table shows the oral ED 50 doses for a representative sample of the compounds of the invention and several standard analgesics.

"1

Cis-decahydroisoquinoline analgesics

Claims (1)

Procedure for the preparation of a therapeutically active compound with the cis configuration of the formula: where R1 is hydrogen, C 1 - Cg alkyl, -CH2 Y where Y is C'2 - C.g alkenyl-or C2 - Cg alkenyl, where. m is 1 or 2, X is Cl, Br, F, CF3 , OCH3 , CH3 , isopropyl, -NH2 or -N(CH3 )2 , a = 0, 1 or 2, or cycloalkylinethyl of the formula where Ry is hydrogen, F or methoxyl, Rg is H or methoxyl, provided that when Ry is F, Rg is H, as well as pharmacologically acceptable salts thereof, characterized in that a compound of the trans configuration of the formula brought into contact with a relatively strong base at temperatures from :20 to 120°C, or by a compound with trans configuration nen of the formula brought into contact with an alkali metal hydride and an alkylating agent part at a temperature of 20 - 120°C.