IE41898B1 - Decahydroisoquinoline derivatives, processes for their preparation and their use in pharmaceutical compositions - Google Patents

Abstract

4A-Aryl-cis-decahydroisoquinolines, such as N-phenethyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline, useful as analgesics.

Description

This invention concerns the discovery that a selected group of 4a-aryl-cis-decahydroisoquinolines are of interest as analgesics, many with little or no addictive properties.

Boekelheide and Schilling, J_. Am. Chem. Soc. 72, 712 (1950), dis5 closed the compound N-methyl-4a-phenyl-cis decahydroisoquinoline, (naming it N-methyl-10-phenyldecahydroisoquinoline) and indicated that it had low analgesic activity.

The present invention results from efforts to develop new compounds with high analgesic potency and low abuse liability.

According to this invention there are provided novel compounds of formula I and their suitable pharmaceutical salts, processes for their manufacture, pharmaceutical compositions containing them, and methods of using them to produce analgesia in mammals. For legal reasons we claim hereinafter the use of the compounds in mammals other than man, but the compounds are thought to be of interest for human therapy. formula I where R1 is hydrogeh; Cy—Cg alkyl; —CH2Y where Y is C2—C6 alkenyl or C2—C6 alkenyl; where m is 1 or 2, X is Cl, Br, F, CF3, 0CH3, CH3, isopropyl, —NH2, or - 2 41898 —N(CH3)2, and a = 0, 1 or 2; cycloalky Unethyl of the formula —CK2CH\^(j;H2)n where n is 2—5; R2 is divalent oxygen (=0), or together with adjacent carbon atom is the group Representative R1 groups are methyl, ethyl, propyl, butyl, hexyl, allyl (—CH2CH = CH2), 2-butenyl, 3-butenyl, 4-heptenyl, 3,3-dimethylallyl {—CH2CH = C(CH3)2}, propargyl (—CH2C = CH), heptynyl, benzyl, phenethyl, cyclopropylmethyl {—CH2CH< (CH2)2), cyclobutylmethyl {—CH2CH<(CH2)3}, cyelohexylmethyl {—CH2CH<(CH2)5}, furylmethyl ( —CH2-φ) )» 2 furyl ethyl { CH2CH2—/p\ ), o xoz - 3 41898 and £-dimethylaminophenethyl.

Representative angular aryl groups are 3-hydroxyphenyl, 3-methoxyphenol, 4-methoxyphenol, 2-acetoxyphenol, 2,3-dihydroxyphenyl, 3,4dimethoxyphenyl, 3,4-diacetoxyphenyl, 3-hydroxy-4-methoxyphenyl, 2methoxy-3-acetoxyphenyl, 3-fluorophenyl and 4-fluorophenyl.

The 4a-aryl-cis-decahydroisoquinolines of formula I include various stereochemical isomers stemming from substitution at position 6, and from optical asymmetry of the whole structure. When monovalent R2 substituents at position 6 are different (e.g. when R2 and its adjacent carbon atom is ,H spatial considerations require the existence of axial and equatorial isomers. In the molecule as a whole, spatial considerations require the existence of d and 2 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 made with physiologically acceptable acids that are known in the art; such salts include hydrochloride, sulfate, phosphate, nitrate, citrate and maleate. - 4 41898 The analgesic compounds (and their pharmaceutically suitable salts) preferred because of their high level of activity are those where R* is H and R3 is ro—OH or ro—QCH3.

Preferred for the same reason are those compounds where R1 is a substituted phenethyl group.

Most preferred are the following two compounds: 4a-m-hydroxyphenylN-phenethyl-cns-deeahydroisoquinoline; 4a-m-hydroxyphenyl-N-(£-toly1e-ethyl-cis-decahydroisoquinoline.

Synthesis The multi-step processes which form a further aspect of the invention start with 2-cyano-3-aryl-3-carbalkoxymethylcyclohexenes which can be obtained according to procedures disclosed by Boekelheide and Schilling (loc. cit.) with respect to 2-cyano-3-phenyl-3-carbethoxymethylcyclohexene (cf. Example 1, Part A). Reaction of a 2-cyano-3aryl-3-carbalkoxymethylcyclohexene with hydrogen chloride in a Cj.i, alkanol such as ethanol forms a 4a-aryl-l,3-diketo-l,2,3,4,4a,5,6,7octahydroisoquinoline (cf, Example 1, Part B). These 1,3-diketo-octahydroisoquinolines possess a conformational arrangement of the fused rings which requires formation of trans-decahydroisoquinoline structures when the 8,8a-double bond is converted to a single bond (cf, Example 1, Part D; Example 6 Part A). A key step in the invention is the novel isomerization of 1,3-di keto-trais-decahydroi soquinol ine to the cis isomer in the presence of a relatively strong base (cf, Example 1, Part E; Example 4, Part A).

The selection of specific preparational steps following the initial formation of a l,3-diketo-l,2,3,4,4a,5,6,7-octahydroisoquinoline depends upon the specific 4a-aryi-ci_s-decahydroi soquinol ine derivative that is desired. The sequence involves at least three steps, A, B, and C, which are illustrated below. Compounds having no unsaturated carbon to carbon bonds in R1 (Ria in process steps) are prepared by steps A, B—1, - 5 41898 and C. Compounds having saturated or unsaturated carbon to carbon bonds in R1 are prepared by steps A, B—2, and C. - 6 41898 Ria in path B—1 is the same as R1 except that it does not include unsaturated groups such as alkenyl or alkynyl. These groups appear to undergo reduction to alkyl, simultaneously with the reduction of the 8,8a bond, in going from compound (3) to compound (4). Thus to obtain compounds of formula I where R1 has alkenyl or alkynyl bonds, path B—2 is followed. In this path the 8,8a bond of compound (2) is first reduced and then the resulting trans product (6) is reacted e.g. with f^Br, R1! or mesylates to form the cis product (5) in which R1 has alkenyl or alkynyl groups. Path B—2 includes the possibility of isolating the N-unsubstituted cis imide followed by normal N-alkylation with either a saturated or unsaturated R1 group.

In the foregoing formulae (1) to (8), the groups R1 have values given previously. R5, together with the adjacent carbon atom is the group Ar1 is R6 is Ci to Ci, alkyl, in which R7 is hydrogen, F or methoxyl; R8 is H or methoxyl; provided that when R7 is F, R8 is H. - 7 41898 The following description sets out preferred methods for performing the process steps illustrated above.

In Step A reactant R50H, which is also the reaction medium, is generally used in excess, but to ensure maximum yield it should be used in an amount of at least one mole per mole of cyanoester. Likewise, the HCl reactant can be used in excess but to ensure maximum yield it should be present in an amount of at least one mole per mole of cyanoester. The reaction is run in the liquid phase under anhydrous conditions. The reaction temperature should generally be in the range of 50 to 12O°C. The reaction pressure is not critical, ordinarily being atmospheric for convenience, but should be consistent with achievement of the stated reaction temperature.

In Step B—1 for the conversion of (2) to (3), or in step B—2 for converting (2) to (6), any reactive alkylating agent can be used, such as hydroearbyl iodide, bromide, mesylate, tosylate or azide. The alkylating agent may thus be generalized as R1—X, where X is an atom or group removable as an anion. Alkyl iodides, bromides, mesylates, tosylates, and azides are included and the hydroearbyl group corresponds to R1 in general formula I. Any base capable of extracting a proton from the imide is satisfactory. Exemplary are alkali metal hydrides (sodium hydride or potassium hydride) in aprotic media (dimethylformamide, hexamethyl phosphoramide, dimethylsulfoxide); alkoxides in aprotic or alcoholic solvents, as, for example, sodium ethoxide in ethanol and potassium t-butoxide in ethanol. Mesylates (Ms = mesyl group = methanesulfonyl group) are described in Fieser and Fieser, Advanced Organic Chemistry, 1961, pp. 292, 293 and 319. Hydroearbyl bromides, iodides or mesylates are readily available, as indicated in the following table (Table I).

The reaction temperature may be in the range 20—120°C.

In paths B—1 and B—2 a strong base, with or without an inert solvent, is used. Representative strong bases include alkali metal hydrox- 8 41898 ides, 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 methoxide, potassium ethoxide or lithium propoxide. An inert solvent can be used if desired; included are Cj_i, alkanols, e.g., methanol, ethanol or t-butanol. The reaction temperature can range from room temperature to reflux temperature of the reaction mixture, e.g. from 20 to 120°C..

TABLE I.

Rl Source C, to Ct Alkyl and Alkenyl bromides Commercially available Allyl bromides Propargyl bromides 3,3-Dimethylallyl bromides Cyclohexylmethyl bromides Benzyl bromides Phenethyl bromides 4-Phenyl-£-butyl bromides Cyclopropylmethyl bromides Cyclobutylmethyl bromides Cyclopentylmethyl bromides 2-Furylmethyl bromides 2-Furylethyl mesylates Commercially available Commercially available Commercially available Commercially available Commercially available Commercially available Bugrova et al., Zh. obshch. Khim. 32, 3575 (1962) Kirmse et al.,Ber.,99, 2855 (1966) Krug et al., J.Am.Chem.Soc., 76 3222 (1954) Smith et al., J.Org.Chem., 21, 1448 (1956) Sharifkanov et al., Khim. Khim Techno! (alma-ata) 1971, 80 Crossland and Servis, J.· Org.Chem. 35, 3195 (1970) give Procedure for mesylates from alcohols - 9 41898 R1 TABLE I (Continued) Source 2-Thienylethyl mesylates Substituted penethyl mesylates In the preparation of a 2-cyano-3-phenyl-3-carbalkoxymethylcyclohexene, the Boekelheide and Schilling procedure involves preliminary steps starting with cyclohexanone, as follows; a. Cyclohexanone + 2-chlorocyclohexanone (Hdrnihg, Organic Syntheses, Coll. Vol. Ill, 1955, p.188). b. 2-Chiorocyclohexanone -»· 2-phenylcyclohexanone {Newman et al. J., Am. Chem. Soc. 66, 1551 (1944)1. c. 2-Phenylcyclohexanone + 2-phenyl-2-carbethoxycyclohexanone {Newman et al., £. Am. Chem. Soc. 69, 942 (1947)}. d. 2-Phenyl-2-carbethoxycyclohexanone 2-cyano-3-phenyl-3-carbethoxycyclohexene.

Final products corresponding to formula I contain certain groups R2 which do not appear to be compatible with the chemistry of the pro15 cess steps. The R5 groups, which are stable to the various process steps, are used in the process and at the end of the synthesis are converted to R2 groups.

The preliminary steps above aid in producing various equivalents defined by the various values of Ar and R2 in general formula I through starting with appropriately substituted cyclohexanones in step (a) and with appropriately substituted arylmagnesiurn bromides as intermediates in step (b). Thus, 4-methylcyclohexanone and 4-methbxycyclohexanone, which are commercially available, can be used as basic starting materials to produce Compounds of formula I in which f'' f {' - 10 41898 R? together with the adjacent carbon atom is ,H ς and ' 'CH·, Ζ , respectively. 'OCH3 The compounds of formula I in which R2 (R5 in the process description) and its adjacent carbon atom is < OCH 3 serve as intermediates to compounds of formula,1 in which R2 had other values. The following table (Table II) shows the additional R2 values and the known methods for obtaining them.

TABLE II R2 Procedure TABLE III.

Ar1 Source Bromides in which R7 is hydrogen, fluorine or methoxyl and R8 is hydrogen are commercially available. The bromide in which R7 is hydrogen and R8 is methoxyl is also commercially available. The bromide in which both R7 and R8 are methoxyl is obtainable by the method of Mason, J.Am.Chem. Soc. 69, 2241 (1947).

The bromides in which R® and R7 are both methoxyl, and in which R8 is hydrogen and R7 is methoxyl or fluorine, are commercially available. The bromide in which R8 and R7 are combined to form dioxymethylene is also commercially available.

Compounds in which Ar1 has methexyl substituents (as in Table III) serve as intermediates to compounds of formula I in which Ar has hydroxyl or acetoxy! substituents by using methods for conversion of R® groups to Rz groups as shown in Table II. This appears necessary since certain substituents such as OH have to he introduced at the end of the synthesis Thus Ar1 contains a methoxyl, or masked hydroxyl, which is subsequently converted to OH.

Process steps A and B—1 and C are illustrated by Examples 1—3, and process step A, B—2 and C are illustrated by Examples 4—7, etc. - 12 41898 In the following illustrative examples all parts are by weight and temperatures are in degrees centigrade unless otherwise stated. The nmr spectra were at 60 Hz and resonance positions are described as cps or in ppm from tetramethylsilane (tms).

EXAMPLE 1.

N-Methyl-4a-phenyl-cis-decahydroisoquinoline {A. 2-Cyano-3-phenyl-3-carbethoxymethylcyclohexene} 2-Carbethoxymethyl-2-phenylcyclohexanone (Beokelheide, et al., above) (90 g., 0.346 mole), 200 ml of hydrogen cyanide and 12 drops of a saturated aqueous solution of potassium cyanide was stirred at 0°C overnight. Concentrated sulfuric acid (15 drops) was then added and the excess hydrogen cyanide evaporated. The crude cyanohydrin was taken up in ether and washed with cold 10% sulfuric acid solution, then dried with Na2S0i, 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 nitrogen at reflux for 5 hours 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 hy-° drochloric acid and extracted with ether. The ether extract was washed with dilute hydrochloric acid, water and brine, then dried (NazS0i,) and evaporated. The residual oil was distilled, yielding 45 g of pale yellow liquid, bp 135°C (0.20 mm), identified as 2-cyano-3-phenyl-3carbethoxymethyl-cyclohexene. - 13 41898 NMR (CDC13)(2): triplet at 64, 71, 78 cps, 3H (—OCH2CH3); methylene envelope from 70—150 cps, ca 6H; singlet at 178 cps, 2H (—c—CH2—C02—); quartet at 234, 242, 249, 256, 2H (-ΟΡΜΗ;,); triplet at 406, 410, 414, IH (h > ~; singlet at 436 cps, 5H (aromatic H).

IR (neat) : 4.50 μ (C = N); 5.5 and 5.85 μ (lactone impurity); 5.75 μ (—C02—).

B. 4a-Phenyl-l,3-diketo-l,2,3,4,4a,5,6,7-0ctahydroisoquinoline The product of Part A (50 g), dissolved in a minimum amount of absolute ethanol, was added to 2.5 liters of absolute ethanol previously saturated with anhydrous hydrogen chloride. The solution was refluxed under nitrogen for 48 hours. It was then cooled and concentrated to about 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 a 4a-‘phenyl-l,3-diketo-l,2,3,4,4a,5,6,7octahydroisoquinoline, mp 241—3°.

Anal. Calcd. for Ci5HisN02: C, 74.65; H, 6,26; N, 5.81 Found: C, 74.67; H, 6.25; N, 5.65.

C. N-Methyl-4a-phenyl-l,3-diketo-l,2,3,4,4a,5,6,7-octahydroisoquinoline (2) Peaks reported in cps from tetramethylsilane (TMS). - 14 41898 The product of Part B (7.20 g, 29.9 mmoles) in 50 ml of dry dimethyl formamide was added to 1.58 g of a 55.5% suspension of sodium hydride in mineral oil (36.5 mmoles NaH), while the reaction mixture was maintained at 70°C under nitrogen. When evolution of hydrogen ceased (about 1 hour) the reaction mixture was cooled to 25°C and a solution of methyl iodide (8.52 g, 60 nmoles) 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 yield 5.56 g (86%) of N-methyl-4a-phenyl-l,3-diketo-l,2,3,4,4a,5,6,7-octahydroisoquinoline.

Anal. Calcd. for C16H17OZN: C, 75.27; H, 6.71; N, 5.49 Found: C, 75.22; H, 6.71; N, 5.71.

Using an analogous procedure but substituting cyclohexylmethyl bromide for methyl iodide, N-cyclohexylmethyl-4a-phenyl-l,3-diketo1,2,3,4,4a,5,6,7-octahydroisoquinoline was prepared. Similarly, substituting cyclopropylmethyl bromide and cyclobutylmethyl bromide for methyl iodide, N-cyclopropylmethyl-4a-phenyl-l,3-diketo-l,2,3,4,4a,5,6,7 octahydroisoquinoline and N-cyclobutylmethyl-4a-phenyl-l,3-diketooctahydroisoquinoline, respectively, were prepared.

D. N-Methyl-4a-phenyl-l,3-diketo-trans-decahydroisoquinoline - 15 41898 A mixture of the product of Part C (2.0g, 7.85 mmoles), 175 ml of absolute ethanol, and 300 mg of 5% palladium on carbon was shaken under 40 psi of hydrogen for 24 hours. The catalyst was removed by filtration and the solvent evaporated from the filtrate. Recrystalliz5 ation of the residue from ethanol gave 1.8 g (90%) of N-methyl-4a-phenyl1,3-diketo-trans- decahydroisoquinoline, mp 151—153°C Anal. Calcd. for C16H18N0;>: C, 74.66; H, 7.44; N, 5.44 Found: C, 74.74; H, 7.66; N, 5.33.

In an analogous procedure reduction of the N-hydrocarbyl-4a10 phenyl-1,3-diketo-l,2,3,4,4a,5,6,7-octahydroisoquinolines described in Part C, yielded N-cyclohexylmethyl-4a-phenyl-l,3-diketo-trans-decahydroi soqui noli ne, N-cyclopropylmethyl-4a-pheny1-1,3-di keto-trans-decahydroisoquinoline and N-cyclobutylmethyl-4a-phenyl-l,3-diketo-trans-decahydroi soqui noli ne, respecti vely.

E. N-Methyl-4a-phenyl-l ,3-diketo-cis_-decahydroisoquinoline N-Methyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline (2.0 g) 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 over20 night at 25°, then poured into 1 N hydrochloric acid and extracted with ether. The ether extracts were washed successively with water and brine, then dried (MgS04) and the ether evaporated to yield 1.9 g of an oil.

NMR (CDC13): methylene envelope from 70 to 140 cps (8H); singlet at 177 cps (3H); multiplet at 145 to 205 cps (3H); singlet at 434 cps (5H).

A small scale experiment (40 mg compound-!, 1 ml methanol and 10 mg - 16 41898 sodium methoxide) conducted in an nmr tube, with spectra being taken at periodic intervals, clearly showed the gradual disappearance of the N-methyl resonance of the starting compound 1 and the 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 formation. Accordingly, the oil mentioned above was considered to be N-methyl-4a-phenyl-l,3-diketo-cis-decahydroisoquinoline.

F. N-Methy1-4a-phenyl-cis-decahydroisoqui noli ne N-Methyl-4a-phenyl-ci£-decahydroisoquinoline (1.9 g) in 75 ml of anhydrous tetrahydrofuran was treated with lithium aluminum hydride (2.0 g) and refluxed overnight. The reaction was quenched by the successive addition of 2.0 ml of water, 2.0 ml of 15% sodium hydroxide and 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 distilled, bp 125° (.05 mm), ηθ20 1.5514, and identified as N-methyl-4a-phenyl-c[s-decahydroisoquinoline.

Anal. Calcd. for Ci6H23N: C, 83.77; H, 10.10; N, 6.11 20 Found: C, 83.74; H, 10.11 N, 6.07 83.41 10.11 EXAMPLE 2.

N-Methyl-4a-(m-methoxyphenyl)-l,3-diketo-cis-decahydroisoqui noline A. 2-Cyano-3-carbethoxymethyl-3-(m-methoxyphenyl)-cyclohexene - 17 41898 A mixture of 2-carbethoxymethyl-2-(m-methoxyphenyl)cyclohexanone, Langlois et al., Tetrahedron 27, 5641 (1971), (25 g, 86.3 mmoles), 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 was added and the excess hydrogen cyanide evaporated. The residual oil was taken up in ether and washed with 10$ aqueous sulfuric acid and then with brine, dried (MgSOq), and the ether evaporated. The crude 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 mixture of 500 ml of ice-water and 100 ml of concentrated hydrochloric acid, and the resulting mixture was extracted with ether. After washing the ether extract with brine, drying and concentrating, 22 g of crude product was obtained. This was distilled by short path distillation to yield 16 g, bp 166°C (0.5 mm). The infrared spectrum of this material indicated it to be 2-cyano-3-carbethoxymethyl-3-(m-methoxyphenyl)cyclohexene with a small amount of an impurity, probably a lactone, with bands at 5.50 μ and 5.85 μ. The material was considered of sufficient purity to carry it on to the next step.

Anal. Calcd. for C18H2103N: C, 72.20; H, 7.07; N, 4.68 Found: C, 72.22; H, 7.13; N, 4.10. - 18 41898 Β. 4a-(m-Methoxyphenyl)-1,3-di keto-1,2,3,4,4a,5,6,7-octahydroisoquinoline The product of Part A (16 g, 53.5 mmoles) dissolved in absolute 5 ethanol was added to 1.5 liters of absolute ethanol previously saturated with anhydrous hydrogen chloride. The solution was refluxed, under nit rogen, for 48 hours and then allowed to stand at 25°C for 24 hours. It was then concentrated on a rotary evaporator to about 500 ml, cooled in ice, and the resulting crystalline precipitate filtered to yield 8.0 g (55%) of 4a-(m-methoxyphenyl)-l,3-diketo-l,2,3,4,4a,5,6,7-octahydroisoquinoline, mp 230—232°.

Anal.Cal cd. for Ci6Hi7NO3: 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 - 19 41898 The product of Part B (4.07 g, 15 mmoles) in 50 ml of dry dimethylformamide was added to a mixture of 790 mg of a 55% suspension of sodium hydride (18.1 mmoles of NaH) in mineral oil in 25 ml of dimethylformamide while the temperature of the reaction mixture was maintained at 60—70°C under nitrogen. After the addition was complete, the reaction mixture was heated to 90°C for 2 hours, by which time evolution of hydrogen had ceased. It was then cooled to 30°C whereupon a solution of 4.25 g (30 mmoles) of methyl iodide in 10 ml of dimethylformamide was added dropwise. The mixture was heated at 90—100°C for 2 hours, then cooled, poured into ice-water and extracted with ether. The ether extracts were washed with water, dried (MgS04) and evaporated. The residue was recrystallized from ethanol to yield crystalline N-methyl-4a-(m-methoxyphenyl)-!,3-diketo-l,2,3,4,4a,5,6,7-octahydroisoquinoline (3.8 g. 89%), mp 139—T41.

Anal. Calcd. for C17H18N03: 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 - transdecahydroisoquinoline The product of Part C (3.2 g, 11.21 mmoles), 100 ml of glacial acetic acid, 50 ml of dioxane and 700 mg of 5% palladium-on-carbon were shaken under 40 psi of hydrogen for 24 hours. The catalyst was then filtered off and washed well with dioxane, and the combined filtrate - 20 41898 was concentrated to a clear oil, yield 3.2 g (99.4%). The product was pure N-methyl-4a-(m-methoxyphenyl)-1,3-di keto-trans-decahydroisoqui noli ne, as determined by thin-layer chromatography (20% etherbenzene on silica gel plates) and by its nmr spectrum.

NMR (CDC13): complex multiplet at 50—150 cps from TMS (9H, —CH2— and —C—H); quartet at 148, 163, 173, 189 cps (2H, —CH2—CO-—); singlet at 180 cps (3H, NCH3); singlet at 220 cps (3H, 0CH3); multiplet at 397—420 cps (4H, Ar—H).

E. N-Methyl-4a-(m-methoxyphenyl)-l,3-diketo-cis-decahydroisoqui no!ine A solution of N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline (4.6 g, 1.6 mmoles) and sodium methoxide (1.84 g, 3.4 mmoles) in 150 ml of methanol was stirred at room temperature under nitrogen for 20 hours. It was poured into 150 ml of ice-water and extracted with ether, and combined extracts were washed with 3N hydrochloric acid and sat. sodium bicarbonate, dried (Na2SOi,) and evaporated. The crude 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 (Rf 0.07). The major component, N-methyl-4a-(m-methoxyphenyl)-1,3-di keto-cis-decahydroisoqui noli ne, was clearly separated by preparative thick layer chromatography and isolated - 21 41893 as a colorless oil.

NMR: 7.2 (q, J = 8, IH, Ar—H, 7.0—6.65 (m's, 3H, Ar—H), 3.76 (s, 3H, —0CH3), 3.0 (s, 3H, NCH3), 3.15—2.95 (m, 2H, —CH2C0—), 3.4—3.2(br, m, IH, —CH—) 2.2—1.4 (m's, 8H, —CH2—).

F. N-Methyl-4a-(m-methoxyphenyl)-ci£-decahydroisoquinoline /x/0CH3 R1 = CH3 R2 = H2 Ar = C6Hu0CH3 A solution of N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline (3.8 g, 1.3 mmoles) in 50 ml of dry tetrahydrofuran was added dropwise to a stirred suspension of 3.8 g of lithium aluminum hydride in 25 ml of tetrahydrofuran under nitrogen. When addition was complete, the reaction mixture was refluxed over night, 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 resultant white salts were filtered off and washed with ether. The organic solution was dried (Na2SOi,) and evaporated, leaving 2.5 g of an opaque oil. This was evaporatively distilled at 50° at 0.3 microns Hg. The product was isolated as a colorless, viscous oil identified as N-methyl-4a-(m-methoxypheny1)ci£-decahydroisoquinoline, yield of 2.38 g.

HRMS: Calc. MW for C17H25N0: 259.1953 Measured: 259.1936 NMR: 7.72 (t, J = 8, IH, An—H), 7.18-6.95 (m's, 2H, An—H), 6.73 (d x t, J = 7.5, 2, IH, Ar—H), 3.78 (s, 3H, —0CH3), 2.6-2.3 (sh, m, 4H, —CH2—), 2.23 (s, 3H, —NCH3), 2.0—1.2 (m, 11H, —CH2, —CH—). - 22 41898 EXAMPLE 3.

N-allyl-4a-(m-methoxyphenyl)-l,3-diketo-ci£-decahydroisoquinoline A. 4a-(m-Methoxyphenyl)-l,3-diketo-trans-decahydroisoguinoline A solution of 4a-(m-methoxyphenyl)-l,3-diketo-l,2,3,4,4a,5,6,7octahydroisoquinoline (6.0 g) in 250 ml of glacial acetic acid was treated with 1 g of 5% palladium on carbon and the mixture hydrogenated under 40 psi of hydrogen for 24 hours in a Parr shaker. The catalyst was then filtered off and the filtrate evaporated. The residual 4a-(m-methoxyphenyl)-l,3-diketo-trans-decahydroisoquinoline was crystallized from ethanol, m.p. 189—190, Anal. Calcd. for ΟχβΗχθΝΟβ: C, 70.31; H, 7.01; N, 5.12 Found: C, 70.60; H, 7.01; N, 5.05 15 70.46 7.02 5.13 B. N-Allyl-4a-(m-methoxyphenyl)-cis-1,3-di ketodecahydroi soqui noli ne - 23 41898 The product of Part A (4.5 g, 16.5 mmoles) 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°. The mixture was heated at 70° and stirred for 1 hour. It was then cooled to 35°, whereupon allyl bromide (2.02 g, 16.7 mmoles) in 30 ml of dimethylformamide was added dropwise. After heating the reaction mixture at 90—110° for 2 hours and allowing it to stand at 25° overnight it was poured into ice-cold 1% hydrochloric acid and extracted with ether. The organic extracts were washed with water, brine, then dried (magnesium sulfate). Evaporation of the ether yielded 5.6 g of crude 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-methoxypheny1)cis-1,3-diketodecahydroisoquinoline (oil), which was evaporatively distilled, bp 160° (.05 mm).

Anal. Calcd. for C19H23O3N: 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) or with potassium t-butoxide in THF left it totally unchanged, confirming that the cis derivative had been formed initially. Also confirmed by spectral analysis. NMR: 7.2 (q, J = 8, IH, Ar—H), 7.05—6.75 (m, 3H, Ar—H), 5.9-5.3 (m, IH, —CH=), 5.1—4.5 (m, 2H, =CHZ), 4.4-4.15 (m, 2H, N-CH2—), 3.75 (s, 3H, —0CH3), 3.4-2.6 (m’s, 3H, —CH2C0 and —CHCO), 2.1—1.4 (m, 8H, —CH2—).

C. N-allyl-4a-(m-methoxypheny1)-cis-decahydroisoquinoli ne 0 19 CH2CH=CH2 h2 c6huoch3 - 24 41898 The product of Part B (4.0 g, 12.8 mmoles) in 75 ml of sodiumdried tetrahydrofuran was treated with 4.0 g (105 mmoles) of lithium aluminum hydride, under nitrogen, and the mixture was stirred and refluxed for 24 hours. It was allowed to cool and then treated success5 ively with 4.0 ml of water, 4.0 ml of 14% aqueous sodium hydroxide, and finally with 12.0 ml of water. The precipitated inorganic salts were filtered off and washed well with ether. The combined filtrates were dried over anhydrous potassium carbonate to yield, after evaporation of the ether, 3.27 g of N-allyl-4a-(m-methoxyphenyl)-cisydecahydroiso10 quinoline (oil), which was evaporatively distilled, bp 150° (.05 mm). NMR (COC13): complex multiplet at 70 to 190 cps from TMS (methylene H, 17H)i singlet at 234 cps (3H, OCH3); multiplets at 300—350 cps (vinyl H) and multiplets at 405 to 460 cps (aromatic H).

JR: 6.10 μ (C = C)j 6.25, 6.35 μ (Ar).

EXAMPLE 4.

N-Phenethy1-4a-(m-methoxypheny1)-cis-decahydroisoqui noli ne A. N-Phenethyl-4a-(m-methoxyphenyl)-l,3-di keto-cis-decahydroi soquinoline A solution of 10,0 g (37 mmoles) of 4a-(m-methoxyphenyl)-l,3di keto-trans-decahydroi soqui noline in 250 ml of anhydrous dimethylformamide was added with stirring to a suspension of 2.8 g (55.5 mmoles) of 50% sodium hydride in mineral oil (washed with pentane) in 125 ml of anhydrous dimethylformamide heated at 50° under nitrogen. The mixture - 25 41898 was heated at 90° for 2 hours, then cooled to 40°, at which time a solution of 14.0 g (74 mmoles) of phenethyl bromide in 20 ml of anhydrous dimethylformamide was added and the reaction mixture heated at 90° overnight. 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, eluting with acetonebenzene). The major fraction was identified as N-phenethyl-4a-(mmethoxyphenyl)-1,3-di keto-cis-decahydroisoquinoline.

NMR (CDC13): 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.ΟΙ.3 (m, 8H).

B. N-Phenethyl-(m-methoxyphenyl)-cis-decahydroisoquinoline The product of Part A (5.0 g, 13.3 mmoles) in 200 ml of sodium15 dried tetrahydrofuran was added to a stirred suspension of 5.0 g of Tithium aluminum hydride in 80 ml of tetrahydrofuran under nitrogen, and the mixture was stirred at reflux for 20 hours. It was cooled and treated successively with 5.0 ml of water, 5.0 ml of 3N sodium hydroxide and 15.0 ml of water. The inorganic salts were filtered and washed with ether. The combined filtrates were evaporated and the residual N-phenethyl-4a-(m-methoxyphenyl)-cis-decahydroisoqui noli ne (oil) was evaporatively distilled, bp 70° (0.002 mm).

NMR (CDC13): 7.21 (s, 5H); 7.3—6.88 (m, 3H); 6.8—6.55 (m, IH); 3.79 (s, 3H); 2.9-2.3 (m, 8Η); 2.1—1.1 (m, ΠΗ). - 26 41898 Anal. Calcd for C24H31N0: C, 82.47; H, 8.94; N, 4.01 Found: C, 82.21; H, 9.06; N, 3.96 8.25 9.04 3.98.

EXAMPLE 5.

N-Phenethy1-4a-(m-hydroxyphenyl)-cis-decahydroisoqui noline N-Phenethyl-4a-(m-methoxy)-cis-decahydroisoquinoline (1.49 g, 4.28 mmoles) was mixed with pyridine hydrochloride (3.0 g, 25.8 mmoles) and stirred under nitrogen for 1 hour while heating at 190°. After cooling the solid mixture was dissolved in chloroform, and the chloroform solution was washed with water, dried (NaaSOi,) and evaporated. The residue was evaporated distilled, bp 95° (0.0002 mm), yielding a glass (mp 70—80°) which was identified as N-phenethy1-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline, hydrochloride salt.

NMR (CDC13): 7.17 (s, 5H); 7.3-6.6 (m, 4H); 3.1—2.5 (m, 9H); 2.31—1.2 (m, 10H).

EXAMPLE 6.

N-methyl-4a-(p-f1uorophenyl)-cis-decahydroisoquinoline A. 2-(p-f1uorophenyl)-cyclohexanone - 27 41898 The Grignard reagent prepared by adding 210 g of p-f1uorobromobenzene in 800 ml, of anhydrous ether to 29.1 g of magnesium turnings in 50 ml. of ether was added, with cooling to keep the temperature of the reaction less than 15°C, to a solution of 158.4 g of 2-chlorocyclohexa5 none in 800 ml. of anhydrous benzene. The reaction was stirred at 25° for 18 hrs. then the ether was distilled off and the resulting benzene solution refluxed for 24 hours. It was then poured into a mixture of 1 liter water and 200 ml. hydrochloric acid and extracted with ether. After evaporation of the ether the residue was distilled to yield 117 g (51%), b.p. 115 (0.2 mm). The material solidified on standing and was recrystallized from hexane, m.p. 56—59°C.

Anal. Calcd. for C12H13E0: C, 74.98; H, 6.82 Found: C, 74.24; H, 6.83 B. 2-(p-f1uoropheny1)-2-carbethoxymethylcyclohexanone The product of Part A (117 g) in 120 ml. of anhydrous tetrahydrofuran was added to sodium amide (from 14.7 g sodium) in 2000 ml of liquid ammonia. The reaction was stirred for 90 minutes then 68 ml a-bromoethyl acetate was added over 45 min. The reaction was stirred for 3 hrs. then the ammonia was allowed to slowly evaporate. Methanol (100 ml.) and water (1000 ml.) were added to the residue. Extraction with ether yielded the product, when distilled, gave 115.4 g (68%), b.p.134 (0.25 mm). - 28 41898 Anal. Calcd. for CleH19F03: C, 69.05; H, 6.88 Found: C, 68.97; H, 6.95 C. 2-Cyano-3-(p-fluorophenyl)-3-carbethoxy-methylcyclohexanone The product from Part B (50 g) was reacted in the manner 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-carbethoxycyclo10 hexene. Yield 33 g, b.p. 160° (0.35 mm).

D. 4a-(p-fluorophenyl)-l,3-diketo-l,2,3,4,4a,5,6,7-0ctahydroisoqui nol ine The product from Part C (75 g) was added to 500 ml. of anhydrous 15 ethanol saturated with anhydrous hydrogen chloride and the mixture refluxed for 48 hrs. The solution was then concentrated, cooled, and the white precipitate collected. Yield 32 g, m.p. 201—203. - 29 41888 Anal. Calcd. for C15Hi„FNO2: C, 69.49; H, 5.44; N, 5.40 Found: C, 69.30; H, 5.27; N, 5.02 E. N-methyl-4a-(p-f 1 uorophenyl)-1,3-diketo-1,2,3s4,4a,5,6,7-0cta- The product Of part 0 (20 g) 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 manner described in Example 1, Part C. Alkylation with 11.5 g of methyl iodide and workup (described in Example 1, Part C) gave N-methyl-4a-(p-fluorophenyl)-l,3-diketo1,2,3,4,4a,5,6,7-octahydroisoquinoline, 12 g, m.p. 124—128.

F. N-methyl-4a-(p-fluorophenyl)-l,3-diketo-trans-decahydroisoquinoline The product from Part E (12 g) in 150 ml. of ethanol and 50 ml of glacial acetic acid was hydrogenated over 3 g of 5% palladium on carbon over 4Q psi of hydrogen in the manner described in Example 1, Part D to - 30 418 98 give, after column chromatography on 350 g of silicon CC—7 and elution with benzene, 9 g, m.p. 141—143.

Anal. Calcd. for C15Hi8F N02: 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)-l,3-diketo-ci£-decahydroisoquinoline The product from Part F (2 g), 100 ml. of methanol and 400 mg of sodium methoxide was stirred at 25° for 4.8 hrs. after initially heating to reflux. The mixture was then poured into dilute hydrochloric acid and extracted with ether to yield a clear oil, 2 g.

NMR (CDCI3) methylenes appear as broad singlet centered at 100 cps (8H); singlet at 181 cps (ΙΊ—CH3, 3H); multiplet plus quartet at 177, 183, 186, 190 cps (CH2C0 and CHCO, 3H); multiplet at 410 to 450 cps (ArH,4H).

H. N-methyl-4a-(p-fluorophenyl)-cis-decahydroisoquinoline - 31 41898 The product from Part G (2 g), 75 ml of anhydrous tetrahydrofuran, and 2 g of lithium aluminum hydride were refluxed for 24 hrs. The reaction was worked up as described in Example 1, Part F to give 1.35 g, b.p. 110° (0.15 mm).

Anal. Calcd. for Οχε^ΕΝ: C, 77.69; H, 8.97; N, 5.66 Found: C, 77.55; H, 9.10; N, 5.63 By the above general procedure of Example 17 N-phenethyl-4a-(mfluorophenyl)-cis-decahydroisoquinoline can be obtained.

EXAMPLE 7.

Salts of N-phenethyl-4a-m-methoxyphenyl-cis-decahydroisoquinoline When N-phenethyl-4a-m-methoxypheny1-cis-decahydroisoqui noline is added to 0.1 to 3N hydrochloric acid a white solid is obtained which can be recrystallized from ethanol. This hydrochloride was m.p. 220—222°C (decomp).

When N-phenethyl -4a-m-n,ethoxyphenyl-cis-decahydroi soqui noline is mixed with a slight molar excess of maleic acid in hot acetonitrile it forms the crystalline maleate salt on cooling, m.p. 167—168°C.

EXAMPLE 8.

Dextro-N-methyl-4a-pheny1-cis-decahydrois oqui noli ne A. laevo- and dextro-2-carboxymathyl-2-phenylcyclohexanone aphenethylamine salt 1. 2-Carboxymethyl-2-phenylcyclohexanone (Boekelheide et al., above) (40 g, 0.154 mole) obtained by alkaline hydrolysis of 2-carbethoxymethyl2-phenylcyclohexanone was dissolved in 140 ml of hot ethanol and treated - 32 41898 with 27 g of (+)-a-phenethyl amine. The mixture was allowed to slowly crystallize to yield 21.8 g of the 1-salt, m.p. 130—132°, ίαΐθ- 94.

A second recrystallization from ethanol yielded material with m.p. 137·— 139°, {α)θ25°- 142°. Further recrystallizations did not change the optical rotation. 2. The mother liquors from above were taken up in 6N hydrochloric acid and the free acid extracted with ether. This material was dissolved in ethanol, treated with (-)a-phenethylamine, and allowed to slowly crystallize. The white crystalline d-salt had m.p. 136—137.5°, ία}025° + 141°.

B. laevo- and dextro-2-carboxymethyl-2-phenylcyclohexanone 1. A solution of the product of Part A—1 (14.0 g) in 250 ml of cold 6N hydrochloric acid was extracted with ether and treated as above to yield 9.6 g of the 1-ketoacid m.p. 94—95° {alD25° - 194 (c. 1.04, CHC13). 2. A solution of the product of Part A—2 (15.9 g) 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 yield 10.0 g, of the d-ketoacid m.p. 94—95°, {αίθ250 + 193° (c. 1.03, CHCI3).

C. laevo- and dextro-2-Carbethoxymethyl-2-phenylcyclohexanone - 33 1. A solution of the product of Part B—1 (28 g) in 700 ml of ethanol containing 3 ml of concentrated sulfuric acid was refluxed in a soxhlet extractor apparatus with the thimble filled with 3A molecular sieves. After refluxing for 24 hrs, excess potassium carbonate was added. The mixture was filtered and the solution evaporated. The residue was distilled to yield 1-ketoester, a clear oil, b.p. 125° (0.1 mm), ία}θ15 * * * * 20 * * * * 25° -207° (c 1.5, CHC13). 2. A solution of the product of Part B—2 (40 g) in 1000 ml of ethanol containing 8 ml of concentrated sulfuric acid was treated as above to yield, after distillation, the d-ketoester as clear oil, b.p. 125° (0.1 mm), {a}DZ5° + 234° (c 1.00, CHC13). 0. laevo- and dextro-2-cyano-3-phenyl-3-carbethoxymethylcyclohexene l. The product of Part C—1 (36 g, 0.138 mole), 200 ml of hydrogen cyanide and 12 drops of a saturated aqueous solution of potassium cyanide was stirred at 0° overnight. Concentrated sulfuric acid was added and the excess hydrogen cyanide evaporated. The residue was taken up in ether, washed successively with 0.1N sulfuric acid, and brine, dried (Na2S0[,), 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, at reflux for 5 hours, then allowed to stand at 25° overnight. It was then poured into a mixture of 1 liter of ice-water and 200 ml of concentrated hydrochloric acid, and the re25 suiting mixture was extracted with ether. The ether extract was washed with dilute hydrochloric acid, water and brine, then dried (Na2S0i,) and - 34 41898 evaporated. The residual oil was distilled yielding 28 g of the 1cyanoester, b.p. 130° (0.1 mm). 2. The product of Part C—2 (35 g, 0.134 mole) was treated as above to obtain 25 g of the d-cyanoester, b.p. 130° (0.1 mm).

E. dextro- and laevo-4a-Phenyl-l,3-diketo-l,2,3,4a,5,6,7-octahydroisoquinoline 1. The product of Part D—1 (28 g), dissolved in 50 ml of absolute ethanol, was added to 600 ml of absolute ethanol previously saturated with anhydrous hydrogen chloride. The solution was refluxed under nitrogen for 48 hours. It was then cooled and concentrated. A white crystalline solid precipitated which was filtered, then recrystallized from ethanol to yield 12.0 g of the unsaturated d-imide, (α}θ25° + 219 (c 1.00, CHC13). 2. The product of Part O—2 (17 g) in 40 ml of absolute ethanol was added to 400 ml of absolute ethanol previously saturated with anhydrous hydrogen chloride, then treated as above to yield 8.9 g of the unsaturated 1-imide, m.p. 169—170, io}D25° - 208 (c 1.20, CHC13).

In this example the sign of rotation changes in the ring-closing reactions.

F. dextro- and 1aevo-N-methyl-4a-phenyl-l,3-diketo-l,2,3,4,4a,5,6,7octahydroi soqui noli ne - 35 1. The product of Part E—1 (7.2 g, 29.9 mmoles) 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 mmoles NaH) in 50 ml of dimethylformamide, while the reaction mixture was maintained at 70° under nitrogen. The mixture was stirred and heated at 70° for 1 hour after the addition was completed, then cooled, and methyl iodide (8.5 g) in 20 ml of dimethylformamide was added dropwise. The mixture was heated at 90° for 30 min. then allowed to stand overnight at 25°. It was poured into water and extracted with ether. The ether extracts were dried (Na2S0ij) and evaporated and the residue recrystallized from ethanol to yield 6.17 g of the unsaturated d-N-methylimide, m.p. 156—158°, ία}θ25° + 245° (c 1.25, CHC13). 2. The product of Part E—2 (8.94 g, 37.1 mmole) in 60 ml of dimethylformamide was added to 1.96 g of a 55.5% suspension of sodium hydride in mineral oil in 50 ml of dimethylformamide as above to yield, after recrystallization in ethanol, 6.0 g of the unsaturated 1-N-methylimide, m.p. 149—153°, WD25° - 258°.

G. dextro- and isoquinoline laevo-N-methyl-4a-phenyl-l,3-di keto-trans-decahydro- 1. A mixture of the product of Part F—1 (6.1 g, 23.9 mmole), 100 ml of glacial acetic acid and 2 g of 5% palladium on carbon was shaken under 40 psi of hydrogen 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°, {alp2*0 + 81°. - 36 41898 2. The product of Part F—2 (6.0 g, 23.5 mmoles) was treated as above to obtain 4.0 g of the trans saturated 1-N-methylimide, m.p. 159—160°, ΐα}θ25° - 72° (c, 1.02, CHC13).

H. Dextro-N-methyl-4a-phenyl-l,3-diketo-cis-decahydroisoquinoline A mixture of 2 g of the product of G—1 above, 100 ml of methanol and 500 mg of sodium methoxide were refluxed for one hour then allowed to stand at 25° for 18 hrs. The reaction was worked up as described in Example 1, Part E to give an oil which was used without further puri10 fication.

I. d-N-methyl~4a-phenyl-ci£-decahydroisoquinoline LAH The crude product from Part H (2 g), 100 ml of anhydrous tetrahydrofuran and 2 g of lithium aluminum hydride were refluxed under nitrogen for 24 hrs. The reaction was quenched 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 and the filtrate concentrated. The residue was evaporatively distilled to give a clear oil, b.p. 100° (.07 mm), + 368°. The picrate derivative was readily formed, m.p. 144—147°.

PHYSICAL DATA Physical Constant ch3 m—OH b.p. 145—155° (0.5 μ) ch3 m—0CH3 b.p. 120° (0.3 μ) ch3 P-F b.p. 110° (0.15 nm) —CH2—*CH=CH2 m—OH b.p. 240° (0.2 μ) —CH2—ch=ch2 111·—OCH 3 b.p. 150° (0.05 nm) —CH2—CH=C(CH3)z nt—OH b.p. 240° (0.2 μ) -C5H11 i? m—0CCH3 b.p. 100—105° (1 μ) —C5Hll in—OCH 3 b.p. 70° (1 μ) _CH2—zj m—OH b.p. 160° (2 μ) m—OCH3 b.p. 120° (1 μ) —ch2— m—OH b.p. 180° (1 μ) m.p.79-81 —CH2— m—OCH 3 b.p. 130—135° (0.5 μ) —CH2CH2— m—OH b.p. 200° (0.5 μ) m.p. 78-80° m—OCH 3 b.p. 140° (1 μ) —CH2CH2—(O/- F m—OCH 3 b.p. 125° (0.3 μ) - 38 4189$ PHYSICAL DATA (Cont.) R X Physical Constant —CH2 CHg—Zq^-F m—OH b.p. 170° (0.5 μ) —cH2cH2~~^5y~c^ m—OH(HC1 salt) b.p. 200° (0.5 μ) 5 —CH2CH2—^O^~C1 m—OCH 3 b.p. 150—156° (0.5 μ) —CHgCHg—ZQ^>— CH3 m—OH b.p. 205—210° (0.5 μ) ——CH 2 CH m—OCH 3 b.p. 120—130° (0.5 μ) —CH2CH2-^^-£H(CH3)2 m—OH b.p. 200—210° (0.5 μ) —CH2CH2—CH (CH 3) 2 m—OCH 3 b.p. 140—145° (0.5 μ) 10 —CH2CH2-^)_ qch3 m—OCH 3 b.p. 165—169° (0.4 μ) —CH 2 CH 2—(CH 3) 2 m—OCH 3 b.p. 155—160° (0.5 μ) —CH2CH2—ί 3) 0 m—OCH 3 b.p. 140° (0.5 μ) —ch2 ch2—j j] m—OH(HC1 salt) m.p. 100° (d) -DHgCHg-TTB m—OCH 3 b.p. 150° (0.5 μ) 15 —CH2CH2-ts j 0 II ΙΠ—OCCH3 b.p. 150° (0.5 μ) - 39 41898 PHYSICAL DATA (Cont.) Physical Constant b.p. 150° (0.4 μ) b.p. 170—180° (1 μ) The analgesic agents of this invention can be administered to alleviate pain by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a phannaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent' of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a daily dosage of active ingredient can be in the range 0.01 to 100 milligrams per kilogram of body weight. Ordinarily 0.1 to 50, and preferably 1 to 25 milligrams per kilogram per day given in divided doses 2 to 4 times a day or in sustained release form is effective to obtain desired results.

Dosage forms (compositions) suitaBle for internal administration contain e.g. from 25 milligrams to 75 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient - 40 41898 will ordinarily 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.

Gelatine capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate or stearic acid. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, 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 contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suppositories contain the active ingredient in a suitable oleaginous 418®8 or water-soluble base. The oleaginous class includes cocoa butter and fats with similar properties; the water-soluble class includes polyethylene glycols.

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

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Example A.

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

Example B.

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

Example C.

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 50 milligrams of active ingredient, 7 milligrams of ethyl cellulose, 0.2 milligrams of colloidal silicon dioxide, milligrams of magnesium stearate, 11 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. - 42 41898 Example D.

Injectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by filtration.

Example E.

Suspension An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 10 milligrams of finely divided active ingredient, 500 milligrams of acacia, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., 5 milligrams of sodium saccharin, and 0.025 milliliters of vanilla tincture.

Example F.

Injectable A parenteral composition suitable for administration by injection is prepared by dissolving 1% by weight of active ingredient in sodium chloride injection U.S.P. XV and adjusting the pH of the solution to between 6 and 7. The solution is sterilized by filtration.

A standard procedure for detecting and comparing the analgesic activity of compounds in this series for which there is good correlation with human efficacy is the standard phenylquinone writhing test modified from Siegmund, et. al., Proc. Soc. Exp. Bi ol Med. 95., 729 (1957). A test compound suspended in 1% methylcellulose was given orally to fasted (17—21 hours) female white mice, 5—20 animals per double blind test. Aqueous (0.1% phenyl-£-benzoquinone) phenylquinone was injected intraperi toneally at 23 or 30 minutes later using 0.25 ml per mouse. Commencing at 30 or 37 minutes, respectively, after the oral administration of the test compound, the mice were observed for 10 minutes for characteristic stretching or writhing syndrome which is indicative of pain - 43 41898 induced by phenylquinone. The effective analgesic dose for 50% of the mice (ED 50) was calculated by the moving average method of Weil, Biometrics 8, 249 (1952). The following table shows the oral ED 50 dosages of a representative sample of the compounds of this invention and several standard analgesics.

CIS-DECAHYDROISOQUINOLINE ANALGESICS -CH3 m—OH 5.2 —ch2— m—OCH3 14. m—OH 30. —-CH2— m—OCH3 37. m—OH 20. —CH2CH2— m—OCH3 14.5 -ch2ch2-@ m—OH 21. —ch3 P-F 26. ——CH 2—CH " CH 2 m—OH 43. _ch2—CH=C(CH3)2 m—OH 40. —C5H11 m—OCH 3 20. - 44 41898 CIS-DECAHYDROISOQUINOLINE ANALGESICS (Continued) R. X ED50(mg/kg) —CH2CH?—/Q^-F m—OCH 3 33. -CH2CH^Q)rCl m—OH 28. —ch2ch2—^Q^-ci m—0CH3 {HCl salt} 16. —CHg CH g m—OH {HCl salt} 9.7 —ch2ch2-^h3 m—OCH 3 11. —CH2 CH2—/Q^—N (CH 3) 2 m—OCH j 15.1 —CH2CH2-y m—OCH3 25. —CHgCHg—Jf S m—OH {HCl salt} 24. fr· "^S —CHgCHg—\S-^ ΙΏ—OCH 3 27. —CH 2 CH 2~^sS i? m—0CCH3 27. STANDARD ANALGESICS ED50(mg/kg) Morphine H2SO^ 1.6 Codeine H3P04 8. - 45 41898 STANDARD ANALGESICS Nalbuphine HCI Pentazocine HCI Aspirin (Continued) ED50 (mg/kg) 8.4 57. 109. - 46 41898

Claims (46)

1. WHAT WE CLAIM IS:I. A compound having a cis configuration of the formula where 5 R 1 is hydrogen; C x —C 6 alkyl —CH 2 Y where Y is C 2 —C 6 alkenyl or C 2 · C 6 alkynyl; Xa -(CH 2 )„ where m is 1 or 2, X is Cl, Br, F, CF 3 , OCH 3 , CH 3 , isopropyl, —MH 2 , or —N(CH 3 ) 2 , and a = 0, 1 or 2; xo -(CH 2 ) -(CH 2 ) cycloalkylmethyl of the formula —CH 2 CH <θΗ 2 ) η , where n is 2—5; R 2 is divalent oxygen (=0), or together with adjacent carbon atom is the group -CH, 3 .< OH 0CCH 3 F - 47 41898 Q II R* is —H, OH, OCH 3 or —OCCH 3 , with the proviso that when R 3 is —F, Ri> must be —H; and pharmaceutically suitable salts thereof.

2. A compound of claim 1 where R z together with the adjacent carbon atom is the group

3. A compound of claim 1 or 2 where R 3 is m-0CH 3 and R 1 * is H.

4. , A compound of claim 1, 2 or 3 where R 1 is

5. A compound of any of claims 1—3 where R 1 is cycloalkylmethyl.

6. A compound of any of the preceding claims which is dextrorotatory.

7. A compound of any of claims 1—5 which is laevorotatory.

8. N-methyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline and pharmaceutically suitable salts thereof.

9. N-phenethyl-4a-(m-methoxyphenyl)-cis-decahydroisoqui noli ne and pharmaceutically suitable salts thereof.

10. N-phenethyl-4a-(m-hydroxypheny 1)-cis-decahydroisoquinoline and pharmaceutically suitable salts thereof.

11. N-cyclopropylmethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline and pharmaceutically suitable salts thereof.

12. N-methyl-4a-(p-f1uorophenyl)-cis-decahydroisoqui noli ne and pharmaceutically suitable salts thereof.

13. N-(g-to1yl-p-ethyl)-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline and pharmaceutically suitable salts thereof. - 48 41898

14. N-(p-toly1-β-ethyl)-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline hydrochloride salt.

15. N-(£-tolyl-β-ethyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline.

16. A compound of claim 1, substantially as herein disclosed.

17. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 1.

18. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 2.

19. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 3.

20. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 4.

21. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 5.

22. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 6.

23. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 7.

24. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 8.

25. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 9.

26. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 10.

27. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 11.

28. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 12.

29. A pharmaceutical composition comprising a suitable pharma- 49 41898 ceutical carrier and a compound of claim 13.

30. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of claim 14.

31. A pharmaceutical composition comprising a suitable pharma5 ceutical carrier and a compound of claim 15.

32. The pharmaceutical composition of any of claims 17—31 in unit dosage form.

33. The pharmaceutical composition of claim 32 wherein each dose comprises 25—75 mg of said compound. 10

34. A pharmaceutical composition, substantially as hereinbefore described with reference to any one of Examples A—F.

35. A method of producing analgesia in a mammal other than man which comprises administering to the mammal an effective analgesic amount of a compound of any of claims 1—16. 15

36. A process for the preparation of a compound of claim 1, comprising the sequential steps of (a) heating a compound of the formula Ar 1 with at least an equimolar amount of anhydrous R S OH in the presence of 20 at least an equimolar amount of anhydrous HCl under inert, anhydrous conditions, wherein R 5 together with the adjacent carbon atom is R 6 is alkyl of 1—4 carbons, and Ar 1 is - 50 41898 in which R 7 is hydrogen, F or methoxyl; R 8 is H or methoxyl; provided that when R 7 is F, R 8 is H, 5 to produce a compound of the formula (b) if desired alkylating the diketo product of step (a) with a strong base and a compound of the formula R ia —X in which X represents an atom or group removable as an anion, and R la is as defined in claim 1 for R 1 10 excluding hydrogen and those groups which contain carbon-carbon unsaturation to form the corresponding N-substituted derivative of the formula (c) contacting the product of step (a) or step (b) with hydrogen in 15 the presence of a reducing catalyst to form the corresponding trans diketo derivative of the formula wherein R 1 is hydrogen or R la . - 51 41898 (d) contacting the trans product of step (c) with a strong base to pro· duce a compound having cis configuration of the formula and then 5 (e) reducing the cis product of step (d) with a suitable reducing agent to form

37. A process according to claim 36 wherein said step (a) is performed at a temperature in the range of 50—120°C. 10

38. A process according to claim 36 or 37 wherein X in step (b) is bromine, iodine, mesylate, tosylate or azide.

39. A process according to any of claims 36—38 wherein step (e) is performed using lithium aluminum hydride.

40. A modification of the process of claim 36, 37 or 39 wherein 15 in step (d) a product of step (c) wherein R 1 is hydrogen is contacted with a strong base and a compound of the formula R 1 —X wherein R 1 is as defined in claim 1 other than H and X is as defined in claim 36 to produce a compound having cis configuration of the formula - 52 41888

41. A process for preparing a compound of claim 1 of the formula wherein R 1 is as defined in claim 1, and R 5 and Ar 1 are as defined in 5 claim 36, which comprises reducing with a suitable reducing agent a compound with a cis configuration of the formula

42. A process according to claim 41 wherein said suitable reducing agent is lithium aluminum hydride. 10

43. The process of any of claims 36—42 including the further step of transforming substituents R 5 and/or Ar 1 into desired substituents . R 2 and as defined in claim 1 by methods known per se for such conversion. 15

44. The process of claim 36 substantially as hereinbefore described with reference to any one of Example IB—IF, 2B—2F, 60—6H and 80—81.

45. The process of claim 41 substantially as herein before described with reference to any one of Examples IF, 2F, 3C, 4B, 6H and 81.

46. Compounds of claim 1 whenever made by the process of any of 20 claims 36—45.