GB1568976A

GB1568976A - Cis-4-phenyl-isoquinolines

Info

Publication number: GB1568976A
Application number: GB52073/76A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1975-12-16
Filing date: 1976-12-14
Publication date: 1980-06-11
Also published as: IL51104A0; AU512799B2; PH13335A; IE44403L; CA1085854A; AU2062576A; FR2335225B1; FR2335225A1; JPS5273881A; DE2655150A1; NZ182883A; IE44403B1; IL51104A

Description

(54) CIS-4A-PHENYL-ISOOUINOLINES (71) We, SANDOZ LTD., of 35 Lichtstrasse, 4002 Basle, Switzerland, a Swiss Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to cis-4a-phenvl-isoquinolines.

The present invention provides compounds of formula 1. wherein

(i) Rl is hydrogen or alkyl of I to 4 carbon atoms.

R2 is hydrogen.

R3 and R4 together are oxygen, and each of R5 and R6 is hydrogen, or (ii) Rl is hydrogen. alkyl of I to 4 carbon atoms. or alkanovl of I to 4 carbon atoms. and R2 is alkyl of 1 to 6 carbon atoms. a radical of formula 11.

Wherein R7 and R8 are. independently. hydrogen or alkyl of l to 4 carbon atoms a radical of formula 111.

wherein m is a whole number from 2 to 4. a radical of formula IV.

wherein n is 1 or 2, or a radical of formula V,

wherein p is 1 or 2, and R9 is hydrogen, halogen, trifluoromethyl, alkoxy of 1 or 2 carbon atoms or alkyl of 1 or 2 carbon atoms, amino, or di(alkyl of 1 or 2 carbon atoms)- amino, and (a) either R3 is azido or hydroxy, and R4 is hydrogen. or R3 and R4, together. are oxygen. or methylene. and each of R5 and R6 is hydrogen. or (b) either R3 and R6, together, form a bond, and each of R4 and R5 is hydrogen, or R4 and R5, together, form a bond, and each of R3 and R6 is hydrogen, with the proviso that when R3 is hydroxy and R4 is hydrogen. or when RR and Rl. together. are oxygen. and (i) when R2 is a radical of formula IV. then n is 1. or (ii) when R2 is a radical of formula V. then p is 2. and R9 is hydrogen or halogen.

Any alkyl or alkoxy radical possessing 1 or 2 carbon atoms. especially has one carbon atom.

R1 is alkanoyl, this preferably is formyl or especially acetyl. The radical OR1 is preferably in the meta position.

R1 is preferably hydrogen.

When R2 is alkyl, this preferably has 1 to 4 carbon atoms, ans especially 1 or 2 carbon atoms. R7 and R8 are preferably identical and are conveniently both hydrogen. m is preferably 2 or 3. n is preferably 1. p is preferably 2. R9 is preferably in the para position, and when R9 is halogen. in the ortho position. R., is conveniently hydrogen or halogen.

Halogen means fluorine. chlorine or bromine. The halogen atom is preferably fluorine or chlorine.

R, is preferably alkyl.

When R3 is azido or hydroxy and R4 is hydrogen. R3 may be cis or trans to the phenyl group in the 4-position.

Preferably R3 and R4 are together oxygen or R3 is azido and R4 is hydrogen.

The present invention provides a process for the production of a compound of formula 1 which comprises a) splitting off the amino protecting group R1(1 present in a compound of formula VI.

wherein R1 is hydrogen or alkyl of I to 4 carbon atoms. and R10 is an amino protecting group. to produce a compound of formula Ia. wherein R@ is as defined above.

b) alkylating a compound of formula la, as defined above. or the corresponding compound wherein the keto group is protected. and if necessary splitting off any keto Protecting group in the resultant product. to produce a compound of formula lb.

wherein R' is as defined above. ano R2 is R. as defined above. with the proviso that it is other than hydrogen. c) reducing a compound of formula Ic.

wherein R1 and R2 are as defined above, to produce a compound of formula Id.

wherein R1 and R2 are as defined above, replacing a leaving group R11 by azido in a compound of formula VII.

wherein R111 is alkyl of 1 to 4 carbon atoms or alkanoyl of 1 to 4 carbon atoms, R21 is as defined above, and R11 is a leaving group, to produce a compound of formula le,

wherein R111 and R2 is as defined above. e) eliminating HR11 from a compound of formula VIII.

wherein R11 and R2 are as defined above, and R12 is a group capable of being split off under the reaction conditions, alkyl of 1 to 4 carbon atoms, or alkanoyl of 1 to 4 carbon atoms, to form a compound of formula If.

wherein R1 and R2 are as defined above, and either R3 and R6, together, form a bond, and each of R4 and R5 is hydrogen, or R4 and R5, together, form a bond, and each of R3 and R6 is hydrogen, f) splitting off a hydroxy protecting group R, from a compound of formula IX.

wherein R2, R. R4. R5 and R" are as defined above. with the proviso that when R3 and R4 are together oxygen, the keto group may be in free form of protected form, and R13 is hydroxy protecting group, to produce a compound of formula I, wherein R1 is hydrogen. g) acylating a compound of formula I, wherein R1 is hydrogen, to produce a compound of formula I, wherein R1 is alkanoyl of 1 to 4 carbon atoms, or h) replacing the oxygen of the keto group of a compound of formula Ic by methylene under Wittig conditions to form a compound of formula Ig.

wherein R1 and R2I are as defined above.

The splitting off of the amino protecting group according to process a) may be effected in conventional manner. Preferablv the amino protecting group is one capable of being split off hydrolytically. especially under acidic conditions.

R10 may be, for example, an acyl group of 2 to 11 carbon atoms, e. g. an aroyl group such as benzoyl, or an alkanoyl group such as acetyl. Alternatively, R10 may be alkoxycarbonyl of 2 to 6 carbon atoms or phenoxycarbonyl.

A suitable acid is hydrochloric acid. An inert solvent such as aqueous n-butanol may be present. Suitable temperatures are between 50 and 110 C.

Process b) may be effected in conventional manner for the alkylation of a secondary amine.

Suitable alkylation agents include compounds of formula X.

R2I - X X wherein R2I is as defined above, and X is a leaving group.

X may be, for example, halogen such as chlorine, bromine or iodine, or the acid radical of an organic sulphonic acid of up to 10 carbon atoms, e.g. an alkyl-sulphonyloxy radical such as mesyloxy or an arylsulphonyloxy radical such as tosyloxy. Conveniently an acid binding agent such as triethylamine is present. An inert solvent such as methanol may be present. Suitable temperatures are from 0 to 100 C.

The keto group is preferably protected. It may be in the form of an open chain or cyclic ketal. thiooxoketal or thioketal. the open chain or cvclic portion thereof. for example having from 2 to 4 carbon atoms in the aggregate thereof. Such protected forms may be deprotected in conventional manner.

Process c) may be effected in conventional manner for the reduction of a cyclohexanone to a cyclohexanol.

The reduction mav be effected hvdrogenolvticallv. A suitable catalvst for such a hydrogenation is. for example. platinium. The process mav be effected at room temperature. and under normal pressure. Suitable solvents include tetrahydrofuran and ethyl acetate.

The reduction may also be effected with a complex hydride, for example with lithium aluminium hydride, sodium dihydrido-bis(2-methoxyethoxy)aluminate, but preferably sodium borohydride. The reaction may be effected in an inert solvent, e.g. methanol in the case of sodium borohydride. Suitable temperatures may be from 0 to 50 C.

It is to be appreciated that the reduction may not be stereospecific in that two epimers, i.e. a compound wherein the hydroxy group is cis to the 4a-phenyl group le.g. the (4aRS.

6RS, 8aRS)isomer] and a compound wherein the hydroxy group is trans to the 4a-phenyl group [e.g. the (4aRS, 6SR, 8aRS)isomer], may be produced. Such compounds may be separated in conventional manner, e.g. by chromatography on silicagel.

Process d) may be effected in conventional manner for a nucleophilic substitution in the presence of an azido anion source, e.g. as described in Example 5b) hereinafter.

The process may be effected in a, preferably polar, inert solvent, such as dimethyl sulphoxide or dimethylformamide. Suitable temperatures may be from 40 to 100 C.

The azido source may be an alkali metal azide such as sodium azide, or a trialkylsilyl azide of 3 to 12 carbon atoms, such as trimethylsilyl azide.

R11 may be for example an alkanoyloxy group of 1 to 4 carbon atoms, or a radical R14SO2O-, wherein R14 is alkyl of 1 to 4 carbon atoms, preferably methyl, or phenyl or p-alkylphenyl of 7 to 11 carbon atoms, especially p-tolyl.

From mechanistic considerations the azido group in the final product will be epimeric to the group R,, in the starting material.

Process e) may be effected in conventional manner for such elimination reactions.

R11 may have the preferred values as indicated above. R12 when it is a group capable of being split off under the reaction conditions may. for example. be a radical Rl4SO2. wherein R14 is as defined above. The final product in such a case would be a compound of formula If, wherein R1 is hydrogen.

The reaction may be effected in a preferably polar inert solvent. such as dimethyl sulphoxide or dimethylformamide. Suitable temperatures are from 4.) to l()()0C. The reaction may proceed as a side reaction to process e) above.

Process f) may be effected in conventional manner for deprotecting analogous phenolic derivatives.

R,3 may be, for example, a protecting group capable of being split off bv hvdrolvsis. Such a group is especially preferred when R3 is azido. and mav be a group of formula R14SO2-, wherein R14 is as defined above. The hydrolysis may be effected in conventional manner for the hydrolysis of similar sulphonic acid esters. For example the reaction may be effected under basic conditions. e.g. in the presence of N-ethvl-diisopropvlamine. Suitable temperatures are between 20 and 1()() C R,3 may alternatively be a group capable of being split off under ether splitting conditions. Such a group is especially preferred when R3 is other than azido.

The ether splitting may be effected in conventional manner for dealkvlation of phenyl alkyl ethers. For example, Lewis acids. such as boron tribromide or aluminium trichloride. or strong mineral acids such as hydrobromic acid or hvdroiodic acid mav be used. Suitable temperatures are between -20 and +3() C An inert solvent such as methylene chloride may be present. If desired, when R3 and R4 together are oxygen. the keto group in the starting material of formula IX is in protected form. which is deprotected during the reaction or during the working-up procedure. Thus. the keto croup may be protected in the form of an open chain or cyclic ketal. thiooxoketal or thioketal. the open chain or cyclic portion thereof, for example. having from 2 to 4 carbon atoms in the aggregate thereof.

Such protected forms may be deprotected in conventional manner. When the deprotecting conditions are acidic. then deprotection will be simultaneous with any dealkvlation carried out with a strong mineral acid.

Process g) may be effected in conventional manner for analogous acylation reactions.

A suitable agent for the introduction of a formyl group mav be the mixed anhvdride of formic acid and acetic acid. Alkanovl radicals of 2 to 4 carbon atoms may be introduced using the corresponding acid chloride. bromide or anhydride.

Conveniently a tertiary amine such as pvridine is present. R However. when R2 is a radical of formula V, wherein R9 is amino. it may be preferred to use acidic conditions. An inert organic solvent such as toluene mav also be present. Suitable temperatures are between 10 and 50 C.

Process h) may be effected in conventional manner for Wittig reactions. A suitable Wittig salt is methyl triphenylphosphonium bromide. A suitable solvent is dimethylformamide. A suitable temperature is from 1() to 7() C The compounds of formula VI mav be produced by a process which comprises reacting a compound of formula XI.

wherein Rl" is as defined above. with a compound of formula XII.

wherein R1I is as defined above. and Y is lithium or MgHal. wherein Hal is chlorine. bromine or iodine. in the presence of a cuprous salt. at from to to J-'C.

The reaction may be effected in conventional manner for a cuprous-induced 1.4 addition to an a, - unsaturated ketone.

The cuprous salt used may, for example be copper (I) iodide. Hydroquinone is preferably present. The reaction is conveniently effected at from -43 to () C. The reaction is conveniently effected in an inert solvent. such as tetrahydrofuran.

R1I is preferably alkvl.

Compounds of formula VIII. wherein R11 is K1 ,SOC)- and K, is R1I i or K,4 SO2-, may be made by reacting a compound of formula Id with R11SO2Cl in conventional manner.

The configuration of the group -OSO2R1, at C6 in the final product and the hydroxy group at C6 in the starting material will be. in general, the same.

It is to be appreciated that a compound of formula VII is a compound of formula Vlll, wherein R12 is alkyl or alkanoyl.

Compounds of formula IX, wherein R3 is azido and R13 is R14-SO2- may be prepared by a nucleophilic substitution with azide anion in analogous manner to process d) from a compound of formula Villa,

wherein , R11 and R14 are as defined above.

Insofar as the production of any starting material is not particularlv described, this is known or may be produced and purified in accordance with known processes, or in a manner analogous to the processes herein described or to known processes.

The compounds of formula I mav exist in racemic or optically active form. The optically active forms may be conveniently made by fractional crvstallization of diastereomeric salts.

In one convenient method the compounds of formula Ia may be resolved bv wav of the diastereomeric salts with (+) or (-) tartaric acid and further opticallv active compounds of formula I may be made therefrom using any of processes b) to h) as mentioned above.

Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation include fumaric acid and tartaric acid.

In the following Examples all temperatures are in degrees Centigrade and are uncorrected.

All compounds obtained are in racemic form unless otherwise stated.

EXAMPLE 1: Octahydro-4a-(3-methoxyphenyl) -cis-6(2H)-isoquinolinone process a) 36.35 g (0.1 mol) of 2-benzoyl-octahydro-4a-(3-methoxyphenyl)-cis-6(2H)isoquinolinone, 100 ml of n-butanol, 33.1 mol of ca. 37% (w/v) aqueous hydrochloric acid (0.4 mol) and 66.9 ml of water are boiled for 40 hours. The mixture is extracted with hexane. The aqueous phase is made basic with aqueous ammonia and extracted with methylene chloride. The organic phases are concentrated bv evaporation to yield the title compound which in hydrogen fumarate form has a M.Pt. of 13()'.

Separatioil of optical isomers 25.93 g (100 mmol) of octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone is dissolved with 15.01 g (100 mmol) of L-(+) tartaric acid with slight heating in 40 ml of water and 160 ml of methanol. The mixture is cooled to 0 and the resultant crystals filtered off. After recrystallization of the crystals three times from methanol/water (80:20 v/v) the (+) tartrate having a constant [α]D20- of +28 [1% w/v in H2O] is obtained. The free base is obtained by treatment with methylene chloride/ethanol [80:20 v/v] and aqueous ammonia.

The mother liquors of the above-mentioned crystallations are treated with ammonia to liberate the free base. After treatment with D(-) tartaric acid as described above the (-) antipode of the tartrate is obtained. [α]D20 = -28 (1% in H2O).

The starting material is obtained as follows: 278 ml of 2.2 N butyl lithium solution (612 mmol) are added to a mixture of 600 ml of absolute tetrahydrofuran, 112.2 g (600 mmol) of 3-bromoanisole and 661 mg (6 mmol) of hydroquinone at -65 under nitrogen. The resulting mixture is kept at -50 for 30 minutes, treated with 57.13 g (0.3 mol) of copper (I) iodide, stirred for 1 hour at -43 , and treated with 51.06 g (0.' mol) of l,3,4.7.8.8a-hexahydro-2-benzoyl-6(2 H)-isoquinolinone. The mixture is allowed to warm to 0 over 2 hours and kept at 0 for 16 hours. 1.2 litres of water and 79.28 g (0.6 mol) of ammonium sulphate are added to the mixture which is then extracted with toluene. The organic extracts are evaporated to yield an oil which is chromatographed on silicagel using ethyl acetate as eluant. The product, 2-benzoyloctahydro-4a-(3-methoxyphenyl)-cis-6(2H)-iso-quinolinone is obtained as colourless crystals from methanol; M. Pt. 78 .

EXAMPLE 2 Octahydro-4a-(3-methoxyphenyl)-2-methyl-cis-6(2H)-isoquinolinone [process b)] 25.93 g (0.1 mol) of octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone (see Example 1), 100 ml of benzene, 11.2 ml (0.2 mol) of ethylene glycol and X. I ml (125 mmol) of methanesulphonic acid are boiled for 3 hours in a water separator. The mixture is cooled, made basic with aqueous ammonia and extracted with methylene chloride. The organic phase is evaporated to dryness to yield octahydro-4a-(3-methoxyphenyl)-cis-6(2H)isoquinoline ethylene ketal. The ketal is dissolved in 50 ml of absolute methanol, cooled to 0 C, and 13.91 ml (0.1 mol) of triethylamine and 7.46 ml (0.12 mol) of methyl iodide are added thereto. The mixture is kept at 22 for 1 hour. The mixture, containing octahydro-4a-(3-methoxyphenyl)-2-methyl-cis-6(2H)-isoquinolinone ethylene ketal, is mixed with 20 ml of dioxane and concentrated by evaporation. 100 ml of dioxane and 100 ml of 2N aqueous hydrochloric acid are added to the residual oil. The resultant mixture is stirred for 2 hours at 40 , made basic with aqueous ammonia, and extracted with toluene.

The extracts are concentrated by evaporation to yield the title compound as an oil, which is crystallized as the hydrogen fumarate from ethanol.

In analogous manner the following compounds may be made: ( i) 2-allyl-octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone.

( ii) 2-cyclopropylmethyl-octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone.

(iii) 2-cyclobutylmethyl-octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone.

(iv) 2-(o-chlorophenylethyl)-octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone.

EXAMPLE 3: Octahydro-4a-(3-hydroxyphenyl)-2-methyl-cis-6(2H)-isoquinolinone [process f)] To a solution of 28g of octahydro-4a-(3-methoxyphenyl)-2-methyl-cis-6(2H)isoquinolinone ethylene ketal obtained as described in Example 2 in 200 ml of methylene chloride at -50 under nitrogen, is added dropwise 28.44 ml (0.3 mol) of boron tribromide in 100 ml of methylene chloride. The mixture is stirred at 0 for 30 minutes, then cooled to -40 , treated with 50 ml of absolute methanol, and concentrated by evaporation. The residue is dissolved in 150 ml of dioxane and 50 ml of water. The resultant mixture is stirred for 1 hour at 40 and partitioned between aqueous ammonia and methylene chloride. The organic phases are then chromatographed on silicagel using a mixture of methylene chloride/methanol/concentrated aqueous ammonia (95:4.5:0.5) as eluant to yield the title compound in amorphous form which crystallizes from isopropyl alcohol; M.Pt. 175 .

In analogous manner there may be obtained: ( i) 2-allyl-octahydro-4a-(3-hydroxyphenyl)-cis-6(2H)-isoquinolinone.

( ii) 2-cyclopropylmethyl-octahydro-4a-(3-hydroxyphenyl)-cis-6(2H)-isoquinolinone.

(iii) 2-cyclobutylmethyl-octahydro-4a-(3-hydroxyphenyl)-cis-6(2H)-isoquinolinone.

( iv) 2-(o chlorophenethyl)-octahydro-4a-(3-hydroxyphenyl)-cis-6(2H)-isoquinolinone.

EXAMPLE 4: The (4aRS,6SR,8aRS) and (4aRS, 6RS, 8aRS) epimers of decahydro-6-hydroxy-4a-(3 hydroxyphenyl-2-methyl-cis-isoquinolinone [process c)] To a stirred suspension of 25.93 g (0.1 mol) octahydro-4a-(3-hydroxyphenyl)-2-methyl cis-6(2H)-isoquinolinone (see Example 3) in 200 ml of methanol at 0 , is added 5.68 g (0.15 mol) of sodium borohydride. The mixture is kept at 22 for 16 hours. The mixture is cooled to 00, and 50 ml of acetone. 39.6 g (() 2 mol) of ammonium sulphate and 200 ml water are added thereto. The reaction mixture is extracted with a mixture of methylene chloride and ethanol (80/20 v/v). The organic phases, containing a mixture of the two epimeric forms as detected by thin layer chromatography on silicagel, are concentrated by evaporation. The residue is mixed with 19.02 g (0.1 mol) of p-toluenesulphonic acid hydrate and 200 ml of ethanol, and crystallized at 0 to yield the p-toluenesulphonate of the less polar (4aRS,6SR,8aRS) epimer; M.Pt. 253 .

The mother liquor is evaporated and partitioned between aqueous ammonia and a mixture of methylene chloride and ethanol (80:20 v/v). The organic extracts are chromatographed on silicagel using a mixture of methylene chloride/methanol/aqueous ammonia (80:18:2 v/v) yielding the polar, (4aRS,6RS,8aRS), epimer as a colourless amorphous powder which liquifies at about 110 .

In analogous manner the following compounds may be obtained: ( i) (4aRS,6SR,8aRS) and (4aRS,6RS,8aRS) 2-allyl-decahydro-6-hydroxy-4a-(3 hydroxyphenyl)-cis-isoquinoline.

( ii) (4aRS,6SR,8aRS) and (4aRS,6RS,8aRS) 2-cyclopropylmethyl-decahydro-6hydroxy-4a-(3-hydroxyphenyl)-cis-isoquinoline.

(iii) (4aRS,6SR,8aRS) and (4aRS,6RS,8aRS) 2-cyclobutylmethyl-decahydro-6 hydroxy-4a-(3-hydroxyphenyl)-cis-isoquinoline.

( iv) (4aRS,6SR,8aRS) and (4aRS,6RS,8aRS) 2-(o-chlorophenethyl)-decahydro-6hydroxy-4a-(3-hydroxyphenyl)-cis-isoquinoline.

EXAMPLE 5; (4aRS,6RS,8aRS) 6-azido-decahydro-4a-(3-hydroxyphenyl-2-methyl-cis-isoquinoline [process f)] a) 4.336 g (10 mmol) of the p-toluenesulphonate of the (4aRS,6SR,8aRS) decahydro-6hydroxy-4a-(3-hydroxyphenyl)-2-methyl-cis-isoquinoline obtained in Example 4, 10 ml of absolute pyridine, and 4.29 g (22.5 mmol) of p-toluenesulphonyl chloride are mixed at 0 under nitrogen and stirred for 16 hours at 22 . 20 ml of toluene and 20 ml of 2N aqueous sodium carbonate solution are added to the mixture, which is then stirred at 22 for 15 minutes and extracted with toluene. The organic phase is concentrated bv evaporation to yield the bis-tosylate as an amorphous powder. b) The bis-tosylate in 10 ml of absolute dimethyl sulphoxide is mixed with 1.3 g (20 mmol) of sodium azide. The mixture is stirred for 16 hours at 70 under nitrogen, and partitioned between toluene and 2N aqueous sodium carbonate. The organic phase is concentrated by evaporation to yield (4aRS,6RS,8RS)-6-azido-decahydro-4a-(3-tosyloxyphenyl)-2-methylcis-isoquinoline. c) 4 g of (4aRS, 6RS, 8aRS)-6-azido-decahydro-4a-(3-tosyloxyphenyl)-2-methyl-cisisoquinoline in 10 ml of 2N methanolic potassium hydroxide solution is boiled for 1 hour, and then adjusted to a pH 8 - 10 by the addition of carbon dioxide. after the addition of 20 ml of toluene and 20 ml of water. The organic phases are concentrated bv evaporation and the residue is crystallized from isopropanol to yield the title compound as colourless crystals; M.Pt. 198 (decomposition).

In an analogous manner there mav be obtained: ( i) (4aRS, 6RS, 8aRS)-2-allyl-6-azido-decahydro-4a-(3-hydroxyphenyl)-cis- isoquinoline, M.Pt. 125 (decomp.).

(ii) (4aRS,6RS,8aRS)-2-cyclopropylmethyl-6-azido-decahydro-4a-(3-hydroxyphenyl)cis-isoquinoline; (iii) (raRS, 6RS, 8aRS)-2-cyclopropylmethyl-6-azido-decahydro-4a-(3-hydroxyphenyl)cis-isoquinoline; (iv) (4aRS,6RS,8aRS)-2-(o-chlorophenethyl)-6-azido-decahydro-4a-(3-hydroxyphenyl)cis-isoquinoline.

EXAMPLE 6: 1,2,3,4,4a,5,8,8a-octahydro-4a-(3-hydroxyphenyl)-2-methyl-cis-isoquinoline, and 1,2,3,4,4a,7,8,8a-ctahydro-4a-(3-hydroxyphenyl)-2-methyl-cis-isoquinoline [process e)] (4aRS,6SR,8aRS)-decahydro-6-tosyloxy-(3-tosyloxyphenyl)-2-methyl-cis-isoquinoline (obtained in Example 5a) in 10 ml of absolute dimethyl sulphoxide and 1 ml of N-ethyl-diisopropylamine is heated at 70 for 16 hours under nitrogen, and then partitioned between toluene and 2N aqueous carbonate. The organic phase is concentrated by evaporation and chromatographed on silicagel using acetone/triethylamine (99:1) as eluant yielding initially 1,2,3,4,4a,5,8,8a-octahydro-4a-(3-hydroxyphenyl)-2-methyl-cisisoquinoline, M.Pt. 159 (from toluene/methylene chloride) and then 1,2,3,4,4a,7,8,8aoctahydro-4a-(3-hydroxyphenyl)-2-methyl-cis-isoquinoline, M.Pt. 183 (from toluene/ methylene chloride).

EXAMPLE 7: 4a-(3-acetoxyphenyl)-octahydro-2-methyl-cis-6(2H)-isoquinolinone [process g] 3.7 ml (40mmol) of acetic anhydride are added dropwise to a stirred mixture of 5.19g (20mmol) of octahydro-4a-(3-hydroxyphenyl-2-methyl-cis-6(2H)-isoquinolinone (see Example 3), 3.22 ml (40 mmol) of pyridine and 20 ml of toluene at :w-. The mixture is then kept at 22 for 2 hours. 20 ml of water is added to the mixture at 5 , and the mixture is stirred for 30 minutes at 22 . 40 ml of methylene chloride are added. Whilst being stirred, the aqueous phase of the resultant two-phase mixture is adjusted to pH 7 by the addition of 4 g of sodium carbonate. The aqueous phase is then separated and extracted with methylene chloride. The organic phases are washed with water, dried. concentrated by evaporation and dried in a high vacuum. The title compound is obtained as a viscous oil which is crystallized as the hydrogen fumarate from isopropanol: M.Pt. 194' (decomposition).

EXAMPLE 8: Decahydro-4a-(3-hydroxyphenyl)-2-methyl-6-methylene-cis-isoquinoline [process h)] 3.93 g (11 mmol) of methyl triphenylphosphonium bromide in 100 ml of absolute dimethylformamide is treated with 1.01 g of a 50% w/w sodium hydride dispersion in oil (21 mmol) under nitrogen. The mixture is stirred for 1 hour at room temperature, and then treated with 2.59 g of octahydro-4a-(3-hydroxyphenyl)-2-methyl-cis-6(2H)-isoquinolinone.

The mixture is stirred for 16 hours at 40 , and partitioned between methylene chloride and aqueous ammonium sulphate. Evaporation of the organic phase and chromatographic purification on silicagel gives the title compound.

The compounds of formula I exhibit pharmacological activitv. In particular, the compounds exhibit analgesic activity, as indicated in standard tests. e.g. in the phenyl-benzoquinone writhing test in mice on p.o. administration of from 1).5 to 5() mg/kg of the compounds, and in the tail flick test in mice on s.c. administration from 0.5 to 100 mg/kg of the compounds.

An indicated daily dose is from 20 to 300 mg. conveniently administered in divided doses 2 to 4 times a day in unit dosage form. containing from 5 to ISO mg of the compound. or in sustained release form.

The compounds of formula I mav be administered in pharmaceuticallv acceptable acid addition salt form. The present invention also provides a pharmaceutical composition comprising a compound of formula I in free base form or in pharmaceuticallv acceptable acid addition salt form in association

Claims

WHAT WE CLAIM IS:

1. A process for the production of a compound of formula I.

wherein ( i) R1 is hydrogen or alkyl of I to 4 carbon atoms.

R2 is hydrogen, R3 and R4 together are oxygen. and each of R5 and K, is hydrogen. or (ii) R1 is hydrogen, alkyl of I to 4 carbon atoms. or alkanovl of l to 4 carbon atoms. and R2 is alkyl of 1 to 6 carbon atoms. a radical of formula II.

wherein R7 and R8 are. independently. hydrogen or alkyl of I to 4 carbon atoms, a radical of formula III.

wherein m is a whole number from 2 to 4. a radical of formula IV.

wherein n is l or 2. or a radical of formula V.

wherein p is 1 or 2, and R, is hydrogen, halogen, trifluoromethyl. alkoxy of I or 2 carbon atoms or alkyl of 1 or 2 carbon atoms, amino. or di(alkvl of I or 2 carbon atoms)-amino, and (a) either R3 is azido or hydroxy. and R4 is hydrogen, or R3 and R4, together, are oxygen or methylene, and each of R5 and R6 is hydrogen, or (b) either R3 and R6, together, form a bond, and each of R4 and R5 is hydrogen, or R4 and R5, together, form a bond, and each of R3 and R6 is hydrogen, with the proviso that when R3 is hydroxy and R4 is hydrogen, or when R3 and R4, together, are oxygen, and (i) when R2 is a radical of formula IV, then n is 1, or (ii) when R2 is a radical of formula V, then p is 2, and R9 is hydrogen or halogen, which comprises a) splitting off the amino protecting group R10 present in a compound of formula VI,

wherein R1' is hydrogen or alkyl of 1 to 4 carbon atoms, and R10 is an amino protecting group, to produce a compound of formula Ia,

wherein RI is as defined above, b) alkylating a compound of formula Ia, as defined above, or the corresponding compound wherein the keto group is protected. and if necessarv splitting off anv keto protecting group in the resultant product, to produce a compound of formula Ib,

wherein R1' is as defined above, and R2' is R2 as defined above, with the proviso that it is other than hydrogen. c) reducing a compound of formula Ic,

wherein R1 and R2' are as defined above. to produce a compound of formula Id,

wherein R1 and R2' are as defined above. d) replacing a leaving group R11 by azido in a compound of formula VII,

wherein, R1' is alkyl of 1 to 4 carbon or alkanoyl of 1 to 4 carbon atoms, R2' is as defined above, and R11 is a leaving group, to produce a compound of formula Ie,

wherein R1' and R2' is as defined above. e) eliminating HR11 from a compound of formula VIII,

wherein, R11 and R2' are as defined above, and R12 is a group capable of being split off under the reaction conditions, alkyl of 1 to 4 carbon atoms, or alkanovl of 1 to 4 carbon atoms. to form a compound of formula If.

wherein R1 and R2' are as defined above, and either R3' and R6', together, form a bond, and each of R4' and R5' is hydrogen, or R4' and R5', together, form a bond, and each of R3' and R6' is hydrogen. f) splitting off a hydroxy protecting group R13 from a compound of formula IX,

wherein R2', R3, R4, R5 and R6 are as defined above, with the proviso that when R3 and R4 are together oxygen, the keto group may be in free form or protected form, and R13 is a hydroxy protecting group, to produce a compound of formula I, wherein R1 is hydrogen. g) acylating a compound of formula I, wherein R1 is hydrogen, to produce a compound of formula I, wherein R1 is alkanoyl of 1 to 4 carbon atoms, or h) replacing the oxygen of the keto group of a compound of formula Ic by methylene under Wittig conditions to form a compound of formula Ig.

wherein R1 and R2' are as defined above.

2. A process for the production of a compound of formula 1. as stated in claim 1. substantially as hereinbefore described with reference to any one of the Examples.

3. A compound of formula 1. whenever produced by a process according to claim 1 or 2.

4. A compound of formula 1. as defined in claim 1.

5. A compound of claim 4. which is octaydro-4a-(3-methoxyphenyl)-cis-6(2H)- isoquinolinone.

6. A compound of claim 4. which is octaydro-4a-(3-methoxyphenyl)-2-methyl-cis- 6(2H)-isoquinolinone.

7. A compound of claim 4, which is 2-allyl-octahydro-4a-(3-methoxyphenyl)-cis-6(2H)- isoquinolinone.

8. A compound of claim 4. which is 2-cyclopropylmethyl-octahydro-4a-(3- methoxyphenyl)-cis-6(2H)-isoquinoline.

9. A compound of claim 4. which is 2-cyclopropylmethyl-octahydro-4a-(3- methoxyphenyl)-cis-6(2H)-isoquinolinone .

10. A compound of claim 4. which is 2-(o-chlorophenyl-ethyl)-octahydro-4a-(3- methoxyphenyl)-cis-6(2H)-isoquinolinone.

11. A compound of claim 4. which is octaydro-4a-(3-hydroxyphenyl)-2-methyl-cis- 6(2H)-isoquinoline.

12. A compound of claim 4. which is 2-allyl-octahydro-4a-(3-hydroxyphenyl)-cis-6(2H)- isoquinolinone.

13. A compound of claim 4. which is 2-cyclopropylmethyl-ocathydro-4a-(3- hydroxyphenyl )-cis-6( ;!H)-isoquinolinone .

14. A compound of claim 4. which is 2-cyclobutylmethyl-octahydro-4a-(3- hydroxyphenyl-cis-6(2H)-isoquinoline.

15. A compound of claim 4. which is 2-(o-chlorophenethyl)-octahydro-4a-(3- hydroxyphenyl)-cis-6(2H)-isoquinoline.

16. A compound of claim 4. which is (4aRS,6SR,8aRS) or (4aRS.6RS.XaRS)- decahydro-6-hydroxy-4a-(3-hydroxyphenyl)-2-methyl-cis-isoquinoline.

17. A compound of claim 4. which is (4aRS,6SR,8aRS) or (4aRS,6RS,8aRS)-2-allyl- decahydro-6-hydroxy-4a-(3-hvdroxyphenyl )-cis-isoquinolinone.

18. A compound of claim 4. which is (4aRS,6SR,8aRS) or (4aRS,6RS,8aRS)-2- cyclopropylmethyl-decahydro-6-hydroxy-4a-( 3-hydroxyphenvl )-cis-isoquinolinone.

19. A compound of claim 4. which is (4aRS,6SR,8aRS) or (4aRS,6RS,8aRS)-2- cyclobutylmethyl-decahydro-6-hydroxy-4a-(3-hydroxyphenvl )-cis-isoquinolinone.

20. A compound of claim i. which is (4aRS,6SR,8aRS) or (4aKS.6KS,8aKS)-2-(o- chlorophenethyl )-decahydro-6-hydroxy-4a-(3-hydroxyphcnvl )-cis-isoquinolinone.

21. A compound of claim 4. which is (4aRS,6RS,8aRS)-6-azido-decahydro-4a-(3- hydroxyphenyl)-2-methyl-cis-isoquinoline.

22. A compound of claim 4. which is (4aRS,6RS,8aRS)-2-allyl-6-azido-decahydro-4a- (3-hydroxyphenyl)-cis-isoquinoline.

23. A compound of claim 4. which is (4aRS,6RS,8aRS)-2-cyclopropylmethyl-6-azido- decahydro-4a-(3-hydroxyphenyl )-cis-isoquinoline.

24. A compound of claim 4. which is (4aRS,6RS,8aRS)-2-cyclobutylmethyl-6-azido- decahydro-4a-(3-hydroxyphenyl )-cis-isoquinoline.

25. A compound of claim i. which is (4aRS,6RS,8aRS)-2-(o-chlorophenethyl)-6-azido- decahydro-4a-(3-hydroxyphenyl )-cis-isoquinoline.

26. A compound of claim 4. which is 1.'.3.4.4a.z.X.Xa-octahvdro-4a-(3- hydroxyphenyl)-2-methyl-cis-isoquinoline.

27. A compound of claim 4. which is I.2.3.4.4a,7.8.a-octahydrn4a-(3- hydroxyphenyl)-2-methyl-cis-isoquinoline.

28. A compound of claim 4. which is a-(3-acetoxyphenyl)-octahydro-2-methyl-cis- 6(2H)-isoquinolinone

29. A compound of claim 4. which is decahydro-4a-(3-hydroxyphenyl)-2-methyl-6- methylene-cis-isoquinoline.

30. A compound of claim 4. wherein R is azido.

31. A compound of claim 4. wherein R3 is hydroxy.

32. A compound of claim 4. wherein R3 and R, together are oxygen.

33. A compound of claim 4, wherein R3 and R6 together are a bond.

34. A compound of claim 4, wherein R4 and R5 together are a bond.

35. A compound of any one of claims 30 to 34, wherein R1 is hydroxy.

36. A compound of any one of claims 30 to 34, wherein R1 is alkyl.

37. A compound of any one of claims 30 to 34, wherein R1 is alkanoyl.

38. A compound of any one of claims 30 to 37, wherein R2 is alkyl.

39. A compound of any one of claims 30 to 37, wherein R2 is a radical of formula 11.

40. A compound of any one of claims 30 to 37, wherein R2 is a radical of formula III.

41. A compound of any one of claims 30 to 37, wherein R2 is a radical of formula IV.

42. A compound of any one of claims 30 to 37, wherein R2 is a radical of formula V.

43. A compound of claim 4, wherein R, is hydrogen, methvl. or acetvl. R. is hydrogen alkyl (C1-C6), alkenyl (C3-C7), a radical of formula III, a radical of formula IV, or a radical of formula V, and either R3 is hydroxy and R4 is hydrogen or R3 and R4 together are oxygen, with the proviso that when R1 is acetyl. R2 is other than hydrogen.

44. A compound of claim 4, wherein R2 is alkyl, a radical II or III, a radical IV, wherein n is 1, or a radical V, wherein p is 2 and R0 is hydrogen or halogen.

45. A compound of claim 44, wherein R1 is hydrogen or alkyl.

46. A compound of claim 45, wherein R3 is hydroxy.

47. A compound of claim 45, wherein R3 is azido.

48. A compound of claim 45, wherein R3 and R4 together are oxygen.

49. A compound of claim 44, wherein R1 is alkanoyl.

50. A compound of claim 49, wherein R3 is hydroxy.

51. A compound of claim 49, wherein R3 is azido.

52. A compound of claim 49, wherein R3 and R4 together are oxygen.

53. A compound of any one of claims 4 to 52 in racemic form.

54. A compound of any one of claims 4 to 52 in opticallv active form.

55. A compound according to any one of claims 4 to 54 in free base form.

56. A compound according to any one of claims 4 to 54 in acid addition salt form.

57. A pharmaceutical composition comprising a compound according to any one of claims 4 to 54 in free base form or in pharmaceutically acceptable acrid addition salt form in association with a pharmaceutical carrier or diluent.