AU594954B2 - Improvements in or relating to organic compounds - Google Patents

Description

COM MON W EA L TH OF AU ST RA L IA PATENT ACT 15.52 COMPLETE~ SPECIFICATION (original) FOR OFFICE USE Class ~Cla~s Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: 5 9 49 Th3 dU~fw t C a13 klI i* SOT" k Name of Applicant: Address oQf Applicant: Actual InvenL-r(s): 0.

a~ SANDOZ LTD.

35 Lichtstrasse, CH-4002 Basle,

SWITZE~RLAND.

Laszlo REVESZ Address for Service: DAVIES COLLXSON, Patent Attorneys, 1 Little Collino Street, Melbourne, 3000.

Complete Specification for the invention entitled: "IMPROVEMENTS IN OR RELhATING TO OR~GANIC COMPOUNDS" The following statement is a full description of this invention, including the best method of~ performing 4t known to us 1 I~ 1A- This invention relates to morphinan, including morphine, derivatives.

The present invention provides compounds of formula I 4 A0 X AZ CH R 2 R3

R

4 wherein X and Y each denote hydrogen or together denote

R

1 denotes allyl optionally substituted by 1 to 3 alkyl groups, the substituent or substituents having in total a maximum of 3 carbon atoms, cyclopropylmethyl or 3-furylmethyl,

R

2 denotes hydrogen, alkyl with 1 to 10 C-atoms, cycloalkyl with 5 or 6 carbon atoms, phenyl which is optionally substituted with halogen, CF 3 hydroxy, nitro, alkyl with 1 to 3 C-atoms, alkoxy with 1 to 3 C-atoms or NRaRb wherein Ra and Rb independently are hydrogen oz alkyl with 1 to 3 C-atoms or phenylalkyl with 7 to 12 C-atoms which is optionally substituted with halogen, CF 3 hydroxy, nitro, alkyl with 1 to 3 C-atoms, alkoxy with 1 to 3 C-atoms or NRaRb wherein Ra and Rb independently are hydrogen or alkyl with 1 to 3 C-atoms or, R3 denotes hydrogen, alkyl with i to 10 C-atoms or phenyl, *f ft J i t NCI 0- iz g 100-6654

R

4 denotes hydrogen, OH, NR 6

R

7 NHCOR, NHSO 2 R' or NH- COOR'

R

6 and R 7 independently of one another, denote hydrogen or alkyl with 1 to 3 C-atoms, R denotes alkyl with 1 to 6 C-atoms, phenyl or -A-COOR' A denotes alkylene or alkenylene each with 2 to 4 C-atoms, R' denotes alkyl with 1 to 6 C-atoms or phenyl, denotes methyl or ethyl and wherein either R 3 is in the a-position and R 4 is in the p-position, or R 3 is in the P-position and R 4 is in the a-position, or

R

3 and R 4 together are O, or CH 2 /and

R

5 denotes hydrogen or methyl, with the provisos that when X Y denotes R denotes hydrogen, R 4 denotes a a-OH group and 3 and R denote hydrgen, R is other than cyclopropylmethyl or allyl, and that when R 2

,R

3

,R

4 and R 5 are each hydrogen, R 1 is other than cyclopropylmethyl, in free base form or in acid addition salt form,as well as the physiologically hydrolysable, pharmaceutically acceptable esters of such compounds, which contain a free OH group, Sin free base form or in acid addition salt formn 2 100-6654 The compounds according to the invention may exist in free base form or in acid addition salt form which may be obtained from the free base forms in conventional manner and vice versa. Examples of acid addition salts are the hydrochlorides, hydrobromides, hydrogen maleates and hydrogen malonates.

The compounds according to the invention may be produced as follows: a) in order to produce a compound of formula la CH 0 41 t 4 44 wherein R' 1 denotes cyclopropylmethyl or 3-furylmethyl a compound of formula VII

J/

i i I -rr. -3- ,.0-6654 is brominated, the resultant compound, which contains a bromine atom in at least position 5, is dehydrobrominated to form a furan ring, and the product is debrominated, b) in order to produce a compound of formula Ib rrs a (P at E i: ii a Pb II ttl D d Br-c~o 4 a (P ar~ Q 6 re the ketal group in a compound of formula X c.

I 100-6654 whereit, L' and Z' derZ te al kyl with 1 3 C-atoms or together denote (CH 2 2 or (CH 2 3 is hydrolysed to an oxo groups c) in order to produce a compound of formula Ic wherein R denotes alkyl with 1 to 10 C-atoms or phenyl a compound of formula IP

'I

4* I 4 4 *4 4 ~o 4# 4 S*4 4 4 44 4 44 4 U 44 4 44 is reacted with an organic metal compound containing the radicalR'3 100-6654 d) in order to produce a compound of formula Id a compound of formula XI 44 t I 4 I 4.4 It 14 4 4 4t~ 4 44 44 4 LII 4 4 44444 4 4 41 4 I I I I It is reduced, e) in order to produce a compound of formula Ie *r c L 4 4441 4 1 44 4 4r 44 4.

4 4~ 100-6654 wherein R4 denotes NR 6

R

7 NHCOR, NHSO2R' or NH-COOR'', a compound of formula I' is reductively aminated to form the corresponding 6-amino compound, and this latter compound is optionally alkylated or acylated on the N-atom, f) in order to produce a compound of formula If the oxo group in a corpound of formula I' i. reduced to a hydroxy group, g) in order to produce a compoun-' of formula Ig a compound of formula XII 2 -7- 100-6654 i s reduced, h) in order to produce a compound of formula Ih

I,

44 4(44 4 *4 LI I I *4 4 49 4 4 44~ 4 the benzyl group in a compound of formula XIII I 4499* I 4 .4 4 4 LI I (4

XIII.

is removed hydrogenolytically, and the 6-amino compound obtained is optionally alkylated or acylated, -0

I'

100-6654 i) in order to produce a compound of formula Ii wherein Rl'denotes al lyl optionally substi tuted by 1 to 3 al kyl grou~ps, the subs ti tuen t or substi tuents having in total a maximum of 3 'C-atoms, a compound of formula XIV 5 i I I

II*~

i LI 14 4 S It 4 (LI 4

I

4,4 III

I

(I I I It

(I

is reacted with a compound of formula Rj''X (X =halogen), i 1 I I~lp L I I 100-6654 jQ

I

i /i j) in order to produce a compound"of formula Ij I) 0

C

2 2 R4 a compound of formula Ik 0k 2 2

-R

R R1 is subjected to an ether splitting, k) in order to produce a compound of formula I wherein

R

3 and R 4 together are CH 2 a compound of formula I wherein R 3 and R 4 together are 0 is reacted with

(C

6

H

5 3 P CH 2 1) in order to produce physiologically hydrolysable and pharmaceutically acceptable esters of the compound of formula I, which contain a free' OH group, such a compound of formula I is reacted with an appropriate acid or with a reactive derivative thereof, or

CL

4444 4 44 14 I 46 I C 100-6654 m) to produce a compound of formula I wherein R 4 is NR6R 7 wherein R 6 and R7 are as defined above with the proviso that one of R6 and R7 is other than hydrogen, NHCOR, NHSO2R' or NHCOOR'', a compound of formula I wherein R4 is NR 6

R

7 wherein R 6 and R7 are as defined above with the proviso that one of R 6 and R is hydrogen/or NH 2 is alkylated or acylated resoectively, wherein in the above formulae the configurations of the group Y if present in the 5 position and .the bonds linking the 9 and 13 positions are the same as in formula I, and the definitions of R 1 to RgX and Y except where otherwise stated are as given above with reference to formula I.

^In the above formula, as well as in the description and the examples, and in intermediate and final products e,g. up to formulae XIV, the chiral carbo, atoms havo r. the configuration as in the natural (levorotatory) mornhinan series i.e. in nosition 9:R; in positon 13:R and in position 1 4 :S.The present invention also covers comoounds of formula I in admixture with e.g. their epimers, e.g. as in I a racemi.c mixture.

ii Preferably the phenyl or phenyl-alkyl ring substituents are monosu.stituted.

In the above formula preferably

R

1 is cyclopropylmethyl and/or

R

2 is alkyl, especially methyl or ethyl and/or

R

2 is cycloalkyl, especially cyclohexyl, and/or

R

2 is optionally substituted phenyl phenyl or pHO-phenyl), and/or

R

3 is hydrogen, alkyl of 1 to 4 C-atoms or phenyl

R

4 is hydroxy or hydrogen, especially hydroxy and/or

R

3 and R 4 together are O or CH 2 and/or

R

5 is hydrogen.

Conveniently R 3 and R 4 together are 0. Conveniently X and Y are each H. Preferably when R 4 is OH it is in the a-position.

All the reactions may be effected in conventional manner, or analogously to the examples given below. As mentioned above, process a) may take place in 3 stages, firstly bromination, e.g. with Br 2 in glacial acetic acid, then splitting of HBr in an alkaline medium, e.g. in NaOH solution, and finally removal by reduction of any Br .atoms which are still present and have been introduced, e.g. into position 1 and 7 during the bromination of stage 1. This removal by reduction may take place e.g.

by hydrogenation in the presence of Pd/C.

4 8 i 9Q1S-kIrI3d~73,IO,1 0

O

Jf 1 i i 0 L -12- 100-6654 Process b) may be effected by means of hydrolysis in an acidic medium, e.g.in HC1 solution.

Process c) may be effected by reacting with a lithiurni organic compound, e.g. in ether.

The reduction processs d) and g) may be effected in a manner which is usual for the hydrogenation of double bonds, e.g. with Pd/C as a catalyst. Process e) may be effected by methods which are known for amination by reduction, e.g. with boron hydride derivatives, such as NaCNBH 3 as reduction agents, in the presence of ammonium S acetate. The subsequent optional alkylation or acylation and process m) may take place in known manner, e.g. with "alkyl or acid halides in the presence of a base e.g. in analogous manner to that described in Example 9.

The reduction of the oxo group to a hydroxy group (process f) may take place in accordance with processes which are known for reduction, e.g. using NaBH as a reduc ing agent.

4 i: The removal of the benzyl group from compounds of formula XIII (process h) may take place in the usual way, by hydrogenolysis, e.g. with Pd/C. Any subsequent reactions S may take place as described for process e).

Process i) may be a conventional alkylation of secondary to tertiary amines.

The ether cleavage of process j) may take place using the conventional reagents,such as HBr, BBr 3 or pyridine hydrochloride.

The process k) may be effected in conventional manner known for Wittig reactions.

c-

J

-13- 100-6654 The acylation of process 1) may take place in conventional manner, e.g. with acid halides in the presence of a base.

The starting compounds of formula VII (process a) may be produced e.g. in accordance with the following scheme: a' tt t it t ti Er (I I

C'

d' II I I I I I i~LiPI r~ I

I

-14- 100-6654 Production of the compounds of formula III (process a') may take place by reacting a compound of formula II with 0 thiosulphinate of formula R 2

CH

2

-S-S-CH

2

R

2 (Diels-Alder reaction) by heating them in an inert solvent, e.g.

in toluene, under reflux.

Opening of the furan ring (with simultaneous changing of position of the S-atom) (process may be effected, e.g.

through the action of HBr.

i« Opening of the S-ring (process in' o tder to produce the I ,r compounds o-f formula V may be attained by reduction of the compounds of formula IV, with simultaneous saturation of the double bond and reduction of the oxo group, e.g.

with Li in liquid ammonia.

Removal of the SH group from the compounds of formula V (process may be effected, e.g. with Raney-Nickel in methanol.

Finally, the 6-hydroxy group in the compounds of formula VI may be transformed into an oxo group (process in conventional manner, e.g. by reacting it with oxalyl S dichloride and dimethyl sulphoxide.

Production of the compounds of formula VII, wherein R 2 denotes phenyl, may be effected directly from the compounds of formula III, by means of a reaction with Raney-Nickel in methanol.

The starting compounds of formula X (process b) may be produced from the compounds of formula VII in accordance with-the following reaction schemet

I

100-6654 VII

VIII

t t ae a 4 4, 44t The compounds of formula VIII may be obtained by conventional etherification of the 4-hydroxy group with e.g.

a halobenzene in the presence of a base and copper (process In the compounds of formula VIII thus obtained, the 6-oxogroup may be then transformed into a ketal group (process in conventional manner,with an alcohol or glycol.

Finally, in the compounds of formula IX thus obtained, the 4-phenoxy group is remov.ed by reduction (process e.g.

with Na in liquid ammonia.

II

-16- 100-6654 The starting compounds XI and XII may be obtained by dehydration of the compounds of formulae Ic or If respectivelyo Dehydration may take place in the usual manner, e.g. by heating in an acidic medium, e.g. in HC1 solution or in pyridine hydrochloride. Mixtures of 5,6 and 6,7didehydro compounds are thus produced.

The starting compounds of formula XIII may be obtained by reacting the 6-oxo group in the compounds of formula I' with benzylamine to form the corresponding 6-benzylimine ompounds, and further reacting the compounds thus obtained with a Grignard compound of formula R MgX, with subsequent hydrolysis.

The starting compounds of formula XIV are obtainable by demethylation with chloro-fo('mic acid vinyl ester or cyanogen bromide) of the corresponding N-methyl compounds (these latter compounds may be produced analogously to the compounds of formula I accordinq to the invention).

During the above-mentioned reactions, if compounds of formula I are obtained in which R3 and R 4 have differing significances, they usually exist as mixtures of the 6a-R 3 6 -R 4 and 6a-R 4 6P-R 3 isomers, which can be separated into their components in conventional manner, e.g. by chroma- *tography.

In reaction c) and in the Grignard reaction to produce the Sstarting compounds of formula XIII, the 6a-OH, 6F-R compounds or 6a-NH 2 6p-R3 compounds respectively are primarily produced.

The present invention covers compounds of formula III to XIV ple :e.

.111-- -17- 100-6654 Insofar as the production of any particular starting material is not particularly described, it is known or may be produced in conventional mannrr in analogous to the examples.

The compounds of formula II are known. They can be produced from thebaine. The present invention also provides a process for the production of a compound of formula I wherein R 3 and R 4 together are oxygen which includes any of the following steps, in any order, of t r i) replacing the 17-methyl group in thebaine by the group R ii) introducing the group CH 2

R

2 into position 14, iii) demethylating as appropriate to conver, the methoxy groups in position 3 and 6 into hydroxy and keto o igroups respectively, and f ft t t iv) if desired removing 'he oxygen bridge in the position.

"Thebaine" includes any alkaloid of the thebaine series.

hese reactions may be effected in one or more idteps as desired, e.g. along the lines indicated above with respect I to processes a) to m) and to and e.g. step iii) may for example involve a rearrang6ment.

Further reactions from e.g. one intermediate into another and from one comp"und of formula I into another m'y be made in conventional manner.

The following non-limitative examples illustrate the invention Temperatures are in degrees Centigrade and are uncorrected.

In the examples maleinate maleate.

_18- -18- 100-6654 Example 1: 17-cyclopropylmethyl-.4 5 a-epoxy-3-methox-10 -ethyl morphinan-6-one a) ,1ed-teo§22IAtt~y~--haS c-methvl-Nq2 9 2E2yLnty1northebaime 46.4 g (0.132 mols) of N-cyclopropylmethylnorthebaine and 17.6 g (0.128 mols) of S-ethylethanethiosulphinate are ref luxed for 1 hour in 1000 ml of toluene, and after coQling are washed twice with water. The organic phase is dried over Na2s ,concentrated, and flash-chromatographed over silica gel with methylene chloride/methanol/conc. NH 3 99.5:5:0.1. The title compound is isolated as pale yellow crystals.

b) N: £~22292Yx9ttY!: L14ethano-1 7a-me~ty 1 -thianorthebainone 40.6 g (0.099 mol) of the compound of stage 1a) are stirred at room temperature into 150 ml of 48% hydrobromic acid, 41whereby the starting material becomes completely dissolved.

As soon as the reaction product starts to crystallise, ml of methanol were added and stirred for one hour at 0 0

C.

4 04 The hydrobromide of the title compound is filtered off and washed with methanol/ether: 256-258*C.

4.3 g (0.62 mols) of lithiurm are dissolved at -45'C in 1.8 1 of liquid ammonia, and 22.5 g (56.7 mu4ols) of the compound I I -19- 100-6654 of stage Ib) dissolved in 500 ml of tetrahydrofuran are added to the deep blue solution. After 20 minutes at the solution is broken down with solid ammonium chloride, the ammonia is distilled off, the residue taken up in water and extracted three times with ether. After drying, concentrating and flash-chromatography with ethyl acetate/hexane (1:4 to 1i2), the organic phases yield the title compound as a colourless oil.

mEhtinan 130 g of Raney-Nickel are added to 1.5 1 of methanol, and 13.4 g (33.3 mMol) of the compound of stage Ic) in 250 ml of methanol are rapidly added with vigorous stirring. After minutes, the reaction mixture is filtered and concentrated by evaporation. The residue is taken up in methylene chloride, dried over Na 2

SO

4 concentrated by evapration, and the title compound is obtained as a light red foam.

e) NZyclorEoElbetZyl 4gethyl-4hydroxy-3methh hiE: 6-one S4.35 ml (50.4 mMol) of oxalyl chloride are added at -60 C "1 to 500 ml of methylene chloride, and mixed with 7.2 ml (100.7 mMol) of DMSO in 85 ml of methylene chloride. Then, 17 g (45.8 mMol) of the compound of stage id) in 100 ml of methylene chloride are rapidly added at -78°C, followed by 32 ml (229 mMol) of triethylamine at -60o to -50 0 C after minutes at -78°C. The reaction mixture is slowly heated 100-6654 to room temperature, water is added, and the mixture is extracted three times with methylene chloride. After drying, concentrating by evaporation and flash-chromatography with ethyl acetate/hexane (1:3 to the organic phases yield the title compound as a colourless oil.

f) 17-cycl2ropylmethyl-4 g5aegoxy-3ethoxy4ethyltmorphinan 6-one 14.6 g (39.6 mMol) of the compound of stage le) are added to 430 ml of glacial acetic acid, and 19.0 g (119 mMol) of Br 2 in 200 ml of glacial acetic acid are added in drops whilst stirring at room temperature over the course of 30 minutes.

After 90 minutes, the reaction mixture is concentrated by evaporation, taken up in 1 1 of methylene chloride, and poured whilst stirring and cooling into 300 ml of 1N NaOH.

The methylene chloride phase is separated, washed with water and a little 10% tartaric acid (pH dried over Na 2

SO

4 and concentrated. The remaining residue is dissolved in 170 ml of glacial acetic acid, and after adding 130 ml of water and 3 g of 10% Pd/C, the mixture is hydrogenated for 15 hours at room temperature and at 1 atm. The Pd/C is Eiltered off, the glacial acetic acid distilled off, the residue taken up in ice/2N Na 2

CO

3 and extracted three times with methylene chloride. Drying of the organic phase over Na 2

SO

4 concentration and flash-chromatography with ethyl acetate/ hexane 1:5 yield the title compound as colourless crystals.

-21 100-6654 Example 2: 17-cyclopropylmethyl-4,5a-epoxy-14(3-ethyl-3-hydroxymorphinan-6-one 3.25 g (8.9 mMol) of the compound of example 1 and 10 g of pyridine hydrochloride are heated for 3 hours to 190 0 C, then taken up in water after cooling, rendered basic with conc.

ammonia, and extracted three times with methylene chloride.

Flash-chromatography with ethyl acetate/hexane 1:5 yields the title compound as colourless crystals. Recrystallisation from ether/pentane yields an analysis-pure product: 157-158 0

C.

Example 3: 141-benzyl-17-cyclopropylmethyl-4,5a-epoxy-3-methoxymorphinan-6 -one a) §,LiLedoethen: ,LZLL 4teat~ahydro-7- Lhia-8ct hnyl -N- 40.4 g (0.115 mols) of N-cyclopropylmethylnorthebaine and 21 g (0.08 mols) of S-benzylphenylmethanethiosulphinate are t 4 ref luxed for 1 hour in 750 ml of toluene. The reaction i ts 4 mixture is concentrated by evaporation, mixed with water, and extracted three times with ether. After drying and evaporating the ether phase, colourless crystals remain, '2 which yield the title compound after washing with a little ethet'. 148-150'C.

6-one g (42.3 ,nMol) of the compound of stage 3a) and 200 g of .i -22- 100-6654 Raney-Nickel are refluxed in 1.3 1 of methanol for 4 hours, and after a further addition of 70 g of Raney-Nickel for a further 3 hours. The Raney-Nickel is filtered off and washed well with methanol. The combined methanol phases are concentrated, the remaining residue is taken up in ether and dried over Na 2

SO

4 concentrated, and yields a colourless oil. Flash-chromatography over 350 g of silica gel with ethyl acetate/hexane 1:8 yields the title compound as colourless crystals. 122-124 0

C.

c) 14rbenzyl-1 7-cl~ylo rolmete mnor2hinan-6-one 2.2 g (5.1 mMol) of the compound of stage 3b) are added to ml of glacial acetic acid, and mixed with 2.45 g (15.3 mMol) of Br 2 in 30 ml of glacial acetic acid, stirred for 4 hours at room temperature and concentrated by evaporation. The remaining residue is taken up in methylene chloride, shaken out with 100 ml of 1N NaOH whilst cooling with ice, the organic phase is separated, shaken with water, and 10% tartaric acid is added until reaching a pH of 6. The organic phase is dried over Na 2

SO

4 and concentrated, mixed with 200 ml of water/glacial acetic acid 1:1, then 4.2 g of sodium acetate and 0.73 g of 10% Pd/C are added, and the mixture is t hydroStenated at 3 atm. and at room temperature. The reaction mixture is filtered, concentrated by evaporation, taken up in methylene chloride and washed with 2N soda. Drying and concentration of the organic phase yield a light yellow oil, which after flash-chromatography with ether/hexane 1:3 yields the title compound as a colourless oil.

-23- 100-6654 Example 4: 148-benzyl-17-cyclopoppylmethyl-4,5c-epoxy-3-hydroxymorphinan-6-one 12.5 g of pyridine hydrochloride and 5.2 g (12 mMol) of the compound of example 3 are mixed at room temperature, and heated to 160 0 C whilst stirring. After 1 hour, a further 12.5 g of pyridine hydrochloride are added, and heating continues for a further hour at 160°C. After coolilig, the mixture is taken up in ice water, rendered basic with cone. ammonia and extracted three times with methylene chloride. The organic phases are dried over Na 2

SO

4 concentrated by evaporation and flashchromatographed over silica gel with ethyl acetate/hexane 1:3.

The following are isolated: the title compound as a colourless oil and unreacted starting material. The title compound is converted into the hydrochloride with ether/ethanol/HCl: 260 0

C.

Example 5: N-cyclopropylmethyl-140-benzyl-3-methoxymorphinan-6-one o a) Ncycloro mehl1 benz3mehoxy4henoxYmor2hinan 6-one *j 8.9 g (19 mMol) of the compound of example 3b), 5 ml (48 mMol) 4 4 of bromobenzene and 8.0 g (58 mMol) of K CO 3 are dissolved in 100 ml of pyridine, 2.0 g of Venus copper are added and heated for 16 hours under argon to 140°C. Ice water is added to the dark reaction mixture, which is extracted three times with ether. The organic phases are dried with Na2Sd4, concentrated by evaporation, and yield the title compound as -24- 100-6654 a dark oil which is reacted to form the next compound without further purification.

b) N:gygSlgE2Eo 2 lme Ylt: 1 QtYltyl bhxy- 4 -h2eoxy 6

L

6 ethYlenedioxy-morghinan 9.2 g (18 mMol) of the compound of stage 5a), 30 ml (0.54 mol) of ethylene glycol and 9.4 g (50 mMol) of p-toluenesulphonic acid monohydrate are refluxed for 4 hours in a water separator in 1 1 of benzene. The reaction mixture is ,'.shed once with 2N soda and once with water, dried over Na 2

SO

4 and concentrated, and yields the title compound as a dark brown oil which is reacted to form the next compound without further purification.

c) N c 6 l o heyl n m e edl- l lB e n z y i6:lf2^^Z^ e ,9 e E e ^3^ x y morEhinan 4 I, 9.7 g (17.6 mMol) of the compound of stage 5b) in 250 ml of in drops toluene are added to 500 ml of liquid ammonia which has been prepared at -55*C, and then 2.5 g (109 mMol) of sodium are added. The reaction mixture is stirred for 4 hours at Sto -350C, then broken down by adding solid ammonium chloride, and the ammonia is distilled off. The residue is taken up in water and extracted three times wjth ether. The ether phases are washed twice with 1N NaOH and once with water, dried over Na 2

SO

4 concentrated, and after flash-chromatography yield the title compound as colourless crystals. [c]20 -28.8

(CH

3

OH).

I 7 100-6654 d) N2cycloproyElmethyl:14-benyl-3-methoxmorE2hinan-6-one 5.8 g (12.6 mMol) of the compound of stage 5c) were refluxed for 4 hours in 750 ml of In HC1, then mixed with ice/conc. ammonia after cooling, and extracted three times with ether. After drying and concentrating the organic phase, followed by recrystallisation from ether, the title compound is obtained. 165-167 0

C.

*o Example 6: N-cyclopropylmethyl-14 -benzyl-3-hydroxymorphinan- 6-one t 1.65 g (4 mMol) of the compound of example 5 and 8.6 g of pyridine hydrochloride are heated to 180 0 C, after one hour 8.6 g of pyridine 88 hydrochloride are added, and the temperature is kept at 180°C for a further hour. Ice/conc. ammonia is added to the reaction *o mixture, which is extracted three tiu.es with methylene chloride.

o °4 After drying, concentrating and flash-chromatography (ethyl Sacetate/hexane the combined organic phases yield the S* 8 hydrochloride of the title compound. 290C.

M.pt. (HBr salt)>280C [c12 0 (free base) -69.60 ECH 3

OH.

base) -69.6 [CH3H].

.80.4 Example 7: 17-cyclopropylmethyl-4,5X-epoxy-140-ethyl-3,6ax-dia hydroxy-6 3-methyl-morphinan 635 mg (1.8 mMol) of the compound of example 2 are added at 00 to 100 mi of ether, and then 14 ml (22.4 mMol) of.a 1.6 molar solution of methyllithium in ether are added. The reaction mixture is slowly heated to room temperature, then broken down after 4 hours with 10% ammonium chloride solution, and extracted -26- 100-6654 three times with methylene chloride. The organic phases are washed with cone. ammonia, dried over Na 2

SO

4 and concentrated.

After flash-chromatography with ethyl acetate/hexane the residue yields the title compound as colourless crystals, togetlher with unreacted starting material. Recrystallisation from ether/hexane yields the analysis-pure title compound.

199-200 0

C.

Example 8: 17-cyclopropylmethyl-6a-amino-4,5a-epoxy-3-hydroxy- 14P-ethylmorphinan and 17-cyclopropylmethyl-63-amino-4, 5a-epoxy-3-hydroxy 148-ethylmorphinan 260 mg (4.13 mMol) of NaCNBH 3 in 10 ml of methanol are added in drops to a preparation at room temperature which consists of 1.5 g (4.25 mMol) of the compound of example 2 and 3.3 g (42.5 mMol) of ammonium acetate. After stirring for 17 hours at room temperature, the reaction mixture is adjusted to a pH of 1 with conc. hydrochloric acid, and is concentrated by evaporation. The residue is taken up in water, adjusted to a pH of 8 with 2N soda, and extracted three tines with methylene chloride. After drying the organic phase over Na 2

SO

4 concentrating by evaporation and flash-chromatography with methylene chloride/methanol/conc. ammonia (98:2:0.2 to 90:10:0.5), the'two title compounds are isolated (firstly the and then the 6a-isomer).

t S 5 i FI~F -27- 100-6654 Example 9: 17-cyclopropylmethyl-4,5a-epoxy-140-ethyl-3-hydroxy- 68- trans-3-methoxycarbonyl)acrvlamidolmorphinan 426 mg (1 mMol) of the 60-isomer of example 8 as the dihydrochloride are added at room temperature to a mixture of 20 ml of tetrahydrofuran, 10 ml of water and 600 mg (4.35 mMol) of

K

2 C0 3 and then a solution of 163 mg (1.1 mMol) of fumaric acid mc omethylester chloride in 10 ml of tetrahydrofuran is slowly added whilst stirring. After 30 minutes, the reaction mixture is extracted three times with ethyl acetate, the organic phases are dried over Na 2 S0 4 and concentrated by evaporation. After flash-cbromate.graphy (methylene chloride/methanol/conc. ammonia 99-1:0.1) and crystallisation as the hydrochloride from ethanol, the residue yields the hydrochloride of the title compound.

300 0

C.

7-cyclopropylmethyl-4,5a-epoxy-148-ethyl-3-hydroxy-6a-[trans- 3-(mnethoxycarbonyl)acrylamidolmorphinan is produced in a similar way from the 6c-isomer of example 8. 233-236 0

C.

Example 10: N-cyclopropylmethyl-140-ethyl-3,6a-dihydroxy-6methylmorphinan S" 1.1 g (3.25 mMol) of N-cyclopropylmethyl-14R-ethyl-3-hydroxymorphinan-6-one (produced analogously to examples 5 and 6 from the compound of example le) are added at 00 to 130 ml of ether, and then mixed with 24.4 ml (39 mMol) of a 1.6 molar solution of methyllithium in ether. The reaction mixture is slowly heated to room temperature and stirred for 4 hours, mixed with ml of 10% ammonimii chloride solution, acidified to a pH of 1 1 -28- 100-6654 with 3N HC1, rendered basic again with conc. ammonia, and extracted twice with ether. After drying over Na 2

SO

4 the ether phases are concentrated, and after flash-chromatography (methylene chloride/methanol/conc. ammonia 98:2:0.2), the hydrogen malonate of the title compound is obtained.

183-184 0

C.

Example 11: N-cyclopropylmethyl-140-ethyl-3-hydroxy-6a-methylmorphinan a) N-cycloropEylmethvl-14 -ethvl- 6a -hydroxv-3-methoxy:-6: 0,76 g (2.16 mMol) of N-cyclopropylmethyl-140-ethyl-3- 6-one methoxymorphinan-(produced analogously to example 5 from the compound of example Ie.) are added at O° to 100 ml of ether, and mixed whilst stirring with 16.3 ml of a 1.6 molar solution of methyllithium in ether. The reaction mixture is slowly heated to room temperature, and after 3 hours is broken down with 10 ml of a 10% ammonium chloride solution. The ether phase is separated, dried over Na 2

SO

4 concentrated, and the title compound is obtained as a light yellow oil which is reacted to form the next compound without further 1 I purification.

b) N-cyclopro~ylmethyl 5,6-(and 6,7)didehydrol4B-ethyl-3- 37 0.8 g (2.16 mMol) of the compound of stage lla and 4 g of pyridine hydrochloride are heated to 180°, and a further .i -29- 100-6654 4 g of pyridine hydrochloride is added at intervals of 1 hours. After 4 hours and after cooling, ice/conc.

ammonia is added, and the mixture is extracted three times with ether. After drying and concentrating, the organic phases yield a green-brown oil, which after chromatography over silica gel (methylene chloride/methanol 98/2 95/5), yields a colourless oil. The proportion of the two olefins 5,6- or 6,7-didehydro is 5:1.

c) N-cycloroimeth14-ethl3h drox-6-meh rhinan 0.45 g (1.33 mMol) of the compound of stage llb are dissolved in 50 ml of glacial acetic acid and 25 ml of water, mixed with 0.3 g of Pd/C and hydrogenated for 15 hours at room temperature and at 3 atm. The reaction mixture is filtered, concentrated by evaporation, taken up 1) in ice/10% ammonia solution and extracted three times with ether. The organic phase is dried, concentrated, and after chromatography over silica gel (methylene chloride/methanol/ conc. ammonia 96/4/0.2), yields the title compound as a colourless oil which crystallises as the hydrogen maleinate, 203-204CC.

Example 12: N-cyclopropylmethyl-4,5a-epoxy-143-ethyl- 3 ,6Pdihydroxymorphinan N-cyclopropylmethyl 4 5-epoxy-14!-ethyl-3 6adihydroxymorphinan 0.92 g (2.6 mMol) of the compound of example 2 are dissolved in 100-6654 100 ml of ethanol, mixed with 0.51 g (0.13 mols) of NaBH 4 and stirred at room temperature for 4 hours. By adding 30 ml of water and subsequently stirring for 30 minutes, the reaction mixture is broken down, the ethanol is distilled off, the remaining aqueous phase is firstly acidified with ice/3N HC1, then rendered basic again with conc. ammonia. The crystalline deposit is filtered off, recrystallised from ether, and the 6a-hydroxy-isomer is obtained. 299 0 C (hydrochloride).

The mother liquor is chromatographed over silica gel (methylene chloride/methanol/conc. ammonia 96/4/0.2), and the 63-hydroxyisomer is obtained as a colourless oil. 182-184 0

C

(hydrogen maleinate).

Example 13: N-cyclopropylmethyl-14 -ethyl-6 -hydroxy-3methoxy-morphinan N-cyclopropylmethyl-14Q-ethyl-6c-hydroxy-3methoxy-morphinan 0.95 g (2.7 mMol) of N-cyclopropylme 46-o-143-ethyl-3-methoxymorphinan-6-one (starting compound of example lla) are dissolved in 70 ml of ethanol, then 0.53 g of NaBH 4 (0.14 mol) are added, S and the mixture stirred for 3 hours at room temperature. The 1 reaction mixture is stopped with 20 ml of water and subsequent stirring for 30 minutes. The ethanol is distilled off and the residue is extracted three times with methylene chloride. After drying and concentrating, the organic phase yields a colourless oil, which is separated by chromatography on silica gel (methylene chloride/methanol/conc. ammonia I -31- 100-6654 99;l0.1) into the two compounds named in the title. Both compounds are isolated as colourless oils.

IExample 14: 140-benzyl-N-cyclopropylmethyl-6f-hyroxy-3- 11 m~ethoxy-morphinan and 13-benzyl-N-cyclopropyliethyl-6a-hyroxymethoxy-morhinan The above-mentioned compounds are produced analogously to example 13 from the comnound of example Examole 15: 140-benzyl-N-cyclopropylmethyl-3,6-dihydroxy- 2 rpt inari g (1.2 mMol) of the 61-hydroxy-isomer of example 14 are heated to 180'C together with 3.5 g of pyrid3,.B hydrochloride.

After every 1 hours, an additional 2.5 g of pyridine hydrochlorlde are added. After a total of 4 hours and a total of g of pyridine Iiydrochloride, 10% aqueous ammonia is added, and the mixt"ure is extracted three times with ether. After drying, concpntrating and chromatography over silica gel ~r (methylene chloride/methanol/conc. ammonia 95:5:0.25) the conbined ether phases yield the title compound. >280*C (hydrochloride) Example 16: I4 ,-benz,l-N-cyclopropylmethyl 3-h droxymorphiaf o2ameh -5-Land 6~7 -l ddeahydo-3b qzykZ-cvlaeomery nnu"*~rrrsrr~t~s~3 i I -32- 100-6654 0.8 g (1.92 mols) of the 6a-hydroxy-isomer of example 14 and 6 g of pyridine hydrochloride are heated to 180 0

C,

and 6 g of pyridine hydrochloride are added again at intervals of 1 hours. After a total of 5 hours and 18 g of pyridine hydrochloride, ice/conc. ammonia is added to the mixture, which is extracted three times with ether.

The combined organic phases are dried, concentrated, and after chromatography over silica gel (methylene chloride/ methanol/conc. aiamonia 99:1:0.1), the title compound is obtained as a colourless oil.

b) 1r-benzyN-cyclo-royethy3hydroxymorghinan 0.57 g (1.48 mMol) of the compound of stage a) are dissolved in 60 ml of glacial acetic acid and 30 ml of water, then 0.4 g of Pd/C are added, and the mixture is hydrogenated for 15 hours at room temperature and at 3-4 atm. The reaction mixture is filtered, concentrated, mixed with ice/conc. ammonia and extracted three times with ether. After drying, concentrating and chromatography over silica gel (metLylene chloride/methanol/conc. ammonia 98:2:0.2), the organic phases yield the title compound as a colourless oil. ?280 0 C (hydrochloride).

The following compounds of formula I, in which R. denotes cyclopropylmethyl and R 5 denotes hydrogen, were produced analogously to the above examples, from corresponding starting compounds. (In the table malonate hydrogen malonate).

1* h I~r r h r C I -rr% bC* nl 1

Z

ixanold no, SY .P.

(salt form) Production analogous to examole no.

17 18 19 21 22 23 24 26 27 28 29 32 32 C2H5

H:

C11 3 Phc ny L ci CH 3 C 2I

C

2 H C2~5 CH3

CH

3

CH

3 a-OI a-OH a-OH a-N H 2 a-NHCOCH-CH-COOCI1 3 -N11COC-C-COOCH 3 a-N1COCH -CHi- COOCH3 a-tNHCOCII 2 -CH 2 COOCH 3 a-NH 2 5NH 2 a-NHCOCH=CH-COOCH 3 5-1411CCCH=CH-CoOCH 3 -0- -0- H H -0- H H

HH

-0- -0- -0- -0- -0-

HH

H H H It 2800 150-1 >2800 >3000 233-50 2500(dtcomp) 211-20 175-70 24 9-510 222-30 >2900 >2900 Base 11C1 HC I Base

HCI

1 and 1 and 5 and 12 Base Ma 1 on a t_

HCI

Base

H'

0 0 0' 0' Example R R R no. 2 4 XY Tn. p. (salt form) production analogous to example no.

33 CIt 3 H H H H 176-70 Malonate 16 31 Plienyl O-CHi a-OR >i00 0 HC1 7 C215 O-CII 3 a-OH 2500 (decomn) HC1 7 36 C2H 5 a-CH 3 O-OH 0- >2800 HC1 7 37 C 2I5 1-n-C 4H a-OH 179-800 Base 7 38. 2 H O-Phenyl a-OH 266-80 HC. 7 39 Phenyl H a-OH H H >2800 HC1 12 Phenyl -aj.C 4 Hq a-OH 93-1120 Base 7 41 Phenyl P-Pheny a-OH 174-1820 Base 7 42 P-OH-Phenyl 0 H v >2300 HC1 2,6 43 Cyclhiexyl 0 H H >2650 HC1 1,2 44 Phenyl 9-Phenyl a-OH H H 240-2650 HC1 7 0 0

C',

M

Jl 100-6654 EXAMPLE 45: NCycl opropyl methyl_4-benzy1-3-hydroxy6 methylene morphinan 760 mg of NaH are washed with dry pentane; 6 ml DMSO are added, the mixture heated for 30 min. at 80 0 C, then cooled to 0 0

C.

63 g of methyltriphenylphosphoni'umbromide are dissolved in 12 ml DMSO and added to this solution. After 15 min.

at room temperature 1 g of N-cyclopropylmethyl-14p-benzyl- 3-hydroxy morphinan-6-one in 6 ml DMSO are added and the reaction mixture stirred at 600 for 12 hours. Ice and

NH

4 C1 solution are added until pH 7, then the solution are extracted 3 times with ether. Evaporation of the solvent and flash chromatography with ethylacetate/hexane 1:8 gives the title compound, which is crystallized as a hydrochloride salt from acetone. M.pt. 212°C.

The compounds of formula I exhibit pharmacological activity, and therefore may be indicated for use in therapy e,g, as pharmaceuticals.

In particular, the compounds have morphine-antagonistic or L mixed morphine-agonistic/morphine-antagonistic activity.

The morphine-antagonistic activity was shown as follows: j :i Female or male rats having a weight of 20-25 g are used in tI, this test. 30 minutes prior to the treatment, the mice are 1 immobilised in special plexiglass tubes, from which the tails protrude and can move freely. Using a lamp of high density, a pointed thermal stimulus is then attached 35 mm cranially to the root of the trial.The response is a swinging movement of the tail. The latent period (time between the stimulus and the response) is determined and 15 minutes prior to intracerebrovascular application of the test substance. Morphine (5.6 mg/kg) is administered s.c. two minutes after the test substance. This dosage is -1 r~l_ IA~ I~YII ~es(C -36- 100-6654 sufficient to induce analgesic activity in 80-100% of the mice (prolonging of the latent period of 75% or more).

The latent period is then determined again 30 minutes after administering the morphine (32 minutes after the test substance)oThe compounds lessen the analgesic activity of morphine at doses of from about 0.5 to about 30 mg/kg p.o.

The morphine-agonistic activity may be shown as analgesic activity, for example in the arthritis pain test (based on the test described by A.W.Pricio et al.in Eur.J.Pharmacol.

31, 207-15, 1975).

The compounds of formula I are generally morphine antagonists, but the morph.ine-agonistic activity can be greatly increased by an appropriate choice of the substituent R 4 For example, compounds of formula I in which R1 denotes cyclopropylmethyl and R 4 denotes a NHCO-A-COOR'' radical show marked analgesic activity.

In general, the morphine agonists/antagonists show analgesic activity in the above-mentioned arthritis pain test in the rat at doses of 0.5 to 30 mg/kg body weight p.o.

Because of thei' analgesic activity, the substances are indicated for the treatment of pain of various origins.

The compounds of formula which have morphine-antagonistic activity,especially those wherein R 4 is H or OH, or wherein

R

3 and R 4 are together 0 or CH 2 also stimulate secretion i luteinising hormone This LH stimulation can be determined e.g. by decapitating adult male rats 15 minutes to I hours,e.g. .1 hour, after administering the test substance, and measuring the LH concentration in the serum by radioimmuno-assay. In this test, the compounds are active from ca. 1 to 30 mg/kg p.o. The compounds of formula I in which

R

2 denotes phenyl show particularly strong LH stimulation.

t IP 4 IA C Vi V #4 4

I

-37- 100-6654 The compounds are therefore indicated for use as opiate agonists/antagonists and especially the compounds wherein

R

4 is H or OH or wherein R 3 and R 4 are together 0 or CH 2 as luteneizing hormone stimulators. The compounds are indicated for use in indications where luteneizing hormone stimulating activity is required, for example, due to impairment of the hypothalmic LHRH function, such as anovulatory syndrome, amenorrhea, infertility, idiophatic hypogonadotrophic hypogonadism, secondary hypothalmic hypogonadism, KalUman's syndrome, delayed puberty, menstrual disorders, e.g. during adolescence and anorexia nervosa. On the basis of opiate antagonist activity the compounds are indicated for use also in obesity, drug addiction, alcohol intoxication, motor disorders, cardiogenic and endotoxic shock, cognitive disorders such as Alzheimer's disease and immune system modulation.

The LH stimulating indication is the preferred indication.

The Example 6 compound is the preferred compound.

For the opiate agonist/antagonist, analgesic and preferably the LH stimulating indication an indicated daily dose is from about 10 to about 100 mg per day, conveniently admini- S stered in unit doses up to 4 times a day containing from about 2 to about 50 mg of the compound.

t The compounds of the invention may be administered in free base form or in pharmaceutically acceptable acid addition salt form. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free base form.

The present invention also provides a pharmaceutical composition comprising a compound of the invention in free hbse 'form or in pharmaceutically acceptable acid addition r lt form in association with a pharmaceutical carrier or diluent, Such compositions may be formulated in conventional manner.

I I i i -LvL -38- 100-6654 The compounds may be administered by any conventional route in particular enterally preferably orally e.g. in the form of tablets or capsules, or parenterally e.g.

in the form of injectable solutions or suspensions.

The present invention also provides a compound of formula I in free base form or in pharmaceutically acceptable acid form for use as a pharmaceutical, in particular anovulatory syndrome, amenorrhea, infertility, idiophatic hypogonadotrophic hypogonadism, secondary hypothalmic hypogonadism, Kal man's syndrome, delayed puberty, menstrual disorders, e.g. during adolescence, anorexia nervosa, obesity, drug addiction, alcohol intoxication, motor dii;6rders, cardiogenic and endotoxin shock, cognitive disorders such as Alzheimer's disease or immune system modulation.

tit 4 ii att I It 1 ii -39- 100-6654

II

t I I It It 49 r9 I 9 *I 9 9* 9 99 9 A group of compounds are those wherein R 2 is hydrogen, alkyl with 1 to 10 C-atoms, phenyl or phenylalkyl with 7 to 12 C-atoms and R 3 and R 4 are as defined above with the proviso that R 3 and R 4 together are other than

CH

2 in free base or in acid addition salt form.

In a first group of compounds R 1 is optionally substituted allyl.

In a 2nd group of compounds R 1 is cyclopropylmethyl.

In a 3rd group of compounds R 1 is 3-furylmethyl.

In a 4th group of compounds R 2 is H.

In a 5th group of compounds R 2 is alkyl.

In a 6th group of compounds R 2 is cycloalkyl.

In a 7th group of compounds R 2 is optionally substituted phenylo In a 8th group of compounds R 2 is optionally substituted phenylalkyl.

In a 9th group of compounds R 3 is H.

10th 11th 12th 13th 14th 16th 17 th 18th 19th 21st 22nd( 23rd group of group of group of group of group of group of group of group of group of group of group of group of group of group of compounds compounds compounds compounds compounds compounds compounds compounds compounds compounds compounds compounds compounds compounds is alkyl.

is phenyl.

is H.

is OH.

is NR 6

R

7 is NCOR.

is NHSO 2

R'.

is NH-COOR''.

is in the a position.

is in the P position.

and R 4 are 0.

and R 4 are CH 2 is

CH

3 is H.

2 1

Claims (2)

1. A process for the production of a compound of formula I 515 R~ R 4 wherein X and Y each denote hydrogen or together denote R 1 denotes allyl optionally substituted by 1 to 3 alkyl groups, the substituent or substituents having in total a maximum of 3 carbon atoms, cyclopropylmethyl or 3-furylethy, CH R? R denotes hydrogen, alkyl with 1 to 0 C-atoms, R4 wherein and Y eachlkyl ith 5 or 6 carbon atoms, pheny which is Sdenotes ionally substituted with halogen, CF 3 hydroxy, groups, the substituent or substituents having in nitro, alkylith 1 tomaxmum of 3 carbon atoms, alkoxy with 1 to 3 or 3-furylmethyl, C-atoms or NRaRb wherein Ra and Rb independently are R denotes hydrogen or alkyl with to 10 C-atoms o phenyl- cycloalky with 5 or 6 carbon atoms which s optionally optionally substituted with halogen, CF3, hydroxy, nitro, alkyl nitro, alkywith 1 to 3 C-atoms, alkoxy with 1 to 3 C-atoms or NRaRboms or NR wherein R and R independently are hydrogen hydrogen or alkyl with 1 to 3 C-atoms or phenyl alkyl with 7 to 12 C-atoms which is optionally substituted with halogen, CF3, hydroxy, nitro, alkyl with 1 to 3 C-atoms, alkoxy with 1 to 3 C-atoms or NRaeb wherein Ra and Rb independently are hydrogen or alkyl with 1 to 3 C-atoms or, R 3 denotes hydrogen, alkyl with 1 to 10 C-atoms or Sphenyl, 0 e O0 9009d9.dbto,Ol3,dt57637,t03,40" c, r Z, i II r 1ir -ri iT m i Ti-r ;i _;fi j ii .j i- 4 r ii i n ii^^ r 1" i M is «p w -41-

100-6654 R 4 denotes hydrogen, OH, NR 6 R 7 NHCOR, NHSO 2 R' or NH- COOR'', R 6 and R 7 independently of one another, denote hydrogen or alkyl with 1 to 3 C-atoms, R denotes alkyl with 1 to 6 C-atoms, phenyl or -A-COOR'', A denotes alkylene or alkenylene each with 2 to 4 C-atoms, R' denotes alkyl with 1 to 6 C-atoms or phenyl, SR'' denotes methyl or ethyl and wherein either R 3 is in the a-position and R4 is in the p-position, or R 3 is in the p-position and R 4 is in the a-position, R 3 and R 4 together are 0, or CH 2 and Rg denotes hydrogen or methyl, with the provisos that when X Y denotes R 2 denotes hydrogen, R 4 denotes a a-OH group:,and R 3 and R 5 denote hydrogen, R is other than cyclopropylmethyl or allyl, and that when R 2 ,R 3 ,R 4 and R are each hydrogen, R 1 is other than cyclopropylmethyl, V in free base form or in acid addition salt formas well as the physiologically hydrolysable, pharmaceutically acceptable esters of such compounds, which contain a free OH group, in free base form or in acid addition salt form charac- terised in that IJ U -42- 100-6654 a) in order to produce a compound of formula la wherein R' 1 denotes cyclopropylmethyl or 3-furylmethyl, a compound of formula VII is brominated, the resultant compound/which contains a bromine atom in at least position 5, is dehydrobro- minated to form a furan ring, and the product is debrominated, b) in order to produce a compound of formula Ib I 00 the ketal group in a compound of formula X A, 43- 100-6654 wherein Z and ZV denote alkyl with 1 3 C-atoms or together denote (CH 2 or(C) 3 is hydrolysed to an ox~o group, c) in order to produce a compound of formula Ic "tat 4 44 4 4 4' 4 4* wherein Rdenotes al kyl with 1 to 10 C-atoms or phenyl a compound of formula I' R 5 0 C2 2 is' reacted with an organic metal compound containing Oe radical R', -44- 100-6654 d) in order to produce a compound of formula Id a compound of formula XI K ii 4 4*4 4 4 ft 4 4 4* is reduced, e) in order to produce a compound of formula le R o0 100-6654 ijwherein R4denotes NR 6 R 7 1 NHCOR, NHSO 2R' or NH-C0OR'' a compound of formula P' is reductively aminated to form the corresponding 6-amino compound, and this latter compound is optionally alkylated or acylated on the N-atom, f) in order to produce a compound of formula If R~O Sx if 2' 2 R, HO 1. the oxo group in a compound of formula T' is reduced to a hydroxy group, g) order to produce a compound of formula ig 0 I 2 2, a compound of formulaXII d4 1,t 4 1 -46- 100-6654 is reduced, h) in order to produce a compound of .formula Ih 4 4, 44 the benzyl group in a compound of formula XIII XII I 3enzy 1- is removed hydrogenolytically,, and the 6-amino. compound obtained is optionally alkylated or acylated, _II~ Y r r -47- 100-6654 i) in order to produce a compound of formula li t IfI r r It t tr wherein R' denotes allyl optionally substituted by 1 to 3 alkyl groups, the substituent or substituents having in total a maximum of 3 C-atoms, a compound of formula XIV I Li II I t t 14 is reacted with a compound of formula R4'X (X halogen), "CI i ~-~8nrrmarrr~ r trpc- -48- 100-6654 j) in order to produce a compound of formula Ij a compound of formula Ik .i 4* is subjected to an ether splitting, k) in order to produce a compound of formula I wherein R 3 and R 4 together are CH 2 a compound of formula I wherein R3 and R 4 together are 0 is reacted with (C 6 H5) 3 P CH 2 1) in order to produce physiologically hydrolysable and pharmaceutically acceptable esters of the compound of formula I, which contai.n a free OH group, such a com- pound of formula I is reacted with an appropriate acid or with a reactive derivative thereof, or -49- 100-6654 m) to produce a compound of formula I wherein R 4 is NR 6 R 7 wherein R 6 and R7 are as defined above with the proviso that one of R 6 and R 7 is other than hydrogen, NHCOR, NHSO 2 R' or NHCOOR' a compound of formula I wherein R 4 is NR 6 R 7 wherein R 6 and R are as defined above with the proviso that one of R 6 and R7 is hydro- gen or NH 2 is alkylated or acylated respectively, wherein in the above formulae the configurations of the group Y if present in the 5 position and the bonds linking the 9 and 13 positions are the same as in formula I, and the definitions of R 1 to R 5 /X and Y except where otherwise stated are as given above with reference to formula I. r t 1 -50- 100-6654 2. A process for the production of a compound of formula I wherein R 3 and R 4 together are oxygen which includes any of the following steps, in any order, of i) replacing the 17-methyl group in thebaine by the group Rl, ii) introducing the group CH 2 R 2 into position 14, iii) demethylating as appropriate to convert the methoxy groups in position 3 and 6 into hydroxy and keto groups respectively, and iv) if desired removing the oxygen bridge in the position. 3, A process according to claim characterised in that the compound of Formula I is N-cyclopropylmethyl-14-benzyl-3- hydroxymorphinan-6-one. 4 4 "1~ SHORT -51- 100-6654 4. A process: for the production of a compound of formula I as defined in claim 1, substantially as hereinbefore described with reference to any one of the examples. A compound of formula I whenever produced according to the process of claim 1, 2 or 3. 6. A compound of formula I as defined in claim 1 in free base or in acid addition salt form. 7. A compound of claim 6 which is N-cyclopropylmethyl-14- benzyl-3-hydroxymorphinan-6-one in free base or in addition salt form. S 8. A compound of any one of claims 5 toJ in free base form or in pharmaceutically acceptable acid addition salt form for use as a pharmaceutical. 9. A pharmaceutical composition comprising a compound of any one of claims 6 to 8 in free base form or in pharma- ceutically acceptable acid addition salt form in associa- tion with a pharmaceutical carrier or diluent. 6 -52- -52- 100-6654 A compound of formula III, IN, V, VI, VII, Mrr, IX or X as defined below, and wherein the substituents are as defined in cl aim 1 and the configuration of the chi ral carbon atoms in positions 5, 9 and 13 are as thebaine. CH 0' H3 t CH 3CH 3 0 CH M CH S R{ IV -53- -53- 100-6654 HC N- Hj CCH R 222 N-R' H HOtH VIi ~CH 2 R 2 iix Vil HC 0' H3 or a compound Qf formula XI, XII, XIII or XIV as defined in claim 1. 54 100-6654 IN referred to or indicated in the spe. inado Iclaims ofthis applic ,individually or collectively, andanycombinations or any two or more of said DATED -this 21st day of May, 1986. SANDOZ LTD. By its Patent Attorneys DAVIE'S &COLLISON 4 44