CA1106369A - 8.beta.-ETHYL-AND 8.beta.-METHYL-4,5.alpha.-EPOXYMORPHINAN-6- ONE COMPOUNDS - Google Patents

Abstract

8.beta.-ETHYL-AND 8.beta.-METHYL-4,5.alpha.-EPOXYMORPHINAN 6-ONE COMPOUNDS

ABSTRACT

Compounds having the structural formula

Description

BACKGROUND OF THE I NYBNT I ON

Fiald o the Invention Certain we~l known narcotic analgesics b~long to tho class of 4,5a-epoxymorphinsn co~pounds which havo tho following basic ring syst~m, in which she ato~ ~r~ numborod as indicat~d.

Q~ ~ 6 ~8 Th~ ~wo most familiar co~pou~ds of this class are morphine and its 3-methyl ~thor~ codsine, wi~h the structures indicated b~low.

CH~ ; ~ 3 Morphine Cod~ino Whon the 6-hydroxyl group of each of these compound~ is oxidizad to an oxo group, the compounds conYaniently are referred to as morphinone and codeinone, resp~c~ively. When -

-2- ~
~.

~ "
6~

the N-methyl groups of the ~att~r co~pounds are replacod by other substituen~ gr~ups thoy ma.y bo referred t~ ~s N-substitut~d normorphinone~ and norcodeinonos, r~spec~ively.
.
There ar~ two types o~ no~nclature commonly u~d for S describing comp~und~-herein. The trivi~l nam~s, such as morphine or mor~,hino~e~ a~ wid~ly acc~ptod and us~d ~or the sake of brevity and:clarity. The Chomical Abstracts nomon-clature ls pro~srrot Qnd is used wherever pr~ci~ion is n~edod, Table A~iu~s the triYial names and Chomical 10 Ab~tracts n~mes for co~monly referrod to ~ompou~ds horein.
Morphine and its relativ~ aro used pri~Qrily for tho relief of pain ri.e., as ana~gesies). Th~y ar~ narcotic and possess dependence-inducing ability ant produce oth~r sido effscts that make ~hem less than ideal analgosics (emesis, 15 constipation, swea~i~g, r~spira~ory depressions, miosis).
A compound wi~h the ~ppropria~e pro~ile of analg2sic (agonist) and nar~otic antagonist &c~ions whieh is not morphine-like has potontial as an analgesic-age~t for treatm~nt of mot~rato : ~o ssYer~ pain without liabili~y of drug dependence.
20 Furthermore, a compound having on~y strong narco~ic anta-gonist action may be a desirable agent for ~reatment of drug dependence.

~I~BLE A

Trivial Name Chemical Abstract Name morphine 7,8-didehydro-4,5a-epoxy-17-methylmorphinan-3,6~-diol.
morphinone 7,8-didehlydro-4,5a-epoxy-3-hydroxy-17-methylmorphinan-6-one.
normorphinone 7,8-didehydro-4,5a-epoxy-3-hydroxymorphinan-6-one~
dihydromorphine 4,6a-dpoly-17-methylmorphinan-dihydromorphinone 4,5a-epoxy-3-hydroxy-17 methyl-morphinan-6-one.
codeine 7,8-didehydro-4,5-spoxy-3-methoxy-17-methylmorphinan-6a-ol.
norcodeinone 7,8-didehydro-4,5~-epoxy-3-methoxy-morphinan-6-one.
dihydrocodeine 4,5a-epoxy-3-me~hoxy-17-methyl-morphinan-6a-ol.
dihydrocodeinone 4,5a-epoxy-3-methoxy~17-methyl-morphinan-6-one.
PRIOR ART

The only known 4,5a-epoxymorphinan compounds possessing substituents other than a hydrogen atom in the 8 position are *hose with a halogen, nitrogen or oxygen ato~ at C-8.
Yeh, et a~ . (J. Pharm. Sci. 6: 902 [1976J) report ~-halo-morphides, i.e., 6,7-didehydro-4,5a-epoxy-8-halo-17-methyl-morphinan-3-ols, which are analgesic compounds. Rapaport and Barber (U.S. Patent 4,054,566; J. Med. Chem. 19: 1175 [1976~) report the prepara~ion of 8-chloro, 8-bromo, and 8-iodocodeinones, used as intermediates in the preparation , 6 3 6 ~

oE codeinone. Seki (Chem. Pharm. Bull. 14: ~45 ~lg66]) has reported various compounds related to eodeinone and sub-stituted at the 8-position with a tertiary amine group or a halogen group. Weiss (J. Org. Chem. 12: 1505 [1957~ has reported 8,14-dihydroxy-7,8-dihydromorphinone and the similar codeinone analog. Tada et al. (Tet. Let. 122], 1805 11969]) have reported 8-hydroxyethoxy-14-hydroxycodeinone and the similar 8-methoxyethoxy analog.
Compounds having a hydroge~ atom a~ the 8-position have also been reported. Dihydrocodeine, dihydrocodeinane, dihydromorphine and dihydromorphinone have long been known (Merçk Index, 9th ed., No. 3148, 4672, 3155, 4700). Gates and Montzka (J. Med. Chem., 7: 127 [1964]) havs synth0sized 7,8-dihydro-17-cyclopropylmethylnorcodeinon~, and 7,8-dihydro 17-cyclopTopylmethylnormorphinone; the latter com-pound had narcotic antagonist activi~y. Telford ~t al. ~J.
Pharmacol. Exp. Therap. 133: 106 [19611; hereafter "TELFORD") reported 7,~-dihydro-N-allylnorcodeinone (17-allyl-4,5~-epcxy-3-methoxymorphin~n-6~on~) and disclosed that it had weak analgesic properties.
Addi~ional references which discuss strusture-activity relationships in general are: Archer ~ Harris ~Progr. in Drug Rese~rch ~: 261 [1965]); Lewis, Bentley ~ Cowan (Ann.
Rev. Pharmaçol. 11: 241 [1971]); ~osterlitz ~ Waterfield ~Ann. Rev. Phar~acol. 15: 29 [1975]); and Merz ~t al. (J.
Med. Chem. 20: ~44 [1977]).

LQ~736~

SUMMARY OP THE INVENTION
. _ _ The subject matter o~ this i.nvention includes:
(a) A compound having the structural formula, Rl -0~

l~ - R2 `~ .
~ R3 in which:
Rl is a hydrogen atom or a methyl group;
R2 is an allyl, cyclopropylmethyl~ cyclobutylmethyl or tetrahydrofururyl group, provided that when R2 is a cyclo-butylmethyl or tetrahydrofurfuryl grou~, then Rl is hydrogen;
R3 is an ethyl or methyl group, provided that when R3 is methyl, then R2 is cyolobuty1methyl; and pharmacologically acceptable acid addition salts thereof;
(b) A method for treatment of drug dependence in an individual for whom such therapy is indicated, comprising, administering to the individual a therapeutically effective amount of a compound having the structure given in part (a) above;
(c) A method for treatment of pain without liability of drug dependence in an individual for whom such therapy is indicated, comprising, administering to the individual a therapeutically effective amount of a compound having the structure given in part ~a) above wherein Rl is a hydrogen atom or a methyl group and R2 is a cyclopropylmethyl, cyclo-butylmethyl or tetrahydroIurfuryl group pro~ided that when R2 is a cyclobutylmethyl or tetrahydrofurfuryl group then R
is hyd~ogen; and wherein R3 is an ethyl or methyl group, . .
-6~

(d) A process for producing a compound having the structure given in part (a) above, wherein Rl is methyl, comprising the steps of (i) reacting codeinone in a halo-genated hydrocarbon or aroma~ic hydrocarbon solve~t with a lithium lower dialkyl copper reagent selected rom the class consisting of lithium diethyl copper or lithium dimethyl copper, via a conjugate 1,4 addition reaction, ~ii) quenching the reaction mixture with an aqueous ammonium compound to produce an 8~-lower alkyl codeinone, (iii) re-acting the 8~-lower alkyl codeinone with a cyanogen halide in a suitable organic solvent to produce an 8~-lower alkyl 17-cyanonorcodeinone, (iv) hydrolyzing the 8~-lower alkyl-17-cyanonorcodeinone with dilute mineral acid to produce an 8~-lower alkyl norcodeinone, (v) reacting the 8~-lower alkyl norcodeinone with an alkylating compound selected from the class consisting of allyl bromide, cyclopropylmethyl bromide, cyclobutylmethyl bromide J tetrahydrofurfuryl bromide or tetrahydrofurfuryl camphor-10-sulfonate in a suitable polar organic solvent in the presence of an acid acceptor to give the desired 8~-lower alkyl-17-substituted compound of ~a) which is then isolated. The term "lower alkyl", as used herein, refers to either methyl or ethyl.
(e) A process for producing a compound having the structure given in part (a) above, wherein Rl is hydrogen, comprising, 0-demethylating the compound of part (d) above by hydrolysis wi.th a hydrolytic reagen~ at eleYated temperature;
(f) A process for producing 8~-ethyl codeinone comprising the steps of (i) reacting codeinone in a halogenated hydro-carbon or aromatic hydrocarbon solvent via a conjugate 1,4-addition reaction with a lithium divinyl copper reagent, Q~36~9 (ii) quenching ~he r~action mixture with an aqueous ammonium compound to produce 8~-vinyl codeinone; (iii) hydro-genating the 8~-vinyl codeinone in the presence of a catalyst and (iv) isolating the product;
~g) Useful intermediate compounds for the preparation of the compounds having the structure given in part (a) above include the compounds having the structural formula

3-~ -R~

wherein R4 is a hydrogen, methyl, cyano, çyclobutylmethyl or tetrahydrofurfuryl radical, and R3 is an ethyl or methyl group, and ~h) The 8~-vinyl codeinone compound, 4,5~-epoxy-3-: methoxy-17-methyl-8~-vinylmorphinan-6-one is a useful inter-mediate for the preparation o~ the 8~-ethyl compounds having I5 the structure given in part ~a) above.

DETAILED DESCRIPTION OF THE INVENTION
.

Compounds of Pormula I, below, constitute a generic class of 4,5a-epoxy-morphinan-6-one compounds with the novel feature of alkyl substitution at the 8-position.

Rl -0~

~-Rz :

In Formula I, Rl is a hydrogen atom or a methyl group.
R2 is selected from the class consisting of allyl, cyclo-propylmethyl, cyclobutylmethyl and -tetrahydrofurfuryl groups provided that when R2 is a cyclobutylmethyl group or a tetra-hydrofurfuryl group, th~n Rl is hydrogen. R3 is an ethyl or methyl group, provided that R3 is a methyl group only when R2 is a cyclobutylmethyl group.
In Formula I, the wedged ( ~-3 line indicates groups projecting above t~e plane of the paper as written and lndicates ~-orientatIon.
The compounds o Formula I form pharmacologically active addition salts with organic and inorganic acids.
Illustrative acid addition salts are the tartrate, hydro-bromide, hydrochloride, maleate and the like. The preferred salt is hydrochloride.
We have discovered that the compounds of Formula I are useful for treating drug dependence in an individual for whom such therapy is indicated, or for treating pain without liability of drug dependence in an individual for whom such therapy is indicated, The term "individual" means a human being or an experi-mental animal that is a model for a human being. The effective dose may vary from individual to indi~idual, but it is easily determined by one skilled in ~he art without undue experimentation. Compounds of Formula I may be administered by any known conventional method of therapeutic administration such as intravenous, parenteral, buccal, rectal, or oral. Dose forms for the administration of compounds of Formula I can be prepared by recognized methods in the pharmaceutical sciences.

~ ~ 6 ~ 9 Compounds of Pormula I are synthesized by reaction of a first starting material, codeinone, Formula II, a known compound prepared from thebaine by the procedure of Gavard et ~l.
(Bull. Soc. Chim. Fr., 486 [1965]), CH3- ~

,~ C1~3 I I
r ~, with a lithium lower alkyl copper reagent selected from the class consisting of lithium diethyl copper and lithium di-methyl copper, via a conjugate 1,4-addition reaction. The use of lithium lower dialkyl copper reagents in 1,4-addition processes has been described by Posner ~Org. Reactions 19:1 [1972]). Posner, however, does not teach the use of such reactions in the codeinone or any other 4,5a-epoxymorphinan system.
The lithium lower dialkyl copper reagent is prepared by the addition of a solution containing about 2 molar equiv-alents of ethyl or me~hyl lithium to a stirred suspension containing about 1 molar equivalent of copper iodide, in a solvent such as ether, tetrahydrofuran, or the like, under a moisture-free atmosphere o~ nitrogen or argon. Lithium diethyl copper is prepared at -78C and allowed to warm to -40C. Lithium dimethyl copper is prepared at 0C.
A solution of codeinone in a halogenated hydrocarbon solvent, such as methylene chloride, ethylene chloride, dichloroethane and the like, prefeTably methylene chloride, or an aromatic hydrocarbon solvent, such as benzene, toluene, .. .
.

~ ~U 6 ~ ~ ~

xylene and the li~e is added t~ and reacted with the stirred suspension of the lithium lower dialkyl copper reagent preferably under an inert, moisture-free atmosphere. The reaction mixture is preferably maintained at about -78C to ~10C, mos-t preferably about -40C to 0C, during the period of addition of the codeinone solution and during the reaction period of up to about 10 minutes. The molar ratio of codeinone to lithium lower dialkyl copper reagent preferably ranges from about 1:1 to 1:3, respectively.
The reaction mixture, preferably warmed to about 0C, is then quenched with an aqueous solution of an ammonium compound, such as ammonium chloride, ammonium hydroxide or the like, preferably in an amount in molar excess of the copper contained in the reaction mixture, and the resulting mixture is stirred ~or up to 1 hour to produce an 8~-lower alkyl codeinone product having the structural Formula III, CH3- ~
C(~h -CH III

~ 3 wherein R3 is ethyl or methyl.
The aqueous phase of the above mixture is separated and adjusted to approximately pH 12 by addition of a strong base, such as 50'~ sodium or potassium hydroxide. Then~ the basic aqueous so:Lution is extTacted with an organic solvent, such as ether, chloroEorm or the like. The organic phase is washed, dried, and evaporated to isolate the product having structural Formula III.

, ~ ~ 6 ~ ~ ~

An alternate method for the preparation of the 8~-ethyl codeinone of Formula III involves the preparation of 8~-vinyl codeinone, which is then hydrogenated.
8~-Vinyl codeinone is synthesized by reaction of ~ codeinone, having Formula II above, with li~hium divinyl copper, via a conjugate 1,4-addition reaction. The lithium divinyl copper reagent is prepared by the addition of a solution containing 2 molar equivalents of vinyl lithium to a stirred suspension containing 1 molar equivalent of copper iodide, in a solvent such as ether, tetrahydrofuran or the like, under a moisture-free atmosphere such as nitrogen or argon at about -78C.
A solution of codeinone in a halogenated hydrocarbon solvent, such as methylene chloride, ethylene chloride, dichloroethane and the likep preferably methylene chloride, or in an aromatic hydrocarbon solvent such as benzene, toluene, xylene and the like, is added to and reacted with the stirred suspension of the lithium divinyl copper reagent preferably under an inert moisture-$ree atmosphere. The reaction mixture is preferably maintained at about -78~C
to -40~C during the period of addition of the codeinone solution and during a reaction period of up to about one hour. The molar ratio of codeinone to lithium divinyl copper reagent preferably ranges from about 1:1 to 1:3, z5 respecti~ely.
The reaction mixture is then quenched, preferably after allowing it to warm to about 0C, with an aqueous solution of an ammonium compound, such as ammonium chloride, ammonium hydroxide or the like, preferably in an amount in molar excess of the copper contained in the reaction mixture, and ~ -12-. . .. ~

a63~

the resulting ~ixture is stirred for up to one hour to produce 8~-vinyl codeinone, which is isolated as described above for the isolation of compound having Formula III.
The 8B-vinylcodeinone is then dissolved in a suitable organic solvent such as ethyl acet:ate, ethanol, acetone OT
the like and reacted with hydrogen in the presence of a catalyst such as Palladium on carbon, Rhodium on carbon, Platinum on carbon and the like under acidic conditions.
The hydrogen pressure is preferably maintained at about 50 psi during the reaction for a sufficient period of time usually from about one to four hours; to complete the hydrogenation.
The acidic condition can be achieved by the addition of a suitable mineral acid such as hydrochloric acid, nitric acid, sulfuric acid and the like. After filtration and remo~al of the solvent, the 8~-ethyl codeinone is isolated as the hydrochloride salt.
The product having Formula III is dissolved in a suitable organic solvent such as ether, chloroform or the liXe, preferably containing a suitable acid acceptor, such as anhydrous potassium carbonate or sodium carbonate or the like.
A solution of a cyanogen halide, such as cyanogen bromide, cyanogen chloride or cyanogen iodide, is then added wi~h stirring over a period up to about 30 minutes. The sus-pension is preferably stirred at a temperature from about 20~C up to the reflux temperature of the solvent for up to 2 hours, to produce an 8~-lower alkyl-17-cyanonorcodeinone product having the structural Formula IV:
CH3- ~
~l -CN IV, ~ 3 6 wherein R3 is as above.
After cooling the suspension to a tempera~ure suff.icient to acilitate removal of insoluble material, the insoluble material is removed by filtration or centrifugation, and the solvent is evaporated to isolate the 8~-lower alkyl-17-cy-anon.orcodeinone product having Formula IV.
The 8~-lower alkyl-17-cyano-norcodeinone product of Formula IV is then hydrolyzed by suspending it in a mineral acid, such as hydrochloric, sulfuric, nitric and the like, preferably about 1 to 6 N, and preferably heating the suspension at reflux temperature for up to about 5 hours, to produce an 8~-lower alkyl-norcodeinone product having the structural Formula V, CH3- ~

~ ~ -H V
r r ~ R3 wherein R3 is as aboveJ which is isolated as the acid addition salt by evaporation of the solvent.
The 8~-lower alkyl norcodeinone product of Formula V, or optionally its acid addition salt, is then reacted with an alkylating agent such as allyl bromide9 cyclopropylmethyl bromide, -cyclobutylmethylbromide, tetrahydrofurfuryl bromide ortetrahydrofurfuryl camphor-10-sulfonate in the presence of an acid acceptor, such as the carbonate or bicarbonate salts o potassium or sodium. The molar ratios of the 8~-lower alkyl-norcodeinone product of ~ormula V to alkylating agent to acid acceptor preferably range from`l:l:2 to 1:2:4 respectively. The ~ o3~ ~

reaction ls carried out in a sui~able polar organic solvent, such as dimethylformamide, dimethylsulfoxide, ethanol and the like, preferably under an inert, moisture-free atmosphere of nitrogen or argon at a temperature of from about 50C ~o about 110C. Dimethylformamide ~DMF) is the preferred solven~.
The resulting product having Formula I, where Rl is methyl, is then isolated by procedures standard to the art, such as solvent extraction or chromatography.
Compounds having Formula I, where Rl is hydrogen, are prepared by 0-demethylating the compound of Formula I, where Rl is methyl, by use of a hydrolytic reagent, such as pyridine hydrochloride, hydrobromic acid, preferably concentrated ~48%) hydrobromic acid, or the like. We prefer to use pyridine hydrochloride at a temperature of from 180C-200C
for 1 to 2 hours.
When it is desired to h~ve a product with increased watcr solubility, the organic or inorganic acid addition salts of compounds having Formula I can be prepared. Examples of pharmaceutically acceptable acid addition salts are the tartrate, hydrochloride, hydrobromide, maleate or the like. We prefer the hydrochloride salt. The hydrochloride salt is preferably obtained by dissolving the free base in an organic solvent, such as ether or ethyl acetate, and adding gaseous hydrogen chlori~e or is obtained by dissolving the free base in a lower alcohol, adding aqueous hydrochloric acid and evaporating the solvents.
Crystallization of the hydrochloride salts can be achieved with a variety of solvents, for example, a lower alcohol such as methanol, ethano:L or isopropanol or the like by the addition of a lower ester, such as methyl acetate, ethyl acetate, or '' ' . :

?~

isopropyl aceta~e or the like~ followed by removal of the alcohol by boiling.
The following examples are provided to further illustrate the inventive concept described above and are not intended to limit the invention.

This Example illustrates the preparation of 17-cyclo-propylmethyl-4,5a-epoxy-8~-ethyl-3-methoxymorphinan-6-one hydrochloride ~TR 5109) and also describes the preparation of intermediates to the title product.

A. 4,5~-Epoxy-8~-ethyl-3-met~y-l?-m~thylmorphinan-6-one.
I. Preparation in Ether-Benzene.
Ethyl lithium was prepared under argon by the dropwise addition of ethyl chloride (11.1 g, 172 mmoles)-in 50 ml of ether to a suspension of finely dispersed lithium (345 mmole, 2.4 g) in 100 ml of e~her followed by stirring at 0C
for 20 minutes. After cooling to -78C, the ethyl lithium suspension was transferred by use of argon pressure to a suspension of CuI (16.0 g, 84 mmole) in 800 ml ether with stirring at -78C. The resultant suspension was allowed to warm to -40C and a warm solution of codeinone (20.0 g, 67 mmole; prepared by the method of Gavard et ~Z. (Bull. Soc.
Chim. Fr., 486 ~1965]) in 400 ml dry benzene was added at a rate to keep the temperature at about -40C. After stirrin~
at -40C for 10 minutes, the mixture was allowed to warm to 0C. The mixture was then poured into saturated NH4Gl solution (500 ml) and stirred rapidly for about 1 hour. l`he 16~369 phases were sep~rated, and the aqueous phase was adjusted to about pH 12 by the addition of 50% NaOH solution. The basic aqueous phase was then extracted with three portions of chloroform, and ~he combined organic phases were backwashed with saturated NH4Cl solution, dried over MgSO4, and evaporated to yield a crystalline residue. The residue was crystallized from ethyl acetate to give TR 5059, 12.2 g (55%~, mp 146.5-148C. Additional product (3.95 g) was obtained from the mother liquor.
Recrystallization from ethanol gave pure TR 5059, mp 147-148C. NMR (CDC13); ~6.70, s, 2H ~aromatic); 4.70, s, lH tH5); 3.93, s, 3H ~CH30-), 2.46, s, 3H (CH3N-), 1.03-0.73, unsymmetrical t, 3H (CH3CH2-).
The HCl salt of TR 5059 was prepared by dissolving the free base in ethanol, adding an excess of concentrated HCl and evaporating to dryness. The residue was azeotroped with ethanol, 1:1 V/V ethanol:benzene, then benzene~ and crystal-lized from ethanol-ethyl acetate to give analytically pure TR 5059-HCl, mp 285-288C.
A~a~. Calcd. for C20H25NO3~HCl: C, 66-02; H, 7-20;
N, 3.85; Cl, 9.74. Found: C, 65.82; H, 7.04; N, 3.79; Cl, 9.87.

II. P`re~aration in Ether-Methylene Chloride.
Ethyl lithium was prepared from lithium (0.9 g) in ether ~30 ml) by the addi~ion of ethyl chloride (5.0 ml) in ether (20 ml) and added to CuI (6.0 g) in ether (100 ml) at -78C as described in part I above. The suspension was warmed to -40C and a solution of codeinone (5.0 g) in .

6~365~

me~hylene chloride (100 ml) added rapidly dropwise. The reaction mixture was treated as above and TR 5059 (5.3 g, 96~) was isolated as a foam whose spectral charac~eristics were identical to the product as prepared in Part I, above.

III. Preparation using a lithium divinyl copper reagent.
~a) 4,5~-Epo~y-3-methoxy-l7-methyl-8 vinylmorphlnan-6-one ~TR 5106).
Vinyl lithium was pTepared at -78C under argon in 60 ml of ether by stirring vinyl bromide (4.5 g, 42 mmol) and t-butyl lithium (84 mmole, 52.5 ml of a 1.6 M
solution in pentane) for one hour. The resulting suspension was added to a stirred suspension of CuI ~1.00 g, 21 mmole) in 200 ml of ether at -78C under argon. Codeinone ~5.00 g, 16.8 mmole) was added as in Example 1 and the mixture slowly allowed to warm to -5C before being poured into NH4Cl solution. Further processing as described in Example 1 gave 5.4 g of a syrup which was chromatographed over Silica Gel G
(500 g) using 15:1 V/V chloroform:methanol as the eluent.
Fractions containing the desired product were pooled and evaporated to give 3.00 g ~55%) of TR 5106 as white crystals, mp 132-134C. NMR (CDC13): ~ 6.70, s, 2H (aromatic); 4.70, s, lH (H5); 5.8-5.4, lH, m (-CH=CH2); 5.1-4.8, 2H, m (-CH=CH2);
3.93, s (CH30-); 2.43, s (CH3N-)-The HCl salt was prepared as in Example 1 and recrystal-lized from ethanol to give pure TR 5106~HCl, mp 276-278C
dec.
AnaZ- Calcd. for C2oH23No3~cl C, 66.38; H, 6.68;
N, 3.87. Found: C, 66.11; H, 6.65; N, 3.82.

~63~

(b) 4,5~-Epox~-8~-ethyl--3-metho~ 7-me-t-h morphin 6-one.
To a solution of 4,5~-epoxy-3-methoxy-17-methyl-8~-vinylmorphinan-6-one ~9.0 g) in 95% ethanol was added 2 ml of concentrated hydrochloric acid followed by 10% palladium/charcoal (1.0 g). The mixture was hydrogenated at an initial pressure of 50 psi for 2.5 hours. The reaction mixture was filtered, the filtra~e made acidic by the addition of hydrochloric acid and evaporated to a crystalline solid. The solid was recrystallized from ethyl acetate with the addition of ethanol to give, after drying, 8.7 g (90%) of the 8-ethyl product TR 50590HCl, mp 285-288C.

B. 17-Cyano-4,5a-ePoxy-8~-ethyl-3-methox~morphinan-6-one.

4,5a-Epoxy-8~-ethyl-3-methoxy-17-methylmorphinan-6-one lS (5.0Q g, 13.7 mmole; prepared in Part A) was dissolved in 50 ml chloroform. After the addition of K2C03 (2.84 g, 20.6 mmole), the stirred suspension was treated dropwise with a solution of cyanogen bromide (1.95 g, 18.4 mmole) in 40 ml chloroform. The mixture was stirred at room tempera-ture for 30 minutes and heated for 1.5 hours at reflux temperature. After cooling, the insoluble material was remoYed from the mixture by filtration and the filtrate was evaporated to a crystalline residue which was boiled with ethanol (30 ml). After chilling, the crystals were collected to give 4.30 ~ (9Z%) of white needles, mp sinters 194C, melts 197-198.5C.

.
' ~ 3 6~

C. 4,5~-Epoxy-8~-ethyl-3-methoxymorphinan 6 one hy~r~hloride A suspension of 17-cyano-4,5~-epoxy-8~-ethyl-3-methoxy-morphinan-6-one (4.30 g; prepared in Part B) in 100 ml 2 N
HCl was refluxed for 4 hours. The solution was evaporated to a crystalline residue which was suspended in e~hanol.
Af~er cooling, the crystals were collected and dried to give 3.95 g ~89%) of product, mp. decomposes slowly above 260C.

D. 17-Cycloprapylmethyl-4,5-epoxy-8B-ethyl-3-methoxy-morphinan-6-one ~drochloride (TR 5109).
A mixture o~ 4~Sa-epoxy-8~-ethyl-3-methoxymorphinan-6-one hydrochlorid~ ~2.30 g, 6.6 mmole; prepared in Part C), NaHCO3 (1.22 g, I4.5 mmole) and cyclopropylmethyl bromide ~1.33 g, 9.9 mmole; prep~red according ~o Neth. Appl.
6~613,986; Chém. Abst. 68: 59608m [1968]) ln 30 ~1 DMF
was heated in an oil bath at 100C for 16 hours under an argon atmosphere. The cooled suspension was filtered, and the iltrate was evaporated to yield a semi-solid residue.
The residue was partitioned between dilu~e ammonia and : chloroform. The aqueous phase was extracted with two additional portions of chloroform. The combined organic phases were dried, filtered and evaporated to give 2.52 g of a syrup. Chromatography of the syrup on Silica Gel G (200 g, 15:1 V/V chloroorm:methanol) gave 1.68 g of TR 5109 as the free base which was converted to the HCl salt as in Part A
and crystallized from ethyl acetate to give pure TR 5109, mp 207-209~C.
AnaZ. Calcd. for C23H29NO3~Cl: C, 68.39; Hg 7.49;
N, 3.47. Found: 68.05; H, 7.33; N, 3.26.

~ ~ 6 17-Cyclopropylmethyl-4,5~-_poxy-8~-ethyl-3-hydroxymorphinan-__ 6-one 5TR 512 6?.
A mixture of TR S109 tl.0 g; prepared in Exampl~ 1) and pyridine hydrochloride (3.0 g) was heated at 200C far 2 hours. To isolate the product, the ]mixture was cooled, diluted with water and made basic by the addition of concentrated ammonium hydroxide. This mixture was then extracted with several portions of methylene chloride, the organic phase was dried and evaporated to give a brown foam (900 mg) which was twice chromatographed over Silica Gel G to give the puriied material.
Pure fractions containing the desired material WeTe evaporated to give a foam.
Ana~- Calcd for C22H27NO3: C, 74.76; H, 7.70; N, 3.96.
Found: C, 75.77; H, 7.77; N, 6.00.

17-Cyclobutylmethy1-4,5~-epoxy-8~-ethyl-3-hydroxymorphinan-6-one Hydrochloride ~TR 5115).
Part A below describes the preparation of an intermediate to the title compound.

A. 17-Cyclobutylmethyl-4,5~-epoxy-8~-ethyl-3-methoxy-mor~hinan-6-one Hydrochloride__~TR 5114).
A mixture of 4,5~-epoxy-8~-ethyl-3-methoxymorphinan-6-one hydrochloride (3.00 g, 8.6 mmole; prepared in Example lC), NaHCO3 (1.59 g, 18.9 mmole) and cyclobutylmethyl bromide (1.92 g, 12.9 mmole; prepared according to Neth.
Appl. 6,613,986; Chem. Abst. 68: 59608m ~1968]) in 40 ml DMF

.

v~

was heated under argon at 100C fo~ 16 hours. Treatment of the reaction mixture as in Example lD gave a syrup (3.00 g) which was chromatographed over Silica Gel G ~300 g~ using 15:1 V/V chloroform:methanol as the solvent. Pure frac~ions were combined to give 2.13 g ~65%) of TR 5114. The HCl sa~t was prepared as in Example lA and was crystalli~ed from ethyl acetate to give 1.44 g of TR 5114~HCl as white needles, mp 174-175.5C.
AnaZ. Calcd. for C24H33N03~HCl: C, 68.97; H, 7.72;
N, 3.35; Cl, 8.48. Found: C, 67.59; H, 7.89; N, 3.27; Cl, 8.73.

B. 17-Cyclobutylmethyl-4~5a-epoxy-8~-ethyl-3-hyd oxy-morphinan-6-one (TR 5115).
A solution of TR 5114HCl ~1.30 g; p~epared in Part A) in 10 ml 48% HBr was refluxed for 15 minutes, cooled, diluted with water, and made basic with NH40H. The resulting suspension was diluted with ethanol and extracted with six portions of methylene chloride. The organic extracts were dried and evaporated to give 1.18 g of a foam which was chromatographed (100 g Silica Gel G, 15:1 V/V chloroform:
methanol) to give 630 mg of pure material as a foam. The foam was dissolved in ethanol, excess concentrated HCl was added and the mixture was evaporated ~o dryness. Azeotropic distillation with an ethanol-benzene mixture followed by azeotropic distillation with benzene gave crystals which were suspended in ethyl acetate and collected to give TR 5115~HCl, 476 mg, mp dec. above 198C. Recrystallization from water gave pure TR 5115~HCl, mp dec. above 200C.
Ana~. Calcd. for C23H29N03~HCl: C, 68-39; H, 7.49;
N, 3.57; Cl, 8.78. Found: C, 68.26; H, 7.65; N, 3.47; Cl9 9.12.

4 3 5~-Epoxy-8~-ethyl-3-~y~r~ te~rahydrofurfur morphinan-6-one Hydrochlo ide (TR 5271).
Part A describes the prepara~ion of an in~ermediate to the title compound.

A 4,5~-Epoxy-8~-ethyl-3-methoxy--17-tetrahydrofurfuryl-.

morphinan-6-one Hydrochloride (TR 5263).
A mixture of 4,5a-epoxy-8~-ethyl-3-methoxymorphinan-6-one hydrochloride (1.00 g, 28.6 mmole; prepared in Example lC), syrupy tetrahydrofurfuryl (R/S) -camphor-10-sulfonate (1.36 g, 42.9 mmole; prepared as described by Merz et a~., J. Med. Chem. 20: 844 [1977]), sodium iodide (0.51 g, 34.3 mmole) and sodium bicarbonate (0.48 g, 57.2 mmole) in 30 ml DMF was heated at 100C under an argon atmosphere for 18 hours. The suspension was cooled and filtered, and the filtrate was evaporated to yield a semi-solid residue. The residue was partitioned between dilute ammonia solution and toluene. The aqueous phase was extracted with two additional portions of toluene and the combined organic phases were dried, filtered7 and evaporated to give 1.07 g of a syrup.
Chromatography of the syrup (Silica Gel G, 15:1 V~V chloro-form:methanol) gave 0.74 g of the desired material, which was con~erted to the hydrochloride salt as in Example lA and crystallized from ethyl acetate to give 0.623 g of TR 5263 mp 185.5-189C. Recrystallization from methanol-ethyl acetate gave 0.49 g of pure TR 5263, mp dec. 190-210C.
A~a~. Calcd. for C24H31N04-HCl: C, 66.42; H, 7.43;
N, 3.23. Found: C, 65.53; H, 7.55; N, 3.24.

, - ~ .

63~9 B. 4,5~-E~xy-8~-ethyl-3-hydroxy-17-tetrahydrofurfur morphinan-6-one Hydrochl _ de (TR 5271).
_ .
A mixture of impure TR 5263 ~2.40 g; prepared in Part A) and 8.00 g of pyridine hydrochloride was heated at 190-200C for 1 hour. Treatmen~ oE the reaction mixture as inExample 2 gave a foam which was purified by chromatography.
The product was obtained as a foam which was converted to the HCl salt, also obtained as a foam.
- AnaZ. Calcd. for C23H29N04~HCl: C, 65.78; H, 7.20;
N, 3.34. Found: C, 64.06; H, 6.92; N, 3.63.

17-Allyl-4,5a-epox~8~-ethyl-3-methoxymorphinan-6-one Hydrochloride ~TR 5256~.
To a sample of 4,5a-epoxy-8~-ethyl-3-methoxymorphinan-6-one hydrochloride ~3.49 g, 10 mmole; prepared in Example lC) and sodium bicarbonate (15 mmole) in 50 ml dimethylformamide there was added allyl bromide tl ml, 11 mmole) and the mixture was stirred under argon at about 100C for about 16 hours. The solids were removed by filtration and the filtrate was evaporated to a residuc under vacuum. The residue was then partitioned between toluene and water. The product (2.97 g) crystallized upon evaporation of the toluene. The hydrochloride salt was prepared as in Example 1~ and was crystallized from methanol-ethyl acetate to yield 2.4 g (62%), mp 230-232C.
Ana~. Calcd. Eor C22H27N03 HCl: C, 67-76; H~ 7-25;
N, 3.59. Found: C, 67.63; H, 7.17; N, 3.47.

~ . ~

~.X~MPLE 6 17-Allyl-4,5~-epoxy-8~-ethyl-3-hydroxymorphinan-6-one Hydrochloride (TR 5266).
A sample of TR 5256 ~1.5 g, prepared in Example 5) and 6.0 g of pyridine hydrochloride was heated at 185-200C for about 1 hour. After cooling, the product was isolated as described in Example 2 to yield 986 mg of syrup which was then chromatographed on 100 g of Silica Gel G using 10:1 V/V
chloroorm:methanol. The purified product (780 mg) was converted to the hydrochloride salt as in Example lA, yield 228 mg, mp 263C dec.
Ana~. Calcd. for C21H25NO3 HCl: C, 67.10; H, 6.97;
N, 3.73. Found: C, 66.40; H, 7.03; N, ~.61.

This example describes the preparation of 17-cyclobutyl-methyl-4 7 5~ - epoxy-3-hydroxy-8~-methylmorphinan-6-one and its ; intermediates, A. 8~,17-Dimethyl-4,5a-epoxymorphinan-6-one (Compound 7A).
A solution of dimethyl copper lithium was prepared ~ 0 under an argon atmosphere by adding methyl lithium ~0.210 mole, 126 ml of a 1.8 M solution in ether; available from Alfa Chem.
Co.) to a suspension of CuI ~20.0g, 0.105 mole) in 400ml o~
anhydrous ether. To this was added in a thin stream a warm solution of codeinone ~25.0 g, 0.084 mole; prepared by the method of Gavard et a~ . (Bull. Soc. Chim. Fr., 486 (1965)) in 500 ml of dry benzene and the resulting yellow suspension was stirred at 0 for about 1 hr. I`he mixture was then poured into S00 ml of saturated NH4Cl solution and stirred at about 20C for about 1 hr. The organic phase was separated from the mixture and the aqueous phase adjusted to about pH 12 by the addition of 50% NaOH solution. The resulting aqueous phase was ex-tracted with three portions of chloroform, and the combined organic phases were backwashed with saturated NH4Cl solution, dried over MgSO~, and evaporated to give a crystalline residue.
The resulting residue was dissolved in a minimal amount of hot ethanol and stored at about 4C overnight. Tan crystals were collected and dried to give 9.3 g of product. An additional 1.2 g of product were obtained from the mother liquor to give an overall yield of 40%. Allalytically pure Compound 7A mp 178-179.59, was prepared by recrystallization from ethanol. Nmr (CDC13~: ~ 6.68 3 S ~ 2H (aromatic); 4.65, s, lH (H5); 3.57, s, 3H (CH30-); 2.45, s, 3H (CH3N-); 1.02, unsymmetrical doublet, 3H, J = 6 Hz (8~CH3-). Ir (CDC13):
1730 cm 1 ~saturated C=0). Mass spectrum. m/e 313 (P); 298 ~P - CH3)-AnaZ. Calcd~ for ClgH23NO3: C~ 72.82; H, 7.40;N, 4.47. Found: C, 72.70; H, 7.59; N, 4.46.
The hydrochloride of Compound 7A prepared by the method described in Example lA was crystallized from ethanol-ethyl acetate to give Compound 7A~HCl, mp 274-276.
AnaZ. Calcd. ~or ClgH23NO3-HCl: C, 65-23; H~ 6-91;
N, 4.00; Cl, 10.13. Found: C, 65.17; H, 6.96; N, 4.05; Cl, 10.19.

36~

B. 17-Cyano-4l5~-epoxy-3-methoxy-8~-methyl-morphinan-6-one ~Compound 7B) To a suspension of Compound 7A (9.39 g, 30 mmole; prepared in Example 7A) and powdered anhydrous K2C03 (6.00 g, 47 mmole)

5 in 60 ml of chloroform was added a solution of cyanogen bromide in chloroform ~1.2eq, l.Og/20ml) dropwise. Stirring was con-tinued for 30 min at about 20C afte~r which the mixture was re1uxed for 2 hr. After cooling the mixture, the insoluble material therein was remo~ed by filtration. The filtrate was evaporated to a syrup which crystallized upon azeotropic distillation with ethanol. The crystals were boiled with 40 ml of ethanol and collected ater storage at 5C overnight to give 7.93g (82% yield) of productJ mp 237-241.
C. 4,5a'-E ox -3-methoxy-8~-methylmorphinan-6-one Hydro-P Y.
- 15 chlorid'e (Compound 7C).
A mixture of 7.9g of Compound 7B ~prepared in Example 7B) and 2N HCl (200 ml) was heated at re'flux for about 5 hr.
E~aporation'of the solvent gave a crystalline residue which was triturated with ethanol. The crystals were collected and air dried to gi~e 8.05g (98~ yield) of product. Recrystal-lization from ethanol ga~e Compound 7C9HCl 297-300C dec.
Ana~ . Calcd. ~or Cl8H2lNO30HCl: C, 64.38; H, 6.60;
N, 4.17; Cl, 10.56. Found: C,64.64; H9 7.00; N, 4.05; Cl, 10 . 90.
D. 17-Cyclobutylmethyl-4~5~-epoxy-3-methoxy-8~-methyl-mo'rphinan-6-one Hydrochlori ~ ound 7Dl.
A mixture of Compound 7C ~6.00g, 18 mmole; prepared in Example 7C), sodium bicarbonate (3.60g, 43 mmole) and cyclobutylmethyl bromide ~3.20g, 21 mmole; prepared ac-cording to Neth. Appl. 6,613~986; Chem. Abst. 68: 59608m, [1968]) in 60 ml of DMF was heated in an oil bath at 100 for .

about 16 hrs un~er an argon atmosphere. Th~ suspension was cooled and filtered and the filtrate was evaporated to give a semisolid residue. The residue was suspended in chloroform and then extracted with a dilute a~nonium hydroxide solution.
The aqueous phase was then extracted with two portions of chloroform, and the combined organic phases were dried, filtered and evaporated to give 6.17g of a brown syrup. The syrup was dissolved in ethanol and an excess of concentrated HCl added. Evaporation of this solution followed by repeated addition and evaporation of ethanol gave crystals which were collected. Air drying gave 4.96g of Compound 7D~HCl as white needles, mp sinters 200, melts 202-205.
AnaZ. Calcd. for C23H29N03~HCl: C, 68.39; H, 7.48;
N, 3.47; Cl, 8.78. Found: C, 68.70; H, /.40; N, 3.53; Cl, 8.57.
E. 17-'Cycl'obutylmethyl-4~5~-epoxy-3-hydroxy-8~-meth morphinan-6-one ~y`drochloride (TR5088) A solution of Compound 7D~HCl (600 mg; prepared in Example 7D) in 2.5 ml of 48~ HBr was heated at reflux for 7 min. The acidic solution was made basic by the addition of concentrated NH40H and extracted with three portions of chloroform. Evaporation of the chloroform gave 280 mg of a syrup which was chromatographed over Silica Gel G ~50g) using 10:1 ~/V chloroform-methanol. Pure fractions were combined to give 230 mg of a foam which was converted to the HCl salt as in ~xample lA. Crystallization from ethanol-ethyl acetate gave pure TR-5088~Cl, mp 220-225.
or C22H27N03 HCl: C, 67-77; H, 7.24; N, 3.59; Cl, 9.09. Found: C, 67.47; H, 7.32; N, 3056; Cl, 9.39.

6~

This example describes the prepara~ion of 17 cyclo-butylmethyl-4,5a-epoxy-3-hydroxymorphinan-6-one (reference Compound 8E) and its intermediates.

A. 4,5~-Epoxy-3-methoxy-17-me~hylmorphinan-6-one ~Compound 8A).
A solution of 1 g of codeinone (preparçd by the method of Gavard et aZ., Bull. Soc. Chim. Fr., 486 (1965)) in 25 ml of 95% ethanol was adjusted to about pH 1 with concen-trated hydrochloric acid and was hydrogenated on a Paar apparatus at 50 psi using mg o~ 10% Palladium on charcoal catalyst for about l hour. The catalyst was then removed by filtration and the filtrate was evaporated to give a solid residue. This residue was dissolved in water and the solution adjusted ~o about pH 11 with concentra~ed ammonium hydroxide solution. The basic solution was ex-tracted with three portions of chloroform. The combined organic extracts ~ere washed with water, dried over MgSO4 and evaporated to leave a solid residue. The residue was crystallized from absolute ethanol to give the product, which had a melting point of 191-194C, in 87% yield.
- B. 17-Cyano-4,5a-epoxy-3-methoxymorphinan-6-one (Compound 8B).
Compound 8B was prepared as described in Example lB
substituting Compound 8A for Compound lA. The crystalline Compound 8B, mp 213-221~CI was obtained in 87~ yield. Ir:N-CN
2200 cm 1.

C. 4,5~-~poxy-3-methoxymorp~ 6-one ~Co~mRound 8C) `A suspension of 1 g of Compound 8B (prepared in Example 8B) in 30 ml of 2N HCl was refluxed for about 5 hours. The solution was azeotropically dis~illed with ethanol to give crystalline 8C as the HCl sal~ mp about 265C, in 83~ yield.
D. 17-Cyclobutylmethyl-4~5~-epoxy-3-methox~mor~hinan-6 one Hydrobromide (Com~ound 8D).
A mixture of 5.50 g of Compound 8C (17.1 mmole; pre-pared in Example 8C), 3O2g of NaHC03 (37.6 mmole), and 3.82g of cyclobutylmethylbromide (25.6 mmole); prepared according ~o Neth. Appl. 6,613,986; Chem. Abst. _: 59608m ~1968]) in SOml of DMF was heated under argon at lOO~C for 16 hours. Treat-ment of the reaction mixture as in Example lD gave a syrup.
The syrup was converted to the HBr salt according to the method of Example lA, substituting HBr or HCl, and the salt (3.20g, 43% yield) was crystallized from ethanol-ethyl acetate. Recrystallization from the same solvent gave Compound 8D HBr mp 232-233C.
An~Z. C~lc~d. for C22H27NO3oHBr: C, 60.83; H, 6.36; N, 3.23.
2Q Found: C, 60.48; H, 6.34; N, 3.10.
E. 17-CYclobutYlmethY1-4,5a-epoxy-3-hydroxymorphinan-6-~ , one (Compound 8E).
A 3.0 g sample of Compound 8D (prepared in Example 8D) and 9 g of pyridine hydrochloride was heated at about 170C for 1 hour. The mixture was cooled, water was added and the solution was extracted with several portions of methylene chloride. The organic extracts were combined, dried, filtered and evaporated to give 1.86g of a dark foam. The foam was .

~ ~ 6 3 ~ ~

twice chromatographed over Silica Gel G using 8:1 V/V chloro-form-methanol as the eluant. The desired product was obtained as a white foam.
21 25NO3: C, 74.31; ~, 7.43; N, 4.13 Found: C, 70.14; H, 6.95; N, 3.82.

Biolo~ical Screen n~

Compounds of this invention were screened to detect the following biological activities:
(a) Analgesic effects upon mice ~Acetic acid writhing test);
~b) Narcotic antagonist activity in rats ~modified rat tail flick test).
~c) Agonist and antagonist action in mouse intestine ~charcoal meal test).

A. Evaluation by Acetic Acid Writing_Test The analgesic effects of test compounds were determined in mice via the acetic acid writhing test described by B. J. R. Whittle, Brit. J. Pharmacol., 22: 246 (1964).

.

~ 3 ~ ~

At least three dose levels of drug were tested using five mice per dose in determining ~he EDS0. Male albino Charles River mice (18-22 g) were used for this study.
Control animals were given l).4 ml of a 0.5~ solution of s acetic acid by intraperitoneal injection. Five minutes later, the total number of writhe!s ~abdominal stretching) was counted for a 20 minute period.
Treated animals were given the compound under investi~
gation by subcutaneous injection. Fifteen minutes later they were given 0.4 ml of a 0.5% solution of acetic acid by intraperitoneal injection. They were then observed as described for the controls. Data were calculated from the following formula.

~ontrol~~rithes) ) x 10 0 Data are plotted on log-probit paper, ED50 values with 95~ confidence limits were determined by the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther., 96: 99 ~1949]).

B. Evaluation of Narcotic Anta~onist Activity The narcotic antagonist effects of test compounds were determined by a modification of the rat tail flick procedure of Harris and Pierson (J. Pharmacol. Exp. Therap. 143: 141 [1964]).
Male albino Wistar rats (100-120 g) were used for this study. A rat's tail was so placed as to cover a photocell.
Heat was applied by a lamp in a reflector. A timer was connected to the lamp and photocell so that the time went on ~v~}~

when the light was turned on and was turned off when the photocell was uncovered. A rheostat 9 corporated into a heating lamp was used to adjust the intensity of the light falling on the tail of the rat such that each rat's control reaction time was from two to four seconds. Animals with a control reaction time outside this range were rejected. The rheostat adjustment was made only if a significant propor-tion (more than 2 out of every lO rats) of the reaction times were outside the range of two to four seconds. Groups of 5 rats were used each time, and two control times were determined at 60 to 30 minutes prior tv subcutaneous injection of the drug. A ten-second cut-off time was employed; if the rat did not flick its tail in 10 seconds the animal was removed from the heat so~rce.
Thirty minutes after the last control run, the test drug was given. This was followed fifteen minutes later by an ED50 dose of morphine intraperi~oneally. The animals were retested at 20 minutes after the morphine injection.
Control animals were given vehicle and morphine only. The data were calculated as follows:

Effect (E) = ~ (tre~ d) - ~RT tcontrol)} x 100 ~ Antagonism = {E (mor~hire controls) ~ lO0 morp ine contro * MRT is d,efined as mean reaction time.
The data are plotted on log-probit paper and AD50 values within 95% confidence limits are determined by the method of Litch:Eield and Wilcoxon.

3~9 Table B provides the resul-ts obtained in the above protocols with the compounds of this invention.

TABLE B
Biological Screenin~ Data Example TR # Mouse Writhing Rat Tail Flick ED50 _ AD50 ~g/kg) ~mg/kg) 1 5109 2.1 0.78 2 5126 7.8 0~25 3 5115 9.2 0.52 4 5271 1.06 1.~0 5256 10.0 5 6 6 5266 NA10.0* 0.58

7 508~ 0.67 1.9 *not active at indicated dose.

The abo~e data shows that the claimed compounds are useful as narcotic antagonists and except for TR 5266 the claimed compounds are useful as analgesics. Compound TR
Nos. 5109, 5126, 5115 and 5266 are especially effective narcotic antagonists. Compound TR Nos. 5109, 5271, and 50~8 are especially effective analgesics.
C. Evaluation by Charcoal Meal Tests The agonist and antagonist effects of TR-5088, reference compound 8E, and prior art compound 17-cyclopropylmethyl 4,5~-epoxy-3-hydroxymorphinan-6-one lCompound 9A) were determined in mice by a modified procedure of Rodriguez and Villarreal (report of the 36th Annual Scientific Meeting, Committ~e on the Problems of Drug Dependence, March 10-14, 1974, Mexico City, D.F.).

Subjects and Procedure for Measurin~ Gastrointestinal Peristaltic Activity. The mice used were albino females of the CFW strain, weighing between 20 and 25 grams; ten animals per dose were used for each compound tested in each experiment except 20 animals were used in the tests of Compound 5088. Gastro-intestinal peristaltic activity was measured using a modii-cation of ~he charcoal meal method described by Macht and Baba-Gose (1931~. Mice were deprived of food 18 hours before the administration of the charcoal meal. In order to facilitate clearance of gastrointestinal contents, 1 ml of physiologic saline was administered by gastric intubation 15 hours before the charcoal meal. This meal consisted of an aqueous suspension of 5% powdered tragacanth and 5% animal charcoal and was freshly made for each ~xperiment. The charcoal meal was administered by gastric intubation, 0.25 ml per mouse. The animals were sacrificed by cervical dislocation.
After the sacrifice, the whole gastrointestinal tract was rapidly removed and freed of epiploon. Then the entire length , of intestine was hung upon a small hook at the level of the ; 20 pylorus. In order to standardize the tension of the intestine, a 5g weight was hung at the level of the ileocecal valve.
Gastrointestinal peristaltic activity was then determined by measuring the distance the charcoal traveled from the pylorus.

Dru~. Morphine hydrochloride, naloxone hydrochloride or test compounds were each dissolved in distilled water with their concentrations adjusted so that the volume of injection was lO ml/kg. Doses are expressed in terms of the salts.

Determination o Ability of Test Co~E~ o Direc_ly Inhibit . _ .
Peristalsis (A~onist test).
Morphine (8 mg/kg) test compound, or saline control w~s administered subcutaneously(s.c.), at time 09 the charcoal meal was administered by mouth(p.o.) at time 15 min, water (10 ml/kg) was administered s.c. at time 30 min, and the animals were sacrificed at time 45 min. The saline control value represents 0% inhibition and the morphine value re-presents 100% inhibition. All test compounds had values between saline and morphine, and results aré expressed as % inhibition compared to morphine.
The data were subjected to analysis of variance. Also the Scheffe test, a statistical test that allows for multiple comparison, was performed.

1 Determination of Ability of Test Compounds to Anta~onize the Anti-Peristaltic Effects of Morphine (Antagonist test).
Morphine (8 mg/kg) was given s.c. at time 0, charcoal ~eal was given p.o. at time 15 min, naloxone or test compound was given s.c. at 30 min, and the animals were sac~ificed at time 45 min. Naloxone is the standard of reference and its maximum effect ~at lO mg/kg) to antagonize the antiperistaltic effects of morphine is assigned the vaiue of 100%; test com-pounds are exp~essed as % of maximum naloxone antagonism.

~ 6 ~

Table C provides the results obtained in the Agonist - Charcoal meal test (Agonist test).

TABLE C
_ Percent Inhibition of Peristalsis By Test Com~ound At Various Dose ~ EL~l GM* 8E*~ 5088 0.01 24.7 17.5 13.5 0.1 25.4 35.6 39.8 1.0 40.8 50.7 50.7 10.0 44.8 76.3 54.0 100.0 47.1 84,2 63.5 ~Compound-GM is the pri`or art reference compound~~l7-cyclop-ropyl`-methyl-4,5~-epoxy-3-hydroxy morphinan-6 one, reported by Gates and Montzka (J. Med. Chem. 7:127 (1964).
**Compound 8E is 17-Cyclobutylmethyl-4,5~-epoxy-3-hydroxy-morphinan-6-one used as a reference compound for comparison.

One of ~he agonist effects of morphine is the undesirable effect of producing constipation. The determination of the ability of the tes~ compound to directly inhibit peristalsis (Agonist test) in the mouse is then a measure of the test compounds undesirable constipating side effect.
An analysis of variance for each o the compounds of Table C indicates that all compounds have an effect in in-hibiting peris~alsis, and that the effects of Compounds GM and 5088 are the same, but inhibit peristalsis to a statistically significantly less degree than 8E.

:~ .

Table D provides the results of the test compounds ability to reverse the anti-peristaltic effects of morphine Antagonist test).

TABLE D
. _ Percent Reversal (S.E.*) Of Anti-Peristaltic Effects Of Morphlne By~Test Compound ~
dose m ~ Naloxone GM 5088 8E
0.01 14.5 (~3.0) - - 0.0 0.031 - - 12.4 (~5.8) 0 ll 39.1 (~4.2) - 27.7 ~7.3) 8.3 (~4.6) 1.0 69.8 (+8.0) - - 13.5 (~7.3) 3.1 56.6 tl8.0~ 54.6 (~6.7) 10.0100.0 (~5.9) - - 19 1 (~5 8) 31.0 - - 69.3 (+6.4) 44.7-(+6.2) 20 4 (~5 3) *The values with~in~t~parentXeses refer -to stand~a~~r~(S.E.~~

The determination of the ability of the test compound to antagonize the anti-peristaltic effects of morphine (Antagonist test) in the mouse is a measure of the narcotic antagonist effect of the compound.
The data from the above two tests clearly demonstrates unexpected structure activity relationships for the compounds of this invention having a methyl group in the 8B-position.
The 17-cyclopropylmethyl-4,5~-epoxy-8-hydrogen-3-hydroxy-morphi-nan-6-one, prior art compound GM, exhibits mixed agonist side effects and an~agonist properties. The 17-cyclobutylmethyl-4, 5~-epoxy 8-hydrogen-3-hydroxy-morphinan-6-one, reference compound 8E, exhibits so low an antagonist ability as to be ineffective in the practical sense. By contrast with the reference compound 8E the 17-cyclobutyl-methyl-4,5~-epoxy-3-hydroxy-

8~-methylmorphinan-6-one compound of this invention unexpectedly possesses less side effects and dramatically increased antagonist properties.

.

Claims (35)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for the preparation of a compound of the formula (I):

(I) or a pharmacologically acceptable acid addition salt thereof, wherein R1 is a hydrogen atom or a methyl group;
R2 is an allyl, cyclopropylmethyl, cyclobutylmethyl or tetrahydrofurfuryl group, provided that when R2 is a cy-clobutylmethyl or tetrahydrofurfuryl group, then R1 is hy-drogen; and R3 is an ethyl or methyl group, provided that when R3 is methyl, then R2 is cyclobutylmethyl, which comprises either a) reacting an 8.beta.-lower alkyl 17-cyanonorcodeinone compound of the formula (IV) (IV) wherein R3 is as defined above; with an alkylating com-pound selected from the class consisting of allylbromide, cyclopropylmethylbromide, cyclobutylmethylbromide, tetra-hydrofurfurylbromide and tetrahydrofurfuryl camphor-10-sulfonate in a suitable polar organic solvent in the pre-sence of an acid acceptor to provide a compound of the formula (V) (V) wherein R2 and R3 are as defined above;
or b) O-demethylating a compound of formula (V) (V) to provide a compound of formula (I) (I) wherein R1 is a hydrogen atom and R2 and R3 are as defined above.

2. The process according to claim 1 wherein the re-action of the 8.beta.-lower alkyl 17-cyanonorcodeinone compound with the alkylating compound in the presence of the acid acceptor is carried out at a molar ratio between 1:1:2 to 1:2:4 respectively.

3. The process according to claim 1 wherein the al-kylating reaction is carried out in the presence of a polar organic solvent.

4. The process according to claim 3 wherein the sol-vent is dimethylformamide, dimethylsulfoxide or ethanol.

5. The process according to claim 1 wherein the al-kylating reaction is carried out under an inert, moisture-free atmosphere.

6. The process according to claim 5 wherein the in-ert atmosphere is nitrogen or argon.

7. The process according to claim 1 wherein the al-kylating reaction is carried out at a temperature of from about 50°C to about 110°C.

8. The process according to claim 1 wherein the al-kylating reaction is carried out using as the acid acceptor a carbonate or bicarbonate salt of potassium or sodium.

9. The process according to claim 1 wherein the O-demethylating reaction is carried out by means of a hydro-lytic agent.

10. The process according to claim 9 wherein the hy-drolytic agent is pyridine hydrochloride or hydrobromic acid.

11. The process according to claim 9 wherein the hy-drolytic agent is pyridine hydrochloride used at a tempera-ture of from about 180°C to about 200°C for 1 to 2 hours.

12. The process according to claim 1, wherein the compound thus prepared is 17-cyclopropylmethyl-4,5.alpha.-epoxy-8.beta.-ethyl-3-methoxymorphinan-6-one.

13. The process according to claim 1, wherein the compound thus prepared is 17-cyclopropylmethyl-4,5.alpha.-epoxy-8.beta.-ethyl-3-hydroxymorphinan-6-one.

14. The process according to claim 1, wherein the compound thus prepared is 17-cyclobutylmethyl-4,5.alpha.-epoxy-8.beta.-ethyl-3-hydroxymorphinan-6-one.

15. The process according to claim 1, wherein the compound thus prepared is 4,5.alpha.-epoxy-8.beta.-ethyl-3-hydroxy-17-tetrahydrofurfurylmorphinan-6-one.

16. The process according to claim 1, wherein the compound thus prepared is 17-allyl-4,5.alpha.-epoxy-8.beta.-ethyl-3-methoxymorphinan-6-one.

17. The process according to claim 1, wherein the compound thus prepared is 17-allyl-4,5.alpha.-epoxy-8.beta.-ethyl-3-hydroxymorphinan-6-one.

18. The process according to claim 1, wherein the compound thus prepared is 17-cyclobutylmethyl-4,5.alpha.-epoxy-3-hydroxy-8.beta.-methylmorphinan-6-one.

19. A process for the preparation of a compound having the structural formula, (I) or a pharmacologically acceptable acid addition salt there-of, in which:
R1 is a hydrogen atom or a methyl group;
R2 is an allyl, cyclopropylmethyl, cyclobutylmethyl or tetrahydrofurfuryl group, provided that when R2 is a cy-clobutylmethyl or tetrahydrofurfuryl group, then R1 is hy-drogen; and R3 is an ethyl or methyl group, provided that when R3 is methyl, then R2 is cyclobutylmethyl, which comprises:
a) reacting codeinone in a halogenated hydrocarbon or aromatic hydrocarbon solvent with a lithium lower di-alkyl copper reagent selected from the class consisting of lithium diethyl copper and lithium dimethyl copper or li-thium divinyl copper via a conjugate 1,4-addition reaction;
b) quenching the reaction mixture with an aqueous ammonium compound and hydrogenating the product in the pre-sence of a catalyst when lithium divinyl copper is used in step a) to produce an 8.beta.-lower alkyl codeinone having the structural formula:

(II) wherein R3 is ethyl or methyl;
c) reacting the 8.beta.-lower alkyl codeinone with a cyano-gen halide to produce an 8.beta.-lower alkyl 17-cyanonorcodeinone compound having the structural formula:

(III) wherein R3 is as defined above;
d) hydrolyzing the 8.beta.-lower alkyl 17-cyanonorcodei-none product with dilute mineral acid to produce an 8.beta.-lower alkyl norcodeinone product having the structural formula (IV) wherein R3 is as defined above;
e) reacting the 8.beta.-lower alkyl norcodeinone product with an alkylating compound selected from the class con-sisting of allylbromide, cyclopropylmethylbromide, cyclo-butylmethylbromide, tetrahydrofurfurylbromide and tetra-hydrofurfuryl camphor-10-sulfonate in a suitable polar or-ganic solvent in the presence of an acid acceptor to pro-duce a compound having the structural formula:

(V) wherein R2 and R3 are as defined above;
and f) if desired O-demethylating compound (V) by hydro-lysis with a hydrolytic reagent at an elevated temperature.

20. The process according to claim 19, wherein the steps further comprise:
(a) reacting the codeinone with the lithium lower dialkyl copper reagent at a molar ratio from about 1:1 to 1:3 respectively under an inert moisture free atmosphere at a temperature from about -78°C to +10°C;
(b) quenching the reaction mixture with an aqueous ammonium compound in molar excess of the copper in the reaction mixture;
(c) reacting the 8.beta.-lower alkyl codeinone with the cyanogen halide at a temperature from about 20°C to the reflux temperature of the solvent for a period of time up to about 2 hours;
(d) hydrolyzing the 8.beta.-lower alkyl-17-cyanonorcodei-none with a mineral acid selected from the class consist-ing of hydrochloric, sulfuric or nitric at reflux tempera-tures; and (e) reacting the 8.beta.-lower alkyl norcodeinone with the alkylating compound in the presence of the acid acceptor at a molar ratio between 1:1:2 to 1:2:4 respectively, under an inert moisture free atmosphere, at a temperature from 50°C to 110°C.

21. A compound having the structural formula, (I) or a pharmacologically acceptable acid addition salt thereof in which:
R1 is a hydrogen atom or a methyl group;
R2 is an allyl, cyclopropylmethyl, cyclobutylmethyl or tetrahydrofurfuryl group, provided that when R2 is a cyclobutylmethyl or tetrahydrofurfuryl group, then R1 is hydrogen; and R3 is an ethyl or methyl group, provided that when R3 is methyl, then R2 is cyclobutylmethyl, whenever prepared by the process of claim 1.

22. A compound, as defined in claim 21, whenever prepared by the process of claim 2 or 3.

23. A compound as defined in claim 21, whenever pre-pared by the process of claim 4 or 5.

24. A compound as defined in claim 21, whenever pre-pared by the process of claim 6 or 7.

25. A compound as defined in claim 21, whenever pre-pared by the process of claim 8 or 9.

26. A compound as defined in claim 21, whenever pre-pared by the process of claim 10 or 11.

27. The compound as defined in claim 21 which is 17-cyclopropylmethyl-4,5.alpha.-epoxy-8.beta.-ethyl-3-methoxymorphinan-6-one, whenever prepared by the process of claim 12.

28. The compound as defined in claim 21, which is 17-cyclopropylmethyl-4,5.alpha.-epoxy-8.beta.-ethyl-3-hydroxymorphinan-6-one, whenever prepared by the process of claim 13.

29. The compound as defined in claim 21, which is 17-cyclobutylmethyl-4,5.alpha.-epoxy-8.beta.-ethyl-3-hydroxymorphinan-6-one, whenever prepared by the process of claim 14.

30. The compound as defined in claim 21, which is 4,5.alpha.-epoxy-8.beta.-ethyl-3-hydroxy-17-tetrahydrofurfurylmorphi-nan-6-one, whenever prepared by the process of claim 15.

31. The compound as defined in claim 21, which is 17-allyl-4,5.alpha.-epoxy-8.beta.-ethyl-3-methoxymorphinan-6-one, whenever prepared by the process of claim 16.

32. The compound as defined in claim 21, which is 17-allyl-4,5.alpha.-epoxy-8.beta.-ethyl-3-hydroxymorphinan-6-one, whenever prepared by the process of claim 17.

33. The compound as defined in claim 21, which is 17-cyclobutylmethyl-4,5.alpha.-epoxy-3-hydroxy-8.beta.-methylmorphi-nan-6-one, whenever prepared by the process of claim 18.

34. A compound having the structural formula, (I) or a pharmacologically acceptable acid addition salt there-of in which:
R1 is a hydrogen atom or a methyl group;
R2 is an allyl, cyclopropylmethyl, cyclobutylmethyl or tetrahydrofurfuryl group, provided that when R2 is a cyclo-butylmethyl or tetrahydrofurfuryl group, then R1 is hydro-gen; and R3 is an ethyl or methyl group, provided that when R3 is methyl, then R2 is cyclobutylmethyl, whenever prepared by the process of claim 19.

35. A compound, as defined in claim 34, whenever pre-pared by the process of claim 20.