7.beta.-Arylalkyl-3-methoxy or 3-hydroxy-4,5.alpha.-epoxy-6.beta.-hydroxy-7.alpha.-hydroxymethyl-17-methyl or 17-cycloalkylmethylmorphinans

BACKGROUND OF THE INVENTION
Morphine is a well-known narcotic analgesic having the structural formula: ##STR2## The compounds of this invention are structurally related to morphine and are named according to the morphinan system of nomenclature using the morphinan nucleus as shown below: ##STR3## The numbering and the stereochemical placement of atoms in the morphinan system is the same as that depicted for morphine. A dashed line is used to represent a covalent bond projecting below the plane of a reference atom while a wedged or heavily accented line signifies a covalent bond above such plane. The compounds of this invention have the same stereochemical placement of atoms as depicted for the morphine nucleus unless otherwise indicated.
In U.S. Pat. No. 4,275,205, there is disclosed 7,7-ditosyloxymethyl-4,5.alpha.-epoxy-3-methoxy-17-methyl-morphinan-6.beta.-ols of the formula: ##STR4## where R is H, CH.sub.3 or CH.sub.2 CH.sub.3. These compounds are precursors for certain 7,7-dimethyl-morphinans having analgesic activity or a combination of analgesic and narcotic antagonist activity.
SUMMARY OF THE INVENTION
The present invention involves 3,7-substituted-4,5.alpha.-epoxy-6.beta.-hydroxy-17-methyl or cycloalkylmethyl-morphinans of the formula: ##STR5## wherein R is H or methyl, R.sub.1 is methyl, cyclopropylmethyl or cyclobutylmethyl, n is 2 to 4 and Y is H or phenyl.
DESCRIPTION OF THE INVENTION
The novel morphinan compounds of the present invention are prepared as outlined in scheme I. Referring to scheme I, starting material A (dihydrocodeinone, prepared by the catalytic hydrogenation of codeinone) is treated with formaldehyde in aqueous dioxane solution in the presence of Ca(OH).sub.2 to give 1 as reported (Leland and Kotick, J. Med. Chem., 1981, 24, 717). Reaction of 1 with acetone in the presence of p-toluene sulfonic acid monohydrate and a molecular sieve gives a mixture of major and minor products which are resolved by chromatography. The minor product (obtained in 19% yield) is the 7,7-bis methyleneoxy adduct B which is not further utilized.
The major product 2, obtained in 72% yield as a foam, was shown by various chemical transformations to have the isopropylidene group trans fused between the 6.beta.-hydroxy and 7.alpha.-hydroxymethyl positions. The 7.beta.-hydroxymethyl group in the 1,3-dioxolane 2 is oxidized, in 90% yield, to the 7.beta.-formyl derivative 3 using a mixture of dimethyl sulfoxide-trifluoroacetic anhydride in methylene chloride solution at about -60.degree. C. Extention of the chain at the C.sub.7 position from the aldehyde 3, is carried out using the Wittig reaction (Maerker, Organic Reactions, 1965, 14, 270). Various triphenylphosphonium ylides are generated from the appropriate halogen salts using either sodium hydride-dimethyl sulfoxide (method of Corey, et al, J. Am. Chem. Soc., 1965, 87, 1345) or phenyl lithium (method of Lambert, et al, J. Am. Chem. Soc., 1977, 99, 3059). The isopropylidene blocking group is removed from the chain extended, unsaturated intermediate 4 by use of dilute HCl in boiling ethanol to give the 7.beta.-unsaturated intermediate 5. When the phenyl lithium method is used to generate the triphenylphosphonium ylide, a side product, namely the tertiary alcohol 6 may also be isolated. This product arises from the reaction of aldehyde 3 directly with the phenyl lithium used to prepare the ylide. Presence of this product indicates incomplete formation of the desired ylide intermediate.
Hydrogenation of 5 over 10% palladium on charcoal in ethanol acidified with concentrated HCl to about pH 2 proceeded slowly. Complete conversion of 5 to 7 could be judged by thin layer chromatography. The 3-0-demethylation of the saturated 3-methoxy compounds 7 to the 3-hydroxy derivatives 8 was accomplished by treatment of 7 with refluxing hydrobromic acid for 10 to 15 minutes. Moderate to good yields of 8 are obtained.
The N-cyclopropylmethyl (P series) or N-cyclobutylmethyl (B series) were prepared by the following sequence. Reaction of N-methyl compounds 7 with cyanogen bromide in chloroform solution in the presence of potassium carbonate gave N-cyano compounds 9. Hydrolysis of the N-cyano compounds 9 to the nor compounds 10 was accomplished by refluxing 9 with 2 N HCl for 8 to 18 hours. Cycloalkylmethylation of 10 to 11 was accomplished by heating 10 with the appropriate cycloalkylmethyl bromide in N,N-dimethylformamide solution containing sodium bicarbonate for 3 to 20 hours until thin layer chromatography indicated completion of the reaction. The 3-methoxy group was cleaved from 11 to give the 3-hydroxy compounds 12 using refluxing HBr as described above. ##STR6##

The method of preparing these compounds is further illustrated by the following examples wherein the numbering of compounds corresponds to that used in scheme I and processing in the usual manner implies that the combined organic phases were washed with dilute NH.sub.4 OH, dried (MgSO.sub.4), filtered and evaporated at a 40.degree.-45.degree. C. bath temperature, finally under high vacuum. Column chromatography was carried out over silica gel 60 G (E. Merck) using CHCl.sub.3 --MeOH mixtures containing 0.25 to 1% v/v concentrated NH.sub.4 OH. All compounds gave NMR and mass spectra consistent with the indicated structures.
EXAMPLE I
A. 4,5.alpha.-Epoxy-7,7-bis(hydroxymethyl)-6.beta.,7.alpha.-O-isopropylidene-3-methoxy-17-methylmorphinan-6.beta.-ol (2) and 4,5.alpha.-epoxy-7,7-bis(hydroxymethyl)-7.alpha.,7.beta.-O-isopropylidene-3-methoxy-17-methylmorphinan-6.beta.-ol (B)
A mixture of the free base of 1 (10.45 g, 28.9 mmole) and pTsOH.H.sub.2 O (6.05 g, 28.9 mmole) in acetone (200 ml) was stirred for 16 hrs. at room temperature. Molecular sieve (4 .ANG., 25 g) was then added and stirring continued for an additional 24 hrs. The suspension was made basic by the addition of concentrated NH.sub.4 OH, filtered and the filtrate evaporated. The residue was partitioned between H.sub.2 O and CHCl.sub.3 and further processed to a foam which was chromatographed. First eluted was 2.20 g (19%) of a minor product B NMR .delta.1.38 (d, 6H, gem CH.sub.3 's, J=7 Hz). Continued elution followed by pooling of appropriate fractions and evaporation gave 8.40 g (72%) of 2 as a foam; NMR .delta.1.33 (d, 6H, gem CH.sub.3 's, J=8 Hz).
B. 4,5.alpha.-Epoxy-7.beta.-formyl-7.alpha.-hydroxymethyl-6.beta.,7.alpha.-O-isopropylidene-3-methoxy-17-methylmorphinan-6.beta.-ol (3)
To an oxidation mixture prepared from DMSO (7.2 ml, 101.8 mmole) in CH.sub.2 Cl.sub.2 (80 ml) and TFAA (10.8 ml, 76.4 mmole) in CH.sub.2 Cl.sub.2 (30 ml) was added 2 (20.0 g, 50 mmole) in CH.sub.2 Cl.sub.2 (400 ml) slowly over a period of 1 hr. After stirring in the dry ice-acetone bath for 1 hr., TEA (20 ml) was added dropwise and the mixture allowed to warm to room temperature. The solution was evaporated, the residue diluted with H.sub.2 O and NH.sub.4 OH and extracted with CHCl.sub.3. Processing in the usual fashion gave 18.0 g (90%) of 3 as a solid residue. Recrystallization from EtOAc-hexane gave 14.4 g of crystals, mp 157.degree.-163.degree. C. Recrystallization from the same solvent pair gave an analytical sample of 3, mp 169.degree.-171.degree. C.; NMR .delta.9.86 (broad s, --CHO), 4.98 (d, 1H, H5, J=6 Hz), 3.90 (CH.sub.3 O--), 2.40 (CH.sub.3 N--), 1.36 (s, 6H, gem CH.sub.3 's).
Anal. Calcd. for C.sub.23 H.sub.29 NO.sub.4 : C, 69.15; H, 7.32; N, 3.51. Found: C, 69.24; H, 7.28; N, 3.33.
C. 4,5.alpha.-Epoxy-7.alpha.-hydroxymethyl-3-methoxy-17-methyl-7.beta.-arylalkylidenemorphinan-6.beta.-ols (5)
Method A-A suspension of 50% NaH (0.66 g, 13.8 mmole) in mineral oil was washed 3 times with hexane while under an argon atmosphere. Dimethylsulfoxide (DMSO) (10 ml) was added and the mixture heated at 60.degree.-70.degree. C. until the evolution of H.sub.2 ceased (ca. 30 min.). The mixture was cooled to 25.degree. C. and the appropriate phosphonium salt (13.8 mmole) in DMSO (50 ml) added dropwise. After 10 min., 3 (5.0 g, 12.5 mmole) in DMSO (50 ml) was added rapidly dropwise. Stirring was continued for 30 min. at room temperature followed by heating of the mixture at 65.degree.-70.degree. C. for 30 min. The cooled mixture was diluted with water and extracted with toluene. The organic phase was evaporated and the residue, consisting of 4 and (C.sub.6 H.sub.5).sub.3 PO dissolved in EtOH (200 ml) and 1 NHCl (50 ml) added. The mixture was gently boiled on the steam bath for 30 min. and then evaporated to a small volume. The acidic concentrate was diluted with H.sub.2 O and washed several times with toluene. The aqueous solution was then made basic with concentrated NH.sub.4 OH and further processing carried out as described below.
Method B-To a suspension of the phosphonium salt (23 mmole) in Et.sub.2 O (200 ml), under argon at room temperature, was added phenyl lithium (23 mmole, 1.9 M solution in 7:3 C.sub.6 H.sub.6 -Et.sub.2 O) and the mixture stirred for 1-2 hrs. A solution of 3 (4.0 g, 10 mmole) in 1:1 toluene-Et.sub.2 O (100 ml) was added to the dark solution and stirring continued for 2 hrs. The reaction was quenched by the addition of H.sub.2 O, concentrated NH.sub.4 OH added and the intermediate 4 extracted with CHCl.sub.3. Evaporation of the organic phase was followed by the addition of EtOH and 1 N HCl, the mixture boiled for 30 min., and then further processed as described below.
Compound 5a was prepared by Method A. Crystals of 5a precipitated from the basic aqueous solution and were obtained in 78% yield. Recrystallization from H.sub.2 O gave pure 5a, mp 181.degree.-182.degree. C. Anal. (C.sub.21 H.sub.21 --NO.sub.4). Intermediate 5b was prepared by Method B and was not further purified, but directly hydrogenated to 7b. In a similar manner, 5c was prepared by Method A and purified by chromatography to give an 89% yield of the desired product as a foam. Compound 5d was prepared by Method B and purified by chromatography to give a 38% yield of 5d as a foam. The HCl salt, mp dec >280.degree. C., was obtained in crystalline form from EtOH. Anal. (C.sub.28 H.sub.33 NO.sub.4.HCl). The intermediate analogous to 5e was prepared by Method A using cinnamyl triphenylphosphonium chloride. The di-unsaturated 4-phenyl-1,3-butadieneyl intermediate was not isolated but directly reduced to 7e. Compound 5g was prepared by Method B and obtained as a foam, after chromatography, in 68% yield. Crystallization from EtOH gave pure 5g, mp 168.degree.-170.degree. C. Anal. (C.sub.30 H.sub.37 NO.sub.4). 5h was prepared by Method A and purified by chromatography to give a 70% yield of 5h as a foam. The HCl salt, mp dec >260.degree. C., was obtained in crystalline form from EtOH. Anal. (C.sub.31 H.sub.39 NO.sub.4.HCl).
D. 4,5.alpha.-Epoxy-7.beta.-(.alpha.-hydroxybenzyl)-7.alpha.-hydroxymethyl-3-methoxy-17-methylmorphinan-6.beta.-ol (6)
This compound was obtained as a side product in the preparation of 5 by Method B. Material obtained by chromatography from several reactions, which migrated as a single spot on TLC, was combined and crystallized from MeOH-EtOAc to give a sample of pure 6, mp 265.degree.-267.degree. C. Anal. (C.sub.26 H.sub.31 NO.sub.5).
E. 7.beta.-Arylalkyl-4,5.alpha.-epoxy-7.alpha.-hydroxymethyl-3-methoxy-17-methylmorphinan-6.beta.-ols (7)
Hydrogenation of 5, as the free base or HCl salt, was carried out over 10% Pd/C (10-25% w/w) at 50 psi in aqueous EtOH acidified with HCl (ca. pH 2) until the uptake of H.sub.2 ceased (2-24 hrs.). After removal of the catalyst by filtration, the filtrate was evaporated to a crystalline residue. In cases where crystallization did not occur, the HCl salt was converted to the free base and further purification carried out by chromatography or crystallization as indicated in table III.
F. 7.beta.-Arylalkyl-4,5.alpha.-epoxy-3-hydroxy-7.alpha.-hydroxymethyl-17-methylmorphinan-6.beta.-ols (8)
A mixture of 7 (free base or HCl salt) and concentrated HBr (1.0 g in 10-15 ml) was immersed in a preheated oil bath (ca. 140.degree. C.) and refluxed for 10 to 20 min. The reaction mixture was cooled, diluted with H.sub.2 O and adjusted to pH 10-11 by the addition of concentrated NH.sub.4 OH. The basic solution was extracted with 3 portions of CHCl.sub.3, the organic extracts processed in the usual manner and the residue chromatographed. Crystals of the free base or HCl salt were obtained from the solvents indicated in table III.
G. 7.beta.-Arylalkyl-17-cyano-4,5.alpha.-epoxy-7.alpha.-hydroxymethyl-3-methoxymorphinan-6.beta.-ols (9)
To a rapidly stirred mixture of 7 (1.0 equiv.) in CHCl.sub.3 (1 g in 15 ml) containing K.sub.2 CO.sub.3 (1.5 equiv.) was added dropwise a solution of BrCN (1.2 equiv.) in CHCl.sub.3 (1 g in 15 ml). The mixture was stirred at room temperature for 30 min. and then refluxed for 2 hrs. The insoluble material was removed by filtration and the filtrate evaporated. The residue was evaporated with EtOH until a foam formed. This foam, obtained in nearly quantitative yield and homogenous by TLC, was hydrolyzed to 10 as described below.
H. 7.beta.-Arylalkyl-4,5.alpha.-epoxy-7.alpha.-hydroxymethyl-3-methoxymorphinan-6.beta.-ols (10)
A mixture of 9 and 2 N HCl (1 g in 15-25 ml) was refluxed for 8 to 18 hrs. The solution was cooled, made basic by the addition of concentrated NH.sub.4 OH and extracted with CHCl.sub.3. Processing of the CHCl.sub.3 extracts in the usual fashion was followed by chromatography to give the following 10 as foams, yield being based on the --NCH.sub.3 compounds 7; 10c, 88%; 10d, 81%; 10f, 75%; 10g, 67%. These foams were used in alkylation reactions described below.
I. 7.beta.-Arylalkyl-17-(cycloalkylmethyl)-4,5.alpha.-epoxy-7.alpha.-hydroxymethyl-3-methoxymorphinan-6.beta.-ols (11P,B).
A solution of 10 in DMF (1 g in 20 ml) containing NaHCO.sub.3 (2.5 equiv.) and cycloalkylmethyl bromide (1.2 equiv.) was heated in an oil bath at 100.degree. C. while under argon until the reaction was complete as indicated by TLC (3-20 hrs.). The mixture was cooled and filtered to remove insolubles. The filtrate was evaporated using an oil pump and the residue dissolved in H.sub.2 O. This mixture was adjusted to pH 10-11 with NH.sub.4 OH and extracted with 3 portions of toluene. The organic phase was processed in the usual manner, the residue chromatographed and the product crystallized as the free base or HCl salt as indicated in table III.
J. 7.beta.-Arylalkyl-17-(cycloalkylmethyl)-4,5.alpha.-epoxy-3-hydroxy-7.alpha.-hydroxymethyl-morphinan-6.beta.-ols (12P,B)
A suspension of the 3-methoxy compound 11 in 48% HBr (1 g in 10 ml) was placed in a preheated, 140.degree. C. oil bath and the mixture refluxed for 10-20 min. The cooled solution was diluted with H.sub.2 O and made basic with NH.sub.4 OH. This was extracted with EtOAc or CHCl.sub.3, the organic extracts processed in the usual fashion and the residue chromatographed. Pure 12 was crystallized as the free base or HCl salt. Further details are given in table III.
PHARMACOLOGICAL EVALUATION
Analgesic effects of the test compounds were determined in mice by use of the acetic acid induced writhing test described by B. A. Whittle, Brit. J. Pharmacol., 22:246 (1964). In this test, at least 3 groups of 5 male CD-1 mice each were given subcutaneous doses of the test drug dissolved in distilled water. In all cases, 0.4 ml of a 0.5% v/v acetic acid in distilled water solution was administered intraperitoneally 15 min. post drug. The number of writhes in a 20 min. interval beginning 5 min. after the acetic acid injection were determined and compared with the number of writhes in a control group which had received only acetic acid.
Percent inhibition of writhing was calculated as: ##EQU1##
The ED.sub.50 dose, i.e., the dose required to reduce the number of writhes by 50%, was determined graphically from a plot of % inhibition as a probit verus log dose. Confidence limits of 95% were calculated on the basis of those results falling in the range 16-84% inhibition. See Lichtfield, J. T. and Wilcoxson, F., J. Pharmacol. Exp. Ther., 96, 99-113 (1949).
The results of this evaluation are set out in table I.
TABLE I______________________________________Narcotic Agonist Activity-Mouse Writhing Assay, s.c.Injection For NMethyl Compounds ##STR7## ED.sub.50 ED.sub.50Compound R R.sub.1 n Y (.mu. mole/kg) (mg/kg)______________________________________ 7a* CH.sub.3 CH.sub.3 2 H 2.7 1.05 7b* CH.sub.3 CH.sub.3 4 H 13.7 5.87c CH.sub.3 CH.sub.3 2 Ph 0.028** 0.012 7d* CH.sub.3 CH.sub.3 3 Ph 0.39 0.197e CH.sub.3 CH.sub.3 4 Ph 0.014 0.00667f CH.sub.3 CH.sub.3 5 Ph 2.3 1.197g CH.sub.3 CH.sub.3 6 Ph 4.5 2.28b H CH.sub.3 4 H 0.56 0.218c H CH.sub.3 2 Ph 0.004 0.00168d H CH.sub.3 3 Ph 0.85 0.378e H CH.sub.3 4 Ph 0.003 0.0014 8f* H CH.sub.3 5 Ph 12.0 6.0 8g* H CH.sub.3 6 Ph >19 >10 codeine 10.3 4.2 morphine 2.1 0.79 dihydrocodeinone 2.4 1.06 dihydromorphinone 0.25 0.08______________________________________ *HCl salt **Repeat 0.014/.0062
TABLE II______________________________________Narcotic Agonist Activity-Mouse Writhing Assay, s.c.Injection For N--Cycloalkylmethyl Compounds ED.sub.50 ED.sub.50Compound R R.sub.1 n Y (.mu. mole/kg) (mg/kg)______________________________________ 11Pc* CH.sub.3 P 2 Ph 0.61 0.3111Pd CH.sub.3 P 3 Ph 0.13 0.06511Pe CH.sub.3 P 4 Ph 0.22 0.12 11Pf* CH.sub.3 P 5 Ph 0.40 0.22 11Bc* CH.sub.3 B 2 Ph 0.70 0.3711Bd CH.sub.3 B 3 Ph 0.04 0.019 11Be* CH.sub.3 B 4 Ph 0.52 0.27 11Bf* CH.sub.3 B 5 Ph 0.30 0.1712Pc H P 2 Ph 0.95 0.44 12Pd* H P 3 Ph 0.47 0.2412Pe H P 4 Ph 11.0 5.4 12Pf* H P 5 Ph >19 >1012Bc H B 2 Ph 2.5 1.21 12Bd* H B 3 Ph 0.57 0.30 12Be* H B 4 Ph 21.3 11.5 12Bf* H B 5 Ph >10 >10______________________________________ *HCl salt P = cyclopropylmethyl B = cyclobutylmethyl
TABLE III______________________________________6.beta. -Hydroxy-7.alpha.-Hydroxymethyl-.alpha.-Substituted Morphinans RecyrstnCompound % Yield mp, .degree.C. Solvent.sup.a______________________________________7a 58.sup.b 200-204 E7b 53.sup.b >270 E7c 72.sup.c 240-242 E7d 81.sup.b 267-270 M--EA7e 89.sup.d 196-198 EA--C7f 83.sup.b 200-202 M--EA7g 67.sup.c 160-161 E8b 81.sup.c 224-226 M--EA8c 54.sup.c 259-262 M--EA8d 62.sup.c 240-245 E8e 82.sup.c 192-193 EA8f 88.sup.c 212-216 M--EA8h 67.sup.c 249-251 E11Pc 85.sup.c 261-264 E11Pd 44.sup.e 198-199.5 E11Pe 63.sup.c 256-258 M--EA11Pf 75.sup.c 240-243 E11Bc 74.sup.c 200.sup.f E11Bd 62.sup.c 152-154 EA11Be 62.sup.c 256-258 M--EA11Bf 77.sup.c 247-250 E12Pc 34.sup.c 252-254 E12Pd 36.sup.c dec >200 M--EA12Pe 86.sup.c 214-216 E--A12Pf 57.sup.c 168-174 M--EA12Bc 77.sup. 255- 257 E12Bd 49.sup. >280 M--EA12Bf 95.sup. 222-225 M--EA12Bf 93.sup. 182-186 M--EA______________________________________ .sup.a C = chlorofoam; E = ethanol; EA = ethyl acetate; M = methanol; W = water. .sup.b HCl salt crystallized directly. .sup.c Yield of free base after chromatography. .sup.d Free base crystallized directly. .sup.e Directly crystallized from toluene. .sup.f Softens
TABLE IV______________________________________ELEMENTAL ANALYSESCompound Formula % C % H % N______________________________________5a C.sub.21 H.sub.27 NO.sub.4 70.56 7.61 3.92 Calc. 70.58 7.60 3.59 Found5d C.sub.28 H.sub.33 NO.sub.4.HCl 69.48 7.08 2.89 69.23 7.22 2.785f C.sub.30 H.sub.37 NO.sub.4 75.76 7.84 2.94 75.54 7.57 2.645g C.sub.31 H.sub.39 NO.sub.4.HCl 70.77 7.66 2.66 71.14 7.30 2.646 C.sub.26 H.sub.31 NO.sub.5 71.37 7.14 3.20 71.34 7.37 3.277a C.sub.21 H.sub.29 NO.sub.4.HCl 63.71 7.64 3.54 63.69 7.99 3.417b C.sub.23 H.sub.33 NO.sub.4.HCl 65.16 8.08 3.30 65.22 8.15 3.327c C.sub.27 H.sub.33 NO.sub.4 74.45 7.64 3.22 74.25 7.80 3.267d C.sub.28 H.sub.35 NO.sub.4.HCl 69.19 7.46 2.88 69.25 7.67 2.787e C.sub.29 H.sub.37 NO.sub.4 75.13 8.04 3.02 74.96 7.96 2.927f C.sub.30 H.sub.39 NO.sub.4.HCl 70.09 7.84 2.72 69.69 7.98 2.747g C.sub.31 H.sub.41 NO.sub.4 75.73 8.41 2.85 74.64 8.54 2.828b C.sub.22 H.sub.31 NO.sub.4 70.75 8.37 3.75 70.94 8.44 3.638c C.sub.26 H.sub.31 NO.sub.4 74.08 7.41 3.32 73.80 7.46 3.388d C.sub.27 H.sub.33 NO.sub.4 74.45 7.64 3.22 74.20 7.77 3.148e C.sub.28 H.sub.35 NO.sub.4 74.80 7.85 3.12 74.56 7.83 2.958f C.sub.29 H.sub.37 NO.sub.4.HCl 69.65 7.66 2.80 69.87 7.39 2.598h C.sub.30 H.sub.39 NO.sub.4.HCl. 67.72 7.95 2.63 H.sub.2 O 67.67 8.14 2.5711Pc C.sub.30 H.sub.37 NO.sub.4.HCl 70.36 7.48 2.74 70.32 7.46 2.8511Pd C.sub.31 H.sub.39 NO.sub.4 76.04 8.03 2.86 75.88 7.82 2.6311Pe C.sub.32 H.sub.41 NO.sub.4.HCl 71.16 7.84 2.59 70.84 7.81 2.4211Pf C.sub.33 H.sub.43 NO.sub.4.HCl 71.52 8.00 2.53 71.38 7.81 2.5311Bc C.sub.31 H.sub.39 NO.sub.4.HCl 70.77 7.66 2.66 70.44 7.66 2.7911Bd C.sub.32 H.sub.41 NO.sub.4 76.31 8.20 2.78 76.12 8.24 2.6111Be C.sub.33 H.sub.43 NO.sub.4.HCl 71.52 8.00 2.53 71.16 7.73 2.4711Bf C.sub.34 H.sub.45 NO.sub.4.HCl 71.87 8.16 2.46 71.53 8.13 2.5312Pc C.sub.29 H.sub.35 NO.sub.4 75.46 7.64 3.03 75.18 7.70 2.9012Pd C.sub.30 H.sub.37 NO.sub.4.HCl 70.36 7.48 2.74 70.10 7.65 2.8512Pe C.sub.31 H.sub.39 NO.sub.4 76.04 8.03 2.86 76.20 8.12 2.8012Pf C.sub.32 H.sub.41 NO.sub.4.HCl 71.16 7.84 2.59 70.69* 7.85 2.5712Bc C.sub.30 H.sub.37 NO.sub.4 75.76 7.84 2.94 75.62 7.93 2.7612Bd C.sub.31 H.sub.39 NO.sub.4.HCl 70.77 7.66 2.66 70.98 7.78 2.6212Be C.sub.32 H.sub.41 NO.sub.4.HCl 71.16 7.84 2.59 71.23 7.67 2.2512Bf C.sub.33 H.sub.43 NO.sub.4.HCl 71.52 8.00 2.53 71.84 8.01 2.30______________________________________
The compounds claimed herein, especially those with small ED.sub.50 values, are very potent narcotic agonists. As such, they are useful for the relief of pain, for pre-operative anesthesia or for the immobolization of large animals. The dose to be administered to achieve the desired result, i.e., the effective dose, may vary from individual to individual but is readily determined by one skilled in the art without undue experimentation.
The compounds of the present invention form pharmacologically active addition salts with organic acids. Typical acid addition salts are the tartrate and maleate. These compounds may be administered by known conventional methods such as intravenous, parenteral, buccal, rectal or oral routes. Dose forms for the administration of these compounds can be prepared by methods recognized in the pharmaceutical sciences.

Number	Name	Date
2178010	Small et al.	Oct 1939
4275205	Kotick et al.	Jun 1981
4347361	Quick et al.	Aug 1982

7.beta.-Arylalkyl-3-methoxy or 3-hydroxy-4,5.alpha.-epoxy-6.beta.-hydroxy-7.alpha.-hydroxymethyl-17-methyl or 17-cycloalkylmethylmorphinans

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Entry
Kotick, et al., J. Med. Chem., 24(12), pp. 1445-1450, (1981).
Bentley, et al., J. Am. Chem. Soc., 89(13), pp. 3267-3273, (1967).
Stork, "The Alkaloids", vol. VI, Manske, ed., Academic Press, New York, (1960), p. 226.
Quick, et al., J. Med. Chem., 25(8), pp. 983-986, (1982).
Leland, et al., J. Org. Chem., 48(11), pp. 1813-1819, (1983).
Kotick, et al., J. Med. Chem., 26(7), pp. 1050-1056, (1983).