IE46575B1 - 2,6-methano-3-benzazocines - Google Patents

Description

This invention relates to certain selected 3,6(eq),11(ax)-trimethyl-8-hydroxy-ll(eq)-(CHgCHgCOR)-1,2,3,4,5,6hexahydro-2,6-methano-3-benzazocines, which are useful as analgesics and narcotic antagonists and having little or no morphine-like narcotic properties.

U.S. Patent 3,932,422 broadly discloses a variety of 3-^-6-(eq) ,ll'(ax)-dimethyl-8-hydroxy-ll (eq)-(CHgCHgCOR) l,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines, where R^ is a variety of substituents, including lower-alkyl, loweralkenyl, lower-alkynyl, cycloalkyl, cycloalkyl-lower-alkyl and phenyl-lower-alkyl or substituted-phenyl-lower-aIky1, and where R is, inter alia, lower-alkyl, phenyl or phenyl-loweralkyl. Although the patent makes the general statement that the compounds disclosed have narcotic antagonist properties, in fact every species for which supporting narcotic antagonist activity data are presented possess a cyclopropylmethyl group on the benzazocine nitrogen atom. This finding of narcotic antagonist activity in N-cyclopropylmethyl-substituted hexahydro-2, 6-methano-3-benzazocines is entirely consistent with what was then known in the art, because up to the present time the prior art has taught that potent narcotic antagonist activity can only be expected in compounds of the hexahydro2, 6-methano-3-benzazocine class by introduction of particular groups, other than methyl on the nitrogen atom, such groups including lower-alkenyl, halo-lower-alkenyl, cyclopropylmethyl -24 6 5 7 5 or cyclobutylmethyl (see for example U.S. Patents 3,250,678; 3,372,165; 3,345,373; and 3,514,463). This empirical rule which requires, for example, a lower-alkenyl group on the nitrogen atom for narcotic antagonist properties even carries over to the morphine class as evidenced by nalorphine and naloxone, i.e. N-allylnormorphine and N-allyl-7,8-dihydro-14hydroxynormorphinone, respectively, two well-known narcotic antagonists of the morphine type. Thus, until the present time, the finding of narcotic antagonist properties in any strong analgesic, including analgesics of the hexahydro-2,6methano-3-benzazocine class, having a methyl group on the nitrogen atom was highly unusual. For example, while Michne et al. J. Med. Chem. 20, 682 (1977) have found narcotic antagonist activity in one species of 3-methyl-hexahydro-2,6-methano-3benzazocine having a lower-alkyl carbinol side chain at the 11 (eq)-position, and while Ager et al., J. Med. Chem. 12., 288 (1969) reported a series of 3-methyl-2,6-methano-3-benzazocine3 which were from 2 to 20% as potent as nalorphine in the morphine-dependent monkey, theseN-methyl antagonists have relatively low potencies.

It has now been surprisingly found that certain species of 3,6(eq),11(ax)-trimethyl-8-hydroxy-ll(eq)-(CH^ CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines, where R represents certain selected lower-alkyl, pheny1-lower alkyl or cycloalkyl-lower-alkyl groups, and acid addition salts thereof, are highly potent narcotic antagonists. These compounds have the formula where R is pentyl, 3-methylbutyl, 2-phenylethyl, 2-cyclopropyl ethyl, 2-cyclobutylethyl or 2-cyclopentylethyl. The narcotic antagonist properties possessed by the above-identified specie are in marked contrast with properties of compounds homologous with them in the lower-alkyl portion of the R group, which com pounds possess precisely the opposite profile of activity in being strong analgesics with either no antagonist properties or in which such antagonist properties have been strongly diminished.

The compounds of Formula I are prepared either by the process described in U.S. Patent 3,932,422 which comprises heating, with formic acid in an organic solvent, for example, toluene, xylene or mesitylene, or with a benzyl-di-lower-alkyl ammonium formate or a tri-lower-alkylammonium formate, a 7-YO-l,5c<-trimethy1-3-COR-l,2,3,4,4a,5,10,lOa-octahydro2,5-methanobenzo[g]quinoline of Formula II: .. .II where Y represents hydrogen or lower-alkyl and R has the 20 meanings given above, followed by cleavage, with aqueous -44 6 5 7 5 hydrobromic acid or sodium propylsulfide as described below, of the lower-alkoxy group (Y-0) in the event that Y is loweralkyl .

Alternatively, and preferably, the compounds of 5 Formula I are prepared by a modification of the above process which comprises heating, with formic acid in an organic solvent, for example, toluene, xylene or mesitylene, or with a benzyldi-lower-alkylammonium formate or a tri-lower-alkylammonium formate, a lower-alkyl l,4a ...III where Y' represents lower-alkyl and R and Alk have the meanings given above as described in Patent Specification No. 45987. In the event that Y is lower-alkyl, one cleaves the lower-alkoxy group (Y-O) , such as with aqueous hydrobromic acid or sodium propylsulfide. When aqueous hydrobromic acid is used to effect cleavage, the reaction is carried out by refluxing a solution of the ether in aqueous hydro20 bromic acid and isolating the compound either directly from the reaction mixture in the form of the hydrobromide salt or from a neutral solution in the form of the free base. When sodium propylsulfide is used to cleave the ether, the reaction is carried out by refluxing a solution of the ether in an inert organic solvent, for example dimethylformamide (DMF), with -546S7S a molar excess of the sodium propylsulfide, which is prepared by addition of propanethiol to sodium hydride. It is preferred to use the starting material of Formula II or III where Y is lower-alkyl whereby the subsequent splitting of the ether is required.

The compounds of Formula II and methods for their preparation are disclosed in U.S. Patent 3,932,422. As described in Patent Specification No. 45987,the compounds of Formula III are prepared either by reacting a lower-alkyl l,4a0(,5<^-trimethyl-7-YO-l,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo [g]quinoline-3-carboxylate (Formula II where R is loweralkoxy) with an alkali metal amide, for example sodamide or lithium diisopropylamide, in an inert organic solvent and reacting the alkali metal salt thus formed with an appropriate acyl halide, R-CO-X, or by reacting a 1,4aqf,5(71“trimethyl-7-YO-3-RCOI, 2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline (Formula II, R has the meanings given above) with an alkali metal amide, as in the former alternative, and reacting the resulting alkali metal salt with a lower-alkyl halo formate.

Due to the presence of a basic amino group, the free base forms represented by Formula I above react with organic and inorganic acids to form acid-addition salts. The acidaddition salt forms are prepared from any organic or inorganic acid. They are obtained in conventional fashion, for instance either by direct mixing of the base with the acid or, when this is not appropriate, by dissolving either or both of the base and the acid separately in water or an organic solvent and mixing the two solutions, or by dissolving both the base and the acid together in a solvent. The resulting acid-addition salt is isolated by filtration, if it is insoluble in the -64 ® S ? $ reaction medium, or by evaporation cf the reaction medium to leave the acid-addition salt as a residue. The acid moieties or anions in these salt forms are in themselves neither novel nor critical and therefore can be any acid anion or acid-like substance capable of salt formation with the base.

All of the acid-addition salts are useful as sources of the free base forms, by reaction with an inorganic base.

It will thus be appreciated that if one or more of the characteristics, such as solubility, molecular weight, physical appearance, toxicity, or the like of a given base or acid-addition salt thereof render that form unsuitable for the purpose at hand, it can be readily converted to another, more suitable form. For pharmaceutical purposes, acid-addition salts of relatively nontoxic, pharmaceutically-acceptable acids, for example, hydrochloric acid, methanesulfonic acid, lactic acid, tartaric acid, and the like, are of course employed.

The compounds of this invention can exist in enantiomeric forms separable into enantiomers. If desired, the isolation or the production of a particular enantiomeric form can be accomplished by application of general principles known in the prior art. In the nomenclature employed for the compounds of Formula I herein, ax stands for axial and eq for equatorial, and the configurations are given with reference to the hydroaromatic ring. Thus, the 6(eq),ll(ax) compounds of Formula I are in the cis configuration, whereas the 6(eq),ll(eq) compounds are in the trans configuration.

The useful properties of the compounds of this invention were demonstrated by standard pharmacological procedures readily carried out by technicians having ordinary -74657S skill in pharmacological test procedures, so that the actual determination of the numerical biological data definitive for a particular test compound can be ascertained without the need for any extensive:experimentation.

The test procedures used to determine the analgesic and narcotic antagonist activities of the compounds of the invention have been described in detail in the prior art and are as follows: The acetylcholine-induced abdominal constriction test, which is a primary analgesic screening test designed to measure the ability of a test agent to suppress acetylcholineinduced abdominal constriction in mice, described by Collier et al. Brit. J. Pharmacol. Chemotherap. 32, 295 (1968); a modification of the anti-bradykinin test, which also is a primary analgesic screening procedure, described by Berkowitz et al., J. Pharmacol. Exp. Therap. 177, 500-508 (1971), Blane et al., J. Pharm. Pharmacol. 19, 367-373 (1967), Botha et al., Eur. J. Pharmacol. 6, 312-321 (1969) and Deffenu et al., J. Pharm. Pharmacol. 18, 135 (1966); the phenyl-js-quinone-induced writhing test, also a primary analgesic screening test, designed to measure the ability of a test agent to prevent phenyl-p-quinoneinduced writhing in mice, described by Pearl and Harris, J. Pharmacol. Exp. Therap. 154, 319-323 (1966); the rat tail flick radiant thermal analgesic (agonist) test described by D'Amour and Smith, J. Pharmacol, Exp, Therap. 72, 74 (1941) as modified by Bass and VanderBroOk, j. Am. Pharm. Assoc. Sci. Ed. 41, 569 (1956); the narcotic antagonist tests (e.g. phenazocine, morphine and meperidine antagonist tests), which are designed to measure the ability of a test agent to antagonize the effect of phenazocine, morphine or meperidine in the above-indicated rat tail flick agonist test, described by Harris and Pierson, J. -8•16 5 ? S Pharmacol. Exp. Therap. 143, 141 <.1964)? and the Straub tail test described by Straub, Dtsch. med. Wochr. (1911), page 1426 and Aceto et al., Brit. J. Pharmacol. 36, 225-239 (1969), which is an observational test which, if positive, lends support to a conclusion of morphine-like narcotic properties.

The structures of the compounds of this invention were established by the modes of synthesis, by elementary analyses and by ultraviolet, infrared and nuclear magnetic resonance spectra. The course of reactions and the homogeneity of the products were ascertained by thin layer chromatography.

Example 1 A solution of 27.5 g. (0.064 mole) of ethyl 1,4a >,5 trimethyl-7-methoxy-3-hexanoyl-l,2,3,4,4a,5,10,lOa-octahydrσ2, 5-methanobenzo [g]quinolme-3-carboxy late in 275 ml. of mesitylene and 37 ml. of 98% formic acid was heated under reflux for twenty-four hours with stirring and then taken to dryness in vacuo. The oily residue was triturated with 200 ml. of water, basified to pH 10 with concentrated ammonium hydroxide and the mixture extracted with diethyl ether. The organic extracts, on washing with water, then with brine, drying over anhydrous sodium sulfate and evaporation to dryness afforded 30 g. of a residue which was treated with a solution of 6.0 g. of oxalic acid in 50 ml. of ethanol. There was thus obtained 27 g. of 3,6(eg),11(ax)-trimethyl-8-methoxy-ll(eq)- (3-oxooctyl)-1,2,3,4,5,6hexahydro-2,6-methano-3-benzazocine oxalate, m.p. 95-97°C.

A solution of 1.9 g. (0.0047 mole) of the latter in the form of the hydrochloride salt in 25 ml. of 48% hydrobr'.·. extracts to dryness and conversion of the residual solid to the hydrochloride salt with ethereal hydrogen chloride afforded 2.5 g. of crude material which was recrystallized from isopropanol to give 1.7 g. of 3,6(eg),11(ax)-trimethyl5 8-hydroxy-ll(eq)- (3-oxooctyl)-1,2,3,4,5,g-hexahydro-2,6methano-3-benzazoclne hydrochloride, m.p. 252-255°C, A small sample of the hydrochloride salt was reconverted to the base and the latter converted to the methanesulfonate having m.p. 178-179°C. (from acetone).

Another sample was converted to the 2-naphthalenesulfonate, m.p. 195-198°C. (from methanol/diethyl ether).

Following a procedure similar to that described in Example 1, the following compounds of Formula I were similarly prepared.

Example 2 3,6(eg),11(ax)-Trimffthyl-8-hydroxy-ll(eq)- (3-oxo-6-methylheptyl)l, 2,3,4,5,g-hexahydro-2,g-methano-3-benzazocine hydrochloride, m. p. 260-253°C. (3.6 g., from isopropanol) prepared by heating .0 g. (0.045 mole) of ethyl l,4ao(, 5a£-trimethyl-7-methoxy-320 (4-methylpentanoyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo [g]quinoline-3-carboxylate in 1 liter of mesitylene and 70 ml. of formic acid to give 17.8 g. of 3,6(eq),ll(ax)-trimethyl-8-methoxy-ll(eg)- (3-oxo-6-methylheptyl)-1,2,3,4,5,6-hexahydro-2,5-methano-3-benzazocine hydrochloride (m.p. 222-229°C. from diethyl ether, and cleavage, with 40 ml. of 488 hydrobromic acid, of 4.0 g..(0.0098 mole) of the latter.

A sample of the free base was isolated from the hydrochloride salt, and the base converted to the corresponding methanesulfonate having m.p. 189-191°C. (from acetone/diethyl ether). -104 6 5 7 5 Example 3 3,6(eg),11(ax)-Trimethy1-8-hydroxy-11(eq)-(3-oxo-5-phenylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine methanesulfonate, m.p. 233-235°C. (1.6 g., from ethanol), prepared by heating 26.2 g. (0.055 mole) of ethyl l,4az?i,5qtrimethyl-7-methoxy-3-(3-phenylproplonyl)-1,2,3,4,4a,5,10,10aoctahydro-2,5-methanobenzo[g]quinoline-3-carboxylate in a solution of 990 ml. of mesitylene and 41.5 ml. of formic acid to give 3,6(eq),11(ax)-trimethyl-8-methoxy-ll(eq)-(3-oxo-5~ phenylpentyl)-1,2,3,4,5,6-hexahydrc-2,6-methano-3-benzazoclne p-toluenesulfonate, m.p. 176-179°C., and cleavage of 3.1 g. (0.02 mole) of the free base corresponding to the latter with 81 ml. of 48% aqueous hydrobromic acid.

Example 4 ’ 3,6(eg),11(ax)-Trimethyl-8-hydroxy-ll(eg)-(3-oxo-5-cyclopropyl~ pentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 128-130°C. (0.9 g., from ethyl acetate/hexane), prepared by heating 14.9 g. (0.034 mole) of ethyl 1,4a^,5 6.2 g. of 3,6(eg),ll(ax)-trimethyl-8-methoxy-ll(eq)-(3-oxo5-cyclopropylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3benzazocine, m.p. 224-226°C. (from ethanol/diethyl ether) and cleavage of the latter with 0.065 mole of sodium propylsulfide (prepared by adding 2.7 g. of a 50% dispersion of sodium hydride in mineral oil to 5.9 ml. of propanethiol) 1/. ml. of dimethylformamide (DMF).

A sample of the free base was converted to the hydrochloride salt to give material having m.p. 271-273’C. 114©g?S(from ethanol/diethyl ether).

Example 5 3,6(eq),11(ax)-Trimethyl-8-hydroxy-ll(eq)-(3-oxo-5-cyclopentylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine sulfate, m.p. 230-235°C. (4.8 g., from ethanol) prepared by heating 43.7 g. (0.094 mole) of ethyl l,4ac(,5if-trifflethyl-7methoxy-3-(3-cyclopentylpropiony1)-1,2,3,4,4a,3,10,1Oa-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate in a solution of 35.3 ml. of formic acid in 437 ml. of mesitylene to give 19.5 g. of 3,6(eg),11(ax)-trlmethyl-8-methoxy-ll(eq)-(3-oxo5-oyclopentyIpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3benzazocine hydrochloride, m.p. 219-223°C. (from ethanol/diethyl ether) followed by cleavage of 12.7 g. of the latter with 127 ml. of 48% hydrobromic acid.

Example 6 A. Ethyl 7-methoxy-l, 4,ag,5,ot-trimethyl-3-(3-cyclobutyl-loxopropyl)-1,2,3,4,4a,5,10,lOa-octahydro-2,S-methanobenzo[g] quinollna-3-carboxylate (12.4 g., 26%, m.p. 121-123’C. from hexane) was prepared by reaction of 36.0 g. (0.105 mole) of ethyl 7-methoxy-l,4a i,5 t-trimethyl-l^fS^^a^ilOjlOa-octahydro^jS-methanobenzoEglquinoline-S-carboxylate with 0.115 mole of lithium diisopropylamide followed by reaction of the resulting salt tilth 7.7 g. (0.052 mole) of ec-cyclcbutanepropionyl chloride.

B. A solution of 12.4 g. (0.027 mole) of the product was boiled vzith 50 ml. of trimethylammonium formate for twenty minutes using the procedure described above .

The product was isolated in the form of the methanesulfonate vzhich was recrystallized from acetone/diethyl ether to give 8.3 g. of 3,6(eg),11(ax)-trlmethyl-8-methoxy-ll(eq)-(3-oxo-5-124 6 5 7 5 cyclobutylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocins methanesulfonate, m.p. 153-155°C.

The latter ¢5.5 g., 0.012 mole) was cleaved with ml. of 48% hydrobromic acid and the product isolated in the form of the hydrochloride salt to give 3.9 g. of 3,6 (aq),11 tax)tnmethy 1-8-hydroxy-ll(eq)- (3-oxo-5-cyclobutylpentyl)-1,2,3,4,5,6hexahydro-2,6-methano-3-benzazocine hydrochloride, m.p. 271-275'C. For purposes of comparison with the claimed species, a series of reference compounds, generally described in U.S.

Patent 3,932,422, were prepared using the procedures described above as follows: Reference Compound 1: 3,6(eq),11(ax)-trimethyl~8~hydroxy11(eq)-(3-oxopentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3benzazocine (R is CgH^)’ Reference Compound 2: 3,6(eq),11(ax)-trimethyl-8-hydroxy11(eq)- (3-oxohexyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3benzazocine hydrochloride [R is (CHg)gCH3J; Reference Compound 3: 3,6(eq),11(ax)-trlmethy1-8-hydroxy-il(eqj(3-oxoheptyl)-1,2,3,4,5,6-hexahydro-2,6-methano~3~benzazceine hydrochloride [R is (CHg^CHg]; Reference Compound 4: 3,6(eq),11(ax)-trimethyl-8-hydroxy11(eq)-(3-oxononyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzaiocine [R is (CHg)gCHg]; Reference Compound 5: 3,6(eq) ,11(ax)-trimethyl-3-hydroxy-ll teci(3-oxo-5-methylhexyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3~ benzazocine hydrochloride [R is (CHgCH (CHg) g] ; Reference Compound 6: 3,6(eq),11(ax)-trimethyl-8-hydroxy-ll(eq,(3-oxo-7-methyloctyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3benzazocine [R is (CHg)3CH(CH3)g]? Reference Compound 7: 3,6(eq),11(ax)-trimethyl-8-hydroxy-ll(eq)-134 © 5 7 S (3-oxo-3-phenylpropyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3benzazocine (R is CgHg); and Reference Compound 8; 3,6(eq),11(ax)-trimethyl-8-hyroxy-ll(eq)- (3 oxo-4-phenylbutyl )-1,2,3,4,5,6-hexahydro-2,6-fliethano-3“benzazocine msthane5 sulfonate (R is CH_C,.Hc) . zoo BIOLOGICAL TEST RESULTS Data obtained on the compounds of the invention, identified by the example numbers above where their preparations are described, and the reference compounds, identified by the reference numbers indicated above, are given in the table below. The abbreviations Ach, BK, PPQ, Phen, Mor, Mep, T.F. Ag and Straub represent, respectively, the acetyl choline-induced abdominal constriction test, the anti-bradykinin test, the phenyl-p-quinone-induced writhing test, the phenazocine, morphine and meperidine tail flick antagonist tests, the tail flick agonist test and the Straub test. Results are expressed either in terms of the EDgg (mg./kg.) for the Ach, BK, PPQ and T.F. Ag. tests or the ADgg for the Phen, Mor and Mep tests or in terms of percent inhibition. The letter I designates inactive, and unless noted otherwise all results were obtained on subcutaneous administration. All doses are expressed in milligrams per kilogram (mg./kg.). -144 6 S3 7 © © CT CO <73 Ο Ο Ο Ο ο ο ό ο ο <Μ Ο Η <Μ •δ* ιΛ Ο Ο Ο I*» Ο Ο OfCOOCMCMOO 1 CM kD V Ο IfMrlCMCMj-IHkpn© rl Ο CM CM — HO ## JK.

Tf ko <§<<> H · W W dP dP dPH Γ* rl n\ \o *r n ri h in ι l t · r4 C II I I I I I till ο ο ,-ί §> Α Α -8 • Ο ' co 0 “} ά, © *-· I (III θ β'-Η Tf n — © © co • CM ·Χ · CO Tf 5 O H © 1-1 . σ\ η ττ in o CM rl © ©OOCO H °. Ώ&ω3 | C Η Κ ® I o cJ o po „ά co Η Γ· , , ©•II * CM © ft 0 σ\ cm ^n · rl rl **· Q, © © Γ* © **·” < * » » rl © © © © rl ci σ\ cm ·—' r-i co l> I CM © © · C M* Qj © rl CM I CM XO O <<#>«♦ O © © rl CM CO CM © o in on © ο κ © • CM * · · · · · · · · ;OO(NO(NCOrlOOMOin © rl © © CM CM © Cl t*» Qj Qj rl CM rH & n O ι Ο O kD CM kD CM H kO Tf co A?S con n n*-* CM cv-> ten © $, % Wr J- logjg *w §iO v in HH CM l0 tt I δ in •15· The tail flick agonist activities of each of Reference Compounds 1, 2, 3, 5 and 7 were prevented in each case by 1.0 mg./kg. (s.c.) of nalorphine, while the same activity of the compound of Example 2 (hydrochloride) was partially prevented by 1.0 mg./kg. (s.c..) of nalorphine. These results indicate that Reference Compounds 1, 2, 3, 5 and 7 are narcotic like, an indication which is further supported by the observation of the Straub tail reaction in each of these species at relatively low doses. The data with respect to the species of Example 2 indicate that, whereas the compound is a strong antagonist as evidenced by activity in each of the narcotic antagonist tests (pentazocine, morphine and meperidine), it nevertheless possesses weak agonist activity in the tail flick agonist test and therefore is indicated to have a degree of morphine-like activity. This latter indication is further evidence by the observation of the Straub tail reaction at a dose level above the effective antagonist doses.

In general the above data show remarkable differences in properties between each of the selected species of this invention and their higher and lower homologs. Thus each of Reference Compounds 1-3, which are lower homologs of the species of Example 1, are shown to be agonists with no antagonist properties evident, whereas the compound of Example 1 is shown to be a strong antagonist in all antagonist tests and is completely inactive as an agonist, although its higher homolog, Reference Compound 4, also shows a profile of activity as an antagonist, the latter is only one-fifth as active as the compound of Example 1 in the phenazocine antagonist test and is only one-fiftieth as active in the acetylcholine and anti-bradykinin tests. -16Similarly, the compound of Example 2 shows very weak agonist activity but strong antagonist activity in all three antagonist tests, while its lower homolog, Reference Compound 5, has precisely the opposite spectrum of activi ty, the latter being active in the tail flick agonist test but inactive in the phenazocine antagonist test. As in the case of the comparison between the compounds of Example 1 and Reference Compound 4, Reference Compound 6, the next higher homolog of the species of Example 2, shows a profile of activity as an antagonist, being inactive in the tail flick agonist test and active in the phenazocine antagonist test. The compound however is from about sixty to one-hundred times less active in the acetylcholine test.

In the case of the compound of Example 3 as compared to its lower homologs, Reference Compounds 7 and 8, the very strong agonist or narcotic-like properties of Reference Compound 7 is totally reversed in the second higher homolog, i.e. the compound of Example 3, which is indicated by the data to be a pure antagonist.

The compounds of Examples 4 and 5, which are not homologous with any presently known compounds where R is cycloalkyl-lower-alkyl, are likewise shown by the data to be antagonists, except that, like the species of Example 2, they also have very weak agonist or narcotic-like properties as shown by the tail flick agonist test and by the observation of the Straub tail reaction which is found at high doses.

The invention also deals with a novel species of Formula I where R is methyl found useful as a narcotic analgesic.

Example 7 3,6(eq),11(ax)-Trimethyl-8-hydroxy-ll(eq)- (3-oxobutyl)-1,2,3,4,5,6hexahydro-2,6-methano-3-benzazoclne was also prepared aa follows: -1740575 A solution of 57.1 g. (0.14 8 mole) of ethyl l,4ao<, Sffb trime thyl7-methoxy-3-acetyl-l,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo [g]quinoline-3-carboxy late in a solution containing 72.5 ml. of formic acid and 571 ml. of mesitylene vzas heated under reflux for five hours, cooled, basified by the addition of excess aqueous sodium hydroxide and extracted with ether. The combined ether extracts were washed with water, then with brine, dried, filtered and taken to dryness in vacuo and the residue steam distilled. The material remaining after steam distillation was extracted again with ether, the ether extracts washed with water, then with brine, dried, filtered and evaporated to dryness to give 42.4 g. of crude product which was converted to the hydrochloride salt. There was thus obtained 6.6 g. of 3,6(eg),11(ax)-trimethyl-8-methoxy-ll(eg)-(3-oxobutyl)-1,2,3,4,5,6hexahydro-2,6-methano-3-benzazocine hydrochloride, m.p. 182.5187.5°C.

The latter (5.8 g., 0.0018 mole) was cleaved by refluxing for two hours in a solution of 58 ml. of 48¾ aqueous hydrobromic acid. The product was isolated in the form of the free base which was recrystallized from ethanol to give 1.3 g. of 3,6(eg),11(ax)-trimethyl-8-hydroxy-ll(eq)-(3-oxobutyl)1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 170-173°C.

A sample of the free base was converted to the methanesulfonate to give material having m.p, 265-268°C. (from ethanol).

Data obtained in the acetylcholine-induced abdominal constriction (Ach), anti-bradykinin (BK), phenyl-p-quinoneinduced writhing (PPQ), tail flick phenazocine antagonist (Phen), tail flick agonist (T.P. Ag) and Straub tail tests on the latter species are set forth in Table 2 where, as -184657S before, doses are expressed in milligrams per kilogram, and unless noted otherwise, data were obtained on subcutaneous administration.

Table 2 Compound R_Ach_BK_PPQ Phen T.F. Ag Straub base CH0.25 CHgSOgH CH, 0.17 1004/0.5 0.19 1/40 70%/60 0.21 2.5 1.5 16(p.o.) 19(p.o.) These data indicate that this species is an analgesic 10 having narcotic properties as evidenced by the finding of inactivity in the phenazocine antagonist test and the finding of agonist activity in the tail flick agonist test and the further observation of Straub tail reaction.

The tail flick agonist activity of the compound is 15 not prevented by nalorphine at 1.0 mg./kg. (s.c.) or naloxone at 0.1 mg./kg. (s.c.). This lack of sensitivity of the subject compound to narcotic antagonists demonstrates an unusual pharmacological profile. On the other hand, the tail flick agonist activity of morphine is completely reversed by the same 20 doses of these narcotic antagonists.

Claims (14)

CLAIMS:

1. Λ compound having the Formula I herein where R is methyl, pentyl, 3-methylbutyl, 2-phenylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl or 2-cyclopentylethyl; or an acid5 addition salt thereof.

2. 3,6{eq1, 11(ax)-Trimethyl-8-hydroxy-ll(eq>-( 3oxooctyl)-1,2,3,4,5,6-hexahydro-2,5-methano-3-benzazocine.

3. 3,6(eq), 11 (ax) -Tnmethyl-8-hydroxy-ll (eq) - (3-oxo6-methylheptyl)-1,2,3,4,5,6-hexahydro-2,6-methano-310 benzazocine.

4. 3,6(eq), 11(ax)-Trimethyl-8-hydroxy-ll(eq)-(3-oxo5-phenylpenty1)-1,2,3,4,5,C-hexahydro-2,C-methano-3benzazocine,

5. 3,6(eq), 11(ax)-Trimethyl-8-hydroxy-ll(eq)-(3-oxo15 5-cyclopropylpenty1)-1,2,3,4,5,C-hexahydxo-2,6-met.hano-3benzazocine.

6. 3,5(eq), 11(ax)-Trimethyl-8-hydroxy-ll(eq)-(3-oxo5-cyclopentylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3benzazocine. 20

7. 3,6(eq), 11(ax)-Trimethyl-8-hydroxy-ll(eq)-(3-oxo5-cyclobutylpentyl)-1,2,3,4,5,C-hexahydro-2,6-methano-3benzazooine.

8. 3,6(eq), 11(ax)-Trimethyl-8-hydroxy-ll(eq)- (3oxobutyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.

9. A process for preparing a compound according to any one of the preceding claims, which comprises heating,- with formic acid in an organic solvent or with a benzyl-di-loweralkylarnmonium formate or a tri-lower-alkylammonium formate, a compound having the Formula II (herein) where Y is hydrogen or lower-alkyl and, when Y is lower-alkyl, cleaving the lower-alkoxy group in the resulting 3,6(eq), 11(ax)-trimethyl8-lower-alkoxy-ll(eq)-(C^CHgCOR)-1,2,3,4,5,6-hexahydro2.6- methano-3-benzazocine.

10. A process for preparing a compound according to any one of claims 1-8, which comprises heating, with formic acid ir. an organic solvent or with a benzyl-di-iowar-aiky1ammonium formate or a tri-lower-alkylammonium formate, a compound having the Formula III (herein) where Y is hydrogen or lower-alkyl and Alk' is lower-alkyl, and, when Y is loweralkyl, cleaving the lower-alkoxy group in the resulting 3,6(eq), ll(ax)-trimethyl-8-lower-alkoxy-ll(eq)-(CH 2 CH 2 COR)1.2.3.4.5.6- hexahydro-2,6-methano-3-benzazocine.

11. A process according to claim 9 or 10, which includes converting a compound obtained in the free base form to an acid-addition salt thereof.

12. A process for preparing a compound according to claim 1, substantially as herein described with reference to the Examples.

13. A compound when prepared by the process according to any one of claims 9-12.

14. A compound according to claim 1, substantially as herein described. F. R. KELLY & CO. AGENTS FOR THE APPLICANTS