CA1097630A - 2,6-methano-3-benzazocines - Google Patents
2,6-methano-3-benzazocinesInfo
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- CA1097630A CA1097630A CA298,735A CA298735A CA1097630A CA 1097630 A CA1097630 A CA 1097630A CA 298735 A CA298735 A CA 298735A CA 1097630 A CA1097630 A CA 1097630A
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- methano
- hexahydro
- trimethyl
- hydroxy
- benzazocine
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Abstract
ABSTRACT OF THE DISCLOSURE
3,6(eq),11(ax)-Trimethyl-8-hydroxy-11(eq)-(CH2CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines, where R
represents certain selected lower-alkyl, phenyl-lower-alkyl or cycloalkyl-lower-alkyl groups, and acid addition salts thereof, are highly potent narcotic antagonists. Such compounds and related compounds containing 7,8,9 or 10-hydroxy-substitution can be prepared by cleaving the corresponding ethers having a lower-alkoxy substituent in that position.
3,6(eq),11(ax)-Trimethyl-8-hydroxy-11(eq)-(CH2CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines, where R
represents certain selected lower-alkyl, phenyl-lower-alkyl or cycloalkyl-lower-alkyl groups, and acid addition salts thereof, are highly potent narcotic antagonists. Such compounds and related compounds containing 7,8,9 or 10-hydroxy-substitution can be prepared by cleaving the corresponding ethers having a lower-alkoxy substituent in that position.
Description
763~
This invention relates to certain selected 3,6(eq),-ll(ax)-tximethyl-~-hydroxy-ll(eq)-(CH2CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines, which are use~ul as analgesics and narcotic antagonists and having little or no morphine-like narcotic properties.
UOS. Patent 3,932,422 broadly discloses a variety of 3-Rl-6-(eq),ll(ax)-dimethyl-8-hydroxy-ll(eq)-(CH2CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3~enzazocines, whexe Rl is a variety of substituent3, including lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl, cycloalkyl-lower-alkyl and phenyl-lower-alkyl or substituted-phenyl-lower-alkyl, and where R is, inter alia, lower-alkyl, phenyl or phenyl-lower-alkyl. Although the patent makes the general ~tatement that the compounds disclosed have narcotic antagonist properties, - lS in fact every species for which supporting narcotic antagonist activity data are presented possess a cyclopropylmethyl group on the benzazocine nitrogen atomO Thi~ finding of narcotic antagonist activity in N-cyclopropylmethyl substituted hexa~
hydro-2,6-methano-3 benzazocines is entirely consistent with wha~ was then known in the art, because up to the present time the prior art has taught tha~ potent narcotic antagonist activity can only be expected in compounds of the hexahydro-
This invention relates to certain selected 3,6(eq),-ll(ax)-tximethyl-~-hydroxy-ll(eq)-(CH2CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines, which are use~ul as analgesics and narcotic antagonists and having little or no morphine-like narcotic properties.
UOS. Patent 3,932,422 broadly discloses a variety of 3-Rl-6-(eq),ll(ax)-dimethyl-8-hydroxy-ll(eq)-(CH2CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3~enzazocines, whexe Rl is a variety of substituent3, including lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl, cycloalkyl-lower-alkyl and phenyl-lower-alkyl or substituted-phenyl-lower-alkyl, and where R is, inter alia, lower-alkyl, phenyl or phenyl-lower-alkyl. Although the patent makes the general ~tatement that the compounds disclosed have narcotic antagonist properties, - lS in fact every species for which supporting narcotic antagonist activity data are presented possess a cyclopropylmethyl group on the benzazocine nitrogen atomO Thi~ finding of narcotic antagonist activity in N-cyclopropylmethyl substituted hexa~
hydro-2,6-methano-3 benzazocines is entirely consistent with wha~ was then known in the art, because up to the present time the prior art has taught tha~ potent narcotic antagonist activity can only be expected in compounds of the hexahydro-
2,6-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 ' .. .
., ,. , . .. - :
Q
or cyclobu~ylme~hyl (see for example U.S. Patents 3,250,678;
., ,. , . .. - :
Q
or cyclobu~ylme~hyl (see for example U.S. Patents 3,250,678;
3,372,165; 3,345,373; and 3,514,463). This empirical rule which re~uires, 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-14-hydroxynormorphinone, respectively, two well-known narcotic antagonists of the morphine type. Thus, until the present time, the finding of narcotic antagonist yroperties in any strong analgesic, including analgesics of the hexahydro-2,6-methano-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 o~ 3-methyl-hexahydro 2,6-methano-3-benzazocine having a lower-alkyl carbinol side chain at the ll(eq)-position, and while Ager et al., J. Med. Chem. 12, 288 (1969) reported a series of 3-methyl-2,6-methano-3-benzazocines 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)-(CH2 CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines, where R represents certain selected lower-alk~l, phenyl-lower-alkyl or cycloalkyl-lower-alkyl groups, and acid addition salts thereof, are highly potent narcotic antagonists. These compounds have the ~ormula .3_ .
, ' ' ' ~ :
f~
rio ~ ~ ~ R
where R i~ methyl, pentyl, 3-methylbutyl, 2-phenylethyl, 2-ayclopropylethyl, 2-cyclobutylethyl or 2-cyclopentylethyl.
The narcotic antagonist pr~pexties possessed by the above-identified specie~ are in marked contrast with propertie~ ofcompounds homologous with them in the lower-alkyl portion of the R group, which compounds p~ precisely the opposite p~ofile of activity in being ~trong ~nalgesics with either no antagoni~t properties or in which su~h antagonist properties have been strongly dimi~l6hed.
~ he compound~ of Formula I are prepared eithex by the method described in U.5. Patent 3,932,422 which compri~es heating, with formic acid in an orgRnic solvent, for example, toluene, xylene or me~itylene, or with a benzyl~di-lower-alkyl-ammonium ~orma~e or ~ txl-lower-alkylammonium formate, a 7-YO-1,4aa,5~-trimethyl-3 COR-1,2,3,4,4~,5,10,10a~octahydr~-2,5-me~hanobenzo[g]quinoline of Formula II:
~H3 Y-O ~ ~ ~`~ ~ 01~
~ H3 3 ...II
whera Y represents hydrogen or lower-alkyl and R has the ~0 meanin~6 given above, followad by ~leavage, with aqueous , . .~ ~ ..
~' .......
-- . ..
.
&~
hydrobromlc acid or sodium prop~lsulfide a~ described below, 7 of the lower-alkoxy group (~-0) in the event that Y i~ 107,7er-.1 alkyl.
Alternatively, and preferably, the compounds of Formula I are prepared by a modification of the above process which comprises heatiny, with formic acid in an organic solvent, for example, toluene, xylene or mesitylene, or with a benzyl-di-lower-alkylammonium formate or a tri-lower-alkylammonium formate, a lower~alkyl 1,4a~,5~-trimethyl-7-Y0-3-RC0-1,2,3,4,-4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate having the Formula III:
COOAlk ' y . . . III
where ~' represents lower-alkyl and R and have the meanings given above as described in ApplicationNo. 2861472 filedSeptember 19,1~7. In~heeVent that Y is lower-alkyl, one cleaves the lower-alkoxy group t -0), such as with aqueous hydrobromic acid or sodium propylsulfide. When aqueous hydro-bromic acid is used to effect cleavage, the reaction is carried out by refluxing a solution of the ether in aqueous hydro-bromic acid and isolating thP compound either directly from thereaction 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 i5 carried out by refluxing a solution of the ether in an inert organic solvent, for example dimethylformamide (DMF), with _5_ ' , - "' i , , ,,' ~ ' .
7$~
a molar excess of the ~odium propylsul~ide, whlch is prepared by addition of propanethiol to sodium hydrldeO It is preferred to use the starting material of Formula II or III where Y is lower-alkyl whereby the subsequent splitting o~ ether is re-qulred.
The eompounds of Formula II and methods for their preparation are disclosed ln U.S. Patent 3,932,422. As (7242c) described in Patent Application ~ ~ the compounds of Formula III are prepared either by reacting a lower-alkyl 1,4a~,-50ttrimethyl-7~Y0-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanO-benzo[g]quinoline-3-carboxylate (Formula II where R is lower-alkoxy) with an alkali metal amide, Eor example sodamlde or lithium diisopropylamide, in an inert organic solvent and re-acting the alkali metal salt thus formed with an appropriate acyl halide, R-C0-X, or by reacting a 1,4a~,5c~trimethyl-7-Y0-3-RC0-1,2,3,4,4a,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 resuliing alkali metal salt with a lower-alk~l halo ormate.
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 acid-addition salt forms are prepared from any organic or inorganic acid. They are obtained in conventional fashion, for instance either by direck mixing of the base ~ith the acid or, when this is not appropriate, by dissolving either or both of the bace and the acid separately ln water or an organic solvent and mixing the two solutions, or by dissolving both the base and the aeid together in a solvent. The resulting acid-addition salt is isolated by ~iltration, if it is insoluble in the .
.
, r~action medium, or by evaporation of the reactlon medium to leave the acid-addition salt as a residue. The acid moieties or anions ~n 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 use~ul as sources of the free base forms, by reaction with an inorganlc base.
It will thus be appreciated that l~ one or more o~ the character-istics, such as solubility, molecular weight, physical appearance,toxicity, or the like of a given ~ase or ac~d-addition salt thereof render that form unsuitabl2 ~or the purpose at hand, it can be readily converted to another, more suitable form. For pharmaceutical purposes, acid-addition salts o~ relatively non-toxic, pharmaceutically-acceptable acids, for example, hydro-chloric acid, methanesulfonic acid, lactic acid, tartar1c acid, and the like, are of course employed.
The compounds of this invention can exist in enantio-meric forms separable into enantiomers. I~ desired, the iso-lation or the production of a particular enantiomeric ~ormcan be accomplished by application of general princlples 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 con~igurations are given with reference to the hydroaromatic ring. Thus, the 6~eq),ll(ax) compounds of Formula I are in the cis conflguration, whereas the 6(eq),ll(eq) compounds are in the trans con~iguration.
The useful propertles of the compounds of this in-vention were demonstrated by s~andard pharmacological pro-cedures readily carried out ~y technicians having ordinary --7~
7~3~
skill in pharmacologlcal test procedures, so that the actua~
determination of the numerical biological data de~initlve or a particular test compound can be ascertained without the need for any extensive experimentation.
~he test procedures used to determlne the analgesic and narcotic antagonist activities of the compounds of the invention have been described in detail in the prlor art and are as follows: The acetylchollne-induced abdominal constriction test, which is a primary analgesic screening test designed to measure the ability of a test agent to suppress acetylcholine-induced abdominal constriction in mice, described by Collier et al. Brit. JO Pharmacol. Chemotherap. 32, 295 tl968); a modi-fication of the anti-bradykinin test, which also ts a primary analgesic screening procedure, described by Berkowltz et al~, J. Pharmacol. Exp. Therap. 177, 500-508 (1971), Blane et al., J. Pharm. Pharmacol. 19, 367-373 (1967), Botha et ai., Eur. J
Pharmacol. 6, 312-321 (1969~ and Deffenu et al., J. Pharm.
Pharmacol. 18, 135 (1966); the phenyl-p-quinone-induced writhing test, also a primary analgesic screenlng test, designed to measure the ability of a test agent to prevent phenyl-_-quinone-induced writhing in mice, d~scribed ~y 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 VanderBrck, J. Am. Pharm. Assoc. Sci. Ed.
41, 5Ç9 ~1956); the narcotic antagonist tests (e.g. phenazocine, morphine and meperidine antagonist t~sts), whtch are designed to measure the ability of a test agent to antagonize the effect of phenaæocine, morphine or meperidine in the above lndicated rat tail flick agonist test, described by Harris and Pierson, J.
:
7~3~
Pharmacol. Exp. TheraP. 143, 141 (19~4); 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 reaction~ and the homoyeneity of the products were ascertained by thin layer chromatography.
Example 1 A solution of 27.5 g. (0.064 mole) of ethyl 1,4arr,5~, trimethyl-7-methoxy-3-hexanoyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate in 275 ml. oE
mesitylene and 37 ml. of 98% ormic acid was heated under reflux for twenty-four hours with stlrring and then taken to dryness ln 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 af~orded 30 g. o a residue which was treated with a solution of 6.0 g. of oxalic acid in 50 ml. o ethanol. There was thus obtained 27 g. of 3,6(eq),1~x)-trimethyl-8~methoxy-ll(eq)-t3-oxooct~)-1,2,3,4,5l,6 hexah~dro-2c6-methano-3-benzazocine oxalate, m.p. 95-97C.
A solution of 1.9 g. (0.0047 mole) of the latter in the form of the hydrochloride salt in 25 ml. of 48% hydrobromic acid was heated under reflux for two hours, concentratPd to dryness in vacuo, and the residue made basic with aqueous alkali and extracted with diethyl ether. Concentration o the ether g_ 7~3~3 extracts to dryness and conver~lo~ o the -~esidual solld ~o the hydrochloride salt: with ethereal hydrogen chlorlde afforded 2.5 g. of crude material wh~ch wa5 recr~gtallized from isopropanol to give l.7 g. cf 3,6~e~),11~ax)--trlmethyl-~ droxy-ll(eq)-(3-oxooctyl~-~1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazoclne hydrochloride, m.p. 252-25rC.
A small sample of the hydrochlorlde salt was re-converted to the base and the latter converted to the methane-sulfonate having m.p. 178-179C. (from acetone)O
Another sample was converted to the 2-naphthalene-sulfonate, m.p. 195-198C~ (from methanolfdiethyl ether).
Following a procedure similar to that described in Example 1, the following compounds of FormulaIwere~lmilarly prepared.
Example 2 3,6(eq),11(ax)-Trimethy~8~hydrox~ eq3-~3-oxo-6-meth~lhep~yl)-1,2,3,4,5,6-hexahy_ro-2,6-methano-3-benzazocine hydrochlorlde, m.p. 260-263~C. (3.6 g., from isopropanol~ prepared by heatiny 20.0 g. (0.045 mole) of ethyl 1,4a~,50~trimethyl-7~methoxy-~
t~-methylpentanoy~ 2~3,4~4a~5~lo~loa-octahydro-2~5~methan benzo[g]quinoline-3-carboxylate in 1 liter o~ mesityl~ne and 70 ml. of formic acid to give 17.8 g. o~ 3,6(eq~,11(ax~-tri-methyl-8-methoxy~ll(eq3-~3-oxo-6-methylheptyl)-1,2!3,4,5,6-h~xa--hydro-2,6-methano-3~benzaæoclne hydrochloride (m.p 222-229~C~
from diethyl ether) and cleavage, with 40 ml. of 48~ hydrobromic acid, of 400 g. (0.0098 moie~ of the latter.
A sample of the free base was iso~ated ~rom the hydrochloride ~alt~ and the base converted ~o ~he corresponding methanesulfonate having mOp. 189-l91~C. ~from acetone,~dieth~tl ether).
3~
Example 3 3,6(eqL,ll(ax)-Trimethyl-8-hyd~ox~-ll(eq~~(3 oxo-5-phenyl-pentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine methanesulfonate, m.p. 233-235C. (1.6 g., from ethanol), prepared by heating 26.2 g. (0.055 mole) of ethyl 1,4a~,5~-trimethyl-7-methoxy-3-(3-phenylpropionyl)-1,2,3,4,4a,5,10,10a-octahydro-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-hexahydro-2,6-methano-3-benzazocine p-toluenesulfona-te, m.p. 176-179C., and cleavage of 8.1 g.
-(0.02 mole) o the free base corresponding to the latter with 81 ml. of 48% aqueous hydrobromic acid.
xample 4 3,6~eq?,11(ax)-T imethyl-8-hydroxy-ll(e~)-(3-oxo-5-cyclopr pentYl)-ll2l3~4~5~6-hexahydro-2l6-methano-3-benzazocinet m p.
128-130C. (0.9 g., from ethyl acetate~hexane), prepared by heating 14.9 g. (0.034 mole~ of ethyll,4a~,5~,-trimethyl-7-methoxy-3-(3-cyclopropylpropionyl)-1,2,3,4,4a,5,10,10a-octa-hydro-2,5-methanobenzotg]quinoline-3-carboxy~ate in a solutlon of 680 ml. of mesitylene and 26 ml. of formic acld to gi~e 6.2 g. of 3,6~eq),11~ax)-trimethyl 8-methoxy-ll(e~ 3-oxo-5-cyclopropylpentyl)-1,2,3,4 ! 5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 224-226C. (from ethanol~diethyl ether) and cl~avage of the latter with 0.065 mole o~ sodium propyl-sulfide (prepared by adding 2.7 g. of a 50% dispersion o~
sodium hydride in mineral oil to 5 9 ml. o propane~hiol~ in 65 ml. of dimethylformamide (DMF).
A sample of the free base was converted to the hydrochloride salt to give material having m.p. 271-273C.
.
, ,' ' 3~3 (from ethanol/diethyl e~her).
Example 5 3,6(eq),11~ax)~Trimethyl-8 hy~rox~-ll(eq~-(3-oxo-5-cYclo-pentylpentyl)-1,2,3,4,5,6-hexah~dro-2,6-methano-3-benzazocine sulfate, m.p. 230-235C. ~4.8 g., from ethanol~ prepared by heating ~3.7 g~ (0.094 mole) of ethyl 1,4a~,5a-trimethyl 7-methoxy-3-~3-cyclopentylpropionyl)-1,2,3,4,4a,5,10,10a-octa-hydro-2,5-methanobenæo[g]quinoline~3-carboxylate in a solu-tion of 35.3 ml. of formic acid in 437 ml of mesitylene to give 19.5 g. of 3,6(eq~,11(ax~-trimekhyl-8-methoxy ll~eq)-(3-oxo-5-~yclopentylpenty~ 2~3~4~s~6-hexahydro-2~6 methano-3-benzazocine hydrochloride, m.p. 219-223C. (from ethanol/-diethyl ether) followed by cleavage of 12.7 g of the latter ~ith 127 ml. of 48~ hydrobromic acid.
A. Ethyl 7-m~et~o3~-1,4a~,5~trimeth ~
oxopropyl~-1,2,3,4 ! 4a,5,10,10a-octahydrov2,5-methanobenzo[g~--carboxylate ~12.4 g., 26%, m~p. 121-123~C. from hexane~ was prepared by reaction of 36.Q g. ~0.105 mole) of ethyl 7-methoxy-1,4a~,5~-trimethyl-1,2,3,4,4a,5,10,10a-octa-hydro 2,5-methanob~nzo[g]quinoline-3-carboxylate with 0.11~
mole of lithium diisopropylamide followed by reaction of the resulting salt with 7.7 g. (0.052 mole) o~ y-cyclobutaneprop-ionyl ohloride.
B. A solution of 12.4 g. ~0.027 mole) of the product was boiled with 50 ml. of trimethylammonium formate for twenty minutes using the procedure described above. The product was isolated in the form of the methanesulfona~e which was recrystallized from acetone~diethyl ether to give 8.3 g. of ?~ 12 ~ . .,,~ ..~,, ~7~
cyclobutylpentylJ-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine methanesulfonate, m.p. 153-155C.
The latter (5.5 g., 0.012 mole3 was cleaved with 35 ml. of 48% hydrobromic acid and the product isolated in the form of the hydrochloride salt to glve 3.9 g. o~ 3,6(eq),11(ax)-trimethyl-8-hydroxy-ll(eq)-(3-oxo-5-cyclobutylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine hydrochloride, m.p. 271-275C.
For purposes of comparison with the claimed species, a series of reference compounds, generaliy descrlbed in U.S.
Patent 3,932,422, were prepared using the procedures described above as follows:
Reference Compound 1: 3,6(eq),ll(ax)-trimethyl-8-hydroxy-ll(eq)-(3-oxopentyl~-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (R is C2H5);
Reference Compound 2: 3,6(eq),lltax)-trlmethyl-8-hydroxy-ll(eq)-(3-oxohexyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine hydrochloride tR is (CH2)2CH3];
Reference Compound 3: 3,6(eq~,11(ax)-trimethyl-8-hydroxy-ll(eq)-(3-oxoheptyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine hydrochloride ~R is (CH2)3CH3~;
Re~erence Compoun _ : 3,6(eq),11(ax3-trimethyl-8-hydroxy-ll(eq)-(3-oxononyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazo-cine [R is (CH2)5CH3];
; Reference Compound 5: 3,6(eq),11(ax)-trimethyl-8-hydroxy-ll(eq)-~3-oxo-5-methylhexyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-- benzaæocine hydrochloride [R is ~CH2CH~CH3)2];
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-3-benzazocine ~R is (CH2)3CH(CH3)2~;
Reference Compound 7- 3,6(eq),11(ax)-trimethyl-8-hydroxy-ll(eq)-. ' ~
.
7~3~
(3-oxo~3-pnenylpropyl)-1,2,3,4,5,6-heYahydro-2,6 methano-3-benzazocine (R is C6H5); and Reference Compound 8: 3,6(eq),11(ax)-trimethyl-8-hyroxy-ll(eq)-(3-oxo-4-phenylbutyl)-1,2,3,4,5,6-he~.ydro-2,6-meth2no-3-benzazocine methane-sulfonate (R is CH2C~H5).
BIOLOGIC;9L TEST RESULTS
Data obtained on the compounds of the invention, identified by the example numbers above where their preparations are described, and the refererce 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, respecti.vely, the ac~tyl 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 1 either in terms of the ~ [mg.~kg.) for the Ach, BK, PPQ
and T.F. Ag. tests or the AD50 for the Phen, Mor and Mep tests or ln terms of percent inhibitlon. The letter "I" designates inactive, and unless noted otherwise all results were obtained Z On subcutaneous administration. ~11 doses ara expressed in milligrams per kilogram (mg.~kg.).
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~ a~ ~~ ~ ,o o~oo ~ o~ ~
E~ o o o _ 1~ ~r a u~
~ ~ o Ll l I 1 O ~
~0 0 i I I I O ' ~
~ _ ~ O
C~ ~ Q~ ~ ~ In O
,~ o o ~ ~r g I ~ o o Ln ' O ~
P- ~ , O ~r ~ o H- O r-l O ,~. 0 0 0 0 _ ^ O
O ~1 0 1` 0 0 ^ ~ O ,_ O _ o L~
¦ I o o t~ o ~ ~ C:~ o, ,~ O O O ~i 0 ~1 ooo o~i ~o c:~
_I N ~ i ~ ~1~ o Irl 1~ ~ O
,S O C~ o ~ o ~ ~ O O ~ C~ i O O ~ O O ~ O 1~
~ ~ ~ Ln --~D S` 00 Pi ~ ~1 ~I t~ 1 ~ ~ ~P Lt~
1~ ~ L~ L~
' ' . .
7~
The tail flick agonist activities o~ each o~
Reference Compounds 1, 2, 3, 5 and 7 were prevented in each case by 1.0 mg./ky. (s.c.) of nalorphine, while the same activity of the compound of Example 2 (hydrochloride) was partially prevented by loO mg.~kg. (s.c.) of nalorphine. These results indicate that Reference Compounds 1, 2, 3, 5 and 7 are narcotic like, an indication which i5 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 o the narcotic antagonist tests ~pentazocine, morphlne and meperidine), it nevertheless possesses weak agonist activity in the tail L lick agonist test and thereore is indicated to have a degree of morphine-like activityO 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 Cbnpounds1-3, which are lower homologs of the species of Example 1, are shown to be agonists with no antagonist properties evident, whereas the compound of -E~ple 1 is shown to be a strong antagonist in all antagonist tests and is completely inactive as an agonis~ Although its higher homolog, Reerence Compound 4, also shows a profile of activity as an antagonist, the latter is only one-fifth as active as the compound of E~ple 1 in the phenazocine antagonist test and is only one-fiftieth as active in the acetylcholine and anti-bradykinin tests.
-16;~
7~
Similarly, the compound o~ Example 2 shows very weak agonist activity but strong antayonist activity in all three antagonist tests, while its lower homolog, Reference Compound 5, has precisely the opposite spectrum of activity, the latter being active in the tail flick agonist test but in-active 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 o 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 S, which are not homologous with any presently known compounds where R5 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 ~arcotic-like properties as shown by the tail flick agonist test and by the observation o~ the Straub tail reaction which is ~ound at high doses~
The invention also deals with a novel species of Formula I where R is methyl ~ound useful as a narcotic analgesic.
~7 3,6te~),11(ax)-Trimeth~l-8-hydroxy-ll(eq)-(3-oxobutyl~-1,2,3,4,5,6-hexahydro-2,6-methano- -b nzazocine was also prepared as follows:
~7~3~3 A solution of 57.1 g. (0.14~3rnole) of ethyl 1,4ar~,5r~'crimethyl-7-methoxy-3-acetyl-1,2,3,4,4a,5,10,l0a-octahydro-2,5-methano-benzo[g]quinoline-3-carboxylate in a solutlon containlng 72.5 ml. of formic acid and S71 ml. of mesltylene was heated under reflux for five hours, cooled, basifled by the ad~ltion 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(eq),11(ax)-trimethyl-8-methoxy~ eq)-(3-oxobut~ 1,2,3,4,5,6-hexahydEo-2,6-meth_no-3-benzazocine hydrochloride, m.p. 182.5-187.5C.
The latter (5.8 g., 0.0018 mole) was cleaved by re-fluxing for two hours in a solution o 58 ml. of 48% aqueous hydrobromic ac.id. The product was isolated in the form of the free base which was recrystallized from ethanol to give 1.3 g.
of 3,6(eq)!11(ax)-trimethyl-8-h~droxy-ll(eq)-(3-oxobutyl)-1,2,3,4,5,6-hexahydro-2,6-methano~3-benzazocine, m.pO 170-173C.
~ sample of the free base was converted to the methanesulfonate to give material having m.p. 265-268C.
(from ethanol).
Data obtained in the acetylcholine-induced abdominal constriction ~Ach), anti-bradykinin lBK), phenyl-p-quinone-induced writhing (PPQ), tail flick phenazocine antagonist (Phen), tail flick ayonist (T.F. Ag) and Straub tail te~ts on the latter species are set forth in Table 2 where, as before, doses are expressed ln milligrams per kilogram, and unless noted otherwise, data were obtained on subcutaneous administration.
Table 2 Compound R Ach BKPPQ Phen T . F . Ag Straub base CH3 0.25 100~0.5- I/40 70~/60 25 CH3SO CH3 0.17 0.1g 0.21 - 2.5 1.5 3 16(p~o.) l9(p.o.) These data indicate that this species ls an analgesic 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 not prevented by nalorphine at 1.0 mg.~kg. (s.c.) or naloxone at 0.1 mg./kg. (s.c.). This lack o~ 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 doses of these narcotic antagonists.
~7242c) Our above Application ~ broadly discloses, initial, novel intermediates o~ the Formula R~ 'OR5 ...IIIA
which can be designated lower-alkyl l-Rl-3-R5CO-4~-R3-5~-R4-6-R2"-7-R2-8~R2'-9~R2'''-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylates and, which are useful 7~3~3 in the prep~ra1ion of novel 3-Rl-6(eq~-R~-7-R2"-8-R2-9-R2'-10-R2'''-ll(ax)-R3-ll(eq)-CH2CH~COR5-2,6-methano-3-benzazocines hav.ing the formula:
R2 " ~ ~1 ' R2-l 4 3 . . .V
wherein in both Formulas IIIA and V:
Rl is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynYl~ halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furylmethyl, or such 2- or 3-~urylmethyl substi-; tuted on the unsubstituted ring carbon atoms by from one to three methyl groups, phenyl-lower-alkyl, or phenyl-lower-alkyl substituted in the phenyl ring by from one to ~wo members of the group consisting of halogen (including bromine, chlorine and fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, tri~luoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent : carbon atoma;
R2, R2', R2" and R2''' are each hydrogen, or three of them are hydrogen and the fourth is halogen (including ~; ~romi~e, chlorine and fluorine), lower-alkyl, hydroxy, lower-: 20 alkanoyloxy, lower-alkoxy, lower alkylmercapto~ tri~luoromethyl, : nitrO, amino, lower-alkanoylamino, lower-alkoxycarbonylamino or phenyl, or two of the adjacent such groups together are methyl-enedioxy;
R3 is hydrogen or lower-alkyl;
R4 is hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower~alkyl, lower-alkylthio~lower-alkyl, lower-alkyl-sulfinyl-lower alkyl, phenylthio-lower-alkyl, phenyl-sulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R3 and R4 together are di~alent lower-alkylene, -~CH2)n~, S where n is one of the integers 3 or 4; and R5 is lower-alkylthio-lower-alkyl, lower-alkoxy-lower-alkyl, lower-alkoxy, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furyl, 2 or 3-furyl-~CH2)m, where m is an integer from 2 to 4, or such 2- or 3-furyl or 2-- or 3-furyl-~CH2)m substituted on the unsubstituted ring carbon atomsby from one to three methyl groups, or phenyl or phenyl-(CH2)m, if desired substituted in the phenyl ring by fxom one to two members of the group consisting of halogen (in-cluding bromine, chlorine and fluorine), lower-alkyl, hydr-oxy, lower~alkanoyloxy, lower-alkoxy, lower-alkyl-mercapto, trifluoromethyl, amino, lower~alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms by utiliz-ing the process described above using starting materials of Fo~mula III.
In accordance with a further aspect of the present invention the compounds of Formula V where one of R2, R2', R2" and R2l" is hydroxy are prepared from the corresponding ethers where the corre~ponding groups are lower alkoxy by cleaving the ether groups~ su~h as either with aqueous hydro-bromic acid or with ~odium propylsulflde. The conditions of cleavage are as described above for preparing compounds of Formula I, .
~7 , .. ~ --~1--- : -,'- ' ;' ' .: ~:
It has now been surprisingly found that certain species of 3,6(eq~,11(ax)-trimethyl-8-hydroxy-ll(eq)-(CH2 CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines, where R represents certain selected lower-alk~l, phenyl-lower-alkyl or cycloalkyl-lower-alkyl groups, and acid addition salts thereof, are highly potent narcotic antagonists. These compounds have the ~ormula .3_ .
, ' ' ' ~ :
f~
rio ~ ~ ~ R
where R i~ methyl, pentyl, 3-methylbutyl, 2-phenylethyl, 2-ayclopropylethyl, 2-cyclobutylethyl or 2-cyclopentylethyl.
The narcotic antagonist pr~pexties possessed by the above-identified specie~ are in marked contrast with propertie~ ofcompounds homologous with them in the lower-alkyl portion of the R group, which compounds p~ precisely the opposite p~ofile of activity in being ~trong ~nalgesics with either no antagoni~t properties or in which su~h antagonist properties have been strongly dimi~l6hed.
~ he compound~ of Formula I are prepared eithex by the method described in U.5. Patent 3,932,422 which compri~es heating, with formic acid in an orgRnic solvent, for example, toluene, xylene or me~itylene, or with a benzyl~di-lower-alkyl-ammonium ~orma~e or ~ txl-lower-alkylammonium formate, a 7-YO-1,4aa,5~-trimethyl-3 COR-1,2,3,4,4~,5,10,10a~octahydr~-2,5-me~hanobenzo[g]quinoline of Formula II:
~H3 Y-O ~ ~ ~`~ ~ 01~
~ H3 3 ...II
whera Y represents hydrogen or lower-alkyl and R has the ~0 meanin~6 given above, followad by ~leavage, with aqueous , . .~ ~ ..
~' .......
-- . ..
.
&~
hydrobromlc acid or sodium prop~lsulfide a~ described below, 7 of the lower-alkoxy group (~-0) in the event that Y i~ 107,7er-.1 alkyl.
Alternatively, and preferably, the compounds of Formula I are prepared by a modification of the above process which comprises heatiny, with formic acid in an organic solvent, for example, toluene, xylene or mesitylene, or with a benzyl-di-lower-alkylammonium formate or a tri-lower-alkylammonium formate, a lower~alkyl 1,4a~,5~-trimethyl-7-Y0-3-RC0-1,2,3,4,-4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate having the Formula III:
COOAlk ' y . . . III
where ~' represents lower-alkyl and R and have the meanings given above as described in ApplicationNo. 2861472 filedSeptember 19,1~7. In~heeVent that Y is lower-alkyl, one cleaves the lower-alkoxy group t -0), such as with aqueous hydrobromic acid or sodium propylsulfide. When aqueous hydro-bromic acid is used to effect cleavage, the reaction is carried out by refluxing a solution of the ether in aqueous hydro-bromic acid and isolating thP compound either directly from thereaction 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 i5 carried out by refluxing a solution of the ether in an inert organic solvent, for example dimethylformamide (DMF), with _5_ ' , - "' i , , ,,' ~ ' .
7$~
a molar excess of the ~odium propylsul~ide, whlch is prepared by addition of propanethiol to sodium hydrldeO It is preferred to use the starting material of Formula II or III where Y is lower-alkyl whereby the subsequent splitting o~ ether is re-qulred.
The eompounds of Formula II and methods for their preparation are disclosed ln U.S. Patent 3,932,422. As (7242c) described in Patent Application ~ ~ the compounds of Formula III are prepared either by reacting a lower-alkyl 1,4a~,-50ttrimethyl-7~Y0-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanO-benzo[g]quinoline-3-carboxylate (Formula II where R is lower-alkoxy) with an alkali metal amide, Eor example sodamlde or lithium diisopropylamide, in an inert organic solvent and re-acting the alkali metal salt thus formed with an appropriate acyl halide, R-C0-X, or by reacting a 1,4a~,5c~trimethyl-7-Y0-3-RC0-1,2,3,4,4a,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 resuliing alkali metal salt with a lower-alk~l halo ormate.
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 acid-addition salt forms are prepared from any organic or inorganic acid. They are obtained in conventional fashion, for instance either by direck mixing of the base ~ith the acid or, when this is not appropriate, by dissolving either or both of the bace and the acid separately ln water or an organic solvent and mixing the two solutions, or by dissolving both the base and the aeid together in a solvent. The resulting acid-addition salt is isolated by ~iltration, if it is insoluble in the .
.
, r~action medium, or by evaporation of the reactlon medium to leave the acid-addition salt as a residue. The acid moieties or anions ~n 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 use~ul as sources of the free base forms, by reaction with an inorganlc base.
It will thus be appreciated that l~ one or more o~ the character-istics, such as solubility, molecular weight, physical appearance,toxicity, or the like of a given ~ase or ac~d-addition salt thereof render that form unsuitabl2 ~or the purpose at hand, it can be readily converted to another, more suitable form. For pharmaceutical purposes, acid-addition salts o~ relatively non-toxic, pharmaceutically-acceptable acids, for example, hydro-chloric acid, methanesulfonic acid, lactic acid, tartar1c acid, and the like, are of course employed.
The compounds of this invention can exist in enantio-meric forms separable into enantiomers. I~ desired, the iso-lation or the production of a particular enantiomeric ~ormcan be accomplished by application of general princlples 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 con~igurations are given with reference to the hydroaromatic ring. Thus, the 6~eq),ll(ax) compounds of Formula I are in the cis conflguration, whereas the 6(eq),ll(eq) compounds are in the trans con~iguration.
The useful propertles of the compounds of this in-vention were demonstrated by s~andard pharmacological pro-cedures readily carried out ~y technicians having ordinary --7~
7~3~
skill in pharmacologlcal test procedures, so that the actua~
determination of the numerical biological data de~initlve or a particular test compound can be ascertained without the need for any extensive experimentation.
~he test procedures used to determlne the analgesic and narcotic antagonist activities of the compounds of the invention have been described in detail in the prlor art and are as follows: The acetylchollne-induced abdominal constriction test, which is a primary analgesic screening test designed to measure the ability of a test agent to suppress acetylcholine-induced abdominal constriction in mice, described by Collier et al. Brit. JO Pharmacol. Chemotherap. 32, 295 tl968); a modi-fication of the anti-bradykinin test, which also ts a primary analgesic screening procedure, described by Berkowltz et al~, J. Pharmacol. Exp. Therap. 177, 500-508 (1971), Blane et al., J. Pharm. Pharmacol. 19, 367-373 (1967), Botha et ai., Eur. J
Pharmacol. 6, 312-321 (1969~ and Deffenu et al., J. Pharm.
Pharmacol. 18, 135 (1966); the phenyl-p-quinone-induced writhing test, also a primary analgesic screenlng test, designed to measure the ability of a test agent to prevent phenyl-_-quinone-induced writhing in mice, d~scribed ~y 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 VanderBrck, J. Am. Pharm. Assoc. Sci. Ed.
41, 5Ç9 ~1956); the narcotic antagonist tests (e.g. phenazocine, morphine and meperidine antagonist t~sts), whtch are designed to measure the ability of a test agent to antagonize the effect of phenaæocine, morphine or meperidine in the above lndicated rat tail flick agonist test, described by Harris and Pierson, J.
:
7~3~
Pharmacol. Exp. TheraP. 143, 141 (19~4); 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 reaction~ and the homoyeneity of the products were ascertained by thin layer chromatography.
Example 1 A solution of 27.5 g. (0.064 mole) of ethyl 1,4arr,5~, trimethyl-7-methoxy-3-hexanoyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate in 275 ml. oE
mesitylene and 37 ml. of 98% ormic acid was heated under reflux for twenty-four hours with stlrring and then taken to dryness ln 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 af~orded 30 g. o a residue which was treated with a solution of 6.0 g. of oxalic acid in 50 ml. o ethanol. There was thus obtained 27 g. of 3,6(eq),1~x)-trimethyl-8~methoxy-ll(eq)-t3-oxooct~)-1,2,3,4,5l,6 hexah~dro-2c6-methano-3-benzazocine oxalate, m.p. 95-97C.
A solution of 1.9 g. (0.0047 mole) of the latter in the form of the hydrochloride salt in 25 ml. of 48% hydrobromic acid was heated under reflux for two hours, concentratPd to dryness in vacuo, and the residue made basic with aqueous alkali and extracted with diethyl ether. Concentration o the ether g_ 7~3~3 extracts to dryness and conver~lo~ o the -~esidual solld ~o the hydrochloride salt: with ethereal hydrogen chlorlde afforded 2.5 g. of crude material wh~ch wa5 recr~gtallized from isopropanol to give l.7 g. cf 3,6~e~),11~ax)--trlmethyl-~ droxy-ll(eq)-(3-oxooctyl~-~1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazoclne hydrochloride, m.p. 252-25rC.
A small sample of the hydrochlorlde salt was re-converted to the base and the latter converted to the methane-sulfonate having m.p. 178-179C. (from acetone)O
Another sample was converted to the 2-naphthalene-sulfonate, m.p. 195-198C~ (from methanolfdiethyl ether).
Following a procedure similar to that described in Example 1, the following compounds of FormulaIwere~lmilarly prepared.
Example 2 3,6(eq),11(ax)-Trimethy~8~hydrox~ eq3-~3-oxo-6-meth~lhep~yl)-1,2,3,4,5,6-hexahy_ro-2,6-methano-3-benzazocine hydrochlorlde, m.p. 260-263~C. (3.6 g., from isopropanol~ prepared by heatiny 20.0 g. (0.045 mole) of ethyl 1,4a~,50~trimethyl-7~methoxy-~
t~-methylpentanoy~ 2~3,4~4a~5~lo~loa-octahydro-2~5~methan benzo[g]quinoline-3-carboxylate in 1 liter o~ mesityl~ne and 70 ml. of formic acid to give 17.8 g. o~ 3,6(eq~,11(ax~-tri-methyl-8-methoxy~ll(eq3-~3-oxo-6-methylheptyl)-1,2!3,4,5,6-h~xa--hydro-2,6-methano-3~benzaæoclne hydrochloride (m.p 222-229~C~
from diethyl ether) and cleavage, with 40 ml. of 48~ hydrobromic acid, of 400 g. (0.0098 moie~ of the latter.
A sample of the free base was iso~ated ~rom the hydrochloride ~alt~ and the base converted ~o ~he corresponding methanesulfonate having mOp. 189-l91~C. ~from acetone,~dieth~tl ether).
3~
Example 3 3,6(eqL,ll(ax)-Trimethyl-8-hyd~ox~-ll(eq~~(3 oxo-5-phenyl-pentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine methanesulfonate, m.p. 233-235C. (1.6 g., from ethanol), prepared by heating 26.2 g. (0.055 mole) of ethyl 1,4a~,5~-trimethyl-7-methoxy-3-(3-phenylpropionyl)-1,2,3,4,4a,5,10,10a-octahydro-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-hexahydro-2,6-methano-3-benzazocine p-toluenesulfona-te, m.p. 176-179C., and cleavage of 8.1 g.
-(0.02 mole) o the free base corresponding to the latter with 81 ml. of 48% aqueous hydrobromic acid.
xample 4 3,6~eq?,11(ax)-T imethyl-8-hydroxy-ll(e~)-(3-oxo-5-cyclopr pentYl)-ll2l3~4~5~6-hexahydro-2l6-methano-3-benzazocinet m p.
128-130C. (0.9 g., from ethyl acetate~hexane), prepared by heating 14.9 g. (0.034 mole~ of ethyll,4a~,5~,-trimethyl-7-methoxy-3-(3-cyclopropylpropionyl)-1,2,3,4,4a,5,10,10a-octa-hydro-2,5-methanobenzotg]quinoline-3-carboxy~ate in a solutlon of 680 ml. of mesitylene and 26 ml. of formic acld to gi~e 6.2 g. of 3,6~eq),11~ax)-trimethyl 8-methoxy-ll(e~ 3-oxo-5-cyclopropylpentyl)-1,2,3,4 ! 5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 224-226C. (from ethanol~diethyl ether) and cl~avage of the latter with 0.065 mole o~ sodium propyl-sulfide (prepared by adding 2.7 g. of a 50% dispersion o~
sodium hydride in mineral oil to 5 9 ml. o propane~hiol~ in 65 ml. of dimethylformamide (DMF).
A sample of the free base was converted to the hydrochloride salt to give material having m.p. 271-273C.
.
, ,' ' 3~3 (from ethanol/diethyl e~her).
Example 5 3,6(eq),11~ax)~Trimethyl-8 hy~rox~-ll(eq~-(3-oxo-5-cYclo-pentylpentyl)-1,2,3,4,5,6-hexah~dro-2,6-methano-3-benzazocine sulfate, m.p. 230-235C. ~4.8 g., from ethanol~ prepared by heating ~3.7 g~ (0.094 mole) of ethyl 1,4a~,5a-trimethyl 7-methoxy-3-~3-cyclopentylpropionyl)-1,2,3,4,4a,5,10,10a-octa-hydro-2,5-methanobenæo[g]quinoline~3-carboxylate in a solu-tion of 35.3 ml. of formic acid in 437 ml of mesitylene to give 19.5 g. of 3,6(eq~,11(ax~-trimekhyl-8-methoxy ll~eq)-(3-oxo-5-~yclopentylpenty~ 2~3~4~s~6-hexahydro-2~6 methano-3-benzazocine hydrochloride, m.p. 219-223C. (from ethanol/-diethyl ether) followed by cleavage of 12.7 g of the latter ~ith 127 ml. of 48~ hydrobromic acid.
A. Ethyl 7-m~et~o3~-1,4a~,5~trimeth ~
oxopropyl~-1,2,3,4 ! 4a,5,10,10a-octahydrov2,5-methanobenzo[g~--carboxylate ~12.4 g., 26%, m~p. 121-123~C. from hexane~ was prepared by reaction of 36.Q g. ~0.105 mole) of ethyl 7-methoxy-1,4a~,5~-trimethyl-1,2,3,4,4a,5,10,10a-octa-hydro 2,5-methanob~nzo[g]quinoline-3-carboxylate with 0.11~
mole of lithium diisopropylamide followed by reaction of the resulting salt with 7.7 g. (0.052 mole) o~ y-cyclobutaneprop-ionyl ohloride.
B. A solution of 12.4 g. ~0.027 mole) of the product was boiled with 50 ml. of trimethylammonium formate for twenty minutes using the procedure described above. The product was isolated in the form of the methanesulfona~e which was recrystallized from acetone~diethyl ether to give 8.3 g. of ?~ 12 ~ . .,,~ ..~,, ~7~
cyclobutylpentylJ-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine methanesulfonate, m.p. 153-155C.
The latter (5.5 g., 0.012 mole3 was cleaved with 35 ml. of 48% hydrobromic acid and the product isolated in the form of the hydrochloride salt to glve 3.9 g. o~ 3,6(eq),11(ax)-trimethyl-8-hydroxy-ll(eq)-(3-oxo-5-cyclobutylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine hydrochloride, m.p. 271-275C.
For purposes of comparison with the claimed species, a series of reference compounds, generaliy descrlbed in U.S.
Patent 3,932,422, were prepared using the procedures described above as follows:
Reference Compound 1: 3,6(eq),ll(ax)-trimethyl-8-hydroxy-ll(eq)-(3-oxopentyl~-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (R is C2H5);
Reference Compound 2: 3,6(eq),lltax)-trlmethyl-8-hydroxy-ll(eq)-(3-oxohexyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine hydrochloride tR is (CH2)2CH3];
Reference Compound 3: 3,6(eq~,11(ax)-trimethyl-8-hydroxy-ll(eq)-(3-oxoheptyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine hydrochloride ~R is (CH2)3CH3~;
Re~erence Compoun _ : 3,6(eq),11(ax3-trimethyl-8-hydroxy-ll(eq)-(3-oxononyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazo-cine [R is (CH2)5CH3];
; Reference Compound 5: 3,6(eq),11(ax)-trimethyl-8-hydroxy-ll(eq)-~3-oxo-5-methylhexyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-- benzaæocine hydrochloride [R is ~CH2CH~CH3)2];
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-3-benzazocine ~R is (CH2)3CH(CH3)2~;
Reference Compound 7- 3,6(eq),11(ax)-trimethyl-8-hydroxy-ll(eq)-. ' ~
.
7~3~
(3-oxo~3-pnenylpropyl)-1,2,3,4,5,6-heYahydro-2,6 methano-3-benzazocine (R is C6H5); and Reference Compound 8: 3,6(eq),11(ax)-trimethyl-8-hyroxy-ll(eq)-(3-oxo-4-phenylbutyl)-1,2,3,4,5,6-he~.ydro-2,6-meth2no-3-benzazocine methane-sulfonate (R is CH2C~H5).
BIOLOGIC;9L TEST RESULTS
Data obtained on the compounds of the invention, identified by the example numbers above where their preparations are described, and the refererce 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, respecti.vely, the ac~tyl 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 1 either in terms of the ~ [mg.~kg.) for the Ach, BK, PPQ
and T.F. Ag. tests or the AD50 for the Phen, Mor and Mep tests or ln terms of percent inhibitlon. The letter "I" designates inactive, and unless noted otherwise all results were obtained Z On subcutaneous administration. ~11 doses ara expressed in milligrams per kilogram (mg.~kg.).
~7k~3~
u~
oo o t~
~ a~ ~~ ~ ,o o~oo ~ o~ ~
E~ o o o _ 1~ ~r a u~
~ ~ o Ll l I 1 O ~
~0 0 i I I I O ' ~
~ _ ~ O
C~ ~ Q~ ~ ~ In O
,~ o o ~ ~r g I ~ o o Ln ' O ~
P- ~ , O ~r ~ o H- O r-l O ,~. 0 0 0 0 _ ^ O
O ~1 0 1` 0 0 ^ ~ O ,_ O _ o L~
¦ I o o t~ o ~ ~ C:~ o, ,~ O O O ~i 0 ~1 ooo o~i ~o c:~
_I N ~ i ~ ~1~ o Irl 1~ ~ O
,S O C~ o ~ o ~ ~ O O ~ C~ i O O ~ O O ~ O 1~
~ ~ ~ Ln --~D S` 00 Pi ~ ~1 ~I t~ 1 ~ ~ ~P Lt~
1~ ~ L~ L~
' ' . .
7~
The tail flick agonist activities o~ each o~
Reference Compounds 1, 2, 3, 5 and 7 were prevented in each case by 1.0 mg./ky. (s.c.) of nalorphine, while the same activity of the compound of Example 2 (hydrochloride) was partially prevented by loO mg.~kg. (s.c.) of nalorphine. These results indicate that Reference Compounds 1, 2, 3, 5 and 7 are narcotic like, an indication which i5 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 o the narcotic antagonist tests ~pentazocine, morphlne and meperidine), it nevertheless possesses weak agonist activity in the tail L lick agonist test and thereore is indicated to have a degree of morphine-like activityO 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 Cbnpounds1-3, which are lower homologs of the species of Example 1, are shown to be agonists with no antagonist properties evident, whereas the compound of -E~ple 1 is shown to be a strong antagonist in all antagonist tests and is completely inactive as an agonis~ Although its higher homolog, Reerence Compound 4, also shows a profile of activity as an antagonist, the latter is only one-fifth as active as the compound of E~ple 1 in the phenazocine antagonist test and is only one-fiftieth as active in the acetylcholine and anti-bradykinin tests.
-16;~
7~
Similarly, the compound o~ Example 2 shows very weak agonist activity but strong antayonist activity in all three antagonist tests, while its lower homolog, Reference Compound 5, has precisely the opposite spectrum of activity, the latter being active in the tail flick agonist test but in-active 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 o 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 S, which are not homologous with any presently known compounds where R5 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 ~arcotic-like properties as shown by the tail flick agonist test and by the observation o~ the Straub tail reaction which is ~ound at high doses~
The invention also deals with a novel species of Formula I where R is methyl ~ound useful as a narcotic analgesic.
~7 3,6te~),11(ax)-Trimeth~l-8-hydroxy-ll(eq)-(3-oxobutyl~-1,2,3,4,5,6-hexahydro-2,6-methano- -b nzazocine was also prepared as follows:
~7~3~3 A solution of 57.1 g. (0.14~3rnole) of ethyl 1,4ar~,5r~'crimethyl-7-methoxy-3-acetyl-1,2,3,4,4a,5,10,l0a-octahydro-2,5-methano-benzo[g]quinoline-3-carboxylate in a solutlon containlng 72.5 ml. of formic acid and S71 ml. of mesltylene was heated under reflux for five hours, cooled, basifled by the ad~ltion 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(eq),11(ax)-trimethyl-8-methoxy~ eq)-(3-oxobut~ 1,2,3,4,5,6-hexahydEo-2,6-meth_no-3-benzazocine hydrochloride, m.p. 182.5-187.5C.
The latter (5.8 g., 0.0018 mole) was cleaved by re-fluxing for two hours in a solution o 58 ml. of 48% aqueous hydrobromic ac.id. The product was isolated in the form of the free base which was recrystallized from ethanol to give 1.3 g.
of 3,6(eq)!11(ax)-trimethyl-8-h~droxy-ll(eq)-(3-oxobutyl)-1,2,3,4,5,6-hexahydro-2,6-methano~3-benzazocine, m.pO 170-173C.
~ sample of the free base was converted to the methanesulfonate to give material having m.p. 265-268C.
(from ethanol).
Data obtained in the acetylcholine-induced abdominal constriction ~Ach), anti-bradykinin lBK), phenyl-p-quinone-induced writhing (PPQ), tail flick phenazocine antagonist (Phen), tail flick ayonist (T.F. Ag) and Straub tail te~ts on the latter species are set forth in Table 2 where, as before, doses are expressed ln milligrams per kilogram, and unless noted otherwise, data were obtained on subcutaneous administration.
Table 2 Compound R Ach BKPPQ Phen T . F . Ag Straub base CH3 0.25 100~0.5- I/40 70~/60 25 CH3SO CH3 0.17 0.1g 0.21 - 2.5 1.5 3 16(p~o.) l9(p.o.) These data indicate that this species ls an analgesic 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 not prevented by nalorphine at 1.0 mg.~kg. (s.c.) or naloxone at 0.1 mg./kg. (s.c.). This lack o~ 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 doses of these narcotic antagonists.
~7242c) Our above Application ~ broadly discloses, initial, novel intermediates o~ the Formula R~ 'OR5 ...IIIA
which can be designated lower-alkyl l-Rl-3-R5CO-4~-R3-5~-R4-6-R2"-7-R2-8~R2'-9~R2'''-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylates and, which are useful 7~3~3 in the prep~ra1ion of novel 3-Rl-6(eq~-R~-7-R2"-8-R2-9-R2'-10-R2'''-ll(ax)-R3-ll(eq)-CH2CH~COR5-2,6-methano-3-benzazocines hav.ing the formula:
R2 " ~ ~1 ' R2-l 4 3 . . .V
wherein in both Formulas IIIA and V:
Rl is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynYl~ halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furylmethyl, or such 2- or 3-~urylmethyl substi-; tuted on the unsubstituted ring carbon atoms by from one to three methyl groups, phenyl-lower-alkyl, or phenyl-lower-alkyl substituted in the phenyl ring by from one to ~wo members of the group consisting of halogen (including bromine, chlorine and fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, tri~luoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent : carbon atoma;
R2, R2', R2" and R2''' are each hydrogen, or three of them are hydrogen and the fourth is halogen (including ~; ~romi~e, chlorine and fluorine), lower-alkyl, hydroxy, lower-: 20 alkanoyloxy, lower-alkoxy, lower alkylmercapto~ tri~luoromethyl, : nitrO, amino, lower-alkanoylamino, lower-alkoxycarbonylamino or phenyl, or two of the adjacent such groups together are methyl-enedioxy;
R3 is hydrogen or lower-alkyl;
R4 is hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower~alkyl, lower-alkylthio~lower-alkyl, lower-alkyl-sulfinyl-lower alkyl, phenylthio-lower-alkyl, phenyl-sulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R3 and R4 together are di~alent lower-alkylene, -~CH2)n~, S where n is one of the integers 3 or 4; and R5 is lower-alkylthio-lower-alkyl, lower-alkoxy-lower-alkyl, lower-alkoxy, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furyl, 2 or 3-furyl-~CH2)m, where m is an integer from 2 to 4, or such 2- or 3-furyl or 2-- or 3-furyl-~CH2)m substituted on the unsubstituted ring carbon atomsby from one to three methyl groups, or phenyl or phenyl-(CH2)m, if desired substituted in the phenyl ring by fxom one to two members of the group consisting of halogen (in-cluding bromine, chlorine and fluorine), lower-alkyl, hydr-oxy, lower~alkanoyloxy, lower-alkoxy, lower-alkyl-mercapto, trifluoromethyl, amino, lower~alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms by utiliz-ing the process described above using starting materials of Fo~mula III.
In accordance with a further aspect of the present invention the compounds of Formula V where one of R2, R2', R2" and R2l" is hydroxy are prepared from the corresponding ethers where the corre~ponding groups are lower alkoxy by cleaving the ether groups~ su~h as either with aqueous hydro-bromic acid or with ~odium propylsulflde. The conditions of cleavage are as described above for preparing compounds of Formula I, .
~7 , .. ~ --~1--- : -,'- ' ;' ' .: ~:
Claims (24)
1. A process for preparing a compound having the formula where R is methyl, pentyl, 3-methylbutyl, 2-phenylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl or 2-cyclopentylethyl;
or a pharmaceutically acceptable acid-addition salt thereof which comprises:
(a) heating with formic acid in an organic solvent or with a benzyl-di-lower-alkylammonium formate or a tri-lower-alkylammonium formate, a compound having the formula ...II
wherein Y is hyarogen or lower alkyl, and R is as defined above; or (b) heating, with formic acid in an oxganic solvent or with a benzyl-di-lower alkylammonium formate or a tri-lower-alkylammonium formate, a compound having the formula ...III
where Y is hydrogen or lower-alkyl, R is as defined above, and Alk' is lower-alkyl, and when Y is lower-alkyl, cleaving the lower-alkoxy group in the resulting 3,6(eq),11(ax)-trimethyl-8-lower-alkoxy-11(eq)-(CH2-CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine; and where required, converting a compound obtained in the free base form to a pharmaceutically acceptable acid add.ition salt thereof~
or a pharmaceutically acceptable acid-addition salt thereof which comprises:
(a) heating with formic acid in an organic solvent or with a benzyl-di-lower-alkylammonium formate or a tri-lower-alkylammonium formate, a compound having the formula ...II
wherein Y is hyarogen or lower alkyl, and R is as defined above; or (b) heating, with formic acid in an oxganic solvent or with a benzyl-di-lower alkylammonium formate or a tri-lower-alkylammonium formate, a compound having the formula ...III
where Y is hydrogen or lower-alkyl, R is as defined above, and Alk' is lower-alkyl, and when Y is lower-alkyl, cleaving the lower-alkoxy group in the resulting 3,6(eq),11(ax)-trimethyl-8-lower-alkoxy-11(eq)-(CH2-CH2COR)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine; and where required, converting a compound obtained in the free base form to a pharmaceutically acceptable acid add.ition salt thereof~
2. A process according to claim 1, for preparing 3,6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxooctyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine where R in the starting material of Formulas II and III is pentyl and Y is methyl and the resulting product is cleaved with hydrobromic acid.
3, A process acco$ding to claim 2, which includes converting the final product obtained to its methanesulfonate salt.
4. A process according to claim 2, which includes converting the final product obtained to its hydrochloride salt.
5, A process according to claim 1, for preparing 3,6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-6-methyl-heptyl)-1,2,3,4,5,6(hexahydro-2,6-methano-3-benzazocine where R in the starting material of Formulas II or III is 3-methylbutyl.
6. A proceas according to claim 5, which includes converting the final product obtained to its hydrochloride salt. .
7. A process accordiny to claim 1, for preparing 3,6(eq),11ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-5-phenyl-pentyl)-1,2,3,4,5,6 hexahydro-2,6-methano-3-benzazocine where R in the starting material of Formulas XI or III is 2-phenylethyl and Y is methyl and the rssulting product is cleaved with hydrobromic acid.
8. A process according to claim 7, which includes converting the final product obtainad to its methanesulfonate salt.
9. A process according to claim 1, for preparing 3,6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-5-cyclo-propylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine where R in the starting material of Formulas II or III is 2-cyclopropylethyl and Y is methyl and the resulting product is cleaved with hydrobromic acid.
10. A process according to claim 9, which includes converting the final product obtained to its hydrochloride salt.
11. A process according to claim 1, for preparing 3,6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxo-5-cyclo-pentylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine where R is the starting material of Formulas II or III
is 2-cyclopentylethyl and Y is methyl and the resulting prod-uct is cleaved with hydrobromic acid.
is 2-cyclopentylethyl and Y is methyl and the resulting prod-uct is cleaved with hydrobromic acid.
12. A process according to claim 11, which includes converting the final product obtained to its sulfate salt.
13. A process according to claim 1, for preparing 3,6(eq),11(ax)trimathyl-8-hydroxy-11(eq)-(3-oxo-5-cyclobutyl-pentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine where R in the starting material of Formulas II or III is 2-cyclo-butylethyl and Y is methyl and the resulting product is cleaved with hydrobromic acid.
14. A process acacording to claim 13, which includes converting the final product obtained to its hydrochloride salt.
15. A process accoding to claim 1, for preparing 3,6(eq),11(ax)-trimethyl-8-hydroxy-11(eq)-(3-oxobutyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocina where R
in the starting material of Formulas II or III is methyl and Y is methyl and the resulting product is cleaved with hydxobromic acid.
in the starting material of Formulas II or III is methyl and Y is methyl and the resulting product is cleaved with hydxobromic acid.
16. A process aacording to claim 15, which includes converting the final product obtained to its methanesulfonate salt.
17. A compound of the Formula I as defined in claim 1, when made by the process according to claim 1 or by an obvious chemical equivalent thrreog.
18. 3,6(eq),11(ax)-Trimethyl-8-hydroxy-11(eq)-(3-oxooctyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine, or its methanesulfonate or hydrochloride salt, when made by the process according to claim 2, 3 or 4, respectively or by an obvious chemical equivalent thereof.
19. 3,6(eq),11(ax)-Trimethyl-8-hydroxy-11(eq)-(3-oxo-6-methyl-heptyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine or its hydrochloride salt when made by the process according to claim 5 or 6, respectively, or by an obvious chemical equivalent thereof.
20. 3,6(eq),11(ax)-Trimethyl-8-hydroxy-11(eq)-(3-oxo-5-phenyl-pentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine or its methanesulfonate salt when made by the process according to claim 7 or 8, respectively, or by an obvious chemical equivalent thereof.
21. 3,6(eq),11(ax) Trimethyl-8-hydroxy-11(eq)-(3-oxo-5-cyclo-propylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine or its hydroahloride salt when made by the process according to claim 9 or 10, respectively, or by an obvious chemical equivalent thereof.
22. 3,6(eq),11(ax)-Trimethyl-8-hydroxy-11(eq)-(3-oxo-5-cyclo-pentylpentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine or its sulfate salt when made by the process according to claim 11 or 12, respectively, or by an obvious chemical equivalent thereof.
23. 3,6(eq),11(ax)Trimethyl-8-hydroxy-11(eq)-(3-oxo-5-cyalobutyl-pentyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine or the hydrochloride salt thereof when made by the process according to claim 13 or 14, respectively. or by an obvious chemical equivalent thereof.
24. 3,6(eq),11(ax)-Trimethyl-8-hydroxy-11(eq)-(3-oxobutyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine or the methanesulfonate salt thereof when made by the process according to claim 15 or 16, respectively, or by an obvious chemical equivalent therof.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA298,735A CA1097630A (en) | 1978-03-13 | 1978-03-13 | 2,6-methano-3-benzazocines |
| CA353,425A CA1102799A (en) | 1978-03-13 | 1980-06-05 | 2,6-methano-3-benzazocines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA298,735A CA1097630A (en) | 1978-03-13 | 1978-03-13 | 2,6-methano-3-benzazocines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1097630A true CA1097630A (en) | 1981-03-17 |
Family
ID=4110964
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA298,735A Expired CA1097630A (en) | 1978-03-13 | 1978-03-13 | 2,6-methano-3-benzazocines |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1097630A (en) |
-
1978
- 1978-03-13 CA CA298,735A patent/CA1097630A/en not_active Expired
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