Note: Descriptions are shown in the official language in which they were submitted.
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-
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
-2-
'
.. .
., ,. , . .. - :
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 '
CH3
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
-6-
.
.
,
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.
--8--
:
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).
-10-
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.
--11--
.
,
,' '
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)-
-13-
. ' ~
.
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.).
-14-
~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~
-15-
'
'
. .
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:
-17-
~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
-18-
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
--19--
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,
-20-
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--
- : -
,'- ' ;' ' .: ~:
