Note: Descriptions are shown in the official language in which they were submitted.
77 ~
100-4997
~ ~ R P~EPARATION AND PHA~'ACEU-
This invention relates to iso~uinoline derivatives,
their preparation and pharmaceutical compositions con-
taining them.
The present inven~ion provides compounds of formula I
. ~ N-R3
wherein R , R2 and R3 are chosen from the following stgni-
ficc~nces (i), (ii) and (iii):-
(i) Rl imd R2, independently, are hydrogen
J (Cl 6)alkyl, trifluoromethyl, halogen, or
(Cl 4)alkoxy, and
R3 is hydrogen, or
(ii) (a) Rl i~nd R2, independently, are hydrogen,
(Cl 6)alkyl, trifluoromethyl or halogen, or
(b) Rl :is (Cl_4)alkoxy and
.. .... ~ . ~ .. - -
8'775
- 2 - 100-4997
R2 is (Cl ~)alkyl, trifluoromethyl, halogen
or (Cl 4)alkoxy, and
R3 is (Cl_6)alkyl,
a radical of formula II,
-CH2.CH=CR4R5 II
wherein R4 and R5,independently, are hydrogen or
- (Cl_4)alkyl,
a radical of formula III,
~ CH -CH (CH2)m
- wherein m is 2, 3 or 4/
a radical of formula IV
~ 2)n ~ IV
wherein n is 1 or 2/ or
a radical of formula V
-(CH2)p ~ 6
wherein p is 1 or 2 and
R~ is hydrogen, halogen, trifluoromethyl,
(Cl_4)alkoxy, (Cl_4)alkyl,
amino, di~(Cl 4)alXyl]amino
(Cl ~)alkylamino, or
(iii) th~ azido group is cis to the phenyl group,
Rl is (Cl 4)alkoxy in the meta position
R2 is hydrogen, and
R3 is methyl.
8~75
- 3 - 100-4997
Any alkyl or alkoxy moiety has preferably 1 or 2
carbon atoms, and especially one carbon atom. Halogen means
fluorine, chlorine or bromine. The azido grou~ in the for-
mula I may be cis or trans to the phenyl group. -~
Rl and R2 are preferably other than halogen. Rl ~s
preferably alkoxy or hydrogen. Rl`is preferably in the meta
position. R2 is preferably hydrogen. R3 is pYeferably alkyl.
R4 and R5 are preferably identical. m is preferably 2 or 3.
n is preferably 1. p is preferably 2.
~he preferred compounds are those under group tiii)
above which have the formula Ia
~ 1
N3~ ~ Ia
~ N~
wherein Rl is ~Cl_4)alkoxy.
These compounds fall under the scope of DOS 2655150 but are
not specifically described therein. They exhibit especially
interesting properties.
The present invention also provides a process
for the production of a compound of formula I which is
defined above, which comprises,
77S
- ~ - 100-~997
a) splitting off a group R7 from a compound of formula VI
1 '
~ - VI
N
. ~ N~
_ H R7 .
wherein Rl and R2 are as defined above un~er slgnificance i)
R7 is an amino protecting ~roup~
to produce a compound of formula I wherein R3 is hydrogen,or
5 b) alkylating a compound of formula VII
R
1 ~ _
3 ~ VII
NH
H . . .
wherein Rl and R2 are as defined above under significance ii) or
iii)l `
to produce a compound of formula I wherein R3 is other
than hydrogen.
The splitting off of an amino protecting group
according to process a) may be effected in conventional
manner. Preferably the amino protecting group is capable
of being split off hydrolytically, especially under acidic
conditions.
- . : :
.
- 5 - 100-4997
R7 may ba for example (C2_11~ acyl, x e-g- benzcyl,
or aoetyl. Alternatively R7 may (C;2 6)a~o~ycarbonyl or phenoxycarbonyl.
A suitable acid is hydrochloric acid. An inert solvent such
as butanol may be present. Sui~able temperatures
are from about 50 to about lOGC.
me alkylation of process b) may be effected in
conventional manner for the alkylation of a secondary amine.
A suitable alkylating agent is an appropriate alkyl iodide,
bromide, mesylate or tosylate. Alternatively when R3 has an
hydrogen atom attached to the -carbon atom thereof, and
preferably when R3 is methyl, reductive alkylation with
the appropriate aldehyde or ketone in the presence of so-
dium borohydride or sodium dihydro-bis-(2-methoxyethoxy-
ethoxy) al~inate may be used.
The starting materials of formula VI may be ob-
.. ..
tained as follows (In the flow sheet Rl and R2 are R
and R2 as defined above with the proviso that they are
other than chlorine or bromine):-
~11877~
- 6 - 100-4997
R'J
R~ ~ -Li ~R2'1
7 Cu ~ 7
-60~ to 0C H
4 ~ i)NaBH4
thenii)(CH300)20
sePara- iii)separa.tiGn of
~ epimers \ epimers
R ~ R2 RlJI R2"
C~3S ~ lj CH3S02Cl no
I ~ - ~ ~ ~\ .
~_,N ~ ii) optionally
1 7 brominate or ~" N~R
yTI~ H chlorinate ~ 7
The mesyloxy group of a compound of formula VIII may be
displaced by an azide group from an appropriate azide with re-
versal of the configuration at C6 to yield a compound of formula
VI.
Compounds of ormula VIII or VI wherein Rl and/or R2
are chlorine or bromine may be conveniently made by chlorina-
ting or brominating selectively the 4a phenyl ring using con-
veniently aromatic chlorinating or brominating agen~s, e.g.
pyridinium tri.bromide.
Compouncls of formula VII are compounds of formula I where-
'
.
'
8775
~ 7 - 100-4997
in R3 is hydrogen or else are known or may be made in analo-
gous manner to compounds of formula I wherein R3 is hydro~en.
The configuration of the compounds may be determined
on the basis that when the 6-substituen~ e.g azido and hy-
droxy is cis to the phenyl ring the compound is more polaron silicagel chromatography, e.g. using CH2C12/CH30H as eluant,
than the corresponding 6~epimer.
In so far as the production of any startin~ material
is not particularly described, this is known or may be produ-
10ced or purified by known processes or in a manner an~logous
to known processes or to processes herein described.
Free base forms of the compounds of formula I may be
converted into acid addition salt forms in conventional
manner and vice versa. Suitable acids include hydrochloric
acid, maleic acid, oxalic acid, hydrobromic acid~ tartaric
acia ,malonic acid and di-0,0'-p-toluoyl-tartaric acid.
Thè compounds of formula I may exist in racemic form
or in individual optically active form. ~he optically active
forms may be obtained by fractional crystallization of dia-
stereoisomeric salts, e.g. their salts with (+) or (-)
di-0,0'-p-toluoyl-tartaric acid.
In the following Examples all temperatures are in
degrees Centigrade and are uncorrected. All ratios are
by volume except where otherwise stated.
377~i
-8- 1~0-4997
EXP~LE 1: (4aRS,_6RS, 8_RS)-6-a~ido-decah~dro-4a-(3-
methoxy~henyl)-cis-iso~uinollne (process a)
(4aRS, 6RS, 8aRS)-6-azido-2-henzoyl-decahydro-4a-
(3-methoxyphenyl)-cis-isoquinoline in 40 ml n-butanol are
eated with 40 ml 4N HCl. The mixture is stirred at 90C
for 72 hours~ cooled and extracted with hexane. The aqueous
phases are made alkaline with 10% (by weight) Na2C03 and
extracted with CH2C12/C2H50H (8:2). The extracts are evapo-
rated and chromatographed on silicagel -using as eluant
CH2C12: CH30H: conc. NH40H (95:4.5:0.5). The title compound
is obtained, M.pt. (HCl salt) 113-115 (from acetone/ether)~
The starting material is obtained as follows:-
a) A mixture of 600 ml absolute tetrahydrofuran, 112.2 g
3-bromoanisole and 661 mg hydroquinone are treated under
n~trogen at -65 with 278 ml 2.2N butyl lithium, maintained
at -50 for 30 minutes and then treated with 57.13 .g
copper (I) iodide, stirred at -43C for 30 minutes and then
treated with 1, 3, 4, 7, ~t 8a-hexahydro-2-benzoyl-6(2H)-
isoquinolinone. The mixture is warmed to 0 over 2 hours,malntained at 0 for 16 hours and then worked up to give
2-benzoyl-octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoqui-
nolone. M.pt:. 78 (from methanol)0
b) 72.6 g of 2-benzoyl-octahydro-4a-(3-methoxyphenyl~ cis-
6(2H)-iso~uinolone in 200 ml CH30H is reduced at 0 with
2,84 g NaBH~ over 2 hours. 20 ml acetone and 200 ml H20 are
'
~ '
:
775
~ 9 ~ 100-~997
added and the mixture continuou31y extracted with methylene
chloride to give,after ~orking up, a mixture of the 6-hydroxy deri-
vatives as an oil. These were acetylated by 19~ ml acetic
anhydride in 100 ml pyridine. The mixture is carefully worked
up to give an oil. The oil ~s treated with 80 ml acetone
and 50 ml ether and (4aRS, 6SR, 8aRS) -6-acetoxy-2-benzoyl-
decahydro-4a-(3-methoxyphenyl)-cis-isoquinoline (M.pt. 133-
135) crystal7izes out.
Chromatography of the mother liquor on silicagel
and elution with CH2C12 + 0.5 -1~ CH30H yields (4aRS, 6RS,
8aRS) -6-acetoxy-2-benzoyl-decahydro-4a-(3-methoxyphenyl)-cis-
isoquinoline ~M.pt. 124-125~after crystallization from
ethyl acetate/ether).
c) A suspension of 40.8 g (4aRS, 6SR, 8aRS) -6-acetoxy-2-
benzoyl-decahydro-4a-(3-methoxyphenyl)-cis~isoquinoline in
200 ml CH30H and 50 ml CH2C12 is stirred and treated with 100
ml 2N K0~ - ln CH30H/H20 (9:1). After 90 minutes the re-
action mixture is evaporated , taken up in CH2C12/C2H50H
~9:1), washed with water, dried and evaporated to yield~
(4aRS, 6SR, 8aRS) -2-benzoyl-decahydro-6-hydroxy-4a-(3-me~
~hoxyphenyl)-cis-isoquinoline as a colourless fam.
d) 44.3 g of (4aRS, 6SR, 8aRS) -2-benzoyl-decahydro-6-hydroxy-
4a-~3-methoxyphenyl)-cis-isoquinoline in 300 ml absolute
tetrahydrofuran and 60 ml triethylamine are stirred and cooled
and treated with 11.4 ml me~hanesulphonyl chloride in 100 ml
absolute telrahydrofuran. After 1 hour the reaction mixture
7~
- 10 - 100-4997
is poured onto ice and extracted with CH2C12.
Concentrat~on under a vacuum yields (4aRS, 6SR, 8a
RS) 2-benzoyl-decahydro-6-mesyloxy-4a-(3-methoxyphenyl)-
cis-isoquinoline. M.pt. 142-143 (from petroleum ether).
e) 3.8 g of sodIum azide, 12.8 g (4aRS, 6SR, 8aRS) 2-ben-
zoyl-decahydro-6-mesyloxy-4a-(3-methoxyphenyl)-cis-isoqui-
noline, and 60 ml DMS0 are stirred for 6 hours at 80
under nitrogen. The mixture is partitioned between toluene
and water. The organic phase is evaporated to yield (4a
RS, 6RS, 8aRS)-6-azido-2-~enzoyl-decahydro-4a-(3-methoxy-
phenyl)-cis-isoquinoline.
EX~PLE 2: (4aRS, 6RS, 8aR~)-6-azi_o-decah~dro-2-methyl-
4a-(3-meth_x~phenyl)-cis-iso~uinoline
(process b)
28.6 g of 14aRS, 6RS, 8aRS)-6-a2ido-2-benzoyl-deca-
hydro-4a-(3-methoxyphenyl)-cis-isoquinoline and 100 ml 35%
aqueous formaldehyde solution in 300 ml C2H50H are stirred
with 19 g NaBH4. After 30 minutes ice-water is added and
}he mixture is extracted with CH2C12. The extracts yield the
tit~e-compo~tnd. M.pt. (hydrogen maleate) 155 from acetone/
ether; (HCl salt) from 190 (decomp).
11.88 g of the title compound and 15.96 g di-0,0?-
p-toluoyl-L(~)-tartaric acid are dissolved in warm methanol,
filtered an~ allowed to afford crystals at room temperature.
2S The cxystals are collected, washed with cold methanol and
dried. The crystals are recrystallized four times from me-
37~5
~ 100-4997
thanol. Treatment with 2N NaOH and CH2C12 yields the
free base of the title compound (-) isomer, [a]D = - 24.3
(c = 0.5 in pyridine) which is converted into the hydro-
chloride M.pt. 170-172 []20 = _50.3o (c = 0.5 in H20~.
In analogous manner the (+) isomer of the title
compound is obtained by ~ractional crystallization of the
di-O,O`-toluoyl-D(-)-tartaric acid salt. [a]D (free base)
- ~ 24.1 (c = 0.5 in pyridine); (hydrochloride) = ~ 48.6
~c = 0.5 in H20).
0 EX~MPLE 3: (4aRS, 6RS, 8aRS)-6-azido-deca_ydro-2-meth~l-
4a-(3-metho~y~henyl)-cis-iso~uinoline
(process b)
1.43 g (4aRS, 6RS, 8aRS)-6-azido-decahydro-4a-(3-
methoxyphenyl)-cis-isoquinoline in 25 ml acetone and 25 ml
15 CH30H as solvent are ~reated with 0.95 ml N-ethyl-diisoprop-
ylamine as condensation agent, 0.91 g potassium iodide and
O.1 ~1 methyl iodide. The mixture is warmed to 50 under
nitrogen. After 20 hours the mixture is worked up to give
the title compound, M.pt. (HC1 salt) 190 (decomp).
:
~18775
- 12 - l00-49g7
In analogous manner to that described above the
following compounds of form.ula I are produced:-
Ex R R2 R3 ~nfigul) M.pt2? Production
ration analogous
to Ex~le
4 3~13 H H 6-SR 138-41 )
1 4-OCH3 H H 6-RS 5)
6 4-OCH3 H H 6~R 5)
7 3 OCH3 4-Br H 6-F6
8 3 OCH3 >24003) ~ 3
9 3-OC2H5 H H 6-RS
lo 3 2 5 H CH3 6--RS ~184 1 2,3.
H H 6--RS 113--114
12 3--o--isoC3H~ c~3 6-RS 188--9 2 ,3
13 3-EH3 H H 6-RS 212-214
3--CH3 H CB3 6--RS ~180 ) 2 ~3
3-CH3 H H 6 - SR
16 3`~CH3 H CH3 6-SR 185 ) 2,3
l? H H H 6-RS
18 H H CH3 6-RS 190 2 ,3
,
- 13 - 100-4997
1) 6-BS = (4aRS, 6RS, 8aRS) isomer
6-SR = (4aRS, 6SR, 8aRS) iscmer
2) HCl salt unless otherwise stated
3) decomposition
4) hydrogen ~.alonate
5) Hydrogen fumarate mixture of 6RS/SR isomers 188
(decomp)
`
,:
3775
- 14 - lOo-4997
The compounds of formula I are eY~ibit analgesic
activity ` as indicated in standard
tests, e.g. ln the phenylbenzoquinone writhing test in mice
on p.o. ac~ministration of from 0.5 to ~0 mg/kg of the co~-
pounds, and in the tail flick test in mice on s.c. and p.o.administration from 0.5 to 100 mg/kg of the compc)unds.
The compounds of formula I~ exhibit nota~le analge-
sic activity in the above tests as well as notable activity
on oral administration in e.g. the arthritlc pain test
- 10 in the rat over 1 to 5 hours on administratlon of fro~ 1 to
10 mg/kg p.o. These compounds also appear to be well tolera-
ted in the mouse and rat at doses of from 50 to 100 mg/kg.
Furthermore thes~ compounds appear to be exhibit less mor-
phine dependent efects ~han expected for such compounds as
15 indicated by the following properties:-
i) These compounds do not appear to bind selectively to rat
brain opiate receptors. In standard tests for indicating
the inhibition of specific 3H-naloxone binding to rat brain
membrane~, e.g. according to the princlples of PertC.~,and
20 Synder S.H.~Science 1~79, 1011-1014 (1973) and Molec~Pharmac.
10, 868-869 (1971)~a high concentration of compound, e.g.
1000 to 100,000 nM, was required to lnhiblt the specific
binding of 3H naloxone (1 nM) both in the presence of 100 nM
sodium chlorlde and in the absence of sodium chloride.
25 ii) These compounds do not appear to be lnduce si~nificant
dose-dependent jumping hehavour in morphine-c'ependent mice on
. ^ ~
7~
_15 _ 100-4997
administration of from 30 to 100 mg/kg i.p. In one
standard test male mice ~OFI) strain weighing about 25 a
were implanted under llght ether anaesthesiawith a pellet
containing 75 mg morphine base. After recovering, the ani~als
were maintained in groups of 10 with free access to ~ood
and water. 6 days after the implantation the mice were
judged to be morphine dependent. The compound was then
administered and the number of jumps recorded in a 5~ ~inute
period thereafter recorded.
10 (iii) These compounds do not appear to markedly inhibit the withdr~al
syndrome in morphine dependent monkeys at a dose of from 1
to 10 mg/kg i.v. One standard test is car~ed out as follows:-
Male rhesus monkéys (2.5 - 3.4 kg) were kept, each
in a metal harness (weight 600 g), ln separate, open-fronted
15 cubicles (70 x 70 x 90 cm) with free access to food and water,
and a 12 hour light-dark cycle (6 a.m. - 6 p.m. light) main-
tained. After 7 days acclimatisation to their harnesses and
to the cages, the monkeys were anaPsthetized w1th pentothal
i.v. and halothane and implanted with a single-lumen silastic
20 catheter into the left jugular vein. l`he free end of the
ca'heter was then led subcutaneously over the shoulder of
each animal cmd out through a small stab wound made in the
skin between the shoulder blades. The monkeys were refltted
lnto their harnesses and connected to a saline-filled cannula
25 coming from the injecticn pumps. During the 7 day recovery
period, all anlmals received 0.8 ml physiological saline
7~
- 16 - 100-4997
every 30 minutes in order to keept the tip o thè cannula
free of clots.
Each monkey received programmed injeclions of mor-
phine (5.6 mg/kg i.v.) at intervals of 4 hours. After several
days the morphine injections are stopped and two hours
after the last morphine injection the compound is admini-
stered to the animal. The nature and intensity of the
withdrawal syndrome is then recorded.
In the above tests the Example 2 title compound
showed especially interesting activity. The (-) form of the
Example 2 compound exhibits more interesting activity than
the (+) form. This indicates that all optical isomers having
the same absolute configuration as the (-) form of the
Example 2 compound are the preferred optical isomers.
The compounds are therefore indicated for
use as analgesic agents. For this use an indicated daily
dose is from about 10 to about 300 mg, conveniently
administered in divided doses 2 to 4 times a day in
unit dosage form containing from about 5 to about 150 mg,
or in sustained release form.
s
~ 17 - 100-4997
The compounds of formula I may be ad~lnistered
in pharmaceutically acceptable acid addition salt for~.
Such acid addition salt fo~ms exhbit the same order
of activity as the free base forms and are readily
prepared in conventional manner. The present invention
also provides a pharmaceutical composition comprising
a compound of formula I, in free base form or in
pharmaceutlcally acceptable acid addition salt form,
~n association with a pharmaceutical carrier or diluent.
Such compositions may be in the form of, for example,
a solution or a tablet.
Example 2 is the preferred compound.
