Note: Descriptions are shown in the official language in which they were submitted.
1~8~ il5~1 case 100-4 4 70
Cis-4 a-Phenylisoquinolines
The present lnvention relates to cls-4a-phenyl-
isoquinolines.
The present invention provides compounds of
formula I,
~ .
~ 1 :
R R5
6 /~ ~\ ~ N R2
__ !
where1n (~) R~ ls hydxogen or al'~yl of 1 to 4 carbon
atoms, :~
R2 i hydrogen,
~; R3 and R4 together are oxygen, and
each of R5 and R6 ls llydrogen, or
(11) Rl is hydro~en, alkyl of 1 to 4 carbon
atoms, or alkanoyl of 1 ~o 4 car~on
atoms, and
R2 is an alkyl group of 1 to 4 carbon atoms, and
(a) either R3 and R4, together, are oxygen, or
methylene, and
each of R5 and R6 is hydrogen, or
(b) R3 and R6~ together, form a bond, and each of R~ :
and R5 is hydrogen~
5~
Any lower alkyl or alkoxy radical, except where
otherwise indicated hereinafter, preferably has 2, or
especially one carbon atom.
When Rl ls alkanoyl, this preferably is formyl
or especially acetyl. The radical ORl is preferahly in
the meta position.
Rl is preferably hydrogen.
When R2 is al~yl, this ~referably has 1 to 4 car~on
atoms, and especially 1 or 2 carbon a-toms. R7 and R8 are
preferably identical and are conveniently both hydrogen.
m is preferably 2 or 3. n is preferably 1. p is pr~ferably
2. Rg is preferably in the para position, and
when R9 Ls halogen, in the ortho position. R9 is
. ~ 3
~ S~ 100-4~70
conveniently hydrogen or halogell. Ilalogen means fluorine,
chlorlne or br~mine. ~he halogen atom is preferably
fluorine or chlorine.
R2 is preferably alkyl.
S When R3 ls azido or hydroxy and R4 is hydrogen,
R3 may be cis or trans to the phenyl group in the 4-positon.
Preferably R3 and R4 are together oxygen or n3
is azido and R4 is hydrogen.
The present invention provides a process for the
production of a compound of formula I, which comprises
a) spl-ittlng o~frthe amino protecting group Rlo present
~n a compound of formula VI,
O , VI
~-~10
wherein Rl is hydrogen or alkyl oE 1 to 4 carbon
atoms, and
Rlo i5 an amino protectiny group,
to produce a compound of formula Ia~
~3 ORl
O Ia
N-H
E~ ' '
- 4 -
100-~70
wherein Rl is as defined above,
~) alkyla~ing a compound o~ formula Ia, as defi.ned above,
ox the correspondin~ compound wheJ-ein the keto yroup
` ls protected, and lf necessary s~lit~ing off any keto
protectin~ group in the resultant product, to produce
a compound of formula Ib,
O Rl
O ' Ib
-R2
H
wherein Rl is a~ defined above, and
R2 is R;~ as defined above, wlt:h the
proviso that it i.s other than
hydrogen,
c) reducin~ a compo~lnd of formula :Lc,
Rl
o , I c
~¦~ N-R 2
H
wherein Rl and R2 àre as defined above,
to pxod~lce a compound of formula Id,
3S~3S~ 100-~ 9 70
~1
. ~-~1
W/~ I d
N-n2
E~
wherein Rl and R2 are as de1ned above,
d) replacing a leaving group Rll by azido in a compound
of formula VII,
OR~
1 lW~ VI I
~N- RI
H
wherein Rl ls alkyl of 1 to 4 carbon atoms o~
alkanoyl of 1 to 4 carbon at:oms,
R2 ls as defined above, and
Rll i 5 a leavlng group,
to produ`ce à cQmpou~nd of formula Ie ,- ~~
.
' ~RlI
~3~ Ie
N-R
H
- 6 -
~LOI~3S~ D4 100-4~70
wherein R1I and ~2 i5 as defined above,
e) elimlnating H~ll from a compound of formula VIII,
~~12
VI I I
\~ ~RI
: ~1 2
whel^ein Rll and R2 are as deflned above, and
R12 is a group capable of being split
off under the reaction conditions,
alkyl of 1 to 4 carbon atoms, or
alkanoyl of 1 to 4 carbon atoms,
to form a compound of formula If,
, ~ ' ,
I 1~ 5 ~ Rl
nI ~ ~ ~ If
. R6 ~ ~ R2
H
wherein Rl and R2 are as defined above, and
elthe~ R3 and R6, together,fonn a bond, and
each o~ R~ and R5 i.5 hydrogen, or
~ 4 and R5, together, form a boncl, and
each of R3.and ~6 is hydrogen,
~35~3~4 loo-~ ~170
f) splitting o~f a hydroxy protectintJ group R13 from
a compound of formula IX,
~3 ~ _ I
~6 ' ~2
2~ ~3r R4, R5 and R6 ~re as defined
above, with the proviso ~hat when
R3 and R4 are together oxygen, the
keto group may be in free form or
protected form, and
R13 ls a hydroxy protecting group,
: to produce a compound of formula I, wherein Rl i8
hydrogen,
.g) acylating a compound of formula I, wherein Rl is
hydrogen and R2 is other than hydrogen to produce
a compound of formula I, wherein Rl is alkanoyl
of 1 to 4 carbon atoms, or
h) replacing the oxygen of the keto group of a compound
of Pormula Ic by methylene under Wittig conditions
to form a compound of formula Ig,
-- 8 --
100-~970
5l55~
¢~ .
H2C ~ I~J
~ N--'~2
~ .
wherein Rl and R2 are as defined above.
The ~plitting off of the amino protect~ng group
according to process a) may be effected in conventlonal
manner. Pxe~erably the amlno protecting group is one
capable of being spllt off hydrolytically, especially
under acldic condltions.
: ~ R~o may be, for example, an aeyl group o~ 2 to 11
carbon atom~ t e.g. an aroyl group such as benzoyl, or an
alkanoyl ~roup such as acetylO Altexnatively, Rlo may be
alkoxycar~onyl of 2 to 6 carhon atoms or phenoxycarbonyl.
A suit~ble acld ls hydrochloric acid. An lnert
solvent such as aqueous n-butanol may he present. Su~tab]e
~emperatures are between 50 and llO~C.
Process b) may be effected in conventi.onal manner
for the alkylatlon of a secondary amine.
Suitable alkylation agents lnclude compounds of
formula X,
R2 - X X
. . .
~ g _ , ~
~s~s~
100-4470
wherein ~2 is as defined above, and
X is a leaving group.
X may be, for example, halogen such as chlorine,
bromine or iodine, or the acid radical of an organic
sulphonic acid of up to 10 carbon atoms, e.g. an al~yl-
sulphonyloxy radical such as mesyloxy or an arylsulphonyl-
oxy radical such as tosyloxy. Conveniently an acid binding
agent such as triethylamine is present. An inert solvent
sucl- as methanol may be ~resent. Suitable temperatures
are from 0 to 100C.
The keto group is preferably protectéd. It may be
in the ~orm of an open cl-ain or cyclic ketal, thiooxoketal
or thioketal, tlle open cnain or cyclic portion thereof, for
example having from 2 to 4 carbon atoms in the aggregate
thereof. Such protected forms may be deprotected in
conv~ntional manner.
Process c) may be effected in conventional manner
for the reduction of a cyclohexanone to a cyclohexanol.
The reduction may be effected hydrogenolytically.
A suitable catalyst for such a hydroyenation is, for
example, platinum. The process may be effected at room
temperature, and under normal pressure. Suita~le solvents
include tetrahydrofuran and ethyl acetate.
The reduction may also be effected with a complex `'
hydride, for example with lithium aluminium hydride,
-- 10 -- ~
~ l()0-q~70
so~ium dihydrido-bis(2-metl-oxyethoxy)al-lminate, ~ut
~referably sodium borohydride. Tlle reaction may ~e
e~fected in an inert solvent, e.g. metl-anol in the case
of sodium borohydride, Sultable temperatures may be from
0 to 50C.
It ls to be appreciated that the reduction may
not be stereospecific ln that two epimers, i~e. a compound
whereln the hydroxy group 19 cis to the 4a-phenyl group
[e.g, the (qa~S,6RS,8aRS)isomerl and a compound wherein
the hydroxy ~roup is trans to the ~a-~henyl group
le.~. the ~4aRS,~SR,8aRS)isomer], may be produced. Such
compou~ds may be separated in convelltional manner, e.g.
by chromato~raphy on sllicagel.
Process d) may be effec~ed in conventional manner
for a llucleophllic substltution in the presence of an
azido anion source, e.g. as descrihed in Example Sb)
hereinafter~
The process may be effeoted in a, preferal~ly polar,
inert solvent, such as dimethyl sulphoxide or diMethyl-
~ormamide. Suitable ~emperatures may b~ from ~0 to100C.
The azido source may be an al~a~i metal azide
such as sodium aælde, or a trialkylsilyl azlde of 3 to 12
carbon atoms, 8uch as trlmethylsllyl azlde.
35~ oo-~ ~70
~11 may be for exampl~ an alkanoyloxy group of 1
to 4 carbon atoms, or a raclical R1~5020-, wherein R14
is alkyl of 1 to 4 carbon atoms, preera~1y methyl,or
phenyl or p~alkylphellyl of 7 to 11 carbon atoms,
espç~cially p-tolyl.
From mechanistic considerations the azldo group
in the final product will be epimeric to the group R
in the starting material.
Process e) may be effected in conventional manner
fox such elimination reactions.
Rll may have the preferred values as indicated
above. R12 when it is a group capable of being split off
under the reaction conditi.ons may, for example, be alkyl
~f 1 to 3 carbon atoms or a radical Rl~S02, wherein R14
is as defined above. The ~inal product i.n such a case
would be a compound of formu].a I~, wherein Rl is hydrogen.
The reaction may be e~fec~ed ill a preferably polar
inert solvent, such as dimetl-yl sulphoxide or di.metllyl-
formamide. Suitable temperat-lres are from 40 to 100C.
'~he reaction may proceed as a side reaction to process e)
a3~ove .
Process f) may be effected i.n conventional manner
for deprotec~ing analoyous ph~nolic d~ri.vatlvesO
Rl 3 may l~e, for example, a prot:ect:ing ~roup
capab].e of being split of~ by hydrolys.i.sO Such a qroup
- 12 -
~ 5~ loo-447c)
is especially preferred when R3 is azido, and may be a
group of :Cormula Rl~S02-, whereil~ is as defined
a~ove. The hydrolysis may be effected in conventi.onal
manner for the hydrolysis of ~imilar sulphonic acid esters.
For example the reaction may be ef~ec~ed under basic
conditions, e.g. :Ln the presence o~ N-ethyl-di.isopropyl-
amine. Sui~able tempera~ures are between 20~ and
100C.
~13 may alternatively be a group capablé of being
spli.t off under ether splitt.~ng conditions. Such a group
ls especially preferred when R3 is other than azido.
The ether splitting may be effected in conventional
manner for dealkylation of phenyl alkyl ethcrs. For examp].e,
Lewis acids, such as boror~ tribromide or aluminium t~i-
cliloride, or strong mineral acids such as hydrobromic
acld or llydroiodic acid may be used. Suitable temperatures
are between -20 and +30C. An i.nert solvent such as
methylene chlori~e rnay be pres~nt. If desired, when R3
and R~ to~et.l-er are o~ygen, the keto group in the ~tarti.ng
: 20 ~naterial of formula IX is in pro~ected ~orm, which is de-
protected.during the reaCtiQn or during the.working-up
procedure. Tl~us, the keto group may be protec-t~d in the
~orm of an open chain or cyclic ketal, thiooxoketal or
thi.oketal, the open chain or cycllc portlon thereof, for
exampl.e, having from 2 to ~ carbon atoms ln the aggxegate
- 13 - ~
~ 5~ 100-4~70
thereof. Such protected fo~ms may be dc~protec~cd in
conventional manner. ~en the depro~ecti,ng conditions
are acidic, tllell deprotec~ion will ~e slmultaneous with
any deallsylation carried out with a stron~J mineral acid.
Process ~) may be effected ln conventional'manner
for analogous acylation reactions.
A suitable a~ent for the introduction of a formyl
group may be the mixed anhydrlde of formic acid and
acetic acid. Alkanoyl radicals of 2 to 4 carbon atoms
may be lntroduced using the correspondin~ acid chloride,
bromide or anllydride.
Conveniently a tertiary amine such as pyridine
: i.9 present- ~lowever, when r~2 is a radical of formula V,
wherein R9 is amino, it--ma~ be~preferred to'use acidic
conditions.,An inert organic solvellt such as toluene may
also be present. Sultable temperatures are between 10
and 50C.
Process h) may be effecte~ in conventional manner
~or Wi~ticJ reactlons. A suitable Witl:i~ salt i~ methyl
triphenyLpllospholliLlm bromide. A suitable ~olv~nt i~
dlmethylfonmamide. A suitable temperatuxe i.s ~rom 10
to 70C.
S~5~ I oo~ o
The compounds of formLlla VI may l~e produced by
a process which comprises reactin~J a compound of formu].a XI,
~J \I X~
Rlo
whe re i n Rlo 1 s as de f i ne d above,
wl.l:ll a compound of formula ~II,
R10 ~ XII
s where1n Rl ls as defined above, and
Y is l~ ium or MgHal, wherein llal is
-
: chlorine, bromine or iodine,
in t:l~e presence of a cuprous sa].t, at from -60 to 0C~
Tbe reaction may be elCfected i n conventi.onal
manner for a cuprous-inducecl 1,4 add.i.tlon to an a,0
unsaturat~d ketone~
Th~ cuprous salt used m~y, for example, be copper
(I) iodi.de. }lydroquinone i9 I referal~ly present. The reaction
iB cc:nvelliently effect~ed at from -43~ to 0C. ~he reaction
is convenient1y e~fected l.n an inert so1vent, st~ch a3
te~rahydrofuran.
- 15 -
100-~70
85~5~
Rl is pre~erabl.y alkyl.
Compounds o~ formula VIII, whereln Rll is Rl,lS020-,
and R12 is RlI-or Rlq S02-, may be made by reacting
a compound of formula Id with r~l4S02Cl i.n conventional ,:
manner.
The confi~uration of the group -OSO~Rl~ at C6 in
the final product and the hydrox~ gr~up 2t C6 in the
startlng material will be~ in general, the same.
It is to be appreciated that a compound of
~ 10 formula VII is a compound of formula VIII, wherein R12 is
: : alkyl or alkanoyl.
Compounds of formula IX, wl-erein R3 is a~ldo and
R13 is Rl~-S02- may be prepared by a nucleopllilic
substltu~l on w~ th azide anion ln analogous manner to
15 process d~ ~rom a compound of formula VIIIa,
~ - OS02R14
11 ~ VIIIa
N-R~
H
2~ 1l ancl R14 are a~ deflned a~ove
- 16 -
:. .: ... . .. . . .
5~s~ ] oo~ 70
Insofar as the production of any st:arl~i.ny materlal
i5 not particularly dcscribed, this is known or may be
pxoduced and purified in accordallce Wi~ll ]cnown processes,
or in a manner analogous to the processes herein described
or to known processes.
The compounds of ~ormula I may exist ln racemic
or optically active form. Tlle optically actlve forms may
be convelllently inade ~y fractional crystallization of
diastereomeric salts . In one conven~ ent method the
comp`ounds`~o`f formula Ja may be resol.ved by way of the
diastereomeric salts ~ith (~) or (-) tartaric acid and
further optically active compounds of formula I may be
made therefrom usil-g any of processes b) to h) as
mentioned above.
/
. '
-- 17 ~
100-q~70 ,"
~85~3S4
Free base forms of tlle comuounds o~ formul.a I
may be conver-~ed into acid addition salt forrns ln
conventional manner an~ vice versa. Suita~le acids for
salt format$on include fumaric acid and tartaric acid.
In tlle followin~3 Examples all temperatures are
in degrees Centigrade and are uncorrected.
All cornpounds obtained are ln racemic form unless
otherwise stated.
, ~ .
'
- 18 -
100-~70
I~XAI~IPI.E 1: Octahyclro-4a-(3_methoxyL~ cn~
isoqntnolinont~ Iprocess a)]
36.35 g ~0.1 mol) o~ 2-benzoyl~octallydro-4a-(3-
methoxyphenyl)-cis-6(2~J)-lsot.~uiIlolinone~ 100 ml of
n-butanol, 33.1 mol of ca. 37~ (w/v) ~queous hydrochlori.c
acld (0.4 mol) and 66.9 ml of wa~er are boiled for 40
hours. The mixture is extracted with hexalle. The aqueous
phase ls made basic witll aqueous ammonia and extracted
with methyltane chloride. The oxganic phases are concentxated
by evaporation to yield the tltle compound which in
hydrogen fumarate ~orm has a M.Pt. of 130.
Se~aratlon of o~tical isomexs
__ ___________ _____________
25.93 ~ (100 n~ol) of octahydro-4a-(3-methoxy-
phenyl)-cls-6(2fI~-~soquinol.inone ls dissolved wlth 15.01 g
tlOO mmol) of L-(~) tartaric acid with sl.tght heating in
40 ml of water and lÇO ml of metllanol. The mixture is
cooled to 0~ and the resultant cryF.tals fll.tered off.
After recrystalllzation of tlle crystals three times from
metllanol/water (80:20 v/v) the ~) tartrate having a
constant [cc] 20 0~ ~28 11% w/v in 1~2] i~ obtained, ~he
free base is obtained by treatment with methylene chlorit~e/
ethanol ~ 80: 20 v/v] and aqueous ammon i~ .
The mother liquors of the al~ove-~nentioned
crystalllzations are treated wi th ammonia to li herate
-- 19 -
100-~70
85i854
the free ~ase. After trea~ment witll D(-) tartaric acid
as describcd above the (-) antipode of the tartra~e is
obtained, ~12 _ -28 (1~ in ~12~).
The startin~ n)aterlal ls obtalned as follows:-
278 ml of 2.2 N butyl lithium solution (612 r~ol)
are added to a mixture of 600 ml of absolll~e tetrahydro-
furan, 1~2.2 g ~600 mmol) of 3-~bromoanisole and 661 mg
~6 ~nol) of hydroquinone at _65D under nitrogen. The
resulting mlxture is kept at -50 for 30 minutes, treated
witll 57.13 5 (0.3 mol) of copper (I) iodidet stirred for
1 hour at -43, and treated wlth 51.06 g (0.2 mol) of
1,3,4,7,8,8a-llexahydro-2 benzoyl 6(2TI)-isoquinollnone.
The mlxture is allowed to warm to 0 over 2 hours and
kept at 0 ~or 16 hours. 1.2 litres of water and 79.28 g
(0.6 mol~ o~ amm~nium sulpha~e are added to the mixture
which is then extracted with toluen~. Tho organic ex~ract~
are evaporatod to yie]d an oil which is chromatographed
on silicayel using ethyl aceta~ a~ eluant. The product,
2-ben20yl-octallydro-qa-(3-methoxypllcnyl)-cis-6(2l-l)-iso-
quinolinone is obtained as colourless crystals fro~
metllanol; ~.Pt. 78.
- 20 -
~.OO-q~70
58~
~:X~M~L~' 2: Octa11ydro-4a-(3-mat1lox~ ryl)-2-m~3t~hy]-cis~
6(211~-iso~ulno].lnone Iproce~s ~)]
25.~3 g (O.l mol) of oc~ahydr~-4a-(3-methoxyp1lenyl)-
cis-6(2~1)-isoqulnoli.none (see ~xample l), lO0 ml of benzene,
5 11.2 ml (0.2 mol) of e~hyl.ene ylycol and 8.1 ml (125 mmol)
of methanesulphonic acid are hoi.led for 3 hours in a water
separator. The mixture is cooled, made ~asic wit1-1 aqueous
ammonia and extracted with methylene chlorlde. T1~e organic
phase is evaporated to dryness to yield octahydro-4a-
(3-metlloxyphenyl)-cis-6(2~ isoqulnolinone e~hylene ketal.
I~he ketal Is dissolv~d in 50 ml of absolute methanol,
cooled to O~C, and 13.~1 ml (O.l mol) of triethylamine
and 7.46 ml (0,12 mol) of methyl iodi.de are added thereto,
The mixture i5 kept at 22 for l hour. The mixture,
~ lS containing octahydro-4a-(3-methoxyphe1lyl) 2-methyl-cis-
~(21~)-isoquinolinone ethylene ketal, is mixed with 20 ml
of dioxan~ and concentrated b~ evaporatlon. lO0 ml o~
dioxane and lO0 ml oE 2N aqueous hydrocl~loric acid are
added to the residual oil. The resultant mi.xture is
stirred for 2 hours at 40, made ~asic with aqueous
ammonia, and extracted with tol.uene. The extracts are
concentrated ~y evaporati.on to yield the title compound
as an oil, which is crystal~ize~ as the hydrogen fumarate
from ethanol.
- 21 -
~ 5~ ~ ~ lO0-~70
In analo~ous manner the followincJ compouncls may
be made:-
1i) 2-allyl-oct.ahydro-9a-(3-metl~oxyphenyI.)~ci.s-6(2
iso~uinolinone.
S (ii) 2-cyclo~ropylmethyl-octahydro-4a-(3-methoxyphenyl)-
cis-6(211)~isoquinolinone.
(i.ii) 2-cyclol~ut~ylme~hyl-octahydro-qa-(3-mctlloxypl3enyl)-
cis-6(2H)-isoquinolinone.
(iv) 2-(o-chlorophenylethyl)-octallydro-4a-(~-metlIoxyphenyl)-
cls-6(211)-isoquinolinone.
~XA~IPI.~ 3: OctalI~dro-4a-l3-hydroxy~henyl)~2-methyl-cis-
6~2llL_1sosuinol inon~3 [process f ) ]
To a ~olution o~ 28 c3 of octahydro-4a- (3-methoxy-
pheny].)-2-methyl-cis-6 ~21~)-isoquinolinone ethylene Icetal
obtail~ed as descri~ed in Example 2 i.n 200 nll of methylene
chloride at -50 under nitrogen, 15 added dropwise
~8.44 ml (0.3 mol) of horon tribromide ln lO0 ml of
methylene chlorida. l'he mixture is stirred at 0 for 30
minutes, then cooled to -~0, tr~ated wlth 50 ml of
20 absolu~ ~3 methanol, and conc~ntrated by evaporatl.on. Th~
residu~ ls dissolved in 150 ml of dloxane ar,d 50 ml of
water~ The resultant mixture ls ~tirred for l hour at
40~ and partitioned hetween aqueous ammonia and methylene
chloride. The or~anlc phases are thel~ chLoma~o~Jraphed on
- 2~ -
].00~ 70
5~L
silica~el USillg a mixt11re of methyle11e chloride/metllano] /
concentrated aqueous ammonia (95:q.5:0.5) as eluar~t to
yiel~ the ti tl.e compou1ld in amorE-11ous form WhiC]l
crystallizes from ~sopropyl alcohol; M.E't. 175.
In analo~3O11s manne.~ ~here may }~e o1~tained:-
li ) 2~a].lyl-octahydro~9 a- ( 3-hydroxyphe11yl ) -cis-6 ( 211) -
iso~ulnoli nolle .
(li) 2-cyclopropylmethyl-octahy(lro-4a- (3-hydroxyp11enyl) -
cis-6 (2}1)-isoquinolinone.
10 ~iii.) 2-cyclobutylrnethyl-octahydro-4a-(3-hydroxyphenyl)-
cis-6 (2H)-i soquinolinoneO
~iv) 2-~o chlorophenethyl)-octahydro-4a-(3-hydroxyphenyl)-
cis-6 (21-1)-isoquinolinone.
~XAMPI.E 4: ~he ( ~ al~S, 6 sr~ sal~S ) and ( 4 aP.S, 61~S, 8aRS )
~ _ _ _ _ _ _ __ _ _ _ _ _ _
eeiml3rs of decfl11ydro-6~hydroxy-4a- t3-hydrox~-
pheny.ll 2-met~ .-CiB~-i soquino] inone ~process c)
~rO a sti.rred suspensi.on of 25~93 cJ (O.l mol) of
octah~dro-4a- ( 3-hydrox~p11e11yl ) -2-methyl-cls-6 (21-~) -iso-
qul1lolinone (see l~xample 3 ) ln 200 ml of metha11ol at 0,
is added 5.6c3 g ~0.l5 mol) of sodl.um 130rohydrlde. The
mixture i~ kcpt at 22" for 16 hours. lrhe mixture 1
cooled to 0, and 50 ml o~ acetone, 39.6 g (0.~ mol~
of amrnonium sulphate and 200 ml water are added thereto.
The reaction mixture i6 extracted wi. t:h ~ mixture of
-- 23 -- .
100-~70
~58~
methylene chloride and ethanol (~0/20 v/v). The organic
L~hases, containillg a mixt:ure o~ the ~wo epimeri c forms
as detect~d by thin layer chromatogra}?l-y on s.~licagel,
are concentrated by evaporati.on. The residue is mlx~d
with 13.02 g (0.1 mol) of p-~oluenesu].~llonic acid h5~drate
and 200 ml of ethanol, and crys~allized at 0 ~o yield
the p-toluenesulpllonate of the less polar ~4aRS,6SR,8aRS)
epimer; M.Pt. 253.
Tlle mother liquor is evaporated and partitioned
between aqueous ammonla and a mixture of m~thylene chloride
and ethanol (80:20 v/v). The organic extracts are chroma-
to~raph~sl on sill.cagel using a mlxture of methylene .
chloride/methallol/aqueous ammonla ~80~ 2 v/v) yielding
the polar~4aRS,6RS,8aRS), epim~r as a colourless amorphous
powder WhiCh liquifies at about 110.
In analogous mann~r the following compounds rnay
be o~tained:-
(i) ~4aRS,6SR,8a~S) and ~4al~S,6~S,~aRS) 2-allyl-dec~-
hydro-~-hydroxy-4a-(3-hydroxyphenyl)-cis-isoquinoline,
(li) (4aRS,6S~,8a~S) and (4aRS,6R5,8aRS~ 2-cyc]opropyl-
methyl-decahydro 6-hydroxy-4a-(3-hydroxyphenyl)-
cis~isoquinoline,
aRS,6SR,8aRS~ and (4aRS,6RS,8clR5) 2-cyc]obutyl-
methyl~d~cahydro-6-hydroxy-4a-~3-hydroxyphenyl)~
cis~isoqulnolille,
- 24 -
- 100-4470
~5~35~
(iv) t4aRS,6SR,8al~S) and (4aRS,6RS,8aRS) 2-(o-chloro-
phenethyl)-decallydro-6-hydro~y-4a-(3-l~ydroxyphenyl)-
cis-isoquinoline.
EXA~iPI.E 5: ~4aRSL6RS,8aRS) 6-azido-decahydro-4a-(3-
h~droxy~henyl)-2-methyl-cis-isoquinoline
[process variant (d)]
a) 4.336 g (10 mmol) of the p-toluenesulphonate
of the ~4aRS,6SR,8aRS) decahydro-6-hydroxy-4a-(3-llydroxy-
phenyl)-2-methyl-cis-isoquinoline obtained in Example 4,
10 ml of absolu~e pyridine, and 4.29 g (22.5 mmol) of
p-toluenesulphonyl chloride are mixed at 0 under
nitrogen and stirred for 16 hours at 22. 20 ml of toluer,e
and 20 ml of 2N aqueous sodium carbonate solution are
added to the mixture, which is then stirred at 22 for ~ -
15 minutes and extracted with toluene. The organic phase
is concentrated by evaporation to yiel~ the bis-tosylate
as an amorphous powder.
~) The bis-tosylate in 10 mL of absolute dimethyl
sulphoxide is mixed with 1.3 g (20 mmol) of sodium azide.
The mixture is stirred for 16 hours at 70 under nitrogen,
and partitioned between toluene and 2N aqueous sodium
carbonate. The organic phase is concentrated by
evaporation to yield (4aRS,6XS,8aRS)-6-azido-decahydro-
4a-(3-tosyloxyp)lenyl)-2-methyl-cis-isoquinoline.
- 25 -
~ S~ 100-4470
c) 4 g of (4a~S,6RS,8aRS)-6-azido-decahydro-4a-
(3~tosylox~phenyl)-2-metllyl-cis-isoquinoline in 10 ml
of 2N methanolic potassium hydroxide solutlon is boiled
for 1 hour, and then adjusted to a pH 8 - 10 by the
addition of carbon dioxide, after the addition of 20 ml
of toluene and 20 ml of water. The oryanic phases are
concentrated by evaporation and the residue is
crystallized from isopropanol to yield the title compound
as colourless crystals; M.Pt. 198~ (decomposition).
10In analogous manner there may l~e ohtained:-
(i) (4aRS,6RS,8aP~S)-2-allyl-6-azido-deca]lydro-4a-(3-
hydroxyphenyl)-cis-isoquinoline; M.Pt~ 125 (decon~.),
(ii) (4a~S,6RS,8aRS)-2~cyclopropylmethyl-6-azido-decahydro-
4a-(3-hydroxypllenyl)-cis-isoquinoline;
15(iii) (4aRS,6RS,8aRS)-2-cyclobutylmethyl-6-azido-decahydro-
4a-(3-l~ydroxyphenyl)-cis-isoquinollne;
(iv) (4aRS,6RS,8aRS)-2-(o-chlorophenethyl)-6-azido-deca-
hydro-4a-(3-hydroxyp]lenyl)-cis-lsoquinoline.
- ~6
, ~, .
~ 5~ ].00-4~7~
L~IPL~ 6: 1~213L~l4~ll5l~L~_oct~ dro~ 3_hyclJ0xy~
~heny]~-2-metl~l-cis-1so~ nc)llne, and
1~2 3 4 4aL7L8 8a-octah~ro-~a-~3-11ydroxy-
L_L_L__ _ _L________ __ ~________ ____ _
phen~l)-2-methyl-cis-isoquinoline ~process e)l
___ _________ _________ ________
(~aRS,6SR,8aRS)-decahydro-6-tosyloxy-(3-tosyloxy-
phenyl)-2-methyl~cis-isoquinoline (ob~ai.ned i.n ~xamp].e 5a)
in 10 ml of absolute dlmethyl sulphoxide and 1 ml of
N-ethyl-diisopropylamine is heated a~ 70 for 16 hours
under nitrogen, and then partitioned betwee3l toluene and
2N aqueous sodium carbonate. The Organic phase is
concentrated by evaporation and chromatograplled on silica-
gel using acetone/triethylamine (99:1) as eluant yielding
initlally 1,2,3,4,4a,5,8,Ba-oct~hydro-9a-[3-hydroxyphenyl~-
2-methyl-cis-isoquinoline, M.Pt. 159 (from toluene/
methylene chloride) and then 1,2,3,4,4a,7, a, 8a-octahydro-
4a-[3-h~droxyphenyl)-2-methyl-~is-isoquinol.ine, M.Pt. 183
~rom toluene/methylene chloride).
.
~XA~PLE ? ~ ace~oxy~h~n~lL_octahydro~2-m th~l-cis
6(2}1L_isoquinol_none ~process ~
3.77 ml 140 mmol.) of acetlc anhydride are added
dropwise to a stirred mixture of 5.19 y (20 mmol) of
oct~hydro-4a-(3-hydxox~phenyl)-2-methyl~cls~6(211)-iso-
guinolinone (see Example 3), 3.22 ml (40 mmoJ.) of
. py~i~ine and 20 ml of toluene at 5. The mixtu~e is then
kept at 22 for 2 hours. ~O ml of water is added to the
- 27
35~5~L l oo-~ 1 70
mixture at 5~, and the mlxture i~ stirrec~ for 30 mlllutes
at 22. 40 ml of met11ylene clllorlde are added. I~lilst
belng stirred, the aqueous phase of ~he re~ultant two-
phase mixture is adjusted to pll 7 by the additio1l of
4 g of sodium carbonate. The aqueous phase is then separated
and extracted witll metnylDne chloride. Tlle orqarllc phases are
washed with water, dried, concentrated by evaporation and
dried in a hi~ll vacuum. The title com~ound is obtained
as a viscous oil whicll is crystallized as the hydrogen
fumarate from isopropanol; M.Pt. l94 (decomposltionj.
EXA~IPL~ 8: Decahydro-4a-(3~ droxy~ellyl)-2-methy]-6-
_ _ _ __ _ _ _ _ _ _
n1eth~lene-cis-isoc~uinollne [process h)~
3.93 g (ll mmol) of methyl triphenylpllosphonium
bromide in lO0 ml of al>solute dimethyl formamlde is
treated with l.Ol g of a 50% ~J~w sodi~ hydride dispersion
in oil (21 mmol) under nitrogen. The mixture is s~irred
for l h~ur at room ter1-perature, and then treated with
2.59 g of octahydro-4a-(3-hydroxyphenyl)-2-methyl-cis-
6(211)-isoquinol1none. The mixture is s~irred fo~ 16 hours
at 40~, and partitioncd between metllylene chlorlde and
aqueous ammonium sulpllat:e. E~vaporation of the or~anic
phase and chromatograF~Ilic purification on silicaqel gives
tlle title compound.
- 28 -
5~ oo-~ ~70
The compounds of formula I exhibit pharmacological
acti~ity, In particular, the compounds exhibit analgesic
activity, as indicated in standard tests, e.g. in the
phenyl-benzoquinone writhing test in mice on p.o.
administration of from 0.5 to 50 mg/kg of the compounds,
and in the tail flick test in mice on s.c. aclministration
from 0.5 to 100 mg/kg of the compounds.
An indicated daily dose is from about 20 to a~out
300 mg, convenien~ly administered in divided doses 2 to 4
times a day irl unit dosa~e form, containlng from abou~
5 to about 150 mg of the compound, or in sustained release
form.
The compounds of formu:La I may be administered in
pharmaceutically acceptable ac:id addition salt form. The
present invention also provides a pharmaceutical composition
comprising a compound of formula I in free base form or
in pharmaceutically acceptable acicl addit$on salt form in
association with a pharmaceutical carrier or diluent.
Such compositions may be formulated in conventional manner
so as to be, for example, a solution or a tablet.
In one 3roup of compounds R2 ls alkyl, a radical
II, a radical III, a radical IV, wherein n is 1, or a
radical V, where~n p is 2 and Rg is hydrogen or halogen,
- 29 -
85~ loo -~ ~ 70
In one suh-group Rl is hydrogell or alkyl. In
another sub-group Rl is al.kanoyl. R3 may be hydroxy,
Alternatively R3 may be azido ~ Alterna~ively R3 and R4
may be together oxyqen.
- .30
